pilate week 12 parkinsons

7/31/2019 Pilate Week 12 Parkinsons

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Parkinsons Disease:

Cognitive Sequelae

Fiona Pilate

Neuropsychology of Aging

CLP 7934


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Abbreviations

PD = Parkinsons Disease

PDD = Parkinsons Disease Dementia

RAC = Dopamine Receptors

NDD = Neurodegenerative diseases

NC = Normal Control

AD = Alzheimers Disease

DLB = Dementia with Lewy Bodies

MCI = Mild Cognitive Impairment

DB S = Deep Brain Stimulation

STN = subthalamic nucleus


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Parkinsons Disease:Introduction

Progressive neurodegenerative disorder that causes motor andnonmotor dysfunction

Characterized by loss of dopaminergic neurons in substantia nigrapars compacta

Can affect other areas of the nervous system including theautonomic2 and enteric nervous systems

Second most common neurodegenerative disorder after Alzheimersdisease

Affects 1 to 1.5 million people in the United States alone


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Parkinsons Disease Epidemiology

A Widespread Problem

As many as one million Americans suffer from Parkinson'sdisease

This is more than the combined number of people diagnosedwith multiple sclerosis, muscular dystrophy and Lou Gehrig'sdisease (ALS)

Incidence of Parkinsons increases with age, but anestimated 15 percent of people with PD are diagnosed beforethe age of 50

Approximately 40,000 Americans are diagnosed withParkinson's disease each year: This numberdoes not reflect the thousands of cases that go undetected.

Parkinsons Disease Foundation, Inc. 2007


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Parkinsons Disease Costs

Combined direct and indirect cost of Parkinsons, includingtreatment, social security payments and lost income from inability towork, is estimated to be more than $5.6 billion per year in the U.S. alone

Parkinsons Disease Foundation, Inc. 2007


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Pathogenesis of Parkinson Disease

ACTUAL CAUSE UNKNOWN FACTORS IMPLICATED INCLUDE:

GENETIC, ENVIRONMENTAL TOXINS, AND ENDOGENOUS TOXINS,

FROM CELLULAR OXIDATIVE REACTIONS. TWO MAJORPATHOGENETIC HYPOTHESES:

MISFOLDING OF PROTEINS, etc.

MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS


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Etiology of Parkinsons Disease

Environmentalagents

Genes

Parkinsonsdisease/parkinsonism

+


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The Problem: Loss of Dopaminergic andNon-Dopaminergic Neurons

A Lang, Neurology 2007;68;948-952.


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Parkinsons DiseaseGeneral Considerations

The second most common progressive neurodegenerative disorder

The most common neurodegenerative movement disorder

It is a complex disease with variable symptoms

Symptoms and neuropathology are well characterized

Pathogenesis of PD is not clear

May be multifactorial and heterogeneous in etiology

Misdiagnosis rate of PD is about 10-25%


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Parkinsons DiseaseClassical Clinical Features

Tremor, resting

Rigidity, cogwheel

Akinesia, bradykinesia

Postural Instability


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Parkinsons DiseaseAssociated Clinical Features

Micrographia Hypophonia Hypomimia

Shuffling gait / festination Drooling Dysphagia Autonomic dysfunction

Depression

Dementia


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Parkinsons Disease

Features supporting diagnosis

Unilateral symptom onset

Characteristic resting tremor

Narrow-based gait with flexed/ stooped posture

Reduced arm swing with tremor Sustained and significant levodopa effect


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NON-MOTOR SYMPTOMS OF PD ARE OFTEN THEGREATEST SOURCE OF DISABILITY

Dysautonomia: Constipation, orthostatic hypotension, sexual dysfunction, bladder

dysfunction

Personality changes: introversion, social viscosity, compulsive behavior (side-effectdopaminergic medications)

Anxiety

Depression / Apathy

Executive cognitive dysfunction & dementia

Sleep disturbances / daytime somnolence

Visual changes

Hyposmia


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PARADIGM SHIFT OF PD:The BRAAK Hypothesis


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Braak Classification of Lewy Neurite/Body Deposition in PD:A New Perspective On PD

Braak et al. 2004


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Braak Model for Pathologic Staging ofParkinsons Disease

Based on Lewy bodylocalization

Suggests that Lewy bodypathology does not begin

in substantia nigra

Begins in dorsal motor nucleus of glossopharyngeal and vagusnerves, anterior olfactory nucleus, and enteric nerve cell plexus

Proceeds in rostral direction toward neocortex

Progression of Parkinsons Disease may not always comply with this model

Braakstage

Clinical symptoms

1-2 Premotor

3-4 Motor

5-6 Cognitive decline


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Clinical correlates of Braak PD staging

Braak stage Site of Lewy neurite formation Clinical Features

I Dorsal motor nucleus Vagus

VIP Neurons Aucherbach pl.

GI dysfunction, i.e., constipation

II Locus Ceruleus, RF,

Raphe Nucleus

Sleep-wake disorders (RBD)

III SNpc, amygdala, basolateral nuclei,basal forebrain, hypothalamus

Dysosmia, motor dysfunction, subtlecognitive change

IV Temporal mesocortex Apparent dysautonomia, neurocognitivechange

V Depigmentation of SN,prefrontal/sensory assoc Cx

Mild dementia, hallucinations, motorimpairment

VI Entire neocortex Marked motor impairment, dementia


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Parkinson DiseasePathology

Proteinacious inclusion bodies:

Lewy bodies & Lewy neurits

Lewy bodies are:

Fibrillar deposits of alpha synuclein


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Neuropathology ofParkinsons Disease

Substantia nigra pathology

Lewy body inclusionsNeuronal loss


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Pathology in Parkinsons Disease


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Pathology in Parkinsons Disease


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Nigrostriatal denervation is only the tip ofthe PD iceberg (Langston, 2006)

PD = a Centrosympathomyenteric neuronopathy


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Characterization of presynaptic degeneration

Characterization of postsynaptic degeneration

Tracers

L-[11C]-DOPA (dopamine synthesis)[11C]-CIT-FE (dopamine re-uptake)

[11C]-RAC (dopamine receptors)

[18F]-FDG (glucose transport)


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Substantia nigraDopamin

Presynaptic neuron

D2-r

Normal

Parkinsons disease withouttreatment

RAC FDGPutamen

NeurodegenerationDOPA/CIT


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Presynaptic neuron

D2-r

Normal

Parkinsons disease

after treatment

RAC FDGPutamen




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Presynaptic neuron

D2-r

Normal

Striato-Nigral degeneration

RAC FDGPutamen


Parkinsons disease

after treatment



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Improved Detection ofLewy Body Pathology

Alpha-synuclein mutations in familial PD

Alpha-synuclein immunoreactivity in

all Lewy bodies Classic brainstem Lewy bodies

Cortical Lewy bodies

Lewy neurites


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Lewy Body Inclusions

Characteristic inclusions in substantia nigra neurons of patientswith Parkinsons disease

Immunoreactive for neurofilaments, ubiquitin and alpha-synuclein,but not tau (NFT are tau and ubiquitin positive)

In substantia nigra it is cytoplasmic, round, eosinophilic with clearhalo

In cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistry


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Alpha-Synuclein Pathology in theSubstantia Nigra and Neocortex

Cerebral cortexSubstantia nigra


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a-Synuclein

a-Synuclein is a tubular-filamentous nonsoluble protein, with important

role in the maintenance of synaptic pool misfolded a-synuclein is part of the abnormal protein aggregate found

in Lewy bodies


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Tau & Taupathies

Tau is a neuronal Microtubule stabilizing protein,

It contribute to axonal transport, growth & morphology.

Tau misregulation and deposition correlates with neuronal cell death in:

Frontotemporal dementia & Parkinsonism associated withChr.17(FTDP-17)

Alzheimers neurofibrillary tangles are composed of phosphrylatedTau. Its role however in pathogenesis is controversial


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Synucleinopathies

NDD characterized by intracellular aggregation of alpha-synuclein:

Parkinsons Disease

Dementia with Lewy Bodies

Lewy Body Variant of AD

Multiple System Atrophies

OPCA & SND & Shy-Drager Syndrome

Neurodegeneration with brain iron accumulation type 1( Hallervorden-Sp.)


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Role of Tau and a-synuclein inneurodegenerative diseases


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Relevant Brain Structures

Motor Circuit


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Imaging Biomarkers for Parkinsons Disease

(PD)

Method Tracer Assessment Expected results with PD

fMRI NA Indirect marker of neuronal activity activation in specific brain areas

SPECT [123I]b-CIT[99mTc]TRODAT

[11C]MP

DA transporter levels levels

PET [18F]DOPA Estimate number of DA terminals andnigral neurons

levels

PET [11C]DTBZ VMAT2 as estimate of number of DAterminals and nigral neurons

levels

PET [11C]RAC

Striatal DA receptor availability Estimate synaptic DA concentration

Early PD: in putamen

Advanced PD or after chronicDRT: in caudate

PET FDG Metabolic activity of basal ganglianetwork

PDRP and PDCP


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Parkinsons

Disease

Progressive cognitive

decline Specific to basal ganglia

Slowing of emotionaland voluntarymovement

Muscular rigidity

Tremor

Dopamine deficiency

Uniform reduction of metabolism butmay have parietal and temporalhypometabolism similar to AD

[18F]fluorodopa PET shows decreaseduptake in the putamen


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FDG PET Findings in Dementia With LewyBodies (DLB)

Patients with DLB(Dementia with Lewy

Bodies) may havehypometabolism of visualassociation cortex andoccipital cortex, inaddition to temporal and

parietal hypometabolism


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Cognitive ageing

Cognitive, or thinking ability is the product of fixed intelligence , theresult of previous thinking , which often increases with age i.e wisdom

fluid intelligence i.e. real time information processing which declines

modestly in old age Intellectual function is maintained until at least 80 years of age, but

processing is slower.

Non critical impairments include: forgetfulness, reduced vocabulary,slower learning

Cognitive impairment in PD


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In PD, selective cognitive deficits, esp. executive dysfunction with difficulties planning,innovating, and sequencing are often present in the absence of clinically diagnosabledementia.

Because of the primary basal ganglia involvement in PD, it has generally been assertedthat executive impairment is mainly attributable to a dopaminergic loss. The contributionof dopamine to the working memory processes in PD has been emphasized However,more pure measures of executive functioning do not show significant benefit withdopaminergic treatment . Therefore, it is clear that the dopaminergic hypothesis cannotexplain why dopaminergic treatment generally does not reverse the dysexecutive

syndrome in PD.

Cognitive impairment in PD

Cognitive Impairment in PD:


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A more satisfying understanding of dysexecutive syndrome in PD has come frompharmacological studies of the cholinergic system.

Dubois et al. (1997, 1999) reported that the use of anti-cholinergic medications inpatients with PD led to severe impairment on tests, such as the Wisconsin card sortingtask, digit span test, and a behavioral indifference scale . Furthermore, anticholinergicdrug administration caused a transient dysexecutive syndrome in PD patients, but not innormal controls, indicating specific anti-cholinergic vulnerability in PD (Bedard et al.,1998).

Cognitive Impairment in PD:The Cholinergic System


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Trster 2009

A Transition in Grouping PD Patients byCognitive Impairment


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Correlation Coefficients Between Individual Cognitive Tests andCortical AChE Activities in Combined PDD and PD Groups

Cognitive testCorrelation coefficient(significance)

California Verbal Learning Test-STM Rs = 0.13 ns

California Verbal Learning Test-LTM Rs = 0.20 nsJudgment of Line Orientation Test Rs = 0.43 (p < 0.05)

Stroop Color Word Test Rs = 0.46 (p < 0.05)

Trail Making Test B-A Rs = 0.44 (p < 0.05)

WAIS-III Digit Span Rs = 0.57 (p < 0.005)

Bohnen NI, et al.J Neurol. 2006;253:242-247.


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Neurochemistry of PDD and ADCholinergic System

Cholinergic basal forebrain

Neuronal loss and Lewy body pathology in PD and PDD

Neuronal loss and neurofibrillary tangles in AD Pedunculopontine (PPT) nucleus

Neuronal loss and Lewy body pathology in PD and PDD

Neuronal loss and neurofibrillary tangles in AD

Jellinger K.J Neurol Neurosurg Psychiatry. 1988;51:540-543.


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Cholinergic deficitCholinergic deficit

PDDLewy body pathology

in cholinergic basal

forebrain and

brainstem PPT

ADNeurofibrillary

tangles in cholinergic

basal forebrain and

brainstem PPT

Two Distinct Disorders With aCommon Cholinergic Deficit


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Trster 2009

Neuropsychological Comparison of DLB/PDD vs. AD

AD involves greater impairment of memory, especially verbal , probablyrelated to greater temporal lobe pathology

AD hallmarks: rapid rates of forgetting and intrusions

DLB involves greater visuoperceptual and constructional deficits whichmay be linked to posterior cortical hypometabolism and vissalhallucinations


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Trster 2009

Neuropsychological Comparison of DLB/PDD vs. AD

DLB/PDD perform worse than AD on complex attention tasks (Stroop,Trailmaking) (Calderon et al. 2001) but not on simple tasks (e.g., digitspan)

DLB/PDD perform worse on executive function tasks (e.g., card sorting)than AD (Simard et al. 2000). Executive dysfunction linked to basalforebrain cholinergic deficits

Language data more equivocal: same naming and fluency deficits in AD

and DLB, worse naming in AD, worse letter fluency in DLB

D ti d P ki i


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Dementia and Parkinsonism

DEMENTIA WITH LEWY BODIES

PARKINSONS DISEASE WITH DEMENTIA

D ti i P ki Di


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Incidence of dementia in PD 40-50%.

The causes of dementia in PD are probably manifold but likely include directcortical involvement as evidenced by the presence of Lewy bodies and Lewy

neurites, dopaminergic degeneration, cholinergic deficits from nucleus basalisatrophy, and concomitant conditions such as Alzheimer disease (AD).

Significant loss of cholinergic forebrain neurons has also been reported in PDbrains (Whitehouse et al., 1983; Candy et al., 1983). Arendt et al. found greaterforebrain neuronal loss in PD than in AD (Arendt et al., 1983), suggesting thatcholinergic deficits may be at least as prominent in (late-stage) PD as in AD.

Dementia in Parkinson Disease


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Dementia with Lewy bodies

Cognitive and behavioural problems precede motor symptoms

Gradual progression, insidious onset

Fluctuations in cognitive function and alertness

Prominent auditory and visual hallucinations, paranoia, dellusions

Levodopa or dopa agonists may worsen the confusion


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Dementia with Lewy Bodies

Most common dementia after Alzheimer's

Tiny protein deposits in nerve cells interruptneurotransmissions

Daily fluxuation of problems

Spatial disorientation often falls, shuffling Visual hallucinations (of animals)

Nightmares

Symptoms similar to Parkinson's and Alzheimer's

Treated very differently than other FT lobe dementias


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Consensus Criteria for Dementia with Lewy Bodies

Progressive cognitive decline with loss of normal socialand occupational function: loss of memory, attention,frontal subcortical skills, visuospatial ability

Two of the following:

a. fluctuating cognition, attention, alertness

b. visual hallucinations

c. motor features of parkinsonism

Supportive features: falls, syncope, LOC, neurolepticsensitivity, delusions, non-visual hallucinations


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Consensus Criteria forDementia with Lewy Bodies

It is suggested that if dementia occurs within 12months of the onset of extrapyramidal motorsymptoms, the patient should be assigned a primarydiagnosis of possible DLB

If the clinical history of parkinsonism is longer than12 months, PD with dementia will usually be amore appropriate diagnostic label


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Consensus Criteria forDementia with Lewy Bodies

Criteria good predictor of Lewy body pathology(with or without concomitant AD pathology) - highpositive predictive value

Criteria poor predictor of the absence of Lewybody pathology - low negative predictive value


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Depression in PD


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Depression in PD

Depression is a frequent non-motor symptom in PD (25-50%) and is a significantsource of disability in this disorder (Weintraub et al., 2004).

There is converging evidence of serotonergic hypofunction as a basis for depressionin PD on the basis of reduced 5-HIAA csf levels (D'Amato et al.)

Depression and Cognition in PD


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Depression and Cognition in PD

A relatively unique feature of depression in PD is that mood disturbance isassociated with a quantitative but not qualitative worsening of cognitive deficits(Trster et al., 1995).

Prospective studies have shown that depression may be a risk factor for incidentdementia in PD (Lieberman, 2006)

This modulatory effect of depression on cognitive impairment in PD suggests that acommon mechanism might underlie both types of symptoms.

PD & DBS Surgery


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PD & DBS Surgery


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Neurobiology

Brain areas targeted in DBS:

1. Vim = ventralis intermedius nucleus of the thalamus

2. GPi = posteroventral portion of the internal segment of the globuspallidus

3. STN = subthalamic nucleus


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Intervention

Patient Selection

Goal: Find ideal patients, where individual benefit > risk of surgery

Advanced idiopathic PD with motor complications is main indication for DBS inPD

Multidisciplinary approach:

1. Neurosurgeon

2. Neurologist

3. Neuropsychologist


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Intervention

Patient Selection

Response to levodopa = best prognostic indicator for DBS suitability

Neuropsychological evaluation

- Depression

- Psychosis

Age

Full medical assessment

Discussion of long-term and short-term effects of DBS

Education regarding environmental concerns with implantable devices


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Intervention

Surgical Procedure

Precise implantation of stimulation electrode in targeted brainarea.

Connecting electrode to internal programmable pulse generator

Intervention


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Intervention

Pre-Operative Stage:

Stereotactic Surgery

- Locate targeted brain areas

- Stereotactic frame

- MRI, CT, or ventriculography

- Stereotactic atlas


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Intervention

Pre-Operative Stage:

Functional Stereotactic Surgery

- Electrophysiological exploration oftargeted regions via test electrodes

- Involves:

1. Microrecording

2. Test-stimulation

- Increases accuracy of localization (i.e.finding optimum target in GPi or STN)

- Under local anesthesia


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Intervention

Optimal Stimulation Sites:- Dorsolateral STN border

- Posteroventral GPi

DBS electrode stereotactically inserted with special rigid guidetube

Patient is awake and in the medication-off state after 12-hourwithdrawal

Implantation of Electrode:

Connections


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Connections

The results of PET revealed activationof the left orbitofrontal cortex, a findingconsistent withinvolvement of the nigrothalamic pathway, which extends totheleft amygdala and limbic structures and is implicated in theprocessing ofunpleasant feelings.

STN Connections


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STN Connections

(Temel et al., 2005)

Brain regions showing activation (red) or deactivation (green) during hypomania induced bystimulation of the STN in patients with Parkinson's disease


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Mallet, Luc et al. (2007) Proc. Natl. Acad. Sci. USA 104, 10661-10666

stimulation of the STN in patients with Parkinson s disease

Method for localizing electrodes implanted in the brain of a patient withParkinson's disease for stimulation of the STN


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Mallet, Luc et al. (2007) Proc. Natl. Acad. Sci. USA 104, 10661-10666

Parkinson's disease for stimulation of the STN

STN DBS on vs off verbal fluency


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STN DBS on vs off verbal fluency

Number of words processed

Regions of decreased activation within the right orbitofrontal cortex and the leftinferior frontal cortex/insular cortex, the left inferior temporal cortex during STNstimulation compared with the OFF state during the fluency task (Schroeder et al.,

2003)

DBS:Non Motor Side Effects


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Cognitive deficits post DBS: verbal memory; verbal fluency; attention and executivefunctions; working memory; mental speeds and response inhibition

Mood changes: depression, incl. suicide, mania, anxiety

Hypersexuality

Pathological laughter

Changes in personality, impulse control disorder

Anatomically, cognitive and limbic information related to the basal ganglia is processed

by the associative and limbic circuits, respectively. These data point towards a potentregulatory function of the STN in the processing of associative and limbic informationtowards cortical and subcortical regions with further evidence from functionalneuroimaging studies

No major behavioral changes from Vim thalamic and GPi target stimulation.

Patient Enrollment and Randomization Assignment DBS


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278 screened for eligibility

255 randomized

23 excluded

134 assigned to receiveBMT

119 patients assessed7 withdrew consent2 withdrew because randomized to BMT6 withdrew when BMT group closed

121 assigned to receiveDBSGPi 61 and STN 60

111 patients assessed7 withdrew due to medical orpsychological problem2 withdrew consent1 died

116 assessed3 no follow-up data

108 assessed at3 no follow-up data

134 included in primary analysis 121 included in primary analysis

3 month assessment

6 month assessment

Patient Baseline Characteristics by Treatment Group


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Patient Baseline Characteristics by Treatment Group

BMT (n=134)

Mean (std) or %

DBS (n=121)

Mean (std) or %

p-value

Beck depression inventory 11.7(8.1) 11.3(8.7) 0.680

Mattis Dementia rating scale 136.6(5.8) 136.7(4.8) 0.842

Processing speed index 89.4(14.1) 91.0(13.9) 0.366

WAIS-III Working memory index 97.3(13.6) 101.2(13.3) 0.023

Phonemic Fluency (FAS) 44.7(12.1) 45.7(12.1) 0.520

Category Fluency (Animal) 49.5(11.6) 50.9(11.3) 0.336

HVLT total (learning/memory) 39.9(11.5) 38.9(11.3) 0.499

HVLT delayed recall 38.1(13.4) 37.3(13.3) 0.619

Finger tapping 37.6(12.9) 37.1(11.4) 0.746

Boston Naming Test (language) 55.9(4.3) 55.5(4.5) 0.444

Neuropsychological Outcomes at Baseline andSix Months by Treatment Group


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Six Months by Treatment Group

BMT (n =134) DBS (n = 121) BMT - DBS

Outcome Baseline 6 Months Baseline6

Months

Diff

(95% CIs) P-value

Boston Naming Test

55.9 (4.3) 56.2 (4.0)

55.5

(4.5)

56.2

(3.8)

-0.4

(-0.8, 0.1) 0.127

Finger Tapping

37.6 (12.9) 38.7 (13.2) 37.1 (11.4) 36.9 (11.3)

1.3

(-1.2, 3.8) 0.319

Stroop Interference

51.0 (7.6) 51.8 (8.4) 50.7 (7.4) 49.8 (7.1)

1.6

(-0.4, 3.5) 0.111

BVMT Delayed Recall

42.4 (13.3) 44.6 (13.7) 42.1 (13.3) 41.1 (13.6)

3.2

(0.4, 6.0) 0.026

Beck DepressionInventory

11.7 (8.1) 10.2 (6.9)

11.3

(8.7) 10.9 (8.6)

-1.0

(-2.7, 0.6) 0.224

l


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Causal Genes

Analysis of large nuclear families with many affectedindividuals have revealed several single genemutations/locus replications that cause PD

-synuclein

Parkin

DJ-1

PINK

LRRK2

Genes Associated with Sporadic Late Onset


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Genes Associated with Sporadic Late OnsetParkinsons Disease

Tau H1 haplotype

-synuclein promoter variant (SNCA gene)

Vesicular monoamine transporter-2 (VMAT2)

UCHL1 variant

LRRK2

Parkinson's disease


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Parkinson s diseaseSummary of genes

Gene Mode Chromosome Gene product

Park 1 AD 4q21-23 a- synuclein

Park 2 AR 6q25.2-27 Parkin

Park 3 AD 2p13 Unknown

Park 4 AD 4p14-16 .3 Unknown


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Summary

PDD is a clinical disease with a unique progression

Begins with Parkinsons disease

Motor signs present for years before onsetof dementia

Dementia syndrome characterized by memory, executive, attentional, andfunctional deficits

Prominent neuropsychiatric symptoms with psychotic features

PDD can be identified and diagnosed in usual settings of care

Need for effective treatments

There are no currently approved treatment options

Summary


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Summary

PD is a multi-systems neurodegeneration syndrome that cannot be fully explained bynigrostriatal dopaminergic denervation. There is also post-mortem and in vivo evidenceof monoaminergic (5HT, NE) and cholinergic denervation.

Pharmacotherapy in PD may (adversely) effects DA, NE, 5HT or ACh neurochemicalsystems with respective non-motor and motor consequences.

DBS, in particular STN, may affect,because of its close anatomic proximity, non-motorassociative and limbocortical circuits with consequences on mood, cognition andbehavior.

Clinical PDD is highly predictive of specific neuropathologic and neurochemicalcharacteristics

Neuropathology

Lewy body pathology

Limited AD pathologic change


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Summary

Because PD is a progressive disorder, early diagnosis and treatmentintervention with neuroprotective therapies to slow or prevent furtherdegeneration and to promote neuronal repair are current goals in themanagement of PD

The development and validation of diagnostic markers in symptom recognitionand neuroimaging will aid in early diagnosis of PD

Advances in neuroimaging and development of quantitative diagnosticbiomarkers will also improve evaluation of potential neuroprotective therapies

pilate week 12 parkinsons

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