Frontotemporal Lobar Degeneration

Florence Pasquier, MD PhD

ECNP-2015

DISCLOSURES
ECNP 2015

Florence Pasquier
Last three years
Nature

Sponsors

Investigator of Clinical studies

phases 2-3

Bayer (Piramal), BMS, GE

Healthcare, Lilly, Noscira,
Pharnext, Pfizer, Roche, Et
bientt : Astra-Zeneca, Biogen,
BioCross, MSD, Probiodrug,
Raman

Occasional member of Scientific

Advisory Boards

Alzprotect, Lilly, Sanofi,

Ethypharm, Nutricia, Novartis

No conflic of interest for this presentation

Fees paid to the University Hospital or ADRINOR

Terminology
Picks disease(s) (1892-1906) (vs Alzheimers disease (1864-1915)
Frontotemporal dementia FTD (Brun et al, 1994)
Frontotemporal lobar degeneration (Neary et al 1998)
Frontotemporal dementia Frontal or Behavioural variant
Non-fluent Primary Progressive Aphasia
Non-Fluent /agrammatic (less often logopenic)

Semantic dementia temporal variant

Language variant

Fluent aphasia and Associative Agnosia

= Generic term for progressive circumscribed degeneration of the

frontal and temporal lobes

Clinical/pathological overlap
The Pick Complex A.Kertesz

Clinical syndromes linked to the location of the degenerative process

CBS

Motoneuron
disease

Progressive
aphasias

FTD
PPA
SemD

Atypical
Corticobasal
parkinsonian
syndrome
Frontotemporal
syndrome
dementia

Frontotemporal lobar degenerations

The different clinical syndromes of FTLD
May occur in the same family
May be combined in a same patient with
progression
Are underpinned by different histological
subtypes : tau, ubiquitin, TDP-43 inclusions,
argyrophilic grains, neurofilaments

Neuropathological/genetic heterogeneity
FTLD Neuropathology

~40%

~ 60%

Tau-positive
inclusions

No inclusion

Ubiquitin-positive
inclusions

Pick bodies
3R Tauopathy

Neurons/Glia
4R Tauopathy

Tangles
3R+4R
Tauopathy

PiD
FTDP-17

PSP
CBD
AGD
FTDP-17

NFTd
FTDP-17

MAPT (Tau)
gene

<1%

90%
TDP-43

10%
FUS
+

FTLD-TDP

FTLD-FUS
aFTLD-U
NIFID
BIBD

Type A
Type B
Type C
Type D

PGRN
(Progranuline)
C9ORF75 gene
gene

FTLDUps

FTLD
ni

CHMP2B gene
FUS gene

VCP gene

Frontotemporal lobar degeneration

No clear correlation between clinical and
neuroanatomical phenotype but frequent
association between
PSP, CBD (bv-FTD, PPA) and Tau
Semantic dementia and FTLD-U-type 1 or 2
Non-Fluent Progressive aphasia, CBD and
FTLD-U-type C
Bv-FTD and FTD with MND and FTLD-Utype B or 3C

Characteristic features of FTLD-FUS

Very early onset (<45 y)

No family history
Fv-FTD with prominent
obsessionality, repetitive
behaviour, rituals, social
withdrawal, lack of
engagement, hyperorality,
severe caudate atrophy
(MND-+/- family-mutation)
FUS

FTLD-TDP

Josephs et al Eur J Neurol 2010

Neuroanathomical features associated with

pathological diagnosis in FTLD
(Rohrer et al Brain 2011)

TL : temporal lobe atrophy; extra-TL: extratemporal atrophy

e.g. frontal lobe; Pick associated with temporal or frontal
asymmetry
TDP-A strongly asymmetrical atrophy especially in association
with PGRN mutation

Genetics and FTLD

40% of FTLD have a positive family history of dementia or other neurological
condition
Of them 50% autosomal dominant inheritance

Chromosome 17
MAPT (tau) (5-11%)
PGRN (progranuline) > 50 mutations. (5-11%)
Various clinical features including Alzheimer like syndrome. Very late onset
possible, incomplete penetrance.
Low plasma progranuline level

Chromosome 3
CHMP-B2

Chromosome 9
VCP inclusion body myopathy + Paget disease of bone = IBMPFT
C9ORF72 (frequent ALS+FTD familial (25-40%) or sporadic (6-33%), Parki,
bipolar dis., psychosis, CBD + extension parietal thal, cereb
[Chromosome 14 : PSN1

FTLD = presenile diseases

Age at onset: 51-58 years (extremes: 21- 89)
20-40% >65 years

(Harvey 2003, Gislason 2003, Ibach 2003)

No gender predominance

Alzheimer

FDT
...

50

60 70 80

90

years

Frontotemporal lobar degeneration

Functional decline difficult to predict
Survival 5-10 years (up to 20 years)
Shorter survival in patients with behavioural variant
(vs semantic dementia)? (Mioshi 2010)
Long-lasting bv-FTD, with normal imaging (Kipps,
2010)
Phenocopies ?
Links with psychiatric diseases (bipolar disorders,
schizophrenia ?)
C9ORF72 mutation (1.7-22 years)

Behavioural variant of
FTLD
Frontotemporal dementia
Progressive deterioration of personality,
social behaviour and cognition

Behavioural-variant FTD
So characteristic that post-mortem diagnosis is
feasible (Barber, 1995)
Reasons for referring:
Atypical psychiatric disease or dementia
Dismissal for misconduct (occupational physician)
Medico-legal problems (Mendez, 2000)

Presentation :

Frontal lobe syndrome

No affect/emotion when the caregiver reports the
symptoms
physical neglect or eccentricity

Behavioural-variant FTD
Behavioural changes = dominant features initially
and throughout the disease course, precede or are
associated with cognitive decline
Usually memory impairment of secondary importance
compared to behavioural disorders ( AD)

1st Symptoms:

Loss of interest depression? (no sadness or feeling of

worthlessness or guilt)
Disinhibition, anxiety, language disorders (including coarse
words), changes in eating and drinking habits
Behavioural dyscontrol (restlessness, rituals)

Behavioural-variant FTD
Do not fit any psychiatric disease criteria (DSM)
Frontotemporal Behavioural scale FBS (Lebert 1998); 4
classes of changes assessed sens & spe if MMSE > 18
Score > 3 :sensitivity = 1; specificity = .93
Distinguishes FTD from AD and VaD :
1 point given for each class if at least 1 symptom present

Self monitoring dyscontrol (hyperorality, change in food taste,

alcohol abuse, verbal disinhibition, lack of social grace, lack of tact,
irritability, restlessness)

Self neglect
Self centred Behaviour (apathy, perseverative stereotyped
behaviour, inflexibility, hypochondriasis, social neglect, selfishness,
lack of empathy)

Affective disorders (elation, apparent sadness, flat affect,

emotionalism)

Other features of fv-FTD

Altered response to sensory stimuli, including
reduced pain response (specific but not sensitive)

Hypersensitivity to neutral stimuli (NearySnowden 2005)

Psychotic symptoms not frequent. Early persistent

hallucinations and delusions, FTLD-U (PGRN, FUS),
C9ORF72. Rarely misdiagnosed for schizophrenia in
young patients

FTD Cognitive Symptoms

Global Scales
Within the normal range at the beginning
MMSE, WAIS
No systematic dissociation between verbal and perform. IQ

Mattis DRS (Moca?) more reliable

Dissociation between
Severe alteration in personality and behaviour,
and breakdown in social competence
Relative preservation of cognitive skills

FTD Frontal variant

Memory
Memory impairment of secondary importance
but common
Suggest absent-mindedness and faulty
attention rather than primary amnesia
They do not pay attention, they remember what
they want to remember

Not evidently amnestic.

Able to give autobiographical information
Do not become lost, do not forget personally
relevant event such as mealtimes

Free and Cued selective reminding test

in FTD and AD
16
14

FTD

AD

12

n=15
MMS=24

n=30
MMS=23

10
8
Tmoins

n=12

Cued recall
Free recall

2
1

3 Delayed
Recall

3 Delayed

3 Diffr

Pasquier et al, 2001

Fv-FTD cognitive impairment

Anterograde memory may be severely impaired
(Graham 2005). Associated with hippocampal
atrophy
On imaging (Lavenu 1998), and on neuropathology (Caine 2001)

No temporally graded pattern in alteration of

autobiographical and remote memory (Hodges
1994; Thomas Antrion 2000)

Artistic creativity ? (Miller 1998, de Souza 2010)

FTD Frontal variant

Memory
Sometimes severe anterograde amnesia
(Graham 2005)
Related to impairment of hippocampal areas
Medial temporal lobe atrophy (Lavenu et al, 1998)
Cell loss in the hippocampi (Caine et al, 2001)

Social cognition in fv-FTD

Impairment of Emotion
recognition
On Faces (Lavenu 1999), of voices
(Keane 2002)
Especially impaired for negative
emotions (fear, sadness, anger,
disgust) (Piguet 2011)

Social cognition in fv-FTD

Impaired social cognition :
notably ability to attribute mental
states to ones self and to others =
Theory of Mind : ability to infer
other's mental states in terms of
beliefs, intentions, and goals
(Gregory 2002, Adenzato, 2010)
Faux pas test,
False belief test (Sally and Ann test,
Wimmer et Perner, 1983)
Sarcasms, moral judgment

Behavioural impairment
associated with
social cognition impairment
Sociopathic behaviour
E.g: pedophilia, stealing, sexual harassment,
automobile violations, violence
Challenge to the criminal justice system to
consider alterations in moral cognition before
ascribing criminal responsibility (Mendez 2010)
Alteration of
moral feelings (ventromedial prefrontal cortex)
emotional empathy (right anterior temporal cortex)
Desinhibited and compulsive behaviours
criminal violations

Behavioural impairement associated with

social cognition impairment
Sociopathic behaviour
May be associated with
Good knowledge of moral rules and conventions,
Can distinguish between good and bad conduct
Awareness of their behaviour and of potential
consequences,
Good memory test and global cognitive tests performance
but impaired moral rationality (Mendez 2010)

FTD patients with sociopathy would not pass

most legal criteria for judgments of not guilty
by reason of insanity.

Behavioural and Functional scales

in FTD

Neuropsychiatric Inventory (Cummings, 1994)

Frontal behavioural Inventory (Kertesz, 1997)
FBS (Lebert 1998)
BEHAVE-AD (Mendez, 1998)
Cambridge Behavioural Inventory (Bozeat, 2000)

FRS Frontotemporal dementia Rating Scale (Mioshi,

2010)

SEA (Social cognition an Emotional Assessment) et la

mini-SEA (30 mn) (Bertoux 2012)

bvFTD Criteria Consortium FTDC

(Raskovsky et al, Brain 2011)

Possible fv-FTD requires 3 of 6 clinically

discriminating features:
1. Disinhibition ventral orbito-frontal cortex and caudate
2. Apathy/inertia prefrontal dorso-medial/ -lateral cortices
3. Loss of sympathy/empathy
4. Perseverative/compulsive behaviours
5. Hyperoralit
6. Dysexecutive neuropsychological profile

bvFTD Criteria Consortium FTDC

(Raskovsky et al, Brain 2011)

Probable fv-FTD requires in addition

functional disability and characteristic
neuroimaging (CSF so far inconclusive)

Definite FTLD requires histopathological

evidence of FTLD or a pathogenic mutation.

Sensitivity and specificity of FTDC criteria for bvFTD

(Harris, Neurology 2013)

Autopsy series of 156 patients,

predominantly early onset dementia.
Possible bvFTD : sensitivity = 95% and
specificity = 82%.
Probable bvFTD criteria :sensitivity =
85% and specificity = 95%.
False positives = predominantly
patients with presenile Alzheimer
disease

FTD: Biomarkers

CSF :

Tau (< AD)

Ab42 (<AD)

Bian, Neurology 2008

30% of of clinically-defined FTLD cohorts may have underlying

AD neuropathologic change (Kertesz 2005, Knopman 2005,
Forman 2006, Knibb 2006) or association (Toledo 2012)

Usefull to exclude AD pathology

Other CSF Biomarkers

(Irwin, Front In Aging Neurosci 2013)

Differential diagnosis of bv-FTD

Alzheimers disease
Vascular dementia
Dementia with Lewy bodies
Psychiatric diseases

Depression (no sadness, guilt, or feeling of

worthlessness)
Pseudo mania (no sleep disorders, or hypersomnia)
OCD (no anxiety no relief)
Schizophrenia

Atypical features of FTLD

Amnestic dementia, of the Alzheimer type
(especially when onset is presenescent) (Hodges
2004)

Primary progressive prosopagnosia (Joubert,

2003)

Primary progressive phonagnosia (impaired

voice recognition) (Hailstone 2010)
Right temporal lobe atrophy: hyper-religiosity,
visual hallucinations, and cross-modal sensory
experiences (Chan 2009)

Language variants of
FTLD
Progressive deterioration of
language

Primary Progressive Aphasia

Predominant Left atrophy
Tasks to assess speech and language:
Speech production (including grammar and motor
speech)
Confrontation naming
Repetition
Sentence comprehension
Single-word comprehension
Object/people knowledge
Reading and spelling

Cortical atrophy
corresponding to primary progressive aphasia syndromes
(Grossman J Mol Neurosci 2011)

Frontal: Non fluent/agrammatic variant PPA

Anterior temporal: semantic variant
Posterior temporal parietal: logopenic variant

Nonfluent progressive aphasia

(Gorno-Tempini Neurology 2011, Deramecourt Neurology 2010)

Progressive anarthria
Necessary criteria

Tau pathologie
PSP, CBD Pick

Motor speech deficit resulting in slow and effortful speech with sound
distorsion
Dysprosodia, Buccofacial apraxia
Optional at early stage: Swallowing difficulties, Suprabulbar paresis

Agrammatic progressive aphasia

Necessary criteria

FTLD-TDP
Decreased rate of language output
(PGRN?)
Syntactic simplification (telegraphic style)
Frequent word-finding, pauses, circumlocution
Normal single word repetition, phonemic distorsion
Optional at early stage: impaired comprehension of complex syntactic
structures

Logopenic progressive aphasia

(Gorno-Tempini Neurology 2011, Deramecourt Neurology 2010)

Necessary criteria

Alzheimers disease > DLFT

Decreased or fluctuating rate of language output

Overall language grammatically simple but normal
Frequent word-finding pauses, circumlocutions
Comprehension of single words is normal, but impaired
for complex syntactic structures
Impaired sentence repetition
Optional at early stage: possible phonologic substitution
errors

Progressive Jargon Aphasia

(Gorno-Tempini Neurology 2011, Deramecourt Neurology 2010)

Necessary criteria

Alzheimers disease

Fluent language or logorrhea

Impaired verbal comprehension
Neologisms
Optional at early stage: Anosognosia

> DLFT

Semantic dementia
(Gorno-Tempini Neurology 2011, Deramecourt Neurology 2010)

Typical semantic dementia

Necessary criteria
Fluent speech, Grammatically normal
Impaired confrontation naming
Loss of word meaning

Type A
> Alzheimers disease

Optional at early stage: Mild behavioral modification: rigidity,

clockwatching, money worries, lack of empathy

Atypical semantic dementia

Necessary criteria

FTLD-TDP

Tau pathologie
CBD AGD

Same as typical semantic dementia

Optional at early stage: Unusual language, cognitive, or
behavioural signs: delusion, spatial orientation, hallucinations,
personal neglect, severe day to day memory disorders

FTD Treatments
No curative treatments
Efforts to develop treatments hampered by the lack of
standardized methods to monitor progression of the
illness
PPA presents unique challenges to clinicians aiming to
quantify impairments for the purposes of full
characterization and monitoring, and ultimately with the
goal of designing clinical trials of interventions to make
a meaningful difference in patients' lives (Rohrer, 2011).

Physiopathological treatments assessed: tau,

progranuline, C9?

Symptomatic treatments of FTLD

Cholinesterase inhibitors

No indication (no cholinergic deficit)

May enhance irritability and aggression

Memantine

DBPC : no statistical difference (Verceletto 2009)

Worsen cognitive decline (Boxer 2013)

Neuroleptics:

Worsen cognitive deficits, aggression, hallucinations, delirium, adverse

effects, failures, incontinence, constipation
Improvement after withdrawal: MMS +5 (3-12) (Pasquier 1999, Pijnenburg
2003))

Treatments of FTLD
Serotonergic treatments

Sertonergic disturbances : impulsivity, irritability, affective change,

eating behavior, OCD (common features of FTD)
Paroxetine, Fluvoxamine, Sertraline (Moretti 2003, Deakin 2004,
Ikeda 2004, Ishikawa 2006, Mendez 2005, Anneser 2007)
Trazodone (Lebert 2004, 2006)

Topiramate

Modulated alcohol abuse and no other compulsive behavior in a

man with FTD (Cruz 2008, Nestor 2011)

Non-pharmaceutical treatment
Speech therapy recommended to limit the decline of
language function and to reduce possible difficulties
with swallowing
A safe place of living requires modifications to
exclude or to adapt workshop using toxic material
and dangerous tools, and a special organization for
the food, to limit over-eating and problems with
swallowing (Lebert 2002)

Non-pharmaceutical treatment
Environment manipulation : important strategy for
improving behavior in FTD which requires considerable
time for clinicians to help the patients and to educate the
families
Psychological AND medical support for caregivers

Conclusions
Currently no clear correlation between clinical and
neuroanatomical phenotype in life and underlying
pathogenetics.
Current and future biomarkers may help make a pathological
diagnosis in life, including clinical and neuropsychological
data, neuroimaging, blood and CSF markers
International effort with GENFI

Identification of FTLD patients with mutations in genes for

tau, TDP-43, and FUS lends strong support for their
pathogenic roles in FTLD, and elucidation of their dysfunction
will pave the way for development of substrate specific
therapy.