Lo spettro delle Demenze con Parkinsonismo · ophthalmoplegia, dementia, dysarthria and...

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!

& % !






&Watts&1994&

%Major%



&Lang&1994*&

%Inclusion%



&Kumar&1998&

%Inclusion%


&&&&&


& % !






&Watts&1994&

%Major%



&Lang&1994*&

%Inclusion%



&Kumar&1998&

%Inclusion%


&&&&&


& % !






&Watts&1994&

%Major%



&Lang&1994*&

%Inclusion%



&Kumar&1998&

%Inclusion%


&&&&&


& % !

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.

… 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

Lo spettro delle Demenze con Parkinsonismo · ophthalmoplegia, dementia, dysarthria and...

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