fronto-temporal lobar degeneration

7/24/2019 Fronto-temporal Lobar Degeneration

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Frontotemporal Lobar Degeneration

Florence Pasquier, MD PhD

ECNP-2015


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DISCLOSURESECNP 2015

Nature Sponsors

Investigator of Clinical studies

phases 2-3

Bayer (Piramal), BM, !"

#ealthcare, $illy, %oscira,Pharne&t, P'er, oche, "t*ient+t stra-.eneca, Biogen,BioCross, M/, Pro*iodrug,aman

0ccasional mem*er of cienti'cdvisory Boards

lprotect, $illy, ano',"thypharm, %utricia, %ovartis

Florence Pasquier$ast three years

1ees paid to the niversity #ospital or /I%0

No confic o interest or this presentation


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Terminology

Picks diseases! (1892-1906 (!s "l#hei$er%s &isease (186'-1915

Frontotemporal dementia FTD (run et al, 199'

Frontotemporal lobar degeneration (Near) et al 1998

* Fron+o+e$oral &e$en+ia Fron+al or eha!ioural !arian+

* Non-luen+ Pri$ar) Pro.ressi!e "hasia Non-Fluen+ /a.ra$$a+ic (less o+en lo.oenic

* e$an+ic &e$en+ia +e$oral !arian+ Fluen+ ahasia an& "ssocia+i!e ".nosia

eneric +er$ or ro.ressi!e circu$scri3e& &e.enera+ion o +he

ron+al an& +e$oral lo3es

4an.ua.e !arian+


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Clinical/a+holo.ical o!erlahe Pic Co$le7 * "er+es#

"typical

parkinsoniansyndrome

#otone$ron

disease

Corticobasal

syndrome

Progressi%e

ap&asias

Frontotemporal

dementia

Clinical syndromes linked to the location of the degenerative process

PPA

FTD

SemD

CBS


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Frontotemporal lobar degenerations

he &ieren+ clinical s)n&ro$es o F4D

* Ma) occur in +he sa$e a$il)

* Ma) 3e co$3ine& in a sa$e a+ien+ :i+h

ro.ression

*"re un&erinne& 3) &ieren+ his+olo.ical

su3+)es ; +au, u3iqui+in, DP-'< inclusions,

ar.)rohilic .rains, neuroila$en+s=


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'e$ropat&ological(genetic &eterogeneity

FTLD Neuropathology

Tau-positive

inclusionsUbiuitin-positive

inclusions

No inclusion

Pick bodies

3R Tauopathy

Neurons/Glia

4R Tauopathy

Tangles

3R+4RTauopathy

PiD

FTDP-!"

PSP

CBD

A#D

FTDP-!"

NFT$

FTDP-!"

TDP-%& FUS'

FTLD-TDPType AType BType CType D

FTLD-FUS

aFTLD-U

N(F(D

B(BD

FTLD-Ups

FTLDni

MAPT)Tau*gene

VCP gene

PGRN(Progranuline*

gene

CHMP2B gene

~40 ~ !0

"0 #0

>1?

C9ORF75 gene

FUS gene


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Frontotemporal lobar degeneration

No clear correla+ion 3e+:een clinical an&

neuroana+o$ical heno+)e 3u+ requen+

associa+ion 3e+:een

* PP, CD (3!-FD, PP" and Ta$

* e$an+ic &e$en+ia and FTLD)U)type * or +

* Non-Fluen+ Pro.ressi!e ahasia, CD and

FTLD)U)type C* !-FD an& FD :i+h MNDand FTLD)U)

type , or -C


9/47$osephs et alEur J Neurol %0#0

Characteristic features of FTLD-FUS

FUS FTLD-TDP

Very early onset (


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'e$roanat&omical .eat$res associated /it&

pat&ological diagnosis in FTLDRo&rer et al ,rain +0**!

TL temporal lo*e atrophy extra-TL e&tratemporal atrophye4g4 frontal lo*e Pickassociated 5ith 6 temporal or frontalasymmetry

TDP-A strongly asymmetrical atrophy especially in association5ith P!% mutation


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1enetics and FTLD

'0? o F4D ha!e a osi+i!e a$il) his+or) o @&e$en+ia% or o+her neurolo.ical

con&i+ion

* A +he$ 50? au+oso$al &o$inan+ inheri+ance

Chro$oso$e 1B

* #"PT (+au (5-11?

* P1R'(ro.ranuline 50 $u+a+ions (5-11?

arious clinical ea+ures inclu&in. "l#hei$er lie s)n&ro$e er) la+e onse+

ossi3le, inco$le+e ene+rance

4o: plasma progran$line le%el

Chro$oso$e /it& normal imaging (is,

2010

Phenocoies K

4ins :i+h s)chia+ric &iseases (3iolar &isor&ers,schi#ohrenia K

C9ALFB2 $u+a+ion (1B-22 )ears


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Behavioural variant o

FTLD7 1rontotemporal dementia 9

Progressive deterioration of personality,social *ehaviour and cognition


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Behavioural-variant FTD

So characteristic that post-mortem diagnosis isfeasible(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 thesymptoms

* physical neglect or eccentricity


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Behavioural changes =dominantfeatures initiallyand throughout the disease course,precedeorareassociatedwith cognitive decline* Usually memory impairment of secondary importance

compared to behavioural disorders ( AD)

1stSymptoms:* Loss of interestdepression? (no sadness or feeling ofworthlessness or guilt)

* Disinhibition, anxiety, language disorders (including coarsewords), changes in eating and drinking habits

* Behavioural dyscontrol (restlessness, rituals)

Behavioural-variant FTD


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Do not fit any psychiatric disease criteria(DSM)

Frontotemporal Behavioural scale FBS(Lebert 1998);4classes of changes assessed sens & spe if MMSE > 18

core < ;sensi+i!i+) 1 seciici+) 9

* False belie. test (all) an& "nn +es+,

Oi$$er e+ Perner, 198


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e av oura "pa r"enassociate $ithsocial co#nition i"pair"ent

Sociopathic %ehaviour "4g pedophilia, stealing, se&ual harassment,

automo*ile violations, violence:

;Challenge to the criminal


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,e&a%io$ral and F$nctional scales

in FTD

Neuros)chia+ric Hn!en+or) (Cu$$in.s, 199'

Fron+al 3eha!ioural Hn!en+or) (er+es#, 199B

F (4e3er+ 1998 EJ"E-"D (Men&e#, 1998

Ca$3ri&.e eha!ioural Hn!en+or) (o#ea+, 2000

FRS Fron+o+e$oral &e$en+ia La+in. cale (Mioshi,2010

E" (ocial co.ni+ion an E$o+ional "ssess$en+ e+ la

$ini-E" (


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b%FTD Criteria Consorti$m FTDC(Laso!s) e+ al, rain 2011

Possible !-FD requires < o 6 clinicall)

&iscri$ina+in. ea+ures;

1 Disinhi3i+ion !en+ral or3i+o-ron+al cor+e7 an& cau&a+e2 "a+h)/iner+ia reron+al &orso-$e&ial/ -la+eral cor+ices


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b%FTD Criteria Consorti$m FTDC(Laso!s) e+ al, rain 2011

Probable !-FD requires in a&&i+ion

unc+ional &isa3ili+) an& charac+eris+ic

neuroi$a.in. (CF so ar inconclusi!e

De.inite F4D requires his+oa+holo.ical

e!i&ence o F4D or a a+ho.enic $u+a+ion


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ensitivity and speci'city of 1>/C criteria for *v-1>/

(#arris, %eurology 2?@3)

utopsy series of @A patients,predominantly early onset dementia4

Possi*le *v1>/ sensitivity DAE andspeci'city F2E4

Pro*a*le *v1>/ criteria sensitivity FAE and speci'city DAE4

False positives & preo"inantl'patients $ith presenile Al(hei"erisease


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FTD: Biomarkers

CSF :

Tau (< AD)

Ab42 (


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Differential diagnosis of bv-FTD

Alzheimers disease

Vascular dementia

Dementia with Lewy bodies

Psychiatric diseases* Depression(no sadness, guilt, or feeling ofworthlessness)

* Pseudo mania(no sleep disorders, or hypersomnia)

* OCD(no anxiety no relief)

* Schizophrenia


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"+)ical ea+ures o F4D

"mnestic &e$en+ia, o +he "l#hei$er +)e

(eseciall) :hen onse+ is resenescen+ (Hodges2004)

Pri$ar) ro.ressi!e prosopagnosia (ouert#200*)

Pri$ar) ro.ressi!e p&onagnosia(i$aire&

!oice reco.ni+ion (Hailstone 2010)

Rig&t temporal lobe a+roh); h)er-reli.iosi+),!isual hallucina+ions, an& cross-$o&al sensor)

e7eriences (Chan 2009)


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Lan#ua#e variants o

FTLDProgressive deterioration of

language


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Primary Progressi%e "p&asia

Pre&o$inan+ 4e+ a+roh)

Tasks to assess speec& and lang$ageB

* eech ro&uc+ion (inclu&in. .ra$$ar an& $o+or

seech* Conron+a+ion na$in.

* Lee+i+ion

* en+ence co$rehension

* in.le-:or& co$rehension

* A3Sec+/eole no:le&.e

* Lea&in. an& sellin.


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Cortical atrop&ycorreson&in. +o ri$ar) ro.ressi!e ahasia s)n&ro$es

(ross$an U Mol Neurosci 2011

Frontal: Non fluent/agrammatic variant PPA

Anterior temporal: semantic variant

Posterior temporal parietal: logopenic variant

' .l t i & i


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'on.l$ent progressi%e ap&asia(orno-e$ini +eurolog,2011, Dera$ecour+ Neurolog,2010

Progressi%e anart&ria 'ecessary criteria

* Mo+or seech &eici+ resul+in. in slo: an& eor+ul seech :i+h soun&

&is+orsion

* D)sroso&ia, uccoacial ara7ia

Optional at early stage; :allo:in. &iicul+ies, ura3ul3ar aresis

"grammatic progressi%e ap&asia

'ecessary criteria

* Decrease& ra+e o lan.ua.e ou+u+* )n+ac+ic si$liica+ion (+ele.rahic s+)le

* Frequen+ :or&-in&in., auses, circu$locu+ion

* Nor$al sin.le :or& ree+i+ion, hone$ic &is+orsion

Optional at early stage; i$aire& co$rehension o co$le7 s)n+ac+ic

s+ruc+ures

Tau pathologieP*P( C'+ Pick

,T-+.T+PPGN12

L i i & i


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Logopenic progressi%e ap&asia(orno-e$ini +eurolog,2011, Dera$ecour+ Neurolog,2010

'ecessary criteria

* Decrease& or luc+ua+in. ra+e o lan.ua.e ou+u+

* A!erall lan.ua.e .ra$$a+icall) si$le 3u+ nor$al* Frequen+ :or&-in&in. auses, circu$locu+ions

* Co$rehension o sin.le :or&s is nor$al, 3u+ i$aire&

or co$le7 s)n+ac+ic s+ruc+ures

* H$aire& sen+ence ree+i+ion Optional at early stage; ossi3le honolo.ic su3s+i+u+ion

errors

3lheimer5s disease 6 +-,T

P i " & i


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Progressi%e argon "p&asia(orno-e$ini +eurolog,2011, Dera$ecour+ Neurolog,2010

'ecessary criteria

* Fluen+ lan.ua.e or lo.orrhea

* H$aire& !er3al co$rehension

* Neolo.is$s

Optional at early stage;"noso.nosia

3lheimer5s disease6 +-,T

S ti d ti


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Semantic dementia(orno-e$ini +eurolog,2011, Dera$ecour+ Neurolog,2010

Typical semantic dementia 'ecessary criteria

* Fluen+ seech, ra$$a+icall) nor$al

* H$aire& conron+a+ion na$in.

* 4oss o :or& $eanin.

Optional at early stage; Mil& 3eha!ioral $o&iica+ion; ri.i&i+),cloc:a+chin., $one) :orries, lac o e$a+h)

"typical semantic dementia

'ecessary criteria* a$e as +)ical se$an+ic &e$en+ia

Optional at early stage; nusual lan.ua.e, co.ni+i!e, or

3eha!ioural si.ns; &elusion, sa+ial orien+a+ion, hallucina+ions,

ersonal ne.lec+, se!ere &a) +o &a) $e$or) &isor&ers

,T-+.T+PType 3

6 3lheimer5s disease

Tau pathologieC'+ 3G+


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FD rea+$en+s

No cura+i!e +rea+$en+s

* Eor+s +o &e!elo +rea+$en+s ha$ere& 3) +he lac o

s+an&ar&i#e& $e+ho&s +o $oni+or ro.ression o +he

illness

* QPP" resen+s unique challen.es +o clinicians ai$in. +oquan+i) i$air$en+s or +he uroses o ull

charac+eri#a+ion an& $oni+orin., an& ul+i$a+el) :i+h +he

.oal o &esi.nin. clinical +rials o in+er!en+ions +o $ae

a $eanin.ul &ierence in a+ien+sV li!esR (-ohrer# 2011)

Ph)sioa+holo.ical +rea+$en+s assesse&; +au,

ro.ranuline, = C9K


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Symptomatic treatments of FTLD

Cholinesterase inhibitors No indication (no cholinergic deficit)

May enhance irritability and aggression

Memantine DBPC : no statistical difference(Verceletto 2009)

Worsencognitive decline (Boxer 2013)

Neuroleptics: Worsen cognitive deficits,aggression, hallucinations, delirium, adverse

effects, failures, incontinence, constipation Improvement after withdrawal: MMS +5(3-12)(Pasquier 1999, Pijnenburg2003))


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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 aman with FTD(Cruz 2008, Nestor 2011)


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'on)p&armace$tical treatment

Speec& t&erapy reco$$en&e& +o li$i+ +he &ecline o

lan.ua.e unc+ion an& +o re&uce ossi3le &iicul+ies

:i+h s:allo:in.

" sa.e place o. li%ing requires $o&iica+ions +o

e7clu&e or +o a&a+ :orsho usin. +o7ic $a+erial

an& &an.erous +ools, an& a secial or.ani#a+ion or

+he oo&, +o li$i+ o!er-ea+in. an& ro3le$s :i+hs:allo:in. (4e3er+ 2002


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'on)p&armace$tical treatment

En%ironment manip$lation ; i$or+an+ s+ra+e.) or

i$ro!in. 3eha!ior in FD :hich requires consi&era3le

+i$e or clinicians +o hel +he a+ien+s an& +o e&uca+e +he

a$ilies

Ps)cholo.ical "ND $e&ical s$pport .or caregi%ers


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Concl$sions

Curren+l) no clear correla+ion 3e+:een clinical an&

neuroana+o$ical heno+)e in lie an& un&erl)in.

a+ho.ene+ics

Curren+ an& u+ure 3io$arers $a) hel $ae a a+holo.ical

&ia.nosis in lie, inclu&in. clinical an& neuros)cholo.ical&a+a, neuroi$a.in., 3loo& an& CF $arers* Hn+erna+ional eor+ :i+h ENFH

H&en+iica+ion o F4D a+ien+s :i+h $u+a+ions in .enes or

+au, DP-'

fronto-temporal lobar degeneration

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