le demenze fronto-temporali - organizzazione eventi · le demenze fronto-temporali recenti criteri...

Le demenze fronto-temporali recenti criteri clinici, alterazioni geniche,

imaging funzionale

Pietro Tiraboschi

Neurologia V / Neuropatologia

Istituto Neurologico “Carlo Besta”

Pesaro, 25 settembre 2014

Frontotemporal dementia (FTD) • FTD refers to a group of conditions that collectively are a major cause of

young onset dementia

• FTD is less common than AD, with estimates of population ranging from 4 to 15 per 100000 before age 65. Altogether they represent < 10% of all dementias in the elderly, but up to 50% of cases below age 60

• Onset is typically in the 6th decade of life, but it may begin as early as the

3rd or as late as the 9th decade, where is certainly underestimated

• FTD produces selective brain atrophy of the frontal and temporal lobes

• Up to 25% of cases arise from dominant mutations in 1 of 3 major causative genes

• FTD is commonly associated with other neurological impairment, in particular parkinsonism or motor neuron disease

Frontotemporal dementia (FTD)

• Behavioral or personality change first developing in later life may signal FTD onset rather than a primary psychiatric disorder, even if there are psychotic features, and particularly if heralded by changes in eating behavior or social faux pas

• Problems articulating longer words, emergence of a stutter, grammatical slips, searching for words, or loss of comprehension of words (asking the meaning of words) may herald the onset of progressive aphasia

• Brain imaging is mandatory in all suspected cases of FTD to rule out mimics such as brain tumors and to confirm the diagnosis

• Neuropathologically, FTD is also very heterogeneous, but predominant subtypes are two, the former characterized by tau-positive inclusions, the latter characterized by tau-negative but TDP-43-positive inclusions.

Frontotemporal dementia • A syndrome with various clinical presentations (essentially behavioral

and/or language alterations) and various associated underlying

pathologies, including the relatively rare pathology of Pick’s disease

• Epidemiology

– In specialty dementia clinics, the 3rd most common degenerative

dementia (after AD and DLB), but almost as frequent as AD below age 65.

Increasing age is not a risk factor!

– Far less common in general population

• Prevalence of 1/10.000-20.000 in a province of the Netherlands

– Death approximately 6 years after diagnosis (Hodges et al, 2003)

• Subtype variability: worse prognosis with early motor involvement

(parkinsonism, and especially MND)

DEMOGRAPHICS

• 3rd most common neurodegenerative dementia

– 15% of all dementias

– most common early onset dementia (50s-60s)

– estimated to affect 250,000 Americans

– typically more rapid decline than AD

– 20% inherited, ~80% sporadic

Terminology of frontotemporal dementia

• Pick’s disease

• Frontal lobe degeneration of the non-Alzheimer type

• Frontotemporal lobar degeneration

• Dementia lacking distinctive histopathology

• Frontotemporal dementia

• Semantic dementia

• Primary progressive aphasia

• Frontotemporal dementia and parkinsonism linked to chromosome 17

• Pick complex

the most used when referring to the pathologic entity

the most used when referring to the clinical entity emphasizes the overlap of clinical and pathologic features

Pick’s Disease (PiD) – Frontotemporal dementia (FTD)

• Definition of PiD

– Confusion from nosological dichotomy risen from the description of PiD as either a clinical (1) or a pathological entity (2)

1. The clinical syndrome of frontotemporal dementia (FTD)

2. The pathological entity characterized by frontotemporal atrophy and, microscopically, by:

a. Silver-stained globular inclusions (Pick bodies): large, round, silver-positive inclusions located in the neuronal cytoplasma, hardly visible on H&E

b. Swollen neurons (Pick cells): also called ballooned neurons owing to the swollen, homogeneously pink appearance of the cytoplasm on H&E

c. Superficial cortical spongiosis, neuronal loss, and gliosis

FTD: Brain Anatomy

bvFTD: Structural Imaging Findings

MRI: atrophy of frontal and temporal lobes

normal bvFTD

Neuropathology of FTD

• Gross pathologic features

– Focal lobar atrophy (initially often asymmetrical) • Combined frontotemporal atrophy (most common)

• Predominant frontal, temporal, and finally parietal atrophy in this order

• Microscopic pathologic features

– Requisite for diagnosis • Neuronal loss and gliosis

– Typically associated findings (not necessary for diagnosis) • Superficial linear spongiosis

• Pick bodies (tau + intraneuronal inclusions, barely visible on H&E stains)

• Pick cells (swollen, ballooned neurons, homogeneously pink on H&E stains)

• Ubiquitin +, tau − intraneuronal inclusions (TDP43 +)

• Coiled bodies (tau + oligodendroglial inclusions)

Examples of typical frontotemporal dementia pathology A. Gross brain demonstrating frontal and temporal atrophy B. Spongiform degeneration in superficial cortical layers C. Intracytoplasmic ubiquitin inclusions typical of FTD with MND D. Pick bodies labeled with tau immunostain E. Glial tau pathology in corticobasal degeneration

Pick bodies

Pick’s disease

Fronto-temporal dementia

Severe neuronal loss and gliosis (“knife-edge” atrophy)

Neocortex, dentate gyrus

Pick bodies

Strongly argyrophilic (silver stains - Bielschowsky, Bodian, not Gallyas)

++tau, +ubiquitin

EM-straight filaments

Pick cells (balloon cells) Pick cell

Tau

MND-inclusion bodies

Motor Neuron Disease (MND) inclusion body

ALS, ALS with dementia or aphasia

FTD (MND-inclusion body dementia)

Primary progressive aphasia

Superficial neocortex, dentate gyrus

Lewy bodies

Parkinson’s Disease

DLB, LBVAD, MSA, age

MND-inclusion bodies

Negative silver stain

Ubiquitin positive

Negative for tau and alpha-synuclein

Composed of TDP-43

ubiquitin

ubiquitin

Pick bodies vs. mnd-inclusion bodies

I

Pick

MND-inclusion

Tau

ubiquitin Bielschowsky

Pick’s Disease (PiD)

• Historical background

– 1892 – 1906: Pick described the clinical picture related to focal frontal-temporal lobe atrophy : 1 patient with PPA + behavioral disturbances. Exclusively gross examination without any microscopic data.

– 1922: Gans suggested the eponymic term and considered the predilection for phylogenetically younger frontal and temporal lobes in the etiology.

– 1926: Onari, Spatz and Stertz riexamined a series of cases of Pick and others and highlighted the microscopic picture associated with focal atrophy, initially described by Alzheimer in 1911.

– 1940: Malamud et al. emphasize that clinical PiD with frontotemporal atrophy is not always associated with typical histological pictures.




– 1974: Costantinidis et al. classified PiD as follows:

a) With Pick bodies (PBs) and Pick cells (PCs)

b) With only Pick cells (PCs)

c) With only gliosis

– 1975 – 1994: flourishing of new labels for the clinical syndrome, such as FLD, PPA, FTD as distinct entities, while the term PiD was reserved to restricted histological criteria

• Acknowledgment that, though some patients have PBs and most do not, the clinical syndrome may be the same, regardless of pathologic variant (Brun, 1987; Gustafson, 1987; Neary et al., 1988).




– 1990 - 1992: Neary et al. report an occasional association with MND for the first time. Ubiquitin-positive, τ-negative inclusion bodies in the dentate gyrus and cortex were described as a marker of this syndrome.

– 1994: Consensus Criteria for the diagnosis of frontotemporal dementia (FTD) were formulated by the Lund and Manchester group. But:

• The term “FTD” did not include the frequent subcortical involvement, parietal pathologic features, extrapyramidal and pyramidal symptoms.

• The term “FTD” did not distinguish between the behavioral presentation of FLD and the aphasic presentation of PPA.

• It did reflect, however, the combination of symptoms arising from frontal and anterior temporal atrophy originally described by Pick.

1998: Kertesz proposed the term Pick Complex to comprise this family of related disorders




– 1998: discovery of tau mutations on chromosome 17 as a cause for familial FTD (Hutton et al., Nature). Subsequently, > 50 mutations have been discovered, occurring in the tau gene exon or intron

– 2000s: more new discoveries than in past 100 years

– 2006: Neumann et al. demonstrated that ubiquitin positive inclusions in most tau negative cases of FTD (50% of bvFTD, 30% od nfPPA, 90% of fPPA/SD), nearly all cases of bvFTD with MND and ALS stained for a DNA and RNA binding protein called TDP-43

– 2006: discovery that mutations in progranulin gene cause tau −, TDP43+ FTD linked to chromosome 17 (Baker et al., Nature). Subsequent discover of > 65 mutations, causing a systemic progranuline deficiency, which has both growth factor activity and a role in the inflammatory response.




– 2011: discovery that a mutation in C9ORF72 (leading to an expanded [>400] hexanucleotide repeat) is a major cause of familial forms of FTD (bv > PPA), ALS, or a combination of the two associated with TDP43 pathology (Renton et al, Neuron)

– 2011: suggestions that the hexanucleotide repeat is likely to lead to the aggregation of large concentrations of hexanucleotide mRNA within the nucleus that, in turn, poisons nuclear function

– 2011: new international consensus diagnostic criteria.


Clinical Syndromes Frontal lobe dementia

• Behavioral and personality changes (subjects are more likely to be presented

to a psychiatrist than to a neurologist)

– Apathy and disinterest may be mistaken for depression • Mainly involving dorsal lateral frontal convexity

– Disinhibition may suggest manic psychosis or a personality disorder • Mainly involving orbitofrontal regions • Nondominant anterior temporal lobe atrophy

– Kluver-Bucy syndrome (hyperorality, hypersexuality, compulsive touching) • Produced in monkeys by bilateral ablation of temporal neocortex and amygdala

– Stereotypes (e.g., clapping thighs, swaying of body, pursing of lips, rubbing legs, arms, or face) • more extrapyramidal involvement and striatal pathologic features

These distinctions become blurred as the disease progresses

Clinical Syndromes Primary Progressive Aphasia (PPA)

• Progressive language impairment without dementia for ≤ 2 years

– Nonfluent variety

– Aphemic variety

– Semantic aphasia

• Often, behavioral disturbances appear, suggesting frontal deficit

• Sometimes, parkinsonism and/or MND supervene

• Coexistence in cases with progressive apraxia and frontal dementia (overlap between PPA and CBD and between PPA and FLD)

Primary progressive aphasias

Word-finding difficulties

(anomia)

Grammatical structure (syntax) impairment

Non-fluent aphasia

Comprehension (semantics) impairment

Fluent aphasia

Verbal + visual processing impairment

Semantic dementia


• Key anatomical areas – Wernicke (left temporoparietal junction)

• Its dysfunction interferes with word meaning

– Broca (inferior gyrus of left frontal lobe) • Its dysfunction interfers with articulation, word order, grammar

• Since damage to any part of language network interferes with word finding, anomia is universal in any PPA subtype – Anomia word-comprehension deficits

– Anomia agrammatism – word production


• Anomic stage of PPA

– Grammar, syntax, comprehension, repetition are largerly spared – Pts who cannot name the object they are shown are still able to indicate it when

the name is provided by the examiner («one-way» deficit lexical retrieval impaired, word meaning and comprehension spared)

– May be category specific (some pts have greater impairment in naming inanimate objects and others in naming living things)

– In some pts, fluency becomes undermined by word-finding pauses, labored speech and, rarely, dysatrhria. In others, fluency and speech melody are spared. Anomia in PPA can thus emerge against a background of either fluent or nonfluent speech


• Beyond the anomic stage

– PPA with agrammatism

• Speech becomes short (telegraphic phrases) and sometimes with syntax abnormalities (incorrect word order and tendency to misuse tenses, pronouns, possessives)

• Comprehension is only slightly impaired (passive clauses)

• The patient may not have any difficulty in reading even complex words (such as alligator), but may be unable to read «to» or «she»

• The stage of PPA with aggrammatism eventually leads to extreme impairments of fluency, to the point where utterances become limited to one or two repetitive syllabes or grunts.

Primary progressive aphasias • Beyond the anomic stage

– PPA with comprehension (verbal semantics) deficits • Fluency is spared, but frequent word-finding pauses can also emerge

• Repetition may be spared, resembling transcortical sensory aphasia, or impaired, resembling Wernicke aphasia

• Comprehension is impaired at different levels of severity: 1. Occasional lexical-sematic lacunae: in the course of an otherwise uneventful

conversation, the patient may suddenly assume a perplexed expression and ask «School? What does school mean?»

2. Patients can neither name an object nor point to it when the examiner provides the name («two-way» deficit), but are still able to describe its function once he/she sees it

3. Even the most common words fail to be decoded and conversation comprehension becomes impossible, though visual recognition of objects and faces may remain spared (object meaning preserved).

4. Speech becomes more and more «empty», paraphasic, circumlocutious

Primary progressive aphasias • Beyond the PPA stage

– PPA with motor disturbances and dysarthria (MND, CBS >> PSP)

• MND is more often associated to bvFTD than PPA

– PPA and frontal dementia

• At least initially, bv FTD is only characterized by decreased language output, but do not display comprehension or grammar deficits

– Autosomal dominant PPA

• Can be seen in pts with dementia linked to chromosome 17, but there is early emergence of behavioral abnormalities (hereditary disphasic dishinibition dementia»)

– Semantic dementia and visual recognition deficits


• Beyond the PPA stage

– Semantic dementia and visual recognition deficits

«Three-way» deficit: the patient is unable to name an object, to point to it when the examiner provides its name and even to explain its function when he/she sees it (deficit of language and visual semantics: PPA + visual agnosia)

Algorithm for PPA differentiation

International consensus criteria for bv FTD Rascovsky et al., Brain 2011

I. Neurodegenerative Disease

The following symptom must be present to meet criteria for bvFTD

A. Shows progressive deterioration of behavior and/or cognition by observation of history (as provided by a knowledgeable informant)


II. Possible bv FTD Three of the following behavioral/cognitive symptoms (A-F) must be present. They should be persistent or recurrent rather than single or rare events.

A. Early (within 3 yrs of onset) behavioral dishinibition ≥ 1 among socially inappropriate behavior, loss of manner/decorum, and impulsive, rash and careless action

B. Early apathy (loss of motivation or interest) or inertia (requires prompts to initiate routine activities)

≥ 1 between apathy and inertia

C. Early loss of sympathy and empathy (indifference, decrease in social engagement) ≥ 1 between decreased response to other people’s needs and feelings and decreased social interest or personal warmth

D. Early perseverative, stereotyped or compulsive/ritualistic behavior ≥ 1 among simple or repetitive movements, compulsive/ritualistic behavior, and stereotipity of speech

E. Hyperorality and dietary changes

≥ 1 among altered food preferences, binge eating, and oral exploration of inedible objects

F. Compatible neuropsychological profile all 3 among dysexecutive deficits, relative sparing of episodic memory, relative sparing of visuospatial skills


III. Probable bv FTD

All of the following behavioral/cognitive symptoms (A-C) must be present:

A. Meets criteria for possible FTD

B. Shows significant functional decline (by caregiver report or as evidenced by CDR)

C. Consistent Imaging ≥ 1 between frontal and/or anterior temporal atrophy on MRI or CT and frontal and/or anterior temporal hypoperfusion/hypometabolism on SPECT/PET

IV. Definite bvFTD

All of the following behavioral/cognitive symptoms (A-C) must be present:

A. Meets criteria for probable bvFTD (A+either B or C)

B. Histopathologic evidence on biopsy or autopsy

C. Presence of a known pathogenic mutation


• Differences of 1998 (Neary et al.) from these criteria

– Require the presence of all 5 core diagnostic features

1. A. insidious onset and gradual progression , B. early decline in personal conduct, C.

early decline in social interpersonal conduct, D. emotional blunting, E. loss of insight

2. large number of exclusion features (at least 11): for example, exclusion based on impaired memory performance (HS) and spatial disorientation may result in erroneous rejection of diagnosis in patients in mid-stage of the illness

Both 1 and 2 substantially decrease sensitivity

3. Furthermore, the 3 most common 1998 core features (A, B, and E), being very common in other dementing disorders, may lead to insufficient specificity

Genetic of FTD

Gene Abbreviation Location Codes for protein

Microtubule-associated protein tau

MAPT 17q21.1 Microtubule-associated protein tau

Progranulin PGRN 17q21.32 Progranuline, granuline

Chromatine-modifying protein 2B

CHMP2B 3p11.2 Charged multivescicular body protein 2b

Fused in sarcoma FUS 16p11.2 RNA-binding protein FUS

TAR-DNA binding protein TARDBP 1p36.22 TAR-DNA binding protein 43

Valosin-containing protein VCP 9p13.3 Transitional endoplasmic reticulum ATPase

2011: iidentification of the FTD/ALS gene defect on chromosome 9p (a massively expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame (C9OEF72) that result in loss of transcript and formation of nuclear RNA foci

Genetic of FTD

• Clinicians should not routinely recommend genetic testing for FTD patients

– Genetic testing is expensive and often fails to reveal a mutation, and clinical, pathologic, and

family history information can help guide testing decisions

– Up to 40% of patients with FTD have a family history of dementia, but only 10% have a clear autosomic dominant inheritance pattern

– Mutation in MAPT , PRG, C9ORF72 each account for 2-10% of all cases and 10-20% of familiar cases.

– MAPT and C9ORF mutations are very rare in sporadic disease, while about 3% of sporadic FTD is caused by mutations in PRG gene

– Pathology

• Ubiquitine +, tau + inclusions (MAPT)

• Ubiquitine +, tau –, TDP-43 + inclusions (PRG, TARDBP, VCP, C9ORF72)

• Ubiquitine +, tau –, TDP-43 – inclusions (CHMP2B, FUS)

Genetic of FTD • MAPT carrier phenotype

– Presenting symptoms, primary diagnosis, age at onset highly variable even within families.

– Clinical presentation include bvFTD (most frequent), CBS, PSPS, or AD (rare). No SD or ALS.

– Some patients develop language problems and parkinsonism.

– Average age at onset 50 – 55 yrs, but range is broad (25 – 65).

– Since penetrance is almost 100%, it is unusual to find a mutation in cases without family history.

• PRGN carrier phenotype

– Presenting symptoms and primary diagnosis even more variable that in MAPT mutation carriers.

– Diagnoses include bvFTD (more frequent), PNFA, CBS, AD + park, DLB. No SD. ALS very rare.

– Mean age at onset older than in MAPT mutation carriers (60 yrs) and range wider (35 – 85).

– Mean disease duration < than in MAPT carriers (5r vs 12 yrs) but range overlaps (3-10 vs 1-12 yrs).

– Up to 70% have episodic memory dysfunction, 25% have visual hallucinations.

– Parietal lobe involvement as seen on testing (dyscalculia, limb apraxia, dysgraphia, visuospatial impairment) is also seen on MRI or PET, where findings also tend to be more asymmetric than in MAPT or C9ORF72 mutation carriers

Genetic of FTD

• C9ORF72 mutation carrier phenotype

– Presenting symptoms may be motor (MND) or behavioral (bvFTD) and are heterogeneous

even within families.

– Early diagnoses include bvFTD (most frequent), PNFA, MND, PNFA-MND

– Wide variation in age at onset (34 – 74 yrs, mean 54.3)

– Mean disease duration about 5 yrs (range 1 – 16 yrs).

– TDP-43 inclusions but, in the cerebellum, inclusions are ubiquitine + / TDP 43 –

FTD genetic testing algorithm • A sequential approach should be taken based on family history, clinical

presentation and neuroimaging findings

Figure 1 Frontotemporal lobar degeneration genetic testing algorithm with no autopsy available ALS = amyotrophic lateral sclerosis; bvFTD = behavioral variant frontotemporal dementia; CBS = corticobasal syndrome; FTD = frontotemporal dementia; FUS = fused in sarcoma protein; hx = history; MAPT = microtubule-associated protein tau gene; PGRN = progranulin gene; PNFA = progressive nonfluent aphasia; PSP = progressive supranuclear palsy; SemD =

semantic dementia; sx = symptoms.

Goldman J et al. Neurology 2011;76:475-483

An algorithm for genetic testing of FTD

C9ORF72

© 2007 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

FIGURE 1.

Links Between Frontotemporal Lobar Degeneration, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Amyotrophic Lateral Sclerosis. Boeve, Bradley Alzheimer Disease & Associated Disorders. 21(4):S31-S38, October/December 2007. DOI: 10.1097/WAD.0b013e31815bf454

FIGURE 1. (Continued)


FIGURE 2.


FIGURE 2. Associations between the various clinical syndromes and possible underlying neurodegenerative and prion diseases. Thick lines represent common associations; thin lines represent less common associations; and dashed lines represent rare associations. FTLD-MND/TDP-43 indicates frontotemporal lobar degeneration and motor neuron disease with TDP-43-positive inclusions; FTLD-U/TDP-43, frontotemporal lobar degeneration with ubiquitin-positive and TDP-43-positive inclusions; MST, multisystem tauopathy; NIBD, neurofilament inclusion body disease; Pick, Pick disease; PPA-LGA, primary progressive aphasia-logopenic subtype; PPA-PNFA, primary progressive aphasia-progressive nonfluent aphasia subtype; PPA-SD, primary progressive aphasia-semantic dementia subtype.


FIGURE 3.


FIGURE 3. Associations between the various clinical syndromes and the most likely underlying neurodegenerative proteinopathies. Thick lines represent common associations; thin lines represent less common associations; and dashed lines represent rare associations. PPA-LGA indicates primary progressive aphasia-logopenic subtype; PPA-PNFA, primary progressive aphasia-progressive nonfluent aphasia subtype; PPA-SD, primary progressive aphasia-semantic dementia subtype.


FIGURE 4.


FIGURE 4. Associations between the various clinical syndromes and the possible genes in which mutations can cause a neurodegenerative or prion disorder. Realizing that mutations in all of these genes are rare, the thick lines represent common associations; thin lines represent less common associations; and dashed lines represent rare associations. pAD indicates probable Alzheimer disease.

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