lo spettro delle demenze con parkinsonismo · ophthalmoplegia, dementia, dysarthria and...
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Lo spettro delle Demenze con Parkinsonismo
Alessandro PadovaniClinica Neurologica
Dipt. Scienze Cliniche e Sperimentali
UNIBS
SommarioPatologie Neurodegenerative con Overlap Cognitivo-Motorio
Malattia di Alzheimer e Parkinsonismo
Malattia di Parkinson e Demenza
Lo spettro delle Degenerazioni Lobari Fronto-Temporali
CBD/CBS
PSP
FTD
5% 10% 65% 5% 7% 8%
Dementia with Lewy bodies
Parkinson’s disease
Diffuse Lewy body disease
Lewy body variant of ADVascular dementias
and AD
Other dementias
Frontal lobe dementia
Creutzfeldt-Jakob disease
Corticobasal degeneration
Progressive supranuclear palsy
Many others
AD and dementia
with Lewy bodies
Vascular dementias
Multi-infarct dementia
Binswanger’s disease
AD
Small et al, 1997; APA, 1997; Morris, 1994.
Differential Diagnosis of Dementia
Modified from Bertram L, J Clin Invest, 2005
Lewy body
plaquestangles
Pure LBD
PSP/LBD
PSP
LBD/PD
LBD/AD
ADPathological
aging
[adapted from Dennis Dickson’s ICAD presentation, 7/08]
But in fact, much dementia is “mixed” and clinical overlap exists
Sindromi Extrapiramidali: non solo sintomi motori
Disturbi non cognitivi
Disturbi Psichici Disturbi Sonno Disturbi Motori
Apatia
Depressione
Psicosi
Wandering
Altro
Insonnia
Parasonnie
Nicturia
Disturbi Marcia
Rigidità
Aprassia
Dolore
ComorbiditàVascolare
incontinenza
Interventi chirurgiciMioclonieSundowning
Demenze: non solo sintomi cognitivi
At 46, he had a decreased arm swing and hand dexterity on the right side, which kept him from continuing his job as a police officer and made him retire early. His facial expression was decreased. Speech was dysarthric and hypophonic.
He had cogwheel rigidity and hypokinesia in the right upper extremity. There was a 6~8 Hz action tremor in the right hand. No resting tremor was observed. His gait was short-stepped with his right foot dragged and the right arm flexed.
A decreased arm swing was noted on the right side. His Unified Parkinson’s Disease Rating Scale (UPDRS) scores were as follows: bradykinesia 2/0, rigidity 2/0, resting tremor 0/0, postural tremor 1/0. Hoehn and Yahr staging was 1
Brain biopsy was performed in left frontal cortex, showing neurofibrillary tangles and neuritic
plaques, which is compatible with Alzheimer’s disease (Fig. 2). No Lewy bodies were found.
Severity of EPS in
AD/neuroleptics-free
patients and control
subjects
Types of EPS with statistically significant difference of presence (p < 0.05) in patients with
AD and control group
Copyright restrictions may apply.
Effect of Extrapyramidal Signs and Lewy Bodies on Survival in Patients
With Alzheimer DiseaseMary N. Haan, MPH, DrPH; William J. Jagust, MD; Douglas Galasko, MD; Jeffrey Kaye, MD
Arch Neurol. 2002;59:588-593
Dalla M. Alzheimer variante Lewy alla LBD e alla PDD
CSF?
PET-FDG?
Amyloid PET?
Personal Data on the role of DATSCAN in possible LBD
Lo spettro della Malattia FrontoTemporale
Sha S et al. (2006) Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases? Nat Clin Pract Neurol 2: 658–665 10.1038/ncpneuro0357
Venn diagram summarizing the similarities and differences between corticobasal
degeneration, progressive supranuclear palsy and frontotemporal lobar degeneration
La Paralisi Supranucleare Progressiva
Progressive Supranuclear Palsy (Litvan et al., 2003)
Prevalence
1.39/100.000 inhabitants 6.4/100.000 inhabitants
Incidence
0.3–0.4 per 100,000 person/yr 5.4 new cases per 100,000
person/yr
Incidence rising with aging population
Clinical Diagnosis
Easy 25% of patients are never diagnosed by specialists
Survival
10 yr 5–6 yr
Shortened if early falls, dysphagia, or supranuclear gaze palsy
are present
Quadro clinico
Eterogeneo: intervallo di tempo mediano tra esordiodella malattia e manifestazione dei sintomi visivi,disartria e disfagia che oscilla da 3 a 5 anni
Altresì caratterizzato da:
Disturbi della deambulazione
Sintomi visivi
Disfagia
Il rallentamento motorio non è sufficiente per spiegarela ridotta performance cognitiva (a differenza dellaMSA)
Criteri diagnosticiLitvan et al, 1996
Criteri di base
Devono essere presenti:
- decorso progressivo
- esordio oltre i 40 anni- paralisi nello sguardo verso l’alto con anomalia dello sguardo verso il basso
Criteri di supporto
Possono essere presenti:- acinesia o rigidità simmetrica più prossimale che distale
- anomalia posturale del collo (retrocollis)
- disfasia o disartria precoce
- decadimento cognitivo precoce con almeno due delle seguenti caratteristiche: apatia,
disturbo di astrazione, ridotta fluenza verbale, comportamento di imitazione, segni di
liberazione frontale.
Criteri di esclusione
Devono essere assenti:
- storia di encefalite- sindrome dell’arto alieno, deficit corticali di sensibilità, atrofia corticale frontale o temporo-parietale
- allucinazioni
- demenza corticale precoce tipo Alzheimer ( amnesia con afasia o agnosia)
- segni cerebellari precoci o marcati
- disautonomia non iatrogena
- distonia unilaterale
Criteri diagnosticiLitvan et al, 1996
Profilo clinico
• L’esordio è insidioso. L’età dell’esordio varia tra i 55 ei 70 anni, soltanto pochi casi prima dei 45 anni.
• I primi sintomi sono generalmente l’ instabilitàposturale e le cadute, che insorgono all’esordio odurante il primo anno della malattia.
• Le modificazioni cognitive o comportamentali inizianonel corso del primo anno, ma sono raramente presentiall’esordio.
• Disartria e bradicinesia sono altri sintomi comunidella paralisi sopranucleare progressiva.
• Presenza di decadimento cognitivo clinicamentesignificativo.
Lang et al. The many faces of Corticobasal Degeneration. Parkinsonism and Related Disorders, 2007
Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism.Williams et al., Brain, 2005
Late clinical features in 89
cases separated
into distinct groups
Early clinical features in
cases with an
incomplete data set
Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism.Williams et al., Brain, 2005
The core clinical features of PSP appear to be bradykinesia, rigidity and postural instability, and are almost always present later in the disease. Together with the supranuclear vertical ophthalmoplegia, dementia, dysarthria and pseudobulbar palsy, they form the classic features of PSP
We have confirmed a high frequency of non-specific visual complaints early in the course of the disease and a predominance of males in the RS subgroup. The expanded clinical phenotype now includes a syndrome that may closely resemble idiopathic PD.
The presence of the PSP-P subgroup may account for the small proportion of cases in clinicopathological reports where an incorrect ante-mortem diagnosis of Parkinson’s disease was made.
The features which most clearly differentiate this syndrome from RS appear to be an asymmetric onset, extra-axial dystonia, tremor and benefit from levodopa.
A 57-year-old man enjoyed excellent health until he developed progressive gait and
balance disturbances. A neurological examination performed by one of the authors
(PPP) showed a slow shuffling broad-based gait with no rigidity,
tremor, disturbance in eye movements, speech or cognitive impairment. Two years later,
he developed gait ignition failure freezing episodes with festination, festinating speech
and micrographia. There was no response to levodopa. At age 61, the patient showed
marked postural instability, hypophonia, hypomimia,
signs of supranuclear vertical gaze palsy, positive frontal signs, moderate postural
tremor of the upper limbs, and rigidity in all four limbs. Mood was labile. The
apomorphine challenge test was negative. His bladder function remained
normal, although the EMG examination revealed signs of denervation of the muscle
sphincter ani externus. The brain MRI showed moderate cortical and subcortical atrophy
with unremarkable brainstem atrophy. Six months later, the patient was bed-ridden with
a debilitating akinetic-rigid syndrome and a further increase in pseudobulbar symptoms,
in particular dysarthria and dysphagia. One year later the patient developed severe
dysautonomic disturbances including urinary incontinence, recurrent episodes of
profuse sweating and hypotension.
Il Ruolo delle Indagini Diagnostiche nella PSP
Looking for new biomarkers: the case of Progressive Supranuclear Palsy
In CSF and in cerebral cortex two Tau isoforms may be detected by
immunoprecipitation: Tau 55kDa (full lenght) and Tau 33kDa (truncated
form)
In PSP patients, there is a significant reduction of 33KDa truncated form.
The ratio between 33kDa/55kDa Tau forms is lower in PSP.
Atrophy linked to 33kDa Tau fragment decrease
Atrophy related to Tau fragment reduction in FTLD spectrum, P<.005
Neuroimaging
Figure 1: Sagittal T2-weighted MR in another patient with PSP shows the tectal plate is
markedly thinned and atrophic. Courtesy Anne Osborn, MD.
Fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrating hypometabolism (as reflected by the regions in
yellow and green) in the dorsolateral and mesial frontal regions, typical of PSP-RS.
Commento
• La PSP è condizione assai più eterogenea dal punto di vista genetico e clinico di quanto noto fino ad alcuni anni fa
• La maggiore difficoltà diagnostica è legata alla identificazione di presentazioni atipiche vedi soprattutto PLS e CBS
• Una attenta e moderna valutazione semeiotica mirata ad alcuni aspetti clinici (vedi olfatto, RBD, Aprassia, etc) può essere di aiuto nella individuazione di casi sospetti
• In questi casi, l’utilizzo di parametri RMN morfologici, della PET e di indagini liquorali oltre che genetiche possono permettere una più accurata diagnosi di PSP
Neuropathological criteria of Corticobasal Degeneration
- Focal frontoparietal atrophy
- 4R tauopathy
- Astrocytic plaques and coiled
bodies
Dickson et al, 2002
Table&e'1:!Previous!CBD!Criteria!
Reference& Clinical&Features& &
Riley&1990& Basal%ganglia%signs% Akinesia,!rigidity,!limb!dystonia,!athetosis,!postural!instability,!falls,!orolingual!dyskinesias!
& Cerebral%cortical%signs% Cortical!sensory!loss,!alien!limb!phenomenon,!dementia,!apraxia,!frontal!release!reflexes,!dysphasia!
& Other%manifestations% Postural>action!tremor,!hyperreflexia,!impaired!ocular!motility,!dysarthia,!focal!reflex!myoclonus,!impaired!eyelid!motion,!dysphagia!
&Watts&1994&
%Major%
!Akinesia,!rigidity,!postural/gait!disturbance,!action/postural!tremor,!alien!limb!phenomenon,!cortical!signs,!dystonia,!myoclonus!
& Minor% Choreoathetosis,!dementia,!cerebellar!signs,!supranuclear!gaze!abnormalities,!frontal!release!signs,!blepharospasm!
&Lang&1994*&
%Inclusion%
!Rigidity!plus!one!cortical!sign!(apraxia,!cortical!sensory!loss,!or!alien!limb)!OR!asymmetric!rigidity,!dystonia,!and!focal!reflex!myoclonus!
& Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
&Kumar&1998&
%Inclusion%
!Chronic!progressive!course,!asymmetric!onset,!presence!of:!"higher"!cortical!dysfunction!(apraxia,!cortical!sensory!loss,!or!alien!limb),!and!movement!disorder!(levodopa>resistant!akinetic!rigid!syndrome,!limb!dystonia,!reflex!focal!myoclonus)!
&&&&&
Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
& % !
Table&e'1:!Previous!CBD!Criteria!
Reference& Clinical&Features& &
Riley&1990& Basal%ganglia%signs% Akinesia,!rigidity,!limb!dystonia,!athetosis,!postural!instability,!falls,!orolingual!dyskinesias!
& Cerebral%cortical%signs% Cortical!sensory!loss,!alien!limb!phenomenon,!dementia,!apraxia,!frontal!release!reflexes,!dysphasia!
& Other%manifestations% Postural>action!tremor,!hyperreflexia,!impaired!ocular!motility,!dysarthia,!focal!reflex!myoclonus,!impaired!eyelid!motion,!dysphagia!
&Watts&1994&
%Major%
!Akinesia,!rigidity,!postural/gait!disturbance,!action/postural!tremor,!alien!limb!phenomenon,!cortical!signs,!dystonia,!myoclonus!
& Minor% Choreoathetosis,!dementia,!cerebellar!signs,!supranuclear!gaze!abnormalities,!frontal!release!signs,!blepharospasm!
&Lang&1994*&
%Inclusion%
!Rigidity!plus!one!cortical!sign!(apraxia,!cortical!sensory!loss,!or!alien!limb)!OR!asymmetric!rigidity,!dystonia,!and!focal!reflex!myoclonus!
& Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
&Kumar&1998&
%Inclusion%
!Chronic!progressive!course,!asymmetric!onset,!presence!of:!"higher"!cortical!dysfunction!(apraxia,!cortical!sensory!loss,!or!alien!limb),!and!movement!disorder!(levodopa>resistant!akinetic!rigid!syndrome,!limb!dystonia,!reflex!focal!myoclonus)!
&&&&&
Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
& % !
Table&e'1:!Previous!CBD!Criteria!
Reference& Clinical&Features& &
Riley&1990& Basal%ganglia%signs% Akinesia,!rigidity,!limb!dystonia,!athetosis,!postural!instability,!falls,!orolingual!dyskinesias!
& Cerebral%cortical%signs% Cortical!sensory!loss,!alien!limb!phenomenon,!dementia,!apraxia,!frontal!release!reflexes,!dysphasia!
& Other%manifestations% Postural>action!tremor,!hyperreflexia,!impaired!ocular!motility,!dysarthia,!focal!reflex!myoclonus,!impaired!eyelid!motion,!dysphagia!
&Watts&1994&
%Major%
!Akinesia,!rigidity,!postural/gait!disturbance,!action/postural!tremor,!alien!limb!phenomenon,!cortical!signs,!dystonia,!myoclonus!
& Minor% Choreoathetosis,!dementia,!cerebellar!signs,!supranuclear!gaze!abnormalities,!frontal!release!signs,!blepharospasm!
&Lang&1994*&
%Inclusion%
!Rigidity!plus!one!cortical!sign!(apraxia,!cortical!sensory!loss,!or!alien!limb)!OR!asymmetric!rigidity,!dystonia,!and!focal!reflex!myoclonus!
& Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
&Kumar&1998&
%Inclusion%
!Chronic!progressive!course,!asymmetric!onset,!presence!of:!"higher"!cortical!dysfunction!(apraxia,!cortical!sensory!loss,!or!alien!limb),!and!movement!disorder!(levodopa>resistant!akinetic!rigid!syndrome,!limb!dystonia,!reflex!focal!myoclonus)!
&&&&&
Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
& % !
Table&e'1:!Previous!CBD!Criteria!
Reference& Clinical&Features& &
Riley&1990& Basal%ganglia%signs% Akinesia,!rigidity,!limb!dystonia,!athetosis,!postural!instability,!falls,!orolingual!dyskinesias!
& Cerebral%cortical%signs% Cortical!sensory!loss,!alien!limb!phenomenon,!dementia,!apraxia,!frontal!release!reflexes,!dysphasia!
& Other%manifestations% Postural>action!tremor,!hyperreflexia,!impaired!ocular!motility,!dysarthia,!focal!reflex!myoclonus,!impaired!eyelid!motion,!dysphagia!
&Watts&1994&
%Major%
!Akinesia,!rigidity,!postural/gait!disturbance,!action/postural!tremor,!alien!limb!phenomenon,!cortical!signs,!dystonia,!myoclonus!
& Minor% Choreoathetosis,!dementia,!cerebellar!signs,!supranuclear!gaze!abnormalities,!frontal!release!signs,!blepharospasm!
&Lang&1994*&
%Inclusion%
!Rigidity!plus!one!cortical!sign!(apraxia,!cortical!sensory!loss,!or!alien!limb)!OR!asymmetric!rigidity,!dystonia,!and!focal!reflex!myoclonus!
& Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
&Kumar&1998&
%Inclusion%
!Chronic!progressive!course,!asymmetric!onset,!presence!of:!"higher"!cortical!dysfunction!(apraxia,!cortical!sensory!loss,!or!alien!limb),!and!movement!disorder!(levodopa>resistant!akinetic!rigid!syndrome,!limb!dystonia,!reflex!focal!myoclonus)!
&&&&&
Exclusion% Early!dementia,!early!vertical!gaze!palsy,!rest!tremor,!severe!autonomic!disturbances,!sustained!responsiveness!to!levodopa,!lesions!on!imaging!studies!indicating!another!pathology!
& % !
Previous criteria of Corticobasal Degeneration
Criteria Common Inclusion Exclusion
Riley 1990 - asymmetry- akinesia- rigidity- apraxia- dystonia- corticalsensory loss- myoclonus- alien limb- falls
dementia -
Watts 1994 cerebellarsigns, tremor
-
Lang 1994 no levo-dopa dementia
Litvan 1998 no levo-dopa
Kumar 1998 no levo-dopa dementia
Halpern 2003 no levo-dopa dementia
Bak, Hodges 2008 dementia
Corticobasal Degeneration (CBD)
Dickson et al., 2002
Corticobasal Syndrome (CBS)
Lang et al., 1994
CBS=CBD25-55%
Study design to identify clinical CBD phenotypes
CBD Case inclusion
• Literature review of proven autopsy CBD cases (MEDLINE 1950-2012, EMBASE 1980-2012) with a) a minimum of 5 CBD reported cases and b) available clinical data
• Cases from 5 brain-banks with published and unpublished reports.
CBD Symptoms
• symptoms were considered “at presentation” and “ever” (durin disease course).
• the denominator for calculating the frequency of any given clinical feature is less than the total number of cases identified, reflecting the number of cases for which that feature was reported.
Literature review and brain-banks
Medline: 204
EMBASE: 603
Total: 808 articles
(37 final)
103 non-overlapping cases
5 brain banks:
Mayo, Western Ontario, UCSF, Mayo
Jack., UPENN
106 brain-bank cases
72% of CBD patients with parkinsonism hadasymmetric symtoms
CBS
bvFTD
PD
atypical PD
aphasia
AD-like
PSPs
Final clinical diagnosis in autopsy proven CBD
CBS
bvFTD
PD
atypical PD
aphasia
AD-like
PSPs
Initial clinical diagnosis in autopsy proven CBDCBS is the most frequent clinical diagnosis, followed by FTD, PD and atypical PD.
In a few cases clinical diagnosis of AD was made
CBS is again the most frequent clinical diagnosis, followed by FTD, PD and aphasia.
In a few cases clinical diagnosis of eaither PSPs or AD was made
CBS
bvFTDPD
AD
Clinical features associated with autopsy proven CBD
Age at onset >50 years, 63.7±7.0 (range 50-77.2)
Disease duration 6.6±2.4 (range 2.0-12.5)
Family history. most patient did not have positive family
history.
Comparison of phenotypes. No conclusive clinical features.
Proposed clinical syndromes associated with pathology of corticobasal degeneration
CBS Fronto-behav-spatial syndr
avPPAPSPs
Probable CBSAsymmetric presentation of 2 of:a) limb rigidity or akinesiab) limb dystoniac) limb myoclonusPlus 2 of:d) orobuccal or limb apraxiae) cortical sensory deficitf) alien limb phenomena (more than simple
lievitation)
Diagnostic criteria for CBD
Exclusion criteria for probable sporadic and possible CBD
1) Evidence of Lewy body disease: classic 4-Hz Parkinson disease resting tremor, excellentand sustained levodopa response, or hallucinations.
2) Evidence of multiple system atrophy: dysautonomia or prominent cerebellar signs.3) Evidence of amyotrophic lateral sclerosis: presence of both upper and lower motor
neuron signs.4) Semantic- or logopenic-variant primary progressive aphasia. 5) Structural lesion suggestive of focal cause. 6) Granulin mutation or reduced plasma progranulin levels; TDP-43 mutations; FUS
mutations. 7) Evidence of Alzheimer disease (this will exclude some cases of CBD with coexisting
amyloid. Data from one brain bank suggest that excluding cases with evidence of amyloidmay result in missing approximately 14% of CBD cases [D. Dickson, personal communication, 2012]): laboratory findings strongly suggestive of AD such as low CSF Ab42 to tau ratio or positive 11C–Pittsburgh compound B PET; or genetic mutation suggestingAD (e.g., presenilin, amyloid precursor protein).
Possible CBD emphasizes clinical presentations consistent with CBD but ones that may also overlap with other t-based pathologies.
Comment
-Diagnosis of CBD is still challenging, and CBD may manifest without clear motor manifestations.
-We are able to identify cases with no-CBD path but we are not able to properly diagnose which ones are CBD cases.
- We have explored the “sensitivity” of symptom pattern in CBD (percentage of associated symptoms in true CBD cases), but we do not know the “specificity”.
- Need to further accomplish clinical phenotypes with molecular and neuroimaging markers of CBD.
Nosology• Pick’s disease (PiD) first described by Arnold Pick (1892) and generally
refers to a clinical diagnosis of FTD
with subsequent autopsy confirmation of the
presence of Pick bodies
• Frontal lobe degeneration of the non-Alzheimer type (FLD) proposed by Brun (1987) and Gustafson (1987)
• Frontotemporal Dementia (FTD) diagnostic characterization initially proposed by the Lund and Manchester Groups (Brun, 1994)
• Pick complex (PC) is a term that has been suggested can encompass all the related entities both clinically and pathologically (Kertesz, 1994)
Clinical features of Frontotemporal Lobar Degeneration
Behavioural variant FTD
Semantic Dementiacomprehension disorder (impaired understanding of
word meaning and/or object identity), difficulty in
naming, and asking for the name of nouns and objects.
Progressive Non-Fluent Aphasiaisolated disorder of expressive language when other
aspects of cognition and daily living functions were
relatively well preserved.
character change and disorder of social
conduct. Apathetic variant vs.
Dishinibited variant.
bvFTD
SD
PNFA
… The clinical, pathological and genetic
heterogeneity of FTLD accounts for its present
nosological controversy, and opens the question of
whether this generic label represents a unique
syndrome best viewed as complex, or if it includes
different and distinct entities…
Andrew Kertesz
Goedert et al, 2012
Frontotemporal lobar degeneration (FTLD) molecular classification
Clinical and pathological heterogeneity in FTLD
Seelaar et al. 2010
FTLD-FUSFTLD-tau
Pick's3R-tau
CBD4R-tau
PSP4R-tau
Frontotemporal Lobar Degeneration (FTLD)
FTDP-17(MAPT)
Tau NOSMSTD/AGD
Type A(GNR)
Type B(c9orf72, TARDBP)
Type CType D(VCP)
aFTLD-U BIBD
NIFID (FUS)
Behavioural variant(bvFTD)
Semantic variant (svPPA)
Agrammatic variant (avPPA)
FTD-MND
PSPCBS
FTLD-TDP FTLD-UPS
p62 (CHMP2B)
Clinical syndrome
NeuropathologyModified from Seeley W, 2011
Clinicopathologic differences among patients with behavioral variant frontotemporal dementia
by Mario F. Mendez, Aditi Joshi, Kanida Tassniyom, Edmond Teng, and Jill S. Shapira
NeurologyVolume 80(6):561-568
February 5, 2013
© 2013 American Academy of Neurology
Behavioral variant frontotemporal dementia–frontotemporal lobar degeneration vs behavioral variant frontotemporal dementia–Alzheimer disease neuropathologic groups: First symptomsAD = Alzheimer
disease; bvFTD = behavioral variant frontotemporal dementia; FTLD = frontotemporal lobar degeneration. *Significant differences between the groups.
Mendez M et al. Neurology 2013;80:561-568© 2013 American Academy of Neurology
Figure 2 Frontotemporal lobar degeneration vs Alzheimer disease neuropathologic groups: Neuropsychiatric Inventory QuestionnaireAD = Alzheimer disease; bvFTD = behavioral variant frontotemporal dementia; FTLD = frontotemporal lobar degeneration. *Significant differences
between the groups.
Mendez M et al. Neurology 2013;80:561-568© 2013 American Academy of Neurology
PGRN vs. TARDBP vs. MAPT monogenic FTLD
PGRN TARDBP MAPT
Gender F:M F:M F:M
Onset, years 55-65 >65 45-55
Phenotype Lang/Behav Behav/MND Behaviour
Progression +++ + ++
Mutacism +++ - +
Parkinsonism ++ - +
Neuroimaging Asymmetric Asymmetric (?) Symmetric
TDP43 TAU
Characterization of frontotemporal dementiaand/or amyotrophic lateral sclerosis associatedwith the GGGGCC repeat expansion in C9ORF72
Bradley F. Boeve,1 Kevin B. Boylan,2 Neill R. Graff-Radford,2 Mariely DeJesus-Hernandez,3David S. Knopman,1 Otto Pedraza,4 Prashanthi Vemuri,5 David Jones,5 Val Lowe,5
Melissa E. Murray,6 Dennis W. Dickson,6 Keith A. Josephs,1 Beth K. Rush,4 Mary M. Machulda,7Julie A. Fields,7 Tanis J. Ferman,4 Matthew Baker,3 Nicola J. Rutherford,3 Jennifer Adamson,3
Zbigniew K. Wszolek,2 Anahita Adeli,1 Rodolfo Savica,1 Brendon Boot,1 Karen M. Kuntz,1Ralitza Gavrilova,1 Andrew Reeves,1 Jennifer Whitwell,5 Kejal Kantarci,5 Clifford R. Jack, Jr,5
Joseph E. Parisi,8 John A. Lucas,4 Ronald C. Petersen1 and Rosa Rademakers3
Summary of clinical phenotypes and demographic data among affected individuals in 43 kindreds with probands
harbouring the non-coding GGGGCC hexanucleotide repeat expansion in the gene C9ORF72
Salient features of c9FTD/ALS due to the GGGGCC hexapeptide repeat expansion in C9ORF72
Key features of c9FTD/ALS compared with FTLD due to mutations
in the genes encoding MAPT and PGRN
Why Bother?
• importance of diagnosis
– ensure diagnosis is correct
– which symptoms are part of the disease, which aren’t
– plan appropriately for future
– potential genetic implications
• multidisciplinary team
– appropriate monitoring
– provide support and education for patient and caregivers
• receive treatment as soon as it becomes available
“This is dementia. There is no cure.”
Acknowledgement
Clinica Neurologica, Univ. di Brescia
Barbara Borroni
Chiara Agosti
Antonella Alberici
Enrico Premi
Carlo Cerini
Maura Cosseddu
III Laboratorio Analisi, Univ. di Brescia
Silvana Archetti
Maria Ferrari
Luigi Caimi
Clinica Neurologica, Mantova
Alessia Lanari
Istituto di Genetica, Brescia
Massimo Gennarelli
Cristian Bonvicini
Scienze Farmacologiche, Univ. di Milano
Monica Di Luca
Fabrizio Gardoni
Elena Marcello
Matteo Malinverno
Genetic Institute, Trieste
Emanuele Buratti
U.O. Geriatria, Cremona
Giuseppe Bellelli
Dipartimento di Statistica, Univ. Di Pavia
Mario Grassi
Queen Square, UCL, London
Rohan De Silva