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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
7/24/2019 Fronto-temporal Lobar Degeneration
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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-'
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