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Parkinson's Disease - Medical Clinical Policy Bulletins | Aetna Page 1 of 99
(https://www.aetna.com/)
Parkinson's Disease
Number: 0307
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
Policy History
Last Review
06/04/2020
Effective: 12/10/1998
Next
Review: 03/25/2021
Review History
Definitions
Ad d i t ion al Information
Clinical Policy Bulletin
Notes
Diagnosis
I. Aetna considers levodopa or apomorphine challenge
medically necessary when the diagnosis of Parkinson
disease (PD) is in doubt.
II. Aetna considers olfactory testing by means of the
University of Pennsylvania Smell Identification Test
(UPSIT) or “Sniffin' Sticks” medically necessary to
differentiate PD from progressive supranuclear palsy
and corticobasal degeneration.
III. Aetna considers neuropsychological testing for the
diagnosis of PD medically necessary.
IV. Aetna considers any of the following tests experimental
and investigational for differentiating PD from other
parkinsonian syndromes because their effectiveness for
this indication has not been established:
A. Electrooculography Proprietary
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B. Growth hormone stimulation with clonidine
C. Iodine-123 meta-iodobenzylguanidine cardiac
imaging
D. Magnetic resonance imaging (MRI)
E. Tilt table testing
F. Transcranial duplex scanning
V. Aetna considers the following genetic testing of PD
experimental and investigational because its
effectiveness for this indication has not been
established:
A. PD (e.g., testing for alpha-synuclein, apolipoprotein E
(APOE),
B. DJ1,
C. fibroblast growth factor 20 rs12720208
polymorphism,
D. glutathione S-transferase M1 (GSTM1) and
glutathione S-transferase T1 (GSTT1) polymorphisms,
E. interleukin-10 polymorphisms (-1082A/G and
-592C/A),
F. LRRK2/PARK8,
G. parkin/PARK2,
H. PARK10 and its variants,
I. PINK1,
J. PITX3, and
K. sphingomyelin phosphodiesterase 1 gene (SMPD1).
VI. Aetna considers cerebrospinal fluid (CSF) α-synuclein,
heart fatty acid-binding protein, neurofilament light
chain, tau (phosphorylated or total) and ubiquitin
carboxy-terminal hydrolase L1 (UCH-L1) as diagnostic
biomarkers for PD experimental and investigational
because the effectiveness of this approach for this
indication has not been established .
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VII. Aetna considers CSF amyloid beta 1-42 as a biomarker
for PD progression experimental and investigational
because its effectiveness for this indication has not been
established.
VIII. Aetna considers quantitative EEG (qEEG) measures as
predictive biomarkers for the development of dementia
in PD experimental and investigational because its
effectiveness for this indication has not been
established.
IX. Aetna considers SPECT scanning (e.g., DaTSCAN
(Ioflupane I-123 injection - a radiopharmaceutical
indicated for striatal dopamine transporter
visualization)) medically necessary to distinguish PD
from essential tremor. Aetna considers SPECT scanning
experimental and investigational for distinguishing PD
from other parkinsonian syndromes; and for monitoring
the progression of PD.
X. Aetna considers the use of serum α-synuclein
autoantibody as a biomarker for PD experimental and
investigational because its effectiveness for this
indication has not been established.
XI. Aetna considers submandibular gland needle biopsy for
the diagnosis of PD experimental and investigational
because its effectiveness for this indication has not been
established.
XII. Aetna considers measurement of telomere length as a
risk factor for development of PD experimental and
investigational because its effectiveness for this
indication has not been established.
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XIII. Aetna considers measurement of urinary LRRK2
phosphorylation to determine PD risk among LRRK2
mutation carriers experimental and investigational
because the effectiveness of this approach has not been
established.
XIV. Aetna considers vagotomy for the prevention and
treatment of PD experimental and investigational
because the effectiveness of this approach has not been
established.
XV. Aetna considers retinal thinning as a biomarker of PD
experimental and investigational because the
effectiveness of this approach has not been established.
XVI. Aetna considers plasma neurofilament light chain (NfL)
as a biomarker for disease severity and progression in
PD experimental and investigational because the
effectiveness of this approach has not been established.
XVII. Aetna considers salivary biomarkers (e.g.,
acetylcholinesterase, alpha-synuclein, cortisol, heme
oxygenase-1, and nitric oxide) for diagnosis of PD
experimental and investigational because the
effectiveness of this approach has not been established.
XVIII. Aetna considers serum fibroblast growth factor 21 (FGF
21), serum growth differentiation factor 15 (GDF-15) and
blood mitochondrial DNA (mtDNA) copy number levels
as biomarkers of PD experimental and investigational
because the effectiveness of these approaches has not
been established.
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See
CPB 0071 - Positron Emission Tomography (PET),
also (../1_99/0071.html)
CPB 0158 - Neuropsychological and Psychological Testing
(../100_199/0158.html)
, CPB 0168 - Tumor Scintigraphy (../100_199/0168.html),
CPB 0221 - Quantitative EEG (Brain Mapping),
(../200_299/0221.html)
and
CPB 0390 - Smell and Taste Disorders: Diagnosis
(0390.html)
.
Surgical Treatment
I. Pallidotomy for the Treatment of PD
Aetna considers pallidotomy medically necessary for the
treatment of PD when all of the following selection criteria are
met:
A. Individuals with idiopathic PD who have tried and
failed medical therapy as indicated by worsening of
Parkinsonian symptoms and/or disabling medication
side effects (motor fluctuations with “wearing off”,
and unpredictable “on/off”, as well as Sinemet
induced dyskinesia); and
B. Members exhibit 2 of 4 major symptoms
(bradykinesia, tremor, rigidity, and gait disturbance);
and
C. Members have a history of positive response to
dopaminergic replacement therapy (e.g., Sinemet or
bromocriptine); and
D. Members have been screened by a neurologist who
has expertise in movement disorders to ensure all
reasonable forms of pharmacotherapies have been
tried and failed.
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Pallidotomy for the treatment of PD is of no proven value in
persons with the following conditions:
A. Members with Parkinso n's plus or atypical
Parkinson's disorders (e.g., multi-system atrophy,
striato-nigral degeneration, progressive
supranuclear palsy, or combined Alzheimer's disease
and PD); or
B. Members with severe dementia or cerebral atrophy;
or
C. Members with Hoehn and Yahr Stage V Parkinson's
disease (see Note below).
Note: Hoehn and Yahr Stage V individuals exhibit the
following characteristics :
▪ Cachectic state
▪ Can not stand or walk (need wheelchair assistance,
or are unable to get out of bed)
▪ Invalidism
▪ Requires constant nursing care
II. Fetal Tissue/Fetal xenografts Transplantation for PD
Aetna considers transplantation of fetal mesencephalic tissue or
fetal xenografts (e.g., from pigs or other animals) experimental
and investigational for the treatment of PD because the long-term
safety and effectiveness of these procedures have not been
established.
III. Stem Cell Transplantation for PD
Aetna considers stem cell transplantation experimental and
investigational for the treatment of PD because its effectiveness
for this indication has not been established.
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IV. Adrenal Medullary Transplantation for PD
Aetna considers adrenal medullary transplantation experimental
and investigational for the treatment of PD because of a lack of
evidence of effectiveness for this indication.
V. Subthalamotomy
Aetna considers subthalamotomy experimental and
investigational for the treatment of PD because it has not been
shown to be effective for that indication.
VI. Intra-striatal Implantation of Human Retinal Pigment
Epithelial Cells
Aetna considers intra-striatal implantation of human retinal
pigment epithelial cells experimental and investigational for the
treatment of PD because its effectiveness has not been
established.
VII. Extra-dural Motor Cortex Stimulation
Aetna considers extra-dural motor cortex stimulation
experimental and investigational for the treatment of PD because
its effectiveness has not been established.
VIII. Gene Therapy
Aetna considers gene therapy for the treatment of PD
experimental and investigational because its effectiveness has not
been established.
IX. Magnetic Resonance Imaging-Guided Focused Ultrasound Neurosurgery
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Aetna considers magnetic resonance imaging-guided focused
ultrasound neurosurgery for the treatment of PD experimental
and investigational because the effectiveness of this approach has
not been established.
See
also CPB 0208 - Deep Brain Stimulation (../200_299/ 0208.html)
for deep brain stimulation of PD,
and CPB 0153 - Thalamotomy (../100_199/ 0153.html) for
thalamotomy for PD.
Non-Surgical Treatments
Levodopa-Carbidopa Intestinal Gel
Aetna considers levodopa-carbidopa intestinal gel (Duopa)
medically necessary for the treatment of motor fluctuations in
members with advanced Parkinson's disease when all of the
following criteria are met:
▪ Member is levodopa responsive with clearly defined
“on” periods ; and
▪ The member has "off" periods greater than 3 hours per
day despite optimization efforts; and
▪ The member must have had an inadequate response or
intolerable adverse event with oral carbidopalevodopa
(IR or CR) and one of the following anti-Parkinson
agents:
• Catechol -O-m ethyl transferase (COMT) inhibitor (e.g.
entacapone)
• Monoamine oxidase B (MAO)-B inhibitor (e.g. oral
selegiline, Azilect)
• Dopamine agonists (e.g. pramipexole, ropinirole,
Neupro) .
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Continued use of levodopa-carbidopa intestinal gel (Duopa) is
considered medically necessary for the treatment of motor
fluctuations in members with advanced Parkinson’s disease
who have demonstrated a positive clinical response to Duopa
therapy.
A pump for administering levodopa-carbidopa intestinal gel
(CADD®‐Legacy 1400 portable infusion pum p) is considered
medically n ecessary DME for persons who meet criteria for
levodopa-carbidopa intestinal gel.
Concurrent use of Duopa and nonselective monoamine
oxidase (MAO) inhibitors (e.g., phenelzine and
tranylcypromine) is considered experimental and
investigational. Duopa is considered experimental and
investigational for all other indications.
Hyperbaric Oxygen Therapy
Aetna considers hyperbaric oxygen therapy for the treatment
of PD experimental and investigational because its
effectiveness has not been established
CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)
(see (../100_199/0172.html) ).
Intravenous Glutathione
Aetna considers intravenous glutathione for the treatment of
PD experimental and investigational because its effectiveness
has not been established.
Transcranial Direct Current Stimulation/Transcranial Magnetic Stimulation
Aetna considers transcranial direct current
stimulation/transcranial magnetic stimulation for the treatment
of PD experimental and investigational because their
effectiveness have not been established.
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Bright Light Therapy
Aetna considers bright light therapy for the treatment of
depression in Parkinson disease experimental and
investigational because the effectiveness of this approach has
not been established.
C u eing Module Device (Auditory Cue)
Aetna considers cueing module device (auditory cue) for the
treatment of Parkinson's freezing experimental and
investigational because the effectiveness of this approach has
not been established.
Dosing Recommendations
Levodopa-Carbidopa Intestinal Gel (Duopa)
▪ Available for enteral suspension: 4.63 mg carbidopa and
20 mg levodopa per mL.
▪ The maximum recom men ded daily dose of Duopa is
2000 mg of levodopa (i.e., one cassette per day)
administered over 16 hours. Prior to initiating
Duopa, individuals should be converted from all forms
of levodopa to oral immediate-release carbidopa
levodopa tablets (1:4 ratio). The total daily dose is
titrated based on the clinical response. Duopa is
administered into the jejunum through a percutaneous
endosco pic gastrostom y with jejunal tube (PEG-J) with
the CADD-Legacy 1400 portable infusion pump.
Source: AbbVie, 2016
Background
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Parkinson disease (PD) is the most common cause of
parkinsonism, which is characterized by bradykinesia, rigidity,
resting tremor, and postural reflex impairment. The diagnosis
of PD is based on a careful taking of medical history and a
thorough physical examination. Currently, there are no
laboratory tests or imaging studies that confirm the diagnosis
(Nutt and Wooten, 2005). It is important for clinicians to
understand the clinical signs that aid to differentiate PD from
various parkinsonism syndromes (also known as Parkinson-
plus syndromes) that include progressive supranuclear palsy
(PSP), multiple system atrophy (MSA), cortico-basal
degeneration (CBD), dementia with Lewy bodies (DLB),
vascular parkinsonism, parkinsonism with no clear etiology,
and Parkinson-dementia-amyotrophic lateral sclerosis
complex.
The correct diagnosis of PD is important for prognostic as well
as therapeutic reasons. Research of the diagnostic accuracy
for the disease and other forms of parkinsonism in community-
based samples of patients taking anti-parkinsonian medication
confirmed a diagnosis of parkinsonism in only 74 % of patients
and clinically probable PD in 53 % of patients.
Clinicopathological studies based on brain bank material from
the United Kingdom and Canada have revealed that clinicians
diagnose the disease incorrectly in about 25 % of patients. In
these studies, the most common reasons for diagnostic errors
were presence of essential tremor, vascular parkinsonism, and
atypical parkinsonian syndromes. Infrequent misdiagnosis
included Alzheimer's disease (AD), DLB, and drug-induced
parkinsonism. Moreover, ancillary tests such as olfactory
testing and dopamine-transporter (DAT) single photon
emission computed tomography (SPECT) imaging may help
with clinical diagnostic decisions (Tolosa et al, 2006).
Winogrodzka et al (2005) noted that DAT scintigraphy with
SPECT has been used to evaluate the dopaminergic function
in patients with PD. Initial studies with several radioligands
show significant loss of DAT binding in PD patients as
compared to controls.
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It should be noted that the role of neuroimaging in the
differential diagnosis of PD has not been clearly established.
Piccini and Whone (2004) noted that recent improvements in
the characterization of the parkinsonian syndromes have led to
improvements in clinical diagnostic accuracy; however, clinical
criteria alone are not always sufficient to distinguish between
idiopathic PD and other parkinsonian syndromes, especially in
the early stages of disease and in atypical presentations.
Thus, in addition to the development and implementation of
diagnostic clinical assessments, there is a need for available
objective markers to aid clinicians in the differential diagnosis
of idiopathic PD (IPD). Functional neuroimaging such as
positron emission tomography (PET) and SPECT holds the
promise of improved diagnosis and allows assessment in early
disease.
Seibyl et al (2005) stated that the development of imaging
biomarkers, which target specific sites in the brain, represents
a major advance in neurodegenerative diseases and PD with
the promise of new and improved approaches for the early and
accurate diagnosis of disease as well as novel ways to monitor
patients and assess treatment. The 3 major applications that
imaging may play a role in PD are: (i) the use of
neuroimaging as a biomarker of disease in order to
improve the accuracy, timeliness, and reliability of
diagnosis; (ii) objective monitoring of the progression of
disease to provide a molecular phenotype of PD that may
illuminate some of the sources of clinical variability;and (iii)
the evaluation of disease-modifying treatments designed to
retard the progression of disease by interfering with
pathways thought to be implicated in the ongoing neuronal
loss or replace dopamine-producing cells. Each of these
areas has shown a numbers of critical clinical investigations
that have better defined the utility of neuroimaging to these
tasks. However, current unresolved issues around the clinical
role of neuroimaging in monitoring PD patients over time and
validation of quantitative imaging measures of dopaminergic
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function are immediate issues for the field and the subject of
current research efforts and the extension of the lessons
learned in PD to other neurodegenerative diseases including
AD.
In a review on conventional and advanced magnetic
resonance imaging (MRI) techniques in the differential
diagnosis of neurodegenerative parkinsonism, Seppi and
Schocke (2005) noted that research findings suggest that
novel MRI techniques such as magnetization transfer imaging,
diffusion-weighted imaging, and magnetic resonance
volumetry have superior sensitivity compared to conventional
MRI in detecting abnormal features in neurodegenerative
parkinsonian disorders. They stated that whether these
techniques will emerge as standard tools in the work-up of
patients presenting with parkinsonism requires further
prospective studies during early disease stages.
Ravina and colleagues (2005) reported that radiotracer
imaging (RTI) of the nigrostriatal dopaminergic system is a
widely used but controversial biomarker in PD. These
investigators reviewed the concepts of biomarker development
and the evidence to support the use of four radiotracers as
biomarkers in PD: (i) [18F]fluorodopa PET, (ii) (+)-[11C]
dihydrotetrabenazi ne PET, (iii) [123I]beta-CIT SPECT,and (iv)
[18F]fluorodeoxyglucose PET. According to the authors,
biomarkers used to study disease biology and facilitate drug
discovery and early human clinical trials rely on evidence that
they are measuring relevant biological processes. The 4
tracers fulfill this criterion, although they do not measure the
number or density of dopaminergic neurons. Biomarkers used
as diagnostic tests, prognostic tools, or surrogate endpoints
must not only have biological relevance but also a strong
linkage to the clinical outcome of interest. No radiotracers
fulfill these criteria, and current evidence does not support the
use of imaging as a diagnostic tool in clinical practice or as a
surrogate endpoint in clinical trials. Mechanistic information
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added by RTI to clinical trials may be difficult to interpret
because of uncertainty about the interaction between the
interventions and the tracer.
In the recent practice parameter on the diagnosis and
prognosis of new onset PD (an evidence-based review) by the
American Academy of Neurology (AAN), Suchowersky, et al
(2006) provided the following conclusions/recommendations:
▪ Levodopa or apomorphine challenge should be considered
for confirmation when the diagnosis of PD is in doubt.
▪ Olfactory testing by means of the University of
Pennsylvania Smell Identification Test (UPSIT) or “Sniffin'
Sticks” should be considered to differentiate PD from PSP
and CBD; but notPD from MSA.
▪ The following tests may not be useful in differentiating PD
from other parkinsonian syndromes:
• Electrooculography
• Growth hormone stimulation with clonidine
• SPECT scanning
▪ There is insufficient evidence to determine if iodine-123
meta-iodobenzylguanidine cardiac imaging is useful in
differentiating PD from MSA or PSP.
▪ In the future, there may be an increasing role for genetic
testing to diagnose PD. However, the development of any
new diagnostic test will require long-term follow-up and
autopsy confirmation to determine its accuracy.
de la Fuente-Fernández (2012) evalauted the role of
DaTSCAN in the diagnosis of PD. Using the sensitivity and
specificity values obtained in the 2 studies that recently led the
Food and Drug Administration to approve the use of
DaTSCAN for the diagnosis of PD, calculations were carried
out to estimate the accuracy of the clinical diagnosis taking
DaTSCAN findings as the standard of truth. In early PD, a
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clinical diagnosis of “possible” or “probable” PD has a
sensitivity of 98 % and a specificity of 67 %. The specificity
increases to 94 % once the clinical diagnosis becomes
established. The overall accuracy of the clinical diagnosis is
84 % in early PD and 98 % at later stages.The clinical
diagnostic accuracy is mathematically identical to the
diagnostic accuracy of DaTSCAN imaging. The authors
concluded that in the absence of neuropathologic validation,
the overall accuracy of a clinical diagnosis of PD is very high
and mathematically identical to the accuracy of DaTSCAN
imaging, which calls into question the use of radiotracer
neuroimaging as a diagnostic tool in clinical practice. They
stated that neuropathological studies are definitely needed to
evaluate the diagnostic accuracy of radiotracer neuro-imaging
compared to the clinical diagnosis. Until these assessments
are available, it may be premature to embark on a large-scale
use of DaTSCAN imaging for the diagnosis of PD.
Beyer and colleagues (2007) noted that the nosologic
relationship between DLB and PD with dementia (PDD) is
continuously being debated. These investigators conducted a
study using voxel-based morphometry (VBM) to explore the
pattern of cortical atrophy in DLB and PDD. A total of 74
patients and healthy elderly were imaged (healthy elderly, n =
20; PDD,n = 15;DLB, n = 18, and AD, n = 21). Three
dimensional T1-weighted MRI were acquired, and images
analyzed using VBM. Overall dementia severity was similar in
the dementia groups. These researchers found more
pronounced cortical atrophy in DLB than in PDD in the
temporal, parietal, and occipital lobes. Patients with AD had
reduced gray matter concentrations in the temporal lobes
bilaterally, including the amygdala, compared to PDD.
Compared to DLB, the AD group had temporal and frontal lobe
atrophy. The authors concluded that despite a similar severity
of dementia, patients with DLB had more cortical atrophy than
patients with PDD, indicating different brain substrates
underlying dementia in the 2 syndromes. Together with
previous studies reporting subtle clinical and neurobiological
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differences between DLB and PDD, the findings of this study
supported the hypothesis that PDD and DLB are not identical
entities, but rather represent 2 subtypes of a spectrum of Lewy
body disease.
While the AAN practice parameter on diagnosis and prognosis
of new onset PD (Suchowersky et al, 2006) stated that there is
insufficient evidence to support or refute the use of MRI as a
means of distinguishing PD from other parkinsonian
syndromes, Seppi and Rascol (2007), in an editorial that
accompanied the article by Beyer et al, stated that further
studies involving larger groups of patients with prospective long
term follow-up and ultimate pathologic diagnosis are needed for
verifying the findings of Beyer et al. Furthermore, while such
confirmatory data might be available in the future at the level of
groups of patients, it is unlikely that MRI will be sufficiently
sensitive and specific to allow differential diagnosis at the level
of a single patient.
Genetic causes of PD have been identified in approximately 3
% of cases with the discovery of mutations in 6 genes. The
most common of these are the gene for leucine-rich repeat
kinase 2 (LRRK2 or PARK8), which is autosomal dominant,
and parkin (PARK2), which is recessive. LRRK2 produces a
phenotype identical to classical PD, with age of onset at
approximately 50 to 70 years. The most common mutation
(G2019S) has been reported to cause 1.5 % of all cases of
PD. Penetrance is age-dependent and is estimated to be 25
% to 35 %. Despite LRRK2 being dominantly inherited,many
people who are heterozygous for LRRK2 mutations do not
develop the disease. Homozygous or compound
heterozygous mutations of parkin are the most common cause
of early-onset PD (10 % to 20 % of cases). However, because
single heterozygous mutations also are seen in many people
with PD, these mutations are thought to confer a risk for PD.
This idea is supported by studies of age of onset and by PET
imaging of the dopamine system. However, examinations of
mutation frequency in control populations have had conflicting
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results. Reduced penetrance can cause LRRK2 to act in an
apparently recessive or sporadic manner, and parkin may
appear to be dominant. Hence, the distinction between
dominant and recessive genes in PD is blurred, because the
disease is likely multi-factorial, involving causative genes,
susceptibility genes, environmental exposures that may have
protective effects such as smoking and caffeine, and
exposures that may induce neurodegeneration such as
pesticides (Factor, 2007).
Klein et al (2007) stated that the association of 6 genes with
monogenic forms of parkinsonism has unambiguously
established that the disease has a genetic component. Of
these 6 genes, LRRK2, parkin, and PINK1 (PTEN-induced
putative kinase 1, or PARK6) are the most clinically relevant
because of their mutation frequency. Insights from initial
familial studies suggested that LRRK2-associated
parkinsonism is dominantly inherited, whereas parkinsonism
linked to parkin or PINK1 is recessive. However, screening of
patient cohorts has revealed that up to 70 % of people
heterozygous for LRRK2 mutations are unaffected, and that
more than 50 % of patients with mutations in parkin or PINK1
have only a single heterozygous mutation. Deciphering the
role of heterozygosity in parkinsonism is important for the
development of guidelines for genetic testing, for the
counselling of mutation carriers, and for the understanding of
late-onset PD. However, much more remains to be
understood regarding the pathogenesis of PD before genetic
testing can be considered definitive.
Commenting on the article by Beyer et al, Factor (2007) stated
that "[b]ecause gene expression in this disease is so complex,
most results will be inconclusive. No published guidelines
currently exist regarding how to test and counsel patients
appropriately; the tests are costly; and the results, even if
conclusive,would not change treatment for individual patients,
although one hopes they soon might. For these reasons, no
good rationale yet exists for the genetic testing of PD patients".
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Williams-Gray et al (2009) noted that in addition to the well-
established association between apolipoprotein E (APOE) and
AD, this gene has also been implicated in both susceptibility
to, and dementia in, PD. However studies to date have
produced contradictory findings. These investigators
conducted a case-control study in a population of 528 PD
patients and 512 healthy controls and found no significant
difference in allele or genotype distribution of APOE between
the 2 groups. An updated meta-analysis showed a modest
increase of APOE-epsilon2 carriers among PD patients
compared to controls (p = 0.017, odds ratios [OR] = 1.16 [95 %
confidence interval (CI): 1.03 to 1.31]). A total of 107 patients
were incident cases participating in a population-based
epidemiological study. Longitudinal follow-up of this cohort
over a mean of 5.0 +/- 0.7 years from diagnosis revealed no
significant impact of APOE-epsilon4 carrier status on risk of
dementia or rate of cognitive decline. An updated meta-
analysis indicated an over-representation of APOE-epsilon4
carriers among PD dementia compared to non-dementia
cases [OR 1.74 (1.36 to 2.23), p = 1 x 10(-4)], although small
sample sizes, heterogeneity of OR and publication bias may
have confounded this finding. The authors concluded that
these findings did not support previously reported associations
between APOE genotype and susceptibility to, or cognitive
decline in, PD. An updated meta-analysis indicates any
association with PD susceptibility is at most modest, an
observation with important implications for further study of this
issue. They stated that large scale longitudinal studies would
be best placed to further evaluate any impact of APOE
genotype on cognitive decline i n PD.
The findings by Williams-Gray et al (2009) are in agreement
with those of Kurz et al (2009) who investigated the role of
APOE alleles in PD and PD dementia. These researchers
determined APOE genotypes in a group of patients with PD (n
= 95) and compared them with those of healthy control
participants (n = 73). Additionally, in 64 longitudinally followed
patients with PD, the allele types were correlated to
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development and progression of dementia and to time from
onset of PD to dementia using multi-variate and survival
analyses. The APOE e4e4 genotype was more common in
patients with PD (7.4 %) than in healthy controls (1.4 %; p =
0.03). No significant associations between the APOE
genotype and development and progression of dementia or
time to dementia were found. The authors stated that more
studies with larger PD samples are needed.
Riley and Chelimsky (2003) stated that formal laboratory
testing of autonomic function is reported to distinguish
between patients with PD and those with MSA, but such
studies segregated patients according to clinical criteria that
select those with autonomic dysfunction for the MSA category.
These researchers attempted to characterize the profiles of
autonomic disturbances in patients in whom the diagnosis of
PD or MSA used criteria other than autonomic dysfunction. A
total of 47 patients with parkinsonism and autonomic
symptoms who had undergone autonomic laboratory testing
were identified and their case records reviewed for non-
autonomic features. They were classified clinically into 3
diagnostic groups: (i) PD (n = 19), (ii) MSA (n = 14), and (iii)
uncertain (n = 14). The performance of the patients with PD
was compared with that of the MSA patients on 5 autonomic
tests: (i) R-R interval variations during deep breathing, (ii)
heart rate changes with the Valsalva maneuvre, (iii) tilt table
testing, (iv) the sudomotor axon reflex test,and (v)
thermoregulatory sweat testing.
None of the tests distinguished one group from the other with
any statistical significance, alone or in combination.
Parkinson's disease and MSA patients showed similar patterns
of autonomic dysfunction on formal testing of cardiac
sympathetic and parasympathetic, vasomotor, and central and
peripheral sudomotor functions. The authors concluded that
these findings supported the clinical observation that PD is
often indistinguishable from MSA when it involves the
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autonomic nervous system. The clinical combination of
parkinsonism and dysautonomia is as likely to be caused by
PD as by MSA. Current clinical criteria for PD and MSA that
direct patients with dysautonomia into the MSA group may be
inappropriate.
Reimann et al (2010) stated that differential diagnosis of
parkinsonian syndromes is a major challenge in movement
disorders. Dysautonomia is a common feature but may vary in
clinical severity and onset. These investigators attempted to
find a pattern of autonomic abnormalities discriminative for
patients with differentparkinsonian syndromes. The cross-
sectional study included 38 patients with MSA, 32 patients with
PSP, 26 patients with IPD, and 27 age-matched healthy
controls. Autonomic symptoms were evaluated by a
standardized questionnaire. The performance of patients and
controls was compared on 5 autonomic function tests: (i) deep
breathing, (ii) Valsalva maneuvre, (iii) tilt-table testing, (iv)
sympathetic skin response, (v) pupillography, as well as 24
hr ambulatory BP monitoring (ABPM).
Disease severity was significantly lower in IPD than PSP and
MSA. Except for pupillography, none of the laboratory
autonomic tests distinguished one patient group from the other
alone or in combination. The same was observed on the
questionnaire. Receiver operating characteristic curve
revealed discriminating performance of pupil diameter in
darkness and nocturnal BP change. The composite score of
urogenital and vasomotor domains significantly distinguished
MSA from IPD patients but not from PSP. These findings
supported the observation that even mild IPD is frequently
indistinguishable from more severe MSA and PSP. Thus,
clinical combination of motor and non-motor symptoms does
not exclusively point at MSA. Pupillography, ABPM and the
questionnaire may assist in delineating the 3 syndromes when
applied in combination.
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Although PD is primarily considered a movement disorder, the
high prevalence of psychiatric complications suggests that it is
more accurately conceptualized as a neuropsychiatric
disease. Depression, dementia, and psychosis are common
manifestations of idiopathic PD; and are associated with
excess disability, worse quality of life, poorer prognosis, as
well as caregiver burden. Rihmer and colleagues (2004)
noted that depression is one of the most disabling symptoms
of PD, with a prevalence of approximately 40 %.
Unfortunately, such depression is frequently unrecognized and
untreated in patients with PD. Papapetropoulos and Mash
(2005) stated that psychotic symptoms are common in patients
with PD, and occur in at least20 % of medication-treated
patients. Benign visual hallucinations often appear earlier,
while agitation, confusion, delirium, delusions, malignant
hallucinations, and paranoid beliefs become more frequent
with disease progression. Nearly all anti-parkinsonian
medications may produce psychotic symptoms. Moreover,
cognitive impairment, increased age, disease duration and
severity, depression, as well as sleep disorders have been
consistently identified as independent risk factors for their
development. Although the exact cause for the pathogenesis
of psychosis in PD is not fully known, there is some evidence
that links over-activity of the ventral dopaminergic pathway
with the involvement of other neurotransmitter system
imbalances as likely contributors.
Dementia occurs in up to 30 % of patients with PD. Cognitive
impairments involve attentional, executive, memory, and
visuospatial dysfunctions (Lauterbach, 2005). Furthermore,
Levin and Katzen (2005) stated that early cognitive changes in
PD patients are often subtle and influenced by factors that
interact with the disease process, including medication, motor
symptoms, and age of disease onset. These factors
notwithstanding, ample evidence exists that specific cognitive
changes occur early in the course of PD. The authors noted
that this evidence does not imply that cognitive deficits are
pervasive during the early stages. On the contrary, they are
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usually subtle and often difficult to detect without formal
neuropsychological testing. Executive-function deficits are the
most frequently reported cognitive problems and, given that
executive skills are an integral part of many tasks, it follows
that subtle difficulties may be seen on a wide range of
cognitive measures, especially in working memory as well as
visuospatial dysfunction, two areas that rely heavily on
executive skills. Whereas apraxia and language processing
deficits occur infrequently, subtle changes in olfaction and
contrast sensitivity have also been repeatedly observed.
In the recent practice parameter on the evaluation and
treatment of depression, psychosis, and dementia in PD (an
evidence-based review) by the AAN, Miyasaki et al (2006)
provided the following conclusions/recommendations:
▪ Tools such as the Beck Depression Inventory (BDI), the
Hamilton Depression R ating Scale (HDRS-17), and the
Montgomery Asberg Depression R ating Scale (MADRS)
should be considered for screening depression as sociated
with PD.
▪ Tools such as the Cambridge Cognitive Examination
(CAMCog) and the Mini-Mental State Examination (MMSE)
should be considered for screening dementia in patients
with PD.
▪ There are no widely used, validated tools for psychosis
screening in PD.
In a systematic review on transcranial duplex (TCD) scanning
in the differential diagnosis of parkinsonian syndromes, Vlaar
and colleagues (2009) concluded that before TCD scanning
can be implicated, more research is needed to standardize the
TCD technique, to investigate the TCD in non-research
settings and to determine the additional value of TCD
scanning compared with currently used clinical techniques.
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Tokuda et al (2010) stated that to-date, there is no accepted
clinical diagnostic test for PD that is based on biochemical
analysis of blood or cerebrospinal fluid (CSF). The discovery
of mutations in the SNCA gene encoding α-synuclein in
familial parkinsonism and the accumulation of α-synuclein in
the PD brain suggested a critical role for this protein in PD
etiology. These researchers investigated total and α-synuclein
oligomers levels in CSF from patients clinically diagnosed with
PD, PSP, or AD, and age-matched controls, using ELISA. The
levels of α-synuclein oligomers and oligomers/total-α-synuclein
ratio in CSF were higher in the PD group (n = 32; p < 0.0001,
Mann-Whitney U test) compared to the control group (n = 28).
The area under the receiver operating characteristic curve
(AUC) indicated a sensitivity of 75.0 % and a specificity of 87.5
%, with an AUC of 0.859 for increased CSF α-synuclein
oligomers in clinically diagnosed PD cases. However, when
the CSF oligomers/total-α-synuclein ratio was analyzed, it
provided an even greater sensitivity of 89.3 % and specificity
of 90.6 %, with an AUC of 0.948. In another cross-sectional
pilot study, these researchers confirmed that the levels of CSF
α-synuclein oligomers were higher in patients with PD (n = 25)
compared to patients with PSP (n = 18; p < 0.05) or AD (n =
35; p < 0.001) or control subjects (n = 43; p < 0.05). The
authors concluded that these findings showed that levels of
α-synuclein oligomers in CSF and the oligomers/total-α-
synuclein ratio can be useful biomarkers for diagnosis and
early detection of PD. Moreover, the authors stated that large-
scale, prospective, and well-controlled studies, especially
those that include subjects with neuroimaging-supported
definite PD and other synucleinopathies, as well as unrelated
neurologic disorders, are necessary to validate the
quantification of CSF α-synuclein oligomers as an urgently
needed surrogate biomarker. It will be critical to carry out
prospective studies to examine if individuals who do not have
PD, but have an elevated oligomer-to-total α-synuclein ratio in
their CSF will be more prone to develop the disease in the
future.
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In an editorial that accompanied the afore-mentioned study,
Ballard and Jones (2010) noted that there is emerging
evidence thatmeasurementof specific forms of α-synuclein in
CSF may contribute to diagnosis and treatment development
in PD and related disorders. Moreover, they stated that further
validation is still needed; it is too preliminary to put this forward
as a diagnostic test for PD.
Siderowf et al (2010) investigated if CSF amyloid beta 1-42
(Aβ[1-42]) would predict cognitive decline i n PD. A total of 45
patients with PD were enrolled in this prospective cohort study
and had at least 1 yearly longitudinal follow-up evaluation.
Cerebrospinal fluid was collected at baseline and cognition
was assessed at baseline and follow-up v isits using the Mattis
Dementia Rating Scale (DRS-2); CSF was tested for Aβ[1-42],
p-tau(181p), and total tau levels using the Luminex xMAP
platform. Mixed linear models were used to test for
associations between baseline CSF biomarker levels and
change in cognition over time. Lower baseline CSF Aβ[1-42]
was associated with more rapid cognitive decline. Subjects
with CSF Aβ[1-42] levels less than or equal to192 pg/ml
declined an average of 5.85 (95 % CI: 2.11 to 9.58, p = 0.002)
points per year more rapidly on the DRS-2 than subjects
above that cut-off, after adjustment for age, disease duration,
and baseline cognitive status. Cerebrospinal fluid total tau and
p-tau(181p) levels were not significantly associated with
cognitive decline. The authros concluded t hat reduced CSF
Aβ[1-42] was an independent predictor of cognitive decline in
patients with PD. This observation is consistent with previous
research showing that AD pathology contributes to cognitive
impairment in PD. This biomarker may provide clinically useful
prognostic information, particularly if combined with other risk
factors for cognitive impairment in PD. Furthermore, they
noted that there are 2 main drawbacks of this study: (i) small
number of patients studied for a relatively short period of
time,and (ii) the results do not address if the association
between reduced Aβ[1-42] and cognitive decline is specific
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to PD. These findings need to be validated with well-designed
studies with larger number of subjects in longer study duration.
In an editorial that accompanied the afore-mentioned study,
Aarsland and Ravina (2010) stated that there are several
limitations of this study: (i) small cohort recruited at a single
center, (ii) lack of a healthy control group,and (iii) large
variations in PD duration, severity of disease, length of follow-
up, and baseline cognitive impairment. They stated that the
potential clinical utility of these findings is not yet known.
The policy on surgical treatment of PD is based primarily on
evidence assessments by the AAN (Hallett et al, 1999), the
National Institute for Clinical Excellence (NICE, 2004), the
BlueCross BlueShield Association Technology Evaluation
Center (BCBSA, 2001), and the Agency for Healthcare
Research and Quality (AHRQ) (Levine et al, 2003).
Arle and colleagues (2008) stated that since the initial 1991
report by Tsubokawa et al, stimulation of the M1 region of the
motor cortex has been used to treat chronic pain conditions
and various movement disorders. The authors reviewed the
literature and found 459 cases in which motor cortex
stimulation (MCS) was used. Of these, 72 were related to a
movement disorder. More recently, up to 16 patients
specifically with PD were treated with MCS, and a variety of
results were reported. In this report, the authors described 4
patients who were treated with extra-dural MCS. Although
there were benefits seen within the first 6 months in Unified
Parkinson's Disease Rating Scale Part III scores (decreased
by 60 %), tremor was only modestly managed with MCS in this
group, and most benefits seen initially were lost by the end of
12 months. The authors concluded that although there have
been some positive findings using MCS for PD, a larger study
may be needed to better determine if it should be pursued as
an alternative surgical treatment to DBS.
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Martin and Teismann (2009) stated that PD is the second most
common neuro-degenerative disease, affecting over a million
people in the United States alone. Its main neuro-pathological
feature is the loss of dopaminergic neurons of the substantia
nigra pars compacta. However, the pathogenesis of this loss
is not understood fully. One of the earliest biochemical
changes seen in PD is a reduction in the levels of total
glutathione (GSH), a key cellular antioxidant. Traditionally, it
has been thought that this decrease in GSH levels is the
consequence of increased oxidative stress, a process heavily
implicated in PD pathogenesis. However, emerging evidence
suggests that GSH depletion may itself play an active role in
PD pathogenesis.
Hauser and colleagues (2009) evaluated the safety,
tolerability, and preliminary efficacy of intravenous GSH in PD
patients. This was a randomized, placebo-controlled, double-
blind, pilot trial in subjects with PD whose motor symptoms
were not adequately controlled with their current medication
regimen. Subjects were randomly assigned to receive
intravenous GSH 1,400 mg or placebo administered 3 times a
week for 4 weeks. A total of 21 subjects were randomly
assigned, 11 to GSH and 10 to placebo. One subject who was
assigned to GSH withdrew from the study for personal reasons
prior to undergoing any post-randomization efficacy
assessments. Glutathione was well-tolerated and there were
no withdrawals because of adverse events in either group.
Reported adverse events were similar in the 2 groups. There
were no significant differences in changes in Unified
Parkinson's Disease Rating Scale (UPDRS) scores. Over the
4 weeks of study medication administration, UPDRS ADL +
motor scores improved by a mean of 2.8 units more in the
GSH group (p = 0.32), and over the subsequent 8 weeks
worsened by a mean of 3.5 units more in the GSH group (p =
0.54). Glutathione was well-tolerated and no safety concerns
were identified. The authors stated that these preliminary
efficacy data suggest the possibility of a mild symptomatic
effect, but this remains to be evaluated in a larger study.
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Sedlacková and associates (2009) examined the effects of
one session of high-frequency repetitive transcranial magnetic
stimulation (rTMS) applied over the left dorsal premotor cortex
(PMd) and left dorsolateral prefrontal cortex (DLPFC) on
choice reaction time in a noise-compatibility task, and cognitive
functions in patients with PD. Clinical motor symptoms of PD
were assessed as well. A total of 10 patients with PD entered
a randomized, placebo-controlled study with a cross-over
design. Each patient received 10 Hz stimulation over the left
PMd and DLPFC (active stimulation sites) and the occipital
cortex (OCC; a control stimulation site) in the OFF motor state,
i.e., at least after 12 hrs of dopaminergic drugs withdrawal.
Frameless stereotaxy was used to target the optimal position
of the coil. For the evaluation of reaction time, a noise-
compatibility paradigm was used. A short battery of
neuropsychological tests was performed to evaluate executive
functions, working memory, and psychomotor speed. Clinical
assessment included a clinical motor evaluation using part III
of the UPDRS. Statistical analysis revealed no significant
effect of rTMS applied over the left PMd and/or DLPFC in
patients with PD in any of the measured parameters. In this
study, these researchers did not observe any effect of 1
session of high frequency rTMS applied over the left PMd
and/or DLPFC on choice reaction time in a noise-compatibility
task, cognitive functions, or motor features in patients with PD;
rTMS applied over all 3 stimulated areas was safe and well-
tolerated in terms of the cognitive and motor effects.
In a double-blind, placebo-controlled study, Arias and co-
workers (2010a) evaluated the effect of 10-day rTMS on sleep
parameters in PD patients. A total of 18 IPD patients
completed the study. Sleep parameters were evaluated
through actigraphy and the Parkinson's Disease Sleep Scale
(PDSS), along with depression (Hamilton Depression Rating
Scale, HDS), and the UPDRS. Evaluations were carried out
before treatment with rTMS (pre-evaluation, PRE), after the
rTMS treatmentprogramme (post-evaluation, POST), and 1
week after POST (POST-2). Nine PD patients received real
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rTMS and the other 9 received sham rTMS daily for 10 days,
(100 pulses at 1Hz) applied with a large circular coil over the
vertex. Stimulation had no effect over actigraphic variables.
Conversely PDSS, HDS, and UPDRS were significantly
improved by the stimulation. Notably, however, these changes
were found equally in groups receiving real or sham
stimulation. The authors concluded that rTMS, using these
researchers' protocol, has no therapeutic value on the sleep of
PD patients, when compared to appropriate sham controls.
They stated that future works assessing the possible
therapeutic role of rTMS on sleep in PD should control the
effect of placebo.
In a double-blind placebo-controlled trial, Arias et al (2010b)
evaluated the effect of low-frequency rTMS on motor signs in
PD. Patients with PD were randomly assigned to received
either real (n = 9) or sham (n = 9) rTMS for 10 days. Each
session comprises 2 trains of 50-stimuli each delivered at 1 Hz
and at 90 % of daily rest motor threshold using a large circular
coil over the vertex. The effect of the stimulation, delivered
during the ON-period, was evaluated during both ON and OFF
periods. Tests were carried out before and after the
stimulation period, and again 1 week after. The effect of the
stimulation was evaluated through several gait variables
(cadence, step amplitude, velocity, the CV(stride-time), and
the turn time), hand dexterity, and also the total and motor
sections of the UPDRS. Only the total and motor section of
the UPDRS and the turn time during gait were affected by the
stimulation, the effect appearing during either ON or OFF
evaluation, and most importantly, equally displayed in both
real and sham group. The rest of the variables were not
influenced. The authors concluded that the protocol of
stimulation used, different from most protocols that apply
larger amount of stimuli, but very similar to some previously
reported to have excellent results, has no therapeutic value
and should be abandoned. This contrasts with the positive
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reported effects using higher frequency and focal coils. These
findings also reinforced the need for sham stimulation when
evaluating the therapeutic effect of rTMS.
Filipović etal (2010) examined the effects of low-frequency
rTMS on OFF-phase motor symptoms in patients with PD. A
total of 10 patients with PD had rTMS (1,800 stimuli at just
below active motor threshold intensity) at 1Hz rate delivered
over the motor cortex for 4 consecutive days on 2 separate
occasions. On 1 of these occasions, real rTMS was used and
on the other sham rTMS (placebo) was used. Evaluations with
UPDRS Part 3 (Motor Scale) were done in practically defined
OFF-phase at the baseline and 1 day after the end of each of
the treatment series. Neither total Motor Scale scores nor
subscores for axial symptoms, rigidity, bradykinesia, and
tremor showed any significant difference. The results did not
confirm presence of residual beneficial clinical after-effects of
consecutive daily applications of low-frequency rTMS on motor
symptoms in PD, at least when 1800 stimuli at sub-threshold
intensity are applied for 4 days.
In a randomized,double-blind, sham-controlled study,
Benninger et al (2011) examined the safety and effectiveness
of intermittent theta-burst transcranial magnetic stimulation
(iTBS), a novel type of rTMS, in the treatmentof motor
symptoms in PD. These researchers investigated safety and
efficacy of iTBS of the motor and dorso-lateral prefrontal
cortices in 8 sessions over 2 weeks (evidence Class I).
Assessment of safety and clinical efficacy over a 1-month
period included timed tests of gait and bradykinesia, UPDRS,
and additional clinical, neuropsychological, and
neurophysiologic measures. A total of 26 patients with mild-to-
moderate PD were included in this study: 13 received iTBS
and 13 sham stimulation. These investigators found beneficial
effects of iTBS on mood, but no improvement of gait,
bradykinesia, UPDRS, and other measures. EEG/EMG
monitoring recorded no pathologic increase of cortical
excitability or epileptic activity. Few reported discomfort or
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pain and 1 experienced tinnitus during real stimulation. The
authors concluded that iTBS of the motor and prefrontal
cortices appears safe and improves mood, but failed to
improve motor performance and functional status in PD. This
study provided Class I evidence that iTBS was not effective for
gait, upper extremity bradykinesia, or other motor symptoms in
PD.
In a randomized,double-blind, sham-controlled study,
Benninger and colleagues (2010) examined the effectiveness
of transcranial direct current stimulation (tDCS) in the
treatment of PD. The effectiveness of anodal tDCS applied to
the motor and pre-frontal cortices was investigated in 8
sessions over 2.5 weeks. Assessment over a 3-month period
included timed tests of gait (primary outcome measure) and
bradykinesia in the upper extremities, UPDRS, Serial Reaction
Time Task, Beck Depression Inventory, Health Survey and self-
assessment of mobility. A total of 25 PD patients were studied,
13 receiving tDCS and 12 sham stimulation.
Transcranial direct current stimulation improved gait by some
measures for a short time and improved bradykinesia in both
the ON and OFF states for longer than 3 months. Changes in
UPDRS, reaction time, physical and mental well being, and self-
assessed mobility did not differ between the tDCS and sham
interventions. The authors concluded that tDCS of the motor
and prefrontal cortices may have therapeutic potential in PD;
but better stimulation parameters need to be established to
make the technique clinically viable. The findings of this
preliminary study need to be validated by well-designed
studies.
Klassen and colleagues (2011) evaluated quantitative EEG
(qEEG) measures as predictive biomarkers for the
development of dementia in PD. A cohort of subjects with PD
in the authors' brain donation program utilizes annual pre-
mortem longitudinal movement and cognitive evaluation.
These subjects also undergo biennial EEG recording. EEG
from subjects with PD without dementia with follow-up
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cognitive evaluation w as analyzed for qEEG measures of
background rhythm frequency and relative power in δ, α, and β
bands. The relationship between the time to onset of
dementia and qEEG and other possible predictors was
assessed by using Cox regression. The hazard of developing
dementia was 13 times higher for those with low background
rhythm frequency (lower than the grand median of 8.5 Hz)
than for those with high background rhythm frequency (p <
0.001). Hazard ratios (HRs) were also significant for greater
than median bandpower (HR = 3.0; p = 0.004) compared to
below, and for certain neuropsychological measures. The
HRs for δ, α, and β bandpower as well as baseline
demographic and clinical characteristics were not significant.
The authors concluded that qEEG measures of background
rhythm frequency and relative pow er in the band are potential
predictive biomarkers for dementia incidence in PD. These
qEEG biomarkers may be useful in complementing
neuropsychological testing for studying PD-D incidence.
In a randomized clinical trial, Espay and colleagues (2011)
evaluated the effectiveness of methylphenidate (MPD) for the
treatment of gait impairment in PD. A total of 27 subjects with
PD and moderate gait impairment were screened for this
6-month placebo-controlled, double-blind study. Subjects
were randomly assigned to MPD (maximum, up to 80 mg/day)
or placebo for 12 weeks and crossed-over after a 3-week
washout. The primary outcome measure was change in a gait
composite score (stride length + velocity) between groups at 4
and 12 weeks. Secondary outcome measures included
changes in motor function, as measured by the UPDRS,
Freezing of Gait Questionnaire (FOGQ), number of gait-diary
freezing episodes, and measures of depression, sleepiness,
and quality of life. Three-factor repeated-measures analysis of
variance was used to measure changes between groups.
Twenty-three eligible subjects with PD were randomized and
17 completed the trial. There was no change in the gait
composite score or treatment or time effect for any of the
variables. Treatment effect was not modified by state or study
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visit. Although there was a trend for reduced frequency of
freezing and shuffling per diary, the FOGQ and UPDRS scores
worsened in the MPD group compared to placebo. There was
a marginal improvement in some measures of depression.
The authors concluded that MPD did not improve gait and
tended to worsen measures of motor function, sleepiness, and
quality of life.
The National Institute for Health and Clinical Excellence's
clinical practice guideline on "Parkinson's disease: Diagnosis
and management in primary and secondary care" (NICE,
2006) stated that "123I-FP-CIT SPECT should be considered
for people with tremor where essential tremor can not be
clinically differentiated from parkinsonism". Furthermore, the
Scottish Intercollegiate Guidelines Network's clinical practice
guideline on "Diagnosis and pharmacological management of
Parkinson's disease" (SIGN, 2010) stated that "Single photon
emission computed tomography (SPECT) with (123I-labeled N
omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)
tropane (123I-FP-CIT SPECT scanning) should be considered
as an aid to clinical diagnosis in patients where there is
uncertainty between Parkinson's disease and non-
degenerative parkinsonism/tremor disorders. Routine use of
functional imaging is not recommended for the differential
diagnosis of Parkinson's disease and Parkinson's plus
disorders such as progressive supranuclear palsy and multiple
system atrophy".
Also, an UpToDate review on "Diagnosis of Parkinson
disease" (Chou, 2012) states that "Positron emission
tomography (PET) and single photon emission computed
tomography (SPECT) may be helpful for the early diagnosis of
PD. With PET, decreased tracer uptake is seen in the mid-
and posterior putamen of patients with early PD when
compared with controls. Striatal dopamine transporter imaging
using SPECT (e.g., 123I-FP-CIT SPECTscan or DaTscan)
can reliably distinguish patients with PD and other
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parkinsonian syndromes from controls or patients with
essential tremor, but it can not differentiate PD and the
parkinsonian syndromes from one another".
Fink et al (2000) stated that the observation that fetal neurons
are able to survive and function when transplanted into the
adult brain fostered the development of cellular therapy as a
promising approach to achieve neuronal replacement for
treatment of diseases of the adult central nervous system.
This approach has been demonstrated to be effective in
patients with PD after transplantation of human fetal neurons.
The use of human fetal tissue is limited by ethical, infectious,
regulatory, and practical concerns. Other mammalian fetal
neural tissue could serve as an alternative cell source. Pigs
are a reasonable source of fetal neuronal tissue because of
their brain size, large litters, and the extensive experience in
rearing them in captivity under controlled conditions. In phase
I studies, porcine fetal neural cells grafted unilaterally into PD
and Huntington's disease patients were being evaluated for
safety and effectiveness. Clinical improvement of 19 % has
been observed in the Unified Parkinson's Disease Rating
Scale "off" state scores in 10 PD patients assessed 12 months
after unilateral striatal transplantation of 12 million fetal porcine
ventral mesencephalic (VM) cells. Several patients have
improved more than 30 %. In a single autopsied PD patient
some porcine fetal VM cells were observed to survive 7
months after transplantation. Twelve Huntington's disease
patients have shown a favorable safety profile and no change
in total functional capacity score 1 year after unilateral striatal
placement of up to 24 million fetal porcine striatal cells.
Xenotransplantation of fetal porcine neurons is a promising
approach to delivery of healthy neurons to the central nervous
system. The major challenges to the successful use of
xenogeneic fetal neuronal cells in neurodegenerative diseases
appear to be minimizing immune-mediated rejection,
management of the risk of xenotic (cross-species) infections,
and the accurate assessment of clinical outcome of diseases
that are slowly progressive.
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Cederfjall et al (2012) noted that it has been suggested that
the beneficial effect of L-DOPA could be re-established by
changing the mode of administration. Indeed, continuous
delivery of L-dopa has been shown to be an effective way to
circumvent many of the side effects seen with traditional oral
administration, which results in an intermittent supply of the
dopamine precursor to the brain. However, all currently tested
continuous dopaminergic stimulation approaches rely on
peripheral administration. This is not ideal since it gives rise to
off-target effects and is difficult to maintain long-term. Thus,
there is an unmet need for an effective continuous
administration method with an acceptable side effect profile.
Viral-mediated gene therapy is a promising alternative
paradigm that can meet this demand. Encouraging pre-clinical
studies in animal models of PD showed therapeutic
effectiveness after expression of the genes encoding the
enzymes required for biosynthesis of dopamine. Although
phase I clinical trials using these approaches have been
conducted, clear positive data in placebo-controlled efficacy
studies are still lacking. The authors stated that “We are now
at a critical junction and need to carefully review the preclinical
data from the clinical translation perspective and identify the
key factors that will determine the potential for success in gene
therapy for Parkinson's disease”.
Besong-Agbo et al (2013) stated that biomarkers are needed
for the diagnosis and monitoring of disease progression in
PD. To date, most studies have concentrated on α-synuclein
(α-Syn), a protein involved in PD pathogenesis, as a potential
biomarker, with inconsistent outcomes. Recently, naturally
occurring autoantibodies againstα-Syn (α-Syn-nAbs) have
been detected in the serum of patients with PD. They
represent a putative diagnostic marker for PD. These
researchers established and validated an ELISA to quantify
α-Syn-nAbs in serum samples. They analyzed serum samples
from 62 patients with PD, 46 healthy controls (HC), and 42
patients with Alzheimer disease (AD) using this newly
established ELISA. Additionally, serum levels of endogenous
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α-Syn were measured. There was a significant difference in
α-Syn-nAbs levels between the investigated groups (p = 0.005;
Kruskal-Wallis test). Levels of α-Syn-nAbs were significantly
lower in patients with PD compared to HC (p < 0.05; Dunn
multiple comparison post-hoc test) or patients with AD (p <
0.05). Furthermore, these investigators detected no difference
between patients with AD and HC. The sensitivity and
specificity of the assay for patients with PD versus HC were 85
% and 25 %, respectively.The α-Syn-nAbs levels did not
correlate with age, Hoehn and Yahr status, or duration of
disease.Endogenous α-Syn had no influence on α-Syn-nAbs
levels in sera. The authors concluded that using a well-
validated assay, they detected reduced α-Syn-nAbs levels in
patients with PD compared to patients with AD and HC. The
assay did not achieve criteria for use as a diagnostic tool to
reliably distinguish PD from HC. They stated that
appropriately powered and independent investigations with
validated assays are needed to further evaluate the utility of
α-Syn-nAbs as a biomarker in PD.
Gan-Or et al (2013) studied the possible association of
founder mutations in the lysosomal storage disorder genes
hexosaminidase A (or HEXA), sphingomyelin
phosphodiesterase 1 gene (SMPD1), and mucolipin 1
(MCOLN1) (causing Tay-Sachs, Niemann-Pick A, and
mucolipidosis type IV diseases, respectively) with PD. Two
PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that
included a total of 938 patients, were studied: (i) a cohort of
654 patients from Tel Aviv, and (ii) a replication cohort of
284 patients from New York. Eight AJ founder mutations in
the HEXA, SMPD1, and MCOLN1 genes were analyzed. The
frequencies of these mutations were compared to AJ control
groups that included large published groups undergoing
prenatal screening and 282 individuals matched for age and
sex. Mutation frequencies were similar in the 2 groups of
patients with PD. The SMPD1 p.L302P was strongly
associated with a highly increased risk for PD (odds ratio 9.4,
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95 % CI: 3.9 to 22.8, p < 0.0001), as 9/938 patients with PD
were carriers of this mutation compared to only 11/10,709
controls. The authors concluded that the SMPD1 p.L302P
mutation is a novel risk factor for PD. Although it is rare on a
population level, the identification of this mutation as a strong
risk factor for PD may further elucidate PD pathogenesis and
the role of lysosomal pathways in disease development.
Moreover, these researchers noted that studies of SMPD1
mutations in other populations are needed to further ascertain
the role of this gene in PD.
In an editorial that accompanied the afore-mentioned study,
Sharma (2013) stated that “While these data do not change
the way in which patients with PD are diagnosed or treated,
they do illustrate the utility of performing genetic studies in
relatively ethnically homogeneous cohorts that have
undergone careful clinical characterization …. The finding that
a specific mutation in the SMPD1 enzyme is associated with
an increased risk of PD gives further support to the hypothesis
that defects in the ALP [autophagy-lysosomal pathway] play a
role in the pathogenesis of PD and identifies another cellular
pathway as a target for drug development”.
Wang and Wang (2014) stated that the glutathione
S-transferase M1 (GSTM1) and glutathione S-transferase T1
(GSTT1) genes have been studied extensively as potential
candidate genes for the risk of PD; however, direct evidence
from genetic association studies remains inconclusive. These
researchers performed an updated and refined meta-analysis
to determine the effect of GSTM1 and GSTT1 polymorphisms
on PD. A fixed-effect model was utilized to calculate the
combined OR, OR of different ethnicities, and 95 % CIs.
Potential publication bias was estimated. Homogeneity of the
included studies was also evaluated. The pooled OR was
1.13 [95 % CI: 1.03 to 1.24)] and 0.96 [95 % CI: 0.82 to 1.12)]
for GSTM1 and GSTT1 polymorphisms, respectively. Analysis
according to different races found no as sociation bet ween
GSTM1/GSTT1 polymorphisms and PD risks except for
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GSTM1 variant in Caucasians, which showed a weak
correlation (OR 1.16 [95 % CI: 1.04 to 1.29), I squared = 6.2
%, p = 0.384]). Neither publication bias nor heterogeneity was
found among the included studies. The authors concluded
that the results of this meta-analysis suggested that GSTM1
polymorphism is weakly associated with the risk of PD in
Caucasians whereas GSTT1 polymorphism is not a PD risk
factor.
Jin and colleagues (2014) noted that several studies have
been conducted in recent years to evaluate the risk of PD and
polymorphisms of interleukin -10 (IL-10); however, the results
were conflicting. These researchers performed a meta-
analysis of published case-control studies to assess this
association. Systematic searches of electronic databases
PubMed Web of Science, BIOSIS Previews, Science Direct,
Chinese Biomedical Database, WANFANG Database, and
Chinese National Knowledge Infrastructure with hand-
searching of the references of identified articles were
conducted. Data were extracted using a standardized form
and pooled ORs with 95 % CIs were calculated to evaluate the
strength of the association. A total of 7 case-control studies
involving 1,912 PD cases and 1,740 controls were included,
concerning 2 polymorphisms (-1082A/G and -592C/A) of IL-10
gene. No significant associations were found in the overall
analysis for both -1082A/G and -592C/A polymorphisms with
PD risk. Similar lacking associations were observed in
subgroup analysis based on ethnicity and age of onset.The
authors concluded that there is inadequate evidence for
association between IL-10 polymorphisms (-1082A/G and
-592C/A) and risk of PD at present. Moreover, they stated that
well-designed studies with larger sample-size and multi-
ethnicity studies are needed in the future.
Mondello et al (2014) stated that α-synuclein, linked to the
pathogenesis of PD, is a promising biomarker candidate in
need of further investigation. The ubiquitin carboxy-terminal
hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin
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proteasome system that seems to be disturbed in PD, may
also be involved in the pathogenesis of this disorder. These
researchers investigated CSF α-synuclein and UCH-L1 levels
from 22 healthy controls, 52 patients with PD, 34 with MSA, 32
with PSP, and 12 with CBD. Cerebrospinal fluid α-Synuclein
levels were significantly decreased in PD and in MSA
compared with controls, and in synucleinopathies compared
with tauopathies; UCH-L1 levels were significantly decreased
in PD, MSA as well as PSP compared with controls, and in PD
compared with APD (p < 0.001). Both markers discriminated
PD well from controls (p < 0.0001; AUC = 0.82 and 0.89,
respectively). Additionally, CSF α-synuclein separated
patients with synucleinopathies from those with tauopathies (p
= 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated
between PD and APD (p = 0.0003; AUC = 0.69). Interestingly,
α-synuclein and UCH-L1 levels were strongly correlated i n PD
and synucleinopathies, and weakly in tauopathies. No
correlation was found in controls. The authors concluded that
CSF levels of α-synuclein and UCH-L1 showed distinct
patterns in parkinsonian syndromes. Their combined
determination may be useful in the differential diagnosis of
parkinsonian disorders and provided k ey to understanding
their pathoetiology and clinical course. Moreover, they stated
that further large studies are needed to validate these findings.
Beach and colleagues (2013) stated that the clinical diagnosis
of PD is incorrect in 30 % or more of subjects particularly at
the time of symptom onset. Because Lewy-type
α-synucleinopathy (LTS) is present in the submandibular
glands of PD patients, these researchers assessed the
feasibility of submandibular gland biopsy for diagnosing PD.
They performed immunohistochemical staining for LTS in
sections of large segments (simulating open biopsy) and
needle cores of submandibular glands from 128 autopsied and
neuropathologically classified subjects, including 28 PD, 5
incidental Lewy body disease, 5 PSP (3 with concurrent PD), 3
CBD, 2 MSA, 22 AD with Lewy bodies,16 AD withoutLewy
bodies, and 50 normal elderly. Immunoreactive nerve fibers
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were present in large submandibular gland sections of all 28
PD subjects (including 3 that also had PSP); 3 AD with Lewy
bodies subjects were also positive, but none of the other
subjects was positive. Cores from frozen submandibular
glands taken with 18-gauge needles (total length, 15 to 38
mm; between 10 and 118 sections per subject examined) were
positive for LTS in 17 of 19 PD patients. The authors
concluded that these results suggested that biopsy of the
submandibular gland may be a feasible means of improving
PD clinical diagnostic accuracy.
Folgoas et al (2013) evaluated the diagnostic performance of
minor salivary gland biopsy for PD. Minor salivary glands were
examined f or Lewy pathology using phosphorylated alpha-
synuclein antibody in 16 patients with clinically diagnosed PD
and 11 control subjects with other neurological disorders.
Abnormal accumulation of alpha-synuclein was found in 3 out
of 16 PD patients. Two control subjects exhibited weak
phosphorylated alpha-synuclein immunoreactivity. The
authors concluded that these results did not support the use
of minor salivary glands biopsy for the detection of Lewy
pathology in living subjects.
Adler et al (2014) examined salivary gland biopsies in living
patients with PD. Patients with PD for greater than or equal to
5 years underwent outpatient transcutaneous needle core
biopsies (18-gauge or 16-gauge) of 1 submandibular gland.
Minor salivary glands were removed via a small incision in the
lower lip. Tissue was fixed in formalin and serial 6-µm paraffin
sections were immunohistochemically stained for
phosphorylated α-synuclein and reviewed for evidence of
LTS. A total of 15 patients with PD were biopsied: 9 females/6
males, mean age of 68.7 years, mean PD duration of 11.8
years. Twelve of the needle core biopsies had microscopically
evident submandibular gland tissue to assess and 9/12 (75 %)
had LTS. Only 1/15 (6.7 %) minor salivary gland biopsies
were positive for LTS; 5 patients had an adverse event; all
were minor and transient. The authors concluded that this
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study demonstrated the feasibility of performing needle core
biopsies of the submandibular gland in living patients with PD
to assess LTS. Moreover, they stated that although this was a
small study, this tissue biopsy method may be important for
tissue confirmation of PD in patients being considered for
invasive procedures and in research studies of other PD
biomarkers. One major drawback of this study was the lack of
control subjects. Also, this study did not include patients with
other parkinsonian disorders, so determination of the
specificity for LTS in submandibular gland biopsies for PD will
require further study. The authors stated that future studies
should include patients with early-stage PD, control subjects,
subjects with other parkinsonian disorders, and when possible,
longitudinal studies extended to autopsy with neuropathologic
confirmation of PD.
Du opa (Levodopa-Carbidopa Intestinal Gel)
Parkinson’s disease (PD) is a common and complex
movement disorder characterized by progressive
neurodegeneration, loss of nigrostriatal dopaminergic and
extra‐nigral neurons, and functional disability because of motor
and nonmotor symptoms.
The goal of PD management is to improve motor and
nonmotor symptoms so that patients obtain the best function
for their stage of disease.
Levodopa is an endogenous chemical that is a precursor to
several neurotransmitters including norepinephrine,
epinephrine, and dopamine. In individuals with Parkinson’s
disease, a loss of dopaminergic cells in the midbrain results in
abnormal nerve functioning, which in turn leads to a reduced
ability or loss of ability to control body movements.
The combination product of carbidopa and levodopa is the
most effective agent for controlling the symptoms of
Parkinson’s disease. Levodopa, the precursor to dopamine,
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crosses the blood brain barrier while dopamine itself cannot.
Levodopa is given concomitantly with carbidopa, as carpidopa
inhibits the peripheral metabolism of levodopa, thus allowing a
higher percentage of levodopa to cross the blood brain barrier
for central nervous system effect, this also limits adverse
effects. Oral carbidopa and levodopa becomes progressively
less effective as the disease progresses. Motor complications
occur in 80% of young patients and 44% of older patients after
5 years of oral levodopa therapy.
Motor complications in Parkinson's disease (PD) are
associated with long-term oral levodopa treatment and linked
to pulsatile dopaminergic stimulation. l-dopa-carbidopa
intestinal gel (LCIG) is delivered continuously by percutaneous
endoscopic gastrojejunostomy tube (PEG-J), which reduces
l-dopa-plasma-level fluctuations and can translate to reduced
motor complications.
Duopa is a combination of carbidopa (an aromatic amino acid
decarboxylation inhibitor) and levodopa (an aromatic amino
acid) which has been approved by the U.S. Food and Drug
Administration (FDA) for the treatment of motor fluctuations in
patients with advanced Parkinson's disease. Duopa (levodopa‐
carbidopa enteral suspension) provides continuous daily 16‐
hour delivery of levodopa directly into the jejunum through a
percutaneous endoscopic gastrostomy with jejunal tube (PEG‐
J) with the CADD‐Legacy 1400 portable i nfusion pum p i n order
to reduce the amount of motor fluctuations that patients with
advanced Parkinson’ disease c urrently taking oral
carbidopa/levodopa are experiencing.
Duopa is administered over a 16‐hour infusion period through
either a naso‐jejunal tube for short‐term administration (i.e.
temporary administration of Duopa prior to PEG‐J tube
placement to observe patient’ clinical response) or through a
PEG‐J for long‐term administration. Each cassette is for single
‐use only and should not be used for longer than 16 hours,
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even if some drug remains. The daily dose is determined by
individualized patient titration and composed of a morning
dose, a continuous dose and an extra dose.
Duopa (carbidopa and levodopa enteral suspension) has been
shown to be an effective and safe therapy compared with oral
immediate release of carbidopa and levodopa tablet, but it
would likely be reserved for patients with persistent, severe, on
‐off fluctuations who are not candidates for deep brain
stimulation (DBS).
Most common adverse reactions (at least 7% greater than oral
carbidopa-levodopa incidence) were complication of device
insertion, nausea, depression, peripheral edema,
hypertension, upper respiratory tract infection, oropharyngeal
pain, atelectasis, and incision site erythema (AbbVie, 2016).
Orthostatic systolic hypotension (≥30 mm Hg decrease)
occurred in 73% of Duopa treated patients compared to 68%
of patients treated with oral immediate‐release carbidopa
levodopa in the controlled clinical study.
There is an increased risk for hallucinations and psychosis
while taking Duopa. In addition, patients may experience
intense urges to gamble, increased sexual urges, intense
urges to spend money, binge or compulsive eating, and/or
other intense urges, and the inability to control these urges
while taking one or more of the medications.
Monitoring for the development of depression and concomitant
suicidal tendencies os recommended.
Duopa may cause or exacerbate dyskinesia. In addition,
patients should have clinical assessments for the signs and
symptoms of peripheral neuropathy before starting Duopa.
Monitoring patients periodically for signs of neuropathy is
recommended.
Because Duopa is administered using a PEG‐J,
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gastrointestinal complications can occur. These complications
include bezoar, ileus, implant site erosion/ulcer, intestinal
hemorrhage, intestinal ischemia, intestinal obstruction,
intestinal perforation, pancreatitis, peritonitis, pneumo‐
peritoneum, and post‐operative wound infection. These
complications may result in serious outcomes, such as the
need for surgery or death. Gastrointestinal hemorrhage may
occur in patients with a history of peptic ulcer.
Melanoma has been reported with a higher risk in patients with
Parkinson’ disease, thus, close monitoring is recommended.
In clinical trials, Duopa significantly reduced daily mean off
time at 12 weeks by 4 hours, which resulted in an average of
1.9 fewer hours of off time compared with carbidopa‐levodopa
IR tablets. Treatment with Duopa was also associated with an
improved mean on time without dyskinesia by 4 hours at 12
weeks, which resulted in an average of 1.9 more hours of on
time compared with carbidopa‐levodopa IR tablets.
Additionally, the mean score increase i n “n”time by 1.9 hours
without dyskinesia from baseline to Week 12 was statistically
significant greater (p=0.0059) for Duopa t han for oral
immediate‐release carbidopa and levodopa. In a long‐term
follow‐up study, initiation of Duopa required an average of 11‐
day of hospitalization stay. The first 3 days involved placement
of a nasogastric tube and dose adjustments to reach maximal
motor performance w ithout relevant dyskinesia. Then the J‐
tube was placed and Duopa was converted to the J‐tube
infusion. The study results showed reduction of motor
fluctuations and dyskinesias along w ith improved quality of life.
Adverse reactions are similar to oral carbidopa and levodopa
(i.e. hallucinations and dyskinesias). There are few
complications associated with the J‐tube such as surgical
placement complications, infections, perforation, tube kinking,
dislocating as well as pump programming malfunction.
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Olanow et al (2014) assessed the efficacy and safety of
levodopa-carbidopa i ntestinal gel delivered continuously
through an intrajejunal percutaneous tube. In a 12-week,
randomized, double-blind, double-dummy, double-titration trial,
investigators enrolled adu lts (aged ≥ 30 years) with advanced
Parkinson's disease and motor complications at 26 centers in
Germany, New Zealand, and the United States. Eligible
participants had jejunal placement of a percutaneous
gastrojejunostomy tube and were then randomly allocated
(1:1) to treatment with immediate-release oral levodopa-
carbidopa plus placebo intestinal gel infusion or levodopa-
carbidopa intestinal gel infusion plus oral placebo.
Randomization was stratified by site, with a mixed block size of
2 or 4. The primary endpoint was change from baseline to final
visit in motor off-time. Investigators assessed change in motor
on-time without troublesome dyskinesia as a prespecified key
secondary outcome. They assessed efficacy in a full-analysis
set of participants with data for baseline and at least one post-
baseline assessment, and imputed missing dat a with the last
observation carried forward approach. They assessed safety
in randomly allocated patients who underwent the
percutaneous gastrojejunostomy procedure. From baseline to
12 weeks in the full-analysis set, mean off-time decreased by
4.04 h (SE 0.65) for 35 patients allocated to the levodopa-
carbidopa intestinal gel group compared w ith a decrease of
2.14 h (0.66) for 31 patients allocated to immediate-release
oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to
-0.76]; p=0.0015). Mean on-time without troublesome
dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel
group and 2.24 h (0.76) in the immediate-release oral group
(difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety
analyses 35 (95%) of 37 patients allocated to the levodopa-
carbidopa intestinal gel group had adverse events (five [14%]
serious), as did 34 (100%) of 34 patients allocated to the
immediate-release oral levodopa-carbidopa group (seven
[21%] serious), mainly associated with the percutaneous
gastrojejunostomy tube. The investigators concluded that
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continuous delivery of levodopa-carbidopa with an intestinal
gel offers a promising option for control of advanced
Parkinson's disease with motor complications.
An accompanying editorial (Rascol, 2014) noted some of the
limitations of the randomized controlled trial (RCT) by Olanow
et al. The editorialist noted that the trial by Olanow et al was
small (71 patients) and short (3 months). This design
prevented long-term conclusions and provided insufficient
power to assess rare adverse events such as polyneuropathy
and Guillain-Barré syndrome, or even more common ones
such as impulse-control disorders. The editorialist noted that
unmasking factors because of efficacy (as with any strongly
efficacious intervention) or black coloration of the tube caused
by levodopa oxidation might have enhanced placebo response
on the active infusion. The editorialist noted that, unfortunately
no formal assessment of masking was done. The editorialist
noted that patients on sustained-release levodopa-carbidopa
formulations had to be converted to immediate-release
levodopa-carbidopa to allow double-blind adjustments during
the trial. This design deprived the trial participants of the
benefit of the long-term oral formulation, thus favoring the
active infusion. Moreover, forbidding changes in oral dosing
frequency during the titration phase might have induced similar
consequences. Finally, head-to-head comparisons have not
been done to assess the respective advantages and
disadvantages of levodopa jejunal infusion versus the two
main alternatives for management of severe problems with
refractory off -time complications: continuous subcutaneous
apomorphine infusion and functional surgery.
Fernandez et al (2015) reported on the results of a
prospective, 54-week, open-label LCIG study. PD patients with
severe motor fluctuations (>3 h/day "off" time) despite
optimized therapy received LCIG monotherapy. Additional PD
medications were allowed >28 days post-LCIG initiation.
Safety was the primary endpoint measured through adverse
events (AEs), device complications, and number of
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completers. Secondary endpoints included diary-assessed off
time, "on" time with/without troublesome dyskinesia, UPDRS,
and health-related quality-of-life ( HRQoL) outcomes. Of 354
enrolled patients, 324 (91.5%) received PEG-J and 272
(76.8%) completed the study. The investigators reported that
most AEs were mild/moderate and transient; complication of
device insertion (34.9%) was the most common. Twenty-seven
(7.6%) patients withdrew because of AEs. Serious AEs
occurred in 105 (32.4%), most commonly complication of
device insertion (6.5%). Mean daily off time decreased by 4.4
h/65.6% (P < 0.001). On time without troublesome dyskinesia
increased by 4.8h/62.9% (P < 0.001); on time with troublesome
dyskinesia decreased by 0.4 h/22.5% (P = 0.023).
Improvements persisted from week 4 through study
completion. UPDRS and HRQoL outcomes were also
improved throughout. In the advanced PD population, LCIG's
safety profile consisted primarily of AEs associated with the
device/procedure, l-dopa/carbidopa, and advanced P D. The
investigators stated that LCIG was generally well tolerated and
demonstrated clinically significant improvements in motor
function daily activities, and HRQoL sustained over 54 weeks.
Caceres-Redondo et al (2014) reported on the motor and
cognitive outcome of LCIG treatment in advanced PD after a
follow-up period of at least 24 months. The investigators
assessed 29 patients with advanced PD who started LCIG
infusion at one center between 2007 and 2013. Motor
fluctuations, parkinsonian symptoms, activities of daily living
and impact on quality of life were evaluated. They also
evaluated the cognitive outcome us ing a battery of
neuropsychological tests. All adverse events were recorded.
Of the 29 PD patients who initiated LCIG, 16 patients reached
the follow-up evaluation (24 months), after a mean time period
of 32.2 ± 12.4 months. Six patients did not fulfil the 24-month
follow-up visit and were evaluated after a mean time period of
8.6 ± 5.4 months. Seven patients discontinued the treatment
before the scheduled visit. The authors reported that "Off" time
and "On" dyskinesia duration w ere s ignificantly reduced. LCIG
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improved quality of life and non-motor symptoms, despite
overall unchanged total levodopa doses prior to LCIG
beginning. Motor and cognitive decline were detected. The
authors noted that a relatively high number of adverse events
occurred during the follow-up, above all, technical problems
with the infusion device and mild problems related with
gastrostomy. There were four cases of peripheral neuropathy
(PN), 2 of which were considered serious. The authors stated
that their data confirm that LCIG is beneficial in the long-term
treatment of advanced PD patients despite a decline in
cognitive functions in a subgroup of patients, probably due to
disease progression. PN in patients with LCIG may be more
frequent than the published data suggest.
Zibetti et al (2014) analyzed all PD patients treated with LCIG
at their center over a 7-year period to determine the duration
of treatment, retention rate, reasons for discontinuation, LCIG
efficacy in motor complications, modifications of concomitant
therapy and adverse events. Of the 59 patients, seven
subjects (12%) died of causes unrelated to LCIG infusion and
11 patients (19%) discontinued therapy prior to the cut-off
date. The authors reported that Duodopa improved motor
complications and over 90% of patients reported an
improvement in their quality of life, autonomy and clinical
global status. The most common adverse events were
dislocation and kinking of the intestinal tube.
Cerebro-Spinal Fluid (CSF) Biomarkers
Leaver and Poston (2015) stated that cross-sectional studies
have shown that certain protein levels are altered in the CSF
of PD patients with dementia and are thought to represent
potential biomarkers of underlying pathogenesis. Recent
studies suggested that CSF biomarker levels may be
predictive of future risk of cognitive decline in non-demented
PD patients. However, the strength of this evidence and
difference between specific CSF biomarkers is not well-
delineated. These investigators performed a systematic
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review to examine if levels of specific CSF protein biomarkers
are predictive of progression to cognitive impairment. A total
of 9 articles were identified that met inclusion criteria for the
review. Findings from the review suggested a convergence of
evidence thata low baseline Aβ42 in the CSF of non-
demented PD patients predicts development of cognitive
impairment over time. Conversely, there is limited evidence
that CSF levels of tau, either total tau or phosphorylated tau, is
a useful predictive biomarker. There are mixed results for
other CSF biomarkers such as α-synuclein, neurofilament light
chain, and heart fatty acid-binding protein. Overall the results
of this review showed that certain CSF biomarkers have better
predictive ability to identify PD patients who are at risk for
developing cognitive impairment. The authors concluded that
given the interest in developing disease-modifying therapies,
identifying this group will be important for clinical trials as
initiation of therapy prior to the onset of cognitive decline is
likely to be more effective.
In a longitudinal, single-center, cohort study, Mollenhauer and
associates (2016) examined multi-modal progression markers
for PD in patients with recently diagnosed PD (n = 123) and
age-matched, neurologically healthy controls (HC; n = 106). A
total of 30 tests at baseline and after 24 months covered non-
motor symptoms (NMS), cognitive function, and REM sleep
behavior disorder (RBD) by polysomnography (PSG), voxel-
based morphometry (VBM) of the brain by MRI, and CSF
markers. Linear mixed-effect models were used to estimate
differences of rates of change and to provide standardized
effect sizes (d) with 95 % CI. A composite panel of 10
informative markers was identified. Significant relative
worsening (PD versus HC) was seen with the following
markers: the UPDRS I (d 0.39;95 % CI: 0.09 to 0.70), the
Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25;
95 % CI: 0.06 to 0.46), the Epworth Sleepiness Scale (ESS) (d
0.47; 95 % CI: 0.24 to 0.71), the RBD Screening
Questionnaire (d 0.44; 95 % CI: 0.25 to 0.64), and RBD by
PSG (d 0.37; 95 % CI: 0.19 to 0.55) as well as VBM units of
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cortical gray matter (d -0.2; 95 % CI: -0.3 to -0.09) and
hippocampus (d -0.15; 95 % CI -0.27 to -0.03). Markers with a
relative improvement included the Non-motor Symptom
(Severity) Scale (d -0.19; 95 % CI: -0.36 to -0.02) and 2
depression scales (BDI; d -0.18:95 % CI: -0.36 to 0; MADRS;
d -0.26; 95 % CI: -0.47 to -0.04). Unexpectedly, cognitive
measures and select laboratory markers were not significantly
changed in PD versus HC participants. The authors
concluded that current CSF biomarkers and cognitive scales
do not represent useful progression markers. However, sleep
and imaging measures, and to some extent NMS, assessed
using adequate scales, may be more informative markers to
quantify progression. Moreover, they stated that future studies
need to examine the validity of these proposed markers,
standardize the assessment of non-motor features, and
identify more sensitive and disease-specific marker candidates
that reflect underlying biological processes (such as
propagation of α-synuclein pathology, inflammation and
neuronal death).
Hu and colleagues (2017) stated that as a biomarker of axonal
injury, neurofilament light chain (NFL) in MSA patients and PD
patients has been investigated by numerous studies.
However, CSF NFL changes are conflicting in MSA patients
relative to PD patients to date. In a meta-analysis, these
researchers attempted to find out possible heterogeneity
sources. Furthermore, "neurofilament", "neurofilament light
chain" and "multiple system atrophy" were employed to search
"PubMed", "Springer" and "Medline" databases until August
2016 with standard mean difference (Std.MD) being
calculated. In addition, subgroup analysis and meta-
regression were performed to assess possible heterogeneity
sources. A total of 9 studies were pooled, in which 212 MSA
patients and 373 PD patients were involved. Moreover, CSF
NFL in MSA patients was higher than that in PD patients
[pooled Std.MD = 1.56, 95 % CI: 1.12 to 2.00, p < 0.00001]
with significant heterogeneity (I 2 = 76 %). Besides,
population variations, sample size, the difference in CSF
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phosphorylated tau (p-tau) levels between MSA patients and
PD patients, and Hoehn-Yahr staging of PD patients were the
main heterogeneity sources. As shown by meta-regression,
Hedges's g of CSF NFL was correlated with CSF Std.MD of
α-synuclein between MSA patients and healthy controls (r =
-1.34824, p = 0.00025). Therefore, CSF NFL increased in
MSA patients relative to PD patients. Meta-regression showed
that NFL was associated with α-synuclein in CSF of MSA
patients relative to healthy controls. The authors concluded
that due to the influence of heterogeneity sources, more
prospective large sample studies are still needed to assess
CSF NFL changes in MSA patients relative to PD patients.
Genetic Testing of PARK10 and Variants
Beecham et al (2015) noted that to minimize pathologic
heterogeneity in genetic studies of PD, the Autopsy-Confirmed
Parkinson Disease Genetics Consortium conducted a
genome-wide association study using both patients with
neuropathologically confirmed PD and controls. A total of 484
cases and 1,145 controls met neuropathologic diagnostic
criteria, were genotyped, and then imputed to 3,922,209
variants for genome-wide association study analysis. A small
region on chromosome 1 was strongly associated with PD
(rs10788972; p = 6.2 × 10(-8)). The association peak lied
within and very close to the maximum linkage peaks of 2 prior
positive linkage studies defining the PARK10 locus. These
researchers demonstrated that rs10788972 is in strong linkage
disequilibrium with rs914722, the SNP defining the PARK10
haplotype previously shown to be significantly associated with
age at onset in PD. The region containing the PARK10 locus
was significantly reduced from 10.6 mega-bases to 100 kilo-
bases and contains 4 known genes: TCEANC2, TMEM59, miR
4781, and LDLRAD1. The authors concluded that they
confirmed the association of a PARK10 haplotype with the risk
of developing idiopathic PD. Furthermore, they significantly
reduced the size of the PARK10 region. None of the
candidate genes in the new PARK10 region have been
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previously implicated in the biology of PD, suggesting new
areas of potential research. They stated that the findings of
this study strongly suggested that reducing pathologic
heterogeneity may enhance the application of genetic
association studies to PD.
In an editorial that accompanied the afore-mentioned study,
Simon-Sanchez and Gasser (2015) stated that “although
spurious associations driven by undetected population
stratification remains a possibility until this findings has been
replicated in other studies, another possible explanation for
this discrepancy is that the PARK10 locus is only associated
with a special subgroup of PD and that its effect size is strong
enough to yield statistical association when a selection of LB
[Lewy body] PD class is made, but not when larger series of
clinical PD cases are studied …. Another limitation of this
study 9and GWAS in general) is the relatively small effect size
associated with the identified loci. This precludes useful
individual disease prediction, and is a problem for risk
stratification and personalized medicine …. Further
applications of the data derived from this and other GWAS
include the possibility to build genetic risk profiles for a disease
of interest. These profiles have the potential to identify at-risk
individuals and apply different therapeutic strategies
depending on the specific genetic underpinnings of the
disease in a given individual”.
Simon-Sanchez et al (2015) stated that a recent study in
autopsy-confirmed PD patients and controls revived the
debate about the role of PARK10 in this disorder. In an
attempt to replicate these results and further understand the
role of this locus in the risk and age at onset of PD, these
researchers explored NeuroX genotyping and whole exome
sequencing data from 2 large independent cohorts of clinical
patients and controls from the International Parkinson's
Disease Genomic Consortium. A series of single-variant and
gene-based aggregation (sequence kernel association test
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and combined multi-variate and collapsing test) statistica l tests
suggested that common and rare genetic variation in this locus
do not influence the risk or age at onset of clinical PD.
Guo et al (2015) noted that PD is the second most common
chronic neuronal degeneration di sorder with motor and non-
motor clinical features. The rs10788972 variant of the
transcription elongation factor A (SII) N-terminal and central
domain containing 2 ( TCEANC2) gene in the PARK10 region
was recently identified to be strongly related to sporadic PD in
the American population. These researchers examined if the
same variant is associated with sporadic PD in Chinese Han
population. They researched 513 sporadic PD patients and
512 normal controls of Chinese Han ethnicity in Mainland
China. No significant difference i n genotypic and allelic
distributions between patients and control groups for either
rs10788972 (for genotypic distribution, χ(2) = 0.412, p = 0.814,
and for allelic distribution, χ(2) = 0.280, p = 0.597) or its
neighbor marker rs12046178 (for genotypic distribution, χ(2) =
1.500, p = 0.472, and for allelic distribution, χ(2) = 1.339, p =
0.247) was found. The authors concluded that these findings
suggested that neither variant is related to sporadic PD in
Chinese Han population.
Genetic Testing of PITX3
Jimenez-Jimenez et al (2014) noted that several single
nucleotide polymorphisms (SNPs) in the PITX3 gene have
been associated with the risk for PD. These investigators
performed a systematic review and a meta-analysis including
all the studies published on the risk of PD related with these
polymorphisms. The systematic review was carried out using
several databases. Eligible studies were included in the meta-
analysis that was carried out using Meta-DiSc 1.1.1 software.
Heterogeneity between studies was tested using the
Q-statistic. The meta-analysis included 8 association studies
for the PITX3 rs3758549 SNP (4,052 PD patients, 3,949
controls), 8 studies for the PITX3 rs2281983 SNP (4,309 PD
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patients, 4,287 controls), and 6 studies for the rs4919621 SNP
(2,724 PD patients, 2,285 controls), and the risk for PD, global
diagnostic ORs (95 % CIs) for rs3758549, rs2281983, and
rs4919621 were, respectively, 1.00 (0.89-1.12) (p = 0.979),
0.99 (0.91-1.09) (p = 0.896), and 0.98 (0.83-1.16) (p = 0.844)
for the total group. The separate analysis in Caucasian and
Chinese subjects on the frequency of the minor allele of the 3
SNPs analyzed did not show significant differences between
PD patients and controls in both subgroups; rs2281983 and
rs4919621 SNPs were related with early-onset PD risk in
Caucasians. The authors concluded t hat the findings of this
meta-analysis suggested t hat rs3758549, rs2281983, and
rs4919621 SNPs are not major determinants of the risk for PD.
Measurement of Telomere Length
Forero et al (2016) stated that differences in telomere length
(TL) have been reported as possible risk factors for several
neuropsychiatric disorders, including PD. Results from
published studies for TL in PD are inconsistent, highlighting
the need for a meta-analysis. In the current work, a meta-
analysis of published studies for TL in PD was carried out.
PubMed, Web of Science and Google Scholar databases
were used to identify relevant articles that reported TL in
groups of PD patients and controls. A random-effects model
was used for meta-analytical procedures. The meta-analysis
included 8 primary studies, derived from populations of
European and Asian descent, and did not show a significant
difference in TL between 956 PD patients and 1,284 controls
(p value: 0.246). The authors concluded that the findings of
this meta-analysis showed that there is no consistent evidence
of shorter telomeres in PD patients and suggested the
importance of future studies on TL and PD that analyze other
populations and also include assessment of TL from different
brain regions.
Partial Body Weight-Supported Treadmill Training
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Ganesan and colleagues (2015) evaluated the effect of
conventional gait training ( CGT) and partial weight-supported
treadmill training (PWSTT) on gait and clinical manifestation in
patients with PD. Patients with idiopathic PD (n = 60; mean
age of 58.15 ± 8.7y) on stable dosage of dopaminomimetic
drugs were randomly assigned into the 3 following groups (20
patients in each group): (i) non-exercising PD group, (ii) CGT
group, and (iii) PWSTT group. The interventions included i n
the study were CGT and PWSTT. The sessions of the CGT
and PWSTT groups were given in patient's self-reported best
on status after regular medications. The interventions were
given for 30 mins/day, 4 day/week, for 4 weeks (16 sessions).
Clinical severity was measured by UPDRS and its sub-scores.
Gait was measured by 2 minutes of treadmill walking and the
10-m walk test. Outcome measures were evaluated in their
best on status at bas eline and after the 2nd and 4th weeks.
Four weeks of CGT and PWSTT gait training showed
significant improvements of UPDRS scores, its sub-scores,
and gait performance m easures. Moreover, the Brabenec and
associates (2017) revieweffects of PWSTT were significantly
better than CGT on most measures. The authors concluded
that PWSTT is a promising intervention tool to improve the
clinical and gait outcome measures in patients with PD.
Progressive Resistance Training
In a systematic review and meta-analysis, Saltychev and
colleagues (2016) examined if there is evidence on
effectiveness of progressive resistance training in rehabilitation
of PD. Data sources included Central, Medline, Embase,
Cinahl, Web of Science, Pedro until May 2014. Randomized
controlled or controlled clinical trials were selected for
analysis. The methodological quality of studies was assessed
according to the Cochrane Collaboration's domain-based
evaluation framework. Adults with primary/idiopathic PD of
any severity, excluding other concurrent neurological condition
were included in this analysis. Progressive resistance training
defined as training consisting of a small number of repetitions
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until fatigue, allowing sufficient rest between exercises for
recovery, and increasing the resistance as the ability to
generate force improves. Of 516 records, 12 were considered
relevant; 9 of them had low risk of bias. All studies were RCTs
conducted on small samples with none or 1 month follow-up
after the end of intervention. Of them, 6 were included in
quantitative analysis. Pooled effect sizes of meta-analyses on
fast and comfortable walking speed, the 6-min walking test,
Timed Up and Go test and maximal oxygen consumption were
below the level of minimal clinical significance. The authors
concluded that there is so far no evidence on the superiority of
progressive resistance training compared with other physical
training to support the use of this technique in rehabilitation of
PD.
Non-Invasive Brain Stimulation (e.g., Transcranial Direct C u rrent Stimulation/Transcranial Magnetic Stimulation)
Dinkelbach and co-workers (2017) noted that cognitive
impairments and depression are common non-motor
manifestations in PD, and recent evidence suggested that both
partially arise via the same fronto-striatal network, opening the
opportunity for concomitant treatment with non-invasive brain
stimulation (NIBS) techniques (e.g., rTMS and tDCS). In this
systematic review, these investigators evaluated the effects of
NIBS on cognition and/or mood in 19 placebo-controlled
studies involving 561 PD patients. Outcomes depended on
the area stimulated and the technique used; rTMS over the
dorsolateral-prefrontal cortex (DLPFC) resulted in significant
reductions in scores of depressive symptoms with moderate- to-
large effect sizes along with increased performance in several
tests of cognitive functions; tDCS over the DLPFC improved
performance in several cognitive measures, including
executive functions with large effect sizes. Additional effects of
tDCS on mood were not detectable; however, only non-
depressed patients were assessed. The authors
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concluded that further confirmatory research is needed to
clarify the contribution that NIBS could make in the care of PD
patients.
Brabenec and associates (2017) review papers on hypokinetic
dysarthria (HD) in PD with a special focus on (i) early PD
diagnosis and monitoring of the disease progression using
acoustic voice and speech analysis, and (ii) functional
imaging studies exploring neural correlates of HD in PD,
and (iii) clinical studies using acoustic analysis to evaluate
effects of dopaminergic medication and brain stimulation.
A systematic literature search of articles written in English
before March 2016 was conducted in the Web of Science,
PubMed, SpringerLink, and IEEE Xplore databases using and
combining specific relevant keywords. Articles were
categorized into 3 groups: (i) articles focused on neural
correlates of HD in PD using functional imaging (n = 13); (ii)
articles dealing with the acoustic analysis of HD in PD (n =
52); and (iii) articles concerning specifically dopaminergic and
brain stimulation-related effects as assessed by acoustic
analysis (n = 31); the groups were then reviewed. These
researchers identified 14 combinations of speech tasks and
acoustic features that can be recommended for use in
describing the main features of HD in PD. While only a few
acoustic parameters correlate with limb motor symptoms and
can be partially relieved by dopaminergic medication, HD in
PD appeared to be mainly related to non-dopaminergic deficits
and associated particularly with non-motor symptoms. The
authors concluded that future studies should combine NIBS
with voice behavior approaches to achieve the best treatment
effects by enhancing auditory-motor integration.
Measurement of Urinary LRRK2 Phosphorylation
Fraser and colleagues (2016) examined if phosphorylated Ser-
1292 LRRK2 levels in urine exosomes predicts LRRK2
mutation carriers (LRRK2+) and non-carriers (LRRK2-) with
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Parkinson disease (PD+) and without Parkinson disease (PD-
). LRRK2 protein was purified from urinary exosomes
collected from participants in 2 independent cohorts. The 1st
cohort included 14 men (LRRK2+/PD+, n = 7; LRRK2-/PD+, n
= 4; LRRK2-/PD-, n = 3). The 2nd cohort included 62 men
(LRRK2-/PD-, n = 16; LRRK2+/PD-, n = 16; LRRK2+/PD+, n =
14; LRRK2-/PD+, n = 16).The ratio of Ser(P)-1292 LRRK2 to
total LRRK2 was compared between LRRK2+/PD+ and
LRRK2- in the 1st cohort and between LRRK2 G2019S
carriers with and without PD in the 2nd cohort. LRRK2+/PD+
had higher ratios of Ser(P)-1292 LRRK2 to total LRRK2 than
LRRK2-/PD- (4.8-fold, p < 0.001) and LRRK2-/PD+ (4.6-fold, p
< 0.001). Among mutation carriers, those with PD had higher
Ser(P)-1292 LRRK2 to total LRRK2 than those withoutPD (2.2
fold, p < 0.001). Ser(P)-1292 LRRK2 levels predicted
symptomatic from asymptomatic carriers with an area under
the receiver operating characteristic curve of 0.844. The
authors concluded that elevated ratio of phosphorylated Ser-
1292 LRRK2 to total LRRK2 in urine exosomes predicted
LRRK2 mutation status and PD risk among LRRK2 mutation
carriers. Moreover, they stated that future studies may explore
whether interventions that reduce this ratio may also reduce
PD risk. In particular, they stated that larger studies that
measure Ser(P)-1292 LRRK2 levels over time in asymptomatic
carriers will be needed to understand the prognostic potential
of this new biomarker.
In an editorial that accompanied the afore-mentioned study,
Grunewald and Klein (2016) stated that “The findings by
Fraser et al are exciting and promising. However, they remain
subject to independent confirmation and have been only
obtained in a relatively small sample of 18 probands per
group”.
CSF Biomarkers
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Mollenhauer and colleagues (2017) analyzed longitudinal
levels of CSF biomarkers in drug-naive patients with PD and
HC, examined the extent to which these biomarker changes
relate to clinical measures of PD, and identified what may
influence them.CSFα-synuclein (α-syn), total and
phosphorylated tau (t- and p-tau), and β-amyloid 1-42 (Aβ42)
were measured at baseline and 6 and 12 months in 173
patients with PD and 112 matched HC in the international
multi-center Parkinson's Progression Marker Initiative.
Baseline clinical and demographic variables, PD medications,
neuroimaging, and genetic variables were evaluated as
potential predictors of CSF biomarker changes. CSF
biomarkers were stable over 6 and 12 months, and there was
a small but significant increase in CSFAβ42 in both patients
with patients with PD and HC from baseline to 12 months. The t-
tau remained stable. The p-tau increased marginally more in
patients with PD than in HC; α-syn remained relatively stable
in patients with PD and HC. Ratios of p-tau/t-tau increased,
while t-tau/Aβ42 decreased over 12 months in patients with
PD. CSF biomarker changes did not correlate with changes in
Movement Disorder Society-sponsored revision of the UPDRS
motor scores or dopamine imaging.CSFα-syn levels at 12
months were lower in patients with PD treated with dopamine
replacement therapy, especially dopamine agonists. The
authors concluded that these core CSF biomarkers remained
stable over 6 and 12 months in patients with early PD and HC;
PD medication use may influence CSFα-syn. Moreover, they
stated that novel biomarkers are needed to better profile
progressive neurodegeneration in PD.
Genetic Testing of Fibroblast Growth Factor 20 rs12720208 Polymorphism
Wang and colleagues (2017) noted that many studies had
examined the association between fibroblast growth factor 20
(FGF20) rs12720208 polymorphism and the susceptibility of
PD. However, published data are still controversial. These
researchers performed a meta-analysis to evaluate the
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association of rs12720208 polymorphism with the risk of PD.
Up to April 2016, PubMed, Embase, Web of science, the
Chinese National Knowledge Infrastructure, and Wanfang
Medicine were reviewed to identify appropriate documents. A
total of 7 articles involving 11 studies with 3,360 PD cases and
3,681 controls were included based on the strict inclusion and
exclusion standards. And STATA 12.0 statistics software was
used to calculate available data from each study. The pooled
OR and 95 % CI were calculated to assess the association
between FGF20 rs12720208 polymorphism and PD risk.
When all studies were pooled into this meta-analysis, neither
the minor T allele frequencies nor the genotypic distributions
were different between PD cases and controls. But the
subgroup analysis stratified by ethnicity showed FGF20
rs12720208 polymorphism was associated with increased risk
in the allele model (T versus C: OR = 1.167, 95 % CI: 1.020 to
1.335) and dominant model (TT + TC versus CC: OR = 1.156,
95 % CI: 1.001 to 1.335) in Caucasians but not in Asians. The
authors concluded that the findings of this meta-analysis
indicated that rs12720208 C/T variant might be associated
with PD susceptibility in Caucasians.
Vagotomy for the Prevention and Treatment of PD
Liu and colleagues (2017) examined if vagotomy decreases
the risk of PD. Using data from nationwide Swedish registers,
these researchers conducted a matched-cohort study of 9,430
vagotomized patients (3,445 truncal and 5,978 selective)
identified between 1970 and 2010 and 377,200 reference
individuals from the general population individually matched to
vagotomized patients by sex and year of birth with a 40:1 ratio.
Participants were followed-up from the date of vagotomy until
PD diagnosis, death, emigration out of Sweden, or December
31, 2010, whichever occurred first. Vagotomy and PD were
identified from the Swedish Patient Register. These
researchers estimated HRs with 95 % CIs using Cox models
stratified by matching variables, adjusting for country of birth,
chronic obstructive pulmonary disease, diabetes mellitus,
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vascular diseases, rheumatologic disease, osteoarthritis, and
co-morbidity index. A total of 4,930 cases of incident PD were
identified during 7.3 million person-years of follow-up. PD
incidence (per 100,000 person-years) was 61.8 among
vagotomized pat ients (80.4 for truncal and 55.1 for selective)
and 67.5 among reference individuals. Overall, vagotomy was
not associated with PD risk (HR 0.96, 95% CI 0.78-1.17).
However, there was a suggestion of lower risk among patients
with truncal vagotomy (HR 0.78, 95 % CI: 0.55 to 1.09), which
may be driven by truncal vagotomy at least 5 years before PD
diagnosis (HR 0.59, 95 % CI: 0.37 to 0.93). Selective
vagotomy was not related to PD risk in any analyses. The
authors stated that although overall vagotomy was not
associated the risk of PD; they found suggestive evidence for
a potential protective effect of truncal, but not selective,
vagotomy against PD development.
In an editorial that accompanied the afore-mentioned study,
Borghammer and Hamani (2017) stated that “At this stage, we
have insufficient knowledge to propose vagotomy as a putative
treatment for PD”.
Brain SPECT for Monitoring the Progression of Parkinson’s Disease
Jeong and colleagues (2018) stated that levodopa-induced
dyskinesia (LID) is a major complication of dopamine
replacement drug usage in PD patients. Since the mechanism
of LID is yet unclear, these researchers analyzed serial [I-123]
N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)
nortropane (I-123 FP-CIT) SPECT images. They examined
the changes of dopaminergic innervation during the
progression of PD in relation to the development of LID. Data
were obtained from the Parkinson's Progression Markers
Initiative (PPMI) database. A total of 290 PD dopamine
replacement drug-naïve patients (age of 61.0 ± 9.7 years, M: F
= 195: 95) were enrolled. I-123 FP-CIT SPECT images from
baseline, 12, 24, and 48 months were analyzed among with
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clinical factors. Specific binding ratios (SBRs) of the striatal
regions from I-123 FP-CIT SPECT images were analyzed.
These investigators used independent tests and logistic
regression for analysis of LID risk association. Among 290
patients, 36 patients developed LID after 48 months follow-up.
Baseline MDS-UPDRS Part II and III scores were significantly
higher in the PD patients with LID, compared with the PD
patients without LID. Striatal SBRs were significantly lower in
the PD patients with LID at baseline, 24 and 48 months (p <
0.001). Multi-variate analysis revealed MDS-UPDRS Part II
and putaminal SBRs at baseline and 24 months to be
significantly associated with the development of LID (p <
0.001). Furthermore, patients who developed LID at 48
months had a higher decrease rate of putaminal SBR at the 24
months (p < 0.05), and 48 months (p < 0.01) period. The
authors concluded that in this study, they demonstrated the
serial changes of the nigrostriatal dopaminergic innervation in
relationship to LID development for the first time. The
deterioration rate of dopaminergic innervation was significantly
higher in the PD patients who developed LID, compared with
the PD patients who did not develop LID. These researchers
stated that serial follow-up I-123 FP-CIT SPECT acquisition
during the course of PD could be helpful in predicting the
development of LID.
The authors stated that this study had several drawbacks.
First, this study did not include the FP-CIT SPECT images of
healthy controls, since the PPMI data did not provide follow-up
FP-CIT SPECT images nor clinical data of healthy controls. It
remains to be seen whether the striatal neuronal loss in PD
patients progress in a higher rate compared with those of age-
and sex-matched healthy controls, and whether these
researchers could exclude the effect of normal aging process.
Second, the PPMI data were collected from multiple
institutions, and could have variations in the FP-CIT SPECT
image acquisition. In order to maintain a uniformly acquired
imaging dataset, quality assurance procedures were
performed. Third, all 3 follow-up FP-CIT SPECT images were
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acquired in 215 patients out of 290 patients. In 75 patients,
only 2 follow-up FP-CIT SPECT images were acquired.
Finally, although these investigators have focused on the pre-
synaptic hypothesis for LID development, this does not
undermine the post-synaptic hypothesis. They stated that
further studies focusing on the post-synaptic striatal signal
transduction are needed.
Djaldetti and co-workers (2018) stated that the role of nuclear
imaging in predicting PD progression is unclear. These
investigators examined if the degree of reduced striatal DAT
binding at diagnosis of PD predicts later motor complications
and time to disease progression. They retrospectively studied
41 patients with early PD who underwent 123I-FP-CIT SPECT
and were followed thereafter with a mean disease dur ation of
9.51 ± 3.18 years. The association of quantitatively analyzed
123I-FP-CIT binding in striatal sub-regions with the
development of motor fluctuations, dyskinesia, freezing of gait
(FOG), and falls as well as the time to Hoehn and Yahr (H&Y)
stage 3 was evaluated. Logistic regression models controlling
for age at diagnosis, sex, disease duration, and L-dopa dose
revealed that 123I-FP-CIT binding in the putamen and striatum
significantly predicted FOG (OR = 0.02, p = 0.03; OR = 0.01,
p = 0.04; respectively); but not falls. Cox proportional hazard
analysis did not reveal significant relationship between 123I-
FP-CIT binding and motor fluctuations, dyskinesia, or H&Y
stage 3. The authors concluded that these findings suggested
that a more severe depletion of pre-synaptic dopamine in early
PD is a bad prognostic sign in terms of FOG development.
They stated that these findings, if replicated, may point to
dopaminergic transmission as part of the mechanism
underlying FOG in PD.
In a retrospective, cohort study, Kim and colleagues (2018)
examined if the degree of pre-synaptic striatal dopamine
depletion could predict the later development of FOG in PD.
This trial included 390 de-novo patients with PD without FOG
at baseline. Subjects were divided into tertiles according to
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the baseline DAT uptake of each striatal sub-region, and the
cumulative risk of FOG was compared using the Kaplan-Meier
method. Cox proportional hazard models were used to assess
the predictive power of DAT uptake of striatal sub-regions for
the development of FOG. During a median follow-up period of
4.0 years, 143 patients with PD (36.7 %) developed FOG. The
severe reduction group of DAT uptake in the caudate nucleus
and putamen had a significantly higher incidence of FOG than
that of the mild and moderate reduction groups. Multi-variate
Cox regression analyses showed t hat DAT uptakes in the
caudate nucleus (HR 0.551; 95 % CI: 0.392 to 0.773;
p = 0.001) and putamen (HR 0.441; 95 % CI: 0.214 to 0.911;
p = 0.027) predicted the development of FOG. In addition,
male sex, higher postural instability and gait difficulty score,
and a lower Montreal Cognitive Assessment score were also
significant predictors of FOG. The authors concluded that
these findings suggested t hat pre-synaptic striatal
dopaminergic denervation predicted the later development of
FOG in de-novo patients with PD, which may provide reliable
insight into the mechanism of FOG in terms of nigrostriatal
involvement.
Kuo and associates (2019) noted that quantitative assessment
of DAT imaging can aid in diagnosing PD and assessing
disease progression i n the context of therapeutic trials.
Previously, the software program SBRquant was applied to
123I-ioflupane SPECT images acquired on healthy controls
and subjects with PD. Earlier work on optimization of the
parameters for differentiating between controls and subjects
with dopaminergic deficits was extended for maximizing
change measurements associated with disease progression
on longitudinally acquired scans. Serial 123I-ioflupane SPECT
imaging for 51 subjects with PD (conducted approximately 1
year apart) were down-loaded from the PPMI database. The
software program SBRquant calculated the SBR separately for
the left and right caudate and putamen regions of interest
(ROI). Parameters were varied to evaluate the number of
summed transverse slices and the positioning of the striatal
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ROIs for determining signal-to-noise associated with their
annual rate of change in SBR. The parameters yielding the
largest change of the lowest putamen's SBR from scan 1 to
scan 2 were determined. For the change from scan 1 to scan
2 in the 51 subjects, the largest annual change was observed
when the putamen ROI was placed 3 pixels away from the
caudate and by summing 5 central striatal slices. This resulted
in an 11.2 ± 4.3 % annual decrease in the lowest putamen's
SBR for the group. The authors concluded that quantitative
assessment of DAT imaging for assessing progression of PD
requires specific, optimal parameters different than those for
diagnostic accuracy.
Furthermore, UpToDate reviews on “Clinical manifestations of
Parkinson disease” (Chou, 2018) and “Cognitive impairment
and dementia in Parkinson disease” (Rodnitzky, 2018) do not
mention SPECT scanning as a management tool.
Retinal Thinning as a Biomarker of Parkinson Disease
Ahn and colleagues (2018) analyzed the relationship between
retinal thinning and nigral dopaminergic loss in de-novo PD. A
total of 49 patients with PD and 54 age-matched controls were
analyzed. Ophthalmologic examination and macula optical
coherence tomography (OCT) scans were performed with
additional micro-perimetry, N-(3-[18F]fluoropropyl)-2-
carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI
scans were done in patients with PD only. Retinal layer
thickness and volume were measured in sub-fields of the 1-,
2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy
Study circle and compared in patients with PD and controls.
Correlation of inner retinal layer thinning with micro-perimetric
response was examined in patients with PD, and the
relationships between retinal layer thickness and dopamine
transporter densities in the ipsilateral caudate, anterior and
posterior putamen, and substantia nigra were analyzed.
Retinal layer thinning was observed in the temporal and
inferior 2.22-mm sectors (false discovery rate-adjusted p <
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0.05) of drug-naive patients with PD, particularly the inner
plexiform and ganglion c ell layers. The thickness of these
layers in the inferior 2.22-mm sector showed a negative
correlation with the Hoehn and Yahr stage (p = 0.032 and
0.014, respectively). There was positive correlation between
macular sensitivity and retinal layer thickness in all 3.45-mm
sectors, the superior 2.22-mm sector, and 1-mm circle (p <
0.05 for all). There was an association between r etinal
thinning and dopaminergic loss in the left substantia nigra
(false discovery rate-adjusted p < 0.001). The authors
concluded that retinal thinning was present in the early stages
of PD, correlated with disease severity, and may be linked to
nigral dopaminergic degeneration. These researchers stated
that retinal imaging may be useful for detection of pathologic
changes occurring in early PD.
Bright Light Therapy for the Treatment of Depression in Parkinson Disease
In a double-blind RCT, Rutten and colleagues (2019)
examined the efficacy of bright light therapy (BLT) in reducing
depressive symptoms in patients with PD and major
depressive disorder (MDD) compared to a control light.
Patients with PD and MDD were randomized to receive
treatment with BLT (± 10,000 lux) or a control light (± 200 lux);
they were treated for 3 months, followed by a 6-month
naturalistic follow-up. The primary outcome of the study was
the HDRS score. Secondary outcomes were objective and
subjective sleep measures and salivary melatonin and cortisol
concentrations. Assessments were repeated halfway, at the
end of treatment, and 1, 3, and 6 months after treatment. Data
were analyzed with a linear mixed-model analysis. These
researchers enrolled 83 subjects; HDRS scores decreased in
both groups without a significant between-group difference at
the end of treatment. Subjective sleep quality improved in
both groups, with a larger improvement in the BLT group (B
[SE] = 0.32 [0.16], p = 0.04). Total salivary cortisol secretion
decreased in the BLT group, while it increased in the control
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group (B [SE] = -8.11 [3.93], p = 0.04). The authors concluded
that BLT was not more effective in reducing depressive
symptoms than a control light. Mood and subjective sleep
improved in both groups; BLT was more effective in improving
subjective sleep quality than control light, possibly through a
BLT-induced decrease in cortisol levels. This study provided
Class I evidence that BLT was not superior to a control light
device in reducing depressive symptoms in patients with PD
with MDD.
In an editorial that accompanied the afore-mentioned study,
Videnovic and Messinis (2019) stated that “This trial
represents an important contribution to a growing body of
literature centered on chrono-therapeutics of PD. While
reported effects of LT on depressive symptoms in PD are
encouraging, further studies are needed to better define the
role of LT in the management of PD”.
Cueing Module Device (Auditory Cue) for the Treatment of Parkinson's Freezing
Lopez et al (2014) noted that evidence supports the use of
rhythmic external auditory signals to improve gait in
Parkinson’s disease (PD) patients. However, few prototypes
are available for daily use, and to the authors’ knowledge,
none utilize a smartphone application allowing individualized
sounds and cadence. These researchers analyzed the effects
on gait of Listenmee, an intelligent glasses system with a
portable auditory device, and presented its smartphone
application, the Listenmee app, offering over 100 different
sounds and an adjustable metronome to individualize the
cueing rate as well as its smartwatch with accelerometer to
detect magnitude and direction of the proper acceleration,
track calorie count, sleep patterns, steps count and daily
distances. The present study included patients with idiopathic
PD presented gait disturbances including freezing. Auditory
rhythmic cues were delivered through Listenmee.
Performance was analyzed in a motion and gait analysis
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laboratory. The results revealed significant improvements in
gait performance over 3 major dependent variables: walking
speed in 38.1 %, cadence in 28.1 % and stride length in 44.5
%. The authors concluded that these findings suggested that
auditory cueing through Listenmee may significantly enhance
gait performance. Moreover, these investigators stated that
further studies are needed to elucidate the potential role and
maximize the benefits of these portable devices.
Zhao et al (2016) stated that new mobile technologies like
smart-glasses could deliver external cues that may improve
gait in people with PD in their natural environment. However,
the potential of these devices must first be assessed in
controlled experiments. These researchers evaluated
rhythmic visual and auditory cueing in a laboratory setting with
a custom-made application for the Google Glass. A total of 12
participants (mean age of 66.8 years; mean disease duration
of 13.6 years) were tested at end of dose. These investigators
compared several key gait parameters (walking speed,
cadence, stride length, and stride length variability) and
freezing of gait for 3 types of external cues (metronome,
flashing light, and optic flow) and a control condition (no-cue).
For all cueing conditions, the subjects completed several
walking tasks of varying complexity; 7 inertial sensors attached
to the feet, legs and pelvis captured motion data for gait
analysis. Two experienced raters scored the presence and
severity of freezing of gait using video recordings. User
experience was evaluated through a semi-open interview.
During cueing, a more stable gait pattern emerged, particularly
on complicated walking courses; however, freezing of gait
(FOG) did not significantly decrease. The metronome was
more effective than rhythmic visual cues and most preferred by
the participants. Subjects were overall positive about the
usability of the Google Glass and willing to use it at home.
The authors concluded that smart-glasses like the Google
Glass could be used to provide personalized mobile cueing to
support gait; however, in its current form, auditory cues
appeared more effective than rhythmic visual cues. These
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researchers stated that smart-glasses have the potential to
become mobile assistive devices for on-demand cueing in
daily life, but further development is needed to better
accommodate the individual needs of patients with PD.
The authors stated that this study had several drawbacks.
First, out of the 12 participants, only 6 experienced FOG more
than once, 4 exhibited no FOG, and 2 had a single FOG
episode. Due to this small sample size of freezers, the effect
of cueing on FOG was inconclusive. Second, a potential
confound was that many of the participants have already used
cues in their daily life and may be more efficient during the
cued walking trials. As the effects of cueing did not generalize
well and none of the participants had prior experience using
the Google Glass, these researchers did not expect that those
with cueing experience would out-perform those with no
previous experience during this study. Visual inspection of
individual performances also did not show consistent
differences between these 2 groups. Third, as the study was
conducted at end of dose, the findings may be less applicable
to daily life when people are mostly in the on state. However,
as FOG is known to be resistant to medication and deep brain
stimulation and motor fluctuations -- alterations between on
and off states -- are the most common complications of long-
term levodopa use, cueing during the on state is still a useful
strategy. Lastly, the version of the Google Glass used in this
study is no longer available for purchase, with Google
pursuing a new Enterprise edition of the Glass tailored for
working environments. As numerous other augmented reality
smart-glasses are appearing on the market, mobile cueing will
continue to advance.
Furthermore, an UpToDate review on “Motor fluctuations and
dyskinesia in Parkinson disease” (Tarsy, 2020) does not
mention auditory cue as a management option.
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Plasma Neurofilament Light Chain (NfL) as a Biomarker for Disease Severity and Progression in Parkinson Disease
In a prospective, follow-up study, Lin and colleagues (2019)
examined if plasma neurofilament light chain (NfL) levels were
associated with motor and cognitive progression i n PD. This
trial enrolled 178 subjects, including 116 with PD, 22 with
multiple system atrophy (MSA), and 40 healthy controls.
These researchers measured plasma NfL l evels with electro-
chemiluminescence i mmunoassay. Patients with PD received
evaluations of motor and cognition at baseline and at a mean
follow-up interval of 3 years. Changes in the UPDRS part III
motor score and MMSE score were used to assess motor and
cognition progression. Plasma NfL levels were significantly
higher in the MSA group than in the PD and healthy groups
(35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/ml, respectively, p <
0.001). In the PD group, NfL levels were significantly elevated
in patients with advanced Hoehn-Yahr stage and patients with
dementia (p < 0.001). NfL levels were modestly correlated
with UPDRS part III scores (r = 0.42, 95 % CI: 0.46 to 0.56, p <
0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox
regression analysis adjusted for age, sex, disease duration,
and baseline motor or cognitive status showed that higher
baseline NfL levels were associated with higher risks for either
motor or cognition progression ( p = 0.029 and p = 0.015,
respectively). The authors concluded that these findings
suggested that the plasma NfL level could serve as a non-
invasive, easily accessible biomarker to evaluate disease
severity and to monitor disease progression in PD. They
stated that future, large longitudinal follow-up s tudies that
incorporate other biomarkers such as neuroimages are
needed to strengthen the possible prognostic role of blood NfL
levels in PD progression. Level of Evidence = Class III.
The authors stated that this study had several drawbacks.
First, these researchers evaluated cognitive function only with
MMSE, a simple measurement of global cognitive function.
Detailed neuropsychological tests for evaluating individual
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cognitive domains are needed for further assessments of
correlations between plasma NfL levels and individual
cognitive domain declines in patients with PD. Second, the
clinical diagnosis of PD and MSA was not confirmed by post-
mortem pathological confirmation and may be susceptible to
mis-classification. However, these researchers based the final
diagnosis on thorough clinical and laboratory examinations
such as autonomic function tests and nuclear imaging studies,
with close clinical follow-up, using the international consensus
criteria in a movement disorder specialist's clinic. Third, the
plasma level of NfL was checked only when the subjects were
enrolled in the study. Future studies that serially follow-up
plasma levels of NfL accompanied by motor and cognitive
function evaluations would further delineate the changes of
NfL in the disease course of PD and MSA. Finally, although
the plasma NfL level was significantly increased in patients
with PD compared to controls and was correlated with disease
severity (both motor and cognition) in the cross-sectional
design of comparison, the Cox progression analysis revealed
a modest significance of higher HRs for either motor or
cognition progression in the follow-up study. The possible
reason may come from the relatively short follow-up time
period for neurodegenerative disorders. A future cohort with a
larger sample size of subjects and longer follow-up is needed
to confirm these findings and to validate the role of plasma NfL
in predicting disease progression.
Magnetic Resonance Imaging-Guided Focused Ultrasound Neurosurgery
Xu and colleagues (2019) stated that magnetic resonance
imaging-guided focused ultrasound (MRgFUS) neurosurgery is
a new option for medication-resistant PD, but its safety and
efficacy remain elusive. These investigators examined the
safety and efficacy of MRgFUS for PD by systematically
reviewing related literature. PubMed and Embase were
searched to identify related studies. Inclusion criteria were
reported the efficacy or safety of MRgFUS for PD and
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published in English. Exclusion criteria were non-human
study, review or meta-analysis or other literature types without
original data, and conference abstract without full text. Data
on study characteristics, treatment parameters, efficacy, and
As were collected. Descriptive synthesis of data was
performed. A total of 11 studies containing 80 patients were
included; 9 studies were observational studies with no
controls; 2 studies included a randomized and controlled
phase. Most studies included tremor-dominant PD; 10 studies
reported decline of UPDRS-III scores after MRgFUS, and 5
reported a statistically significant decline; 9 studies evaluated
the quality of life (QOL). Significant improvement of QOL was
reported by 4 studies using the 39-item PD questionnaire; 4
studies examined the impact of MRgFUS on non-motor
symptoms. Most tests indicated that MRgFUS had no
significant effect on neuropsychological outcomes; most AEs
were mild and transient. The authors concluded that MRgFUS
is a potential treatment for PD with satisfying efficacy and
safety. Studies in this field are still limited. These researchers
stated that more studies with strict design, larger sample size,
and longer follow-up are needed to further examine its safety
and efficacy for PD.
Respiratory Muscle Training
In a systematic review, Rodríguez and colleagues (2019)
examined the effectiveness of respiratory muscle training in
persons with PD. PubMed/Medline, Embase, Web of Science,
Scopus and PEDro electronic databases were searched unt il
November 15, 2019. Reference lists of included studies were
hand-searched; RCTs assessing the effects of respiratory
muscle training programs (both inspiratory and expiratory) in
patients with PD were included. Two reviewers independently
identified eligible studies and extracted data; method quality
was appraised with the PEDro scale. A total of 5 papers
including 3 RCTs with a total of 111 patients were identified.
Method appraisal showed a mean score of 5 in the PEDro
scale. One study analyzed inspiratory muscle training, 1
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expiratory muscle training and 2 es tablished a comparison
between both of them. Statistically positive results were found
in maximal inspiratory pressure (p < 0.05 and d = 0.76),
maximal expiratory pressure (p < 0.01 and d = 1.40),
perception of dyspnea (p < 0.01), swallowing function (d = 0. 55)
and phonatory measures, without significant differences
in spirometric indices. The authors concluded that respiratory
muscle training may be an effective alternative f or improving
respiratory muscle strength, swallowing function and
phonatory parameters in subjects with PD. Moreover, these
researchers stated that the lack of primary studies regarding
this type of training prevents obtaining robust evidence.
Salivary Biomarkers of Parkinson's Disease
Bougea and colleagues (2019) noted that the search for a
reliable, early-disease biomarker for PD that reflects
underlying pathology is a high priority in PD research. Salivary
alpha-synuclein (α-Syn) is an easily accessible biomarker for
PD with promising results. These researchers examined the
performance of salivary α-Syn as a diagnostic biomarker of
PD. They identified 476 studies through a systematic literature
review according to PRISMA guidelines. A total of 8 studies
reporting data on salivary α-Syn were included in the review
(1,240 participants). The quality of studies was assessed by
Newcastle-Ottawa scale: 3 studies showed that the total α-Syn
levels were significantly lower in PD patients compared to
healthy controls, while in another 5 there was no significant
association. In some studies, total salivary α-Syn was
associated with demographic and clinical features; however,
no consistent pattern emerged. In 1 study, total α-Syn levels
were associated with poor cognitive performance i n PD
patients. Four studies showed a higher salivary oligomeric
α-Syn and oligomeric α-Syn/total α-Syn ratio in PD compared
to healthy controls, while in another 4 there was no
association. One study concluded that genetic polymorphisms
may influence total salivary α-Syn in PD patients. The authors
concluded that the potential of salivary total α-Syn as a PD
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biomarker is still uncertain,whereas salivary oligomeric α-Syn
appeared quite promising. Pre-analytical and analytical
factors of included studies were important limitations to justify
the introduction of salivary α-Syn into clinical practice.
Vivacqua and associates (2019) stated thatα-Syn aggregation
is the pathological hallmark of PD. These investigators
measured α-Syn total (α-Syntotal), oligomeric α-Syn
(α-Synolig) and α-Synolig/α-Syntotal ratio in the saliva of
patients affected by PD and in age and sex-matched healthy
subjects.They also compared salivary α-Sntotal measured in
PD with those detected in progressive supranuclear palsy
(PSP), in order to examine if salivary α-Syn could be used as a
biomarker for PD and for the differential diagnosis between PD
and PSP. These researchers studied 100 PD patients, 20
patients affected by PSP and 80 age- and sex-matched
healthy subjects; ELISA analysis was performed using 2
commercial ELISA platforms and a specific ELISA assay for
α-Syn aggregates.They detected lower α-Syntotal and higher α-
Synolig in PD than in healthy subjects. Conversely in PSP
salivary α-Syntotal concentration was comparable to that
measured in healthy subjects. Receiver operating
characteristic (ROC) analyses revealed specific cut-off values
able to differentiate PD patients from healthy subjects and
PSP patients with high sensitivity and specificity. However,
there was no significant correlation between clinical and
molecular data.The authors concluded that salivary α-Syn
detection could be a promising and easily accessible
biomarker for PD and for the differential diagnosis between PD
and PSP.
Figura and Friedman (2020) stated that the identification of
reliable biomarkers of PD is a pivotal step in the introduction of
causal therapies. Saliva is a biofluid that may be involved in
synuclein pathology in PD. These researchers have reviewed
current studies on salivary proteins and compounds in PD
patients and healthy controls, and their potential application as
biomarkers. They carried out a systematic literature search of
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the PubMed and Scopus databases. A total of 198 studies
were screened, of which 20 were included in this qualitative
analysis. The authors concluded that the oligomeric form of
salivary α-Syn was higher in PD patients, and that this may
serve as a potential biomarker of PD. Salivary DJ-1
concentrations failed to differentiate PD patients from controls.
Other enzymes and substances (heme oxygenase-1, nitric
oxide, acetylcholinesterase) have been assessed in single
studies. Salivary cortisol levels were higher in PD than in
healthy subjects. These researchers stated that saliva may be
a promising source of biomarkers in PD; moreover, further
validation of these findings is needed.
Serum FGF-21, GDF-15, and Blood mtDNA Copy Number as Biomarkers of Parkinson Disease
Davis and colleagues (2019) noted that strong evidence of
mitochondrial dysfunction exists for both familial and sporadic
PD. A simple test, reliably identifying mitochondrial
dysfunction, could be important for future stratified medicine
trials in PD. These researchers previously undertook a
comparison of serum biomarkers in classic mitochondrial
diseases and established that serum growth differentiation
factor 15 (GDF-15) out-performed fibroblast growth factor 21
(FGF-21) when distinguishing patients with mitochondrial
diseases from healthy controls. These investigators evaluated
serum FGF-21 and GDF-15, together with mitochondrial DNA
(mtDNA) copy number levels in peripheral blood cells from
patients with PD and healthy controls, to examine if these
measures could act as a biomarker of PD. A total of 121
patients with PD and 103 age-matched healthy controls were
recruited from a single center. Serum FGF-21 and GDF-15,
along with blood mtDNA copy number, were quantified using
established assays. There were no meaningful differences
identified for any of the measures when comparing patients
with PD with healthy controls. This highlighted a lack of
diagnostic sensitivity that is incompatible with these measures
being used as biomarkers for PD. The authors concluded that
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in this study, serum FGF-21, serum GDF-15, and blood
mtDNA levels were similar in patients with PD and healthy
controls and thus unlikely to be satisfactory indicators of
mitochondrial dysfunction in patients with PD.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
Diagnostic Tests:
CPT codes covered if selection criteria are met:
96132 -
96133
Neuropsychological testing evaluation s ervices
by physician or other qualified health care
professional, including integration of patient
data, interpretation of standardized test results
and clinical data, clinical decision m aking,
treatment planning and r eport, and interactive
feedback to the patient, family member(s) or
caregiver(s), when performed
96146 Psychological or neuropsychological test
administration, with single automated,
standardized instrument via electronic platform,
with automated result only
CPT codes not covered for indications listed in the CPB: Genetic testing of fibroblast growth factor 20
rs12720208 polymorphism, plasma neurofilament light
chain (NfL) as a biomarker , salivary biomarker s, serum
fibroblast growth factor 21 (FGF-21), serum growth
differentiat ion factor 15 (GDF-15) and blood
mitochondrial DNA (mtDNA) copy number levels as
biomarkers of PD - no specific code
Parkinson's Disease - Medical Clinical Policy Bulletins | Aetna Page 75 of 99
Proprietary
Code Code Description
70551 -
70553
Magnetic resonance (eg, proton) imaging, brain
(including brain stem) [for differentiating PD
from other parkinsonian syndromes]
78607 Brain imaging, tomographic (SPECT) [to
distinguish PD from other parkinsonian
syndromes]
80428 Growth hormone stimulation panel (e.g.,
arginine infusion, l-dopa administration)
81330 SMPD1 (sphingomyelin phosphodiesterase 1,
acid lysosomal)(eg, Niemann-Pick disease,
Type A) gene analysis, common variants (eg,
R496L, L302P, fsP330)
81401 Molecular pathology procedure level 2 [Not
covered for urinary LRRK2 phosphorylation for
parkinson’s disease risk]
82013 Acetylcholinesterase [salivary biomarker]
82172 Apolipoprotein, each [not covered for
apolipoprotein E (APOE)]
82530 Cortisol; free [salivary biomarker]
82533 total [salivary biomarker]
88184 Flow cytometry, cell surface, cytoplasmic, or
nuclear marker, technical component only; first
marker [measurement of telomere length]
88185 Flow cytometry, cell surface, cytoplasmic, or
nuclear marker, technical component only;
each additional marker (List separately in
addition to code for first marker) [measurement
of telomere length]
Parkinson's Disease - Medical Clinical Policy Bulletins | Aetna Page 76 of 99
Proprietary
Code Code Description
88341 -
88344
Immunohistochemistry or
immunocytochemistry, per specimen [ICSF
alpha-synuclein test as a biomarker for PD]
[cerebrospinal fluid ubiquitin c arboxy-terminal
hydrolase L1 (UCH-L1] ], [not covered for CSF
levels of heart fatty acid-binding protein,
neurofilament light chain, and tau
(phosphorylated or total) as biomarkers of PD]
Surgical Procedures:
CPT codes covered if selection criteria are met:
61720 Creation of lesion by stereotactic method,
including burr hole(s) and localizing and
recording techniques, single or multiple stages;
globus pallidus or thalamus
61735 subcortical structure(s) other than global
pallidus of thalamus
61863 Twist drill, burr hole, craniotomy, or craniectomy
with stereotactic implantation of neurostimulator
electrode array in subcortical site (e.g.,
thalamus, globus pallidus, subthalamic nucleus,
periventricular, periaqueductal gray), without
use of intraoperative microelectrode recording;
first array
+ 61864 each additional array (List separately in
addition to primary procedure)
61867 Twist drill, burr hole, craniotomy, or craniectomy
with stereotactic implantation of neurostimulator
electrode array in subcortical site (e.g.,
thalamus, globus pallidus, subthalamic nucleus,
periventricular, periaqueductal gray), with use
of intraoperative microelectrode recording, first
array
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Proprietary
Code Code Description
+ 61868 each additional array (List separately in
addition to primary procedure)
CPT codes not covered for indications listed in the CPB:
0398T Magnetic resonance image guided high
intensity focused ultrasound (MRgFUS),
stereotactic ablation lesion, intracranial for
movement disorder including stereotactic
navigation and frame placement when
performed
38232 Bone marrow harvesting for transplantation;
autologous
38240 Hematopoietic progenitor cell (HPC); allogeneic
transplantation per donor
38241 autologous transplantation
42400 Biopsy of salivary gland; needle
[submandibular]
61850 Twist drill or burr hole(s) for implantation of
neurostimulator electrodes, cortical
61860 Craniectomy or craniotomy for implantation of
neurostimulator electrodes, cerebral, cortical
64760 Transection or avulsion of; vagus nerve
(vagotomy), abdominal
90867 Therapeutic repetitive transcranial [direct
current] magnetic stimulation treatment;
planning [for the treatment of PD]
90868 Delivery and management, per session [for the
treatment of PD]
90869 subsequent delivery and management, per
session [for the treatment of PD]
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Proprietary
Code Code Description
92270 Electro-oculography with interpretation and
report
93660 Evaluation of cardiovascular function w ith tilt
table evaluation, with continuous ECG
monitoring, with or without pharmacological
intervention [for differentiating P D from other
parkinsonian syndromes]
93890 Transcranial Doppler study of the intracranial
arteries; vasoreactivity study
95961 Functional cortical and subcortical mapping by
stimulation and/or recording of electrodes on
brain surface, or of depth electrodes, to
provoke seizures or identify vital brain
structures; initial hour of attendance by a
physician or other qualified hea lth care
professional
95962 each additional hour of attendance by a
physician or other qualified hea lth care
professional (List separately in addition t o code
for primary procedure)
99183 Physician attendance and supervision of
hyperbaric oxygen therapy, per session
HCPCS codes covered if selection criteris are met:
A9584 Iodine 1-123 ioflupane, diagnostic, per study
dose, up to 5 millicuries [to distinguish PD from
essential tremor]
J7340 Carbidopa 5 mg/levodopa 20 mg enteral
suspension
HCPCS codes not covered for indications listed in the CPB:
Parkinson's Disease - Medical Clinical Policy Bulletins | Aetna Page 79 of 99
Cueing module device (auditory cue) - no specific code
Proprietary
Code Code Description
A4575 Topical hyperbaric oxygen chamber, disposable
C9734 Focused ultrasound ablation/therapeutic
intervention, other than uterine leiomyomata,
with magnetic resonance ( MR) guidance
E0446 Topical oxygen delivery system, not otherwise
specified, includes all supplies and accessories
G0277 Hyperbaric oxygen under pressure, full body
chamber, per 30 minute interval
G0461 Immunohistochemistry or
immunocytochemistry, per specimen; first
single or multiplex antibody stain
G0462 each additional single or multiplex antibody
stain (list separately in addition to code for
primary procedure)
S8042 Magnetic resonance imaging (MRI), low-field
[for differentiating PD from other parkinsonian
syndromes]
Other HCPCS codes related to the CPB:
J0364 Injection, apomorphine hydrochloride, 1 mg
J0735 Injection, clonidine HCl, 1 mg
J1265 Injection, dopamine HCl, 40 mg
ICD-10 codes covered if selection criteria are met:
F06.8 Other specified mental disorders due to known
physiological condition [development of
dementia in parkinsonism]
G20 Parkinson's disease
G21.0 -
G21.9
Secondary parkinsonism
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Proprietary
Code Code Description
G23.1 Progressive supranuclear ophthalmoplegia
[Steele-Richardson-Olszewski] [supranuclear
palsy associated with parkinsonism] [covered
for levodopa or apomorphine challenge,
olfactory testing by UPSIT or Sniffin' Sticks, and
neuropsychological testing]
G31.85 Corticobasal degeneration [covered f or
levodopa or apomorphine challenge, olfactory
testing by UPSIT or Sniffin' Sticks, and
neuropsychological testing]
ICD-10 codes not covered for indications listed in the CPB:
F02.80 -
F02.81
Dementia in other diseases classified
elsewhere [not covered for continued use of
levodopa-carbidopa intestinal gel]
F03.90 -
F03.91
Unspecified dementia [not covered for
continued use of levodopa-carbidopa intestinal
gel]
F06.0 -
F06.4
Other mental disorders due to known
physiological condition
G30.0 -
G30.9
Alzheimer's disease
R64 Cachexia
Z74.01 Bed confinement status
SPECT Scanni ng:
CPT codes covered if selection criteria are met:
78607 Brain imaging, tomographic (SPECT) [to
distinguish PD from essential tremor]
HCPCS codes covered if selection criteria are met:
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Parkinson's Disease - Medical Clinical Policy Bulletins | Aetna Page 82 of 99
A9584 Iodine 1-123 ioflupane, diagnostic, per study
dose, up to 5 millicuries [to distinguish PD from
essential tremor]
ICD-10 codes covered if selection criteria are met:
G20
Code Code Description
Parkinson's Disease
G21.11 -
G21.19
Other drug-induced secondary parkinsonism
G25.0
-G25.2
Essential, drug-induced and other specified
forms of tremor
ICD-10 codes not covered for indications listed in the CPB:
H35.89 Other specified retinal disorders brackets
thinning brackets [retinal thinning as a
biomarker of PD]
The above policy is based on the following references:
1. Aarsland D, Ravina B. Biomarkers of PD progression: Is
CSF the answer? Neurology. 2010;75( 12):1036-1037.
2. AbbVie, Inc. Duopa (carbidopa and levodopa) intestinal
suspensio n. Prescribing Information. North Chicago,
IL: AbbVie; revised May 2015.
3. AbbVie, Inc. Duopa (carbidopa and levodopa) intestinal
suspensio n. Prescribing Information. North Chicago,
IL: AbbVie; revised Septem ber 2016.
4. Adler CH, Dugger BN, Hinni ML, et al. Submandibular
gland needle biopsy for the diagnosis of Parkinson
disease. Neurology. 2014;82( 10) :858-864.
5. Ahn J, Lee JY, Kim TW, et al. Retinal thinning associates
with nigral dopaminergic loss in de novo Parkinson
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors
in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely
responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is
subject to change.
Copyright © 2001-2020 Aetna Inc.
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0307 Parkinson's
Disease
For the Pennsylvania Medical Assistance Plan, effective 1/1/20 medication coverage requests for medications on the statewide preferred drug list will be reviewed using the guidelines for determination of medical necessity developed by the Pennsylvania Department of Human Services.
www.aetnabetterhealth.com/pennsylvania revised 06/04/2020
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