Frontotemporal Frontotemporal lobar degeneration: lobar degeneration: demographic and clinical characteristics demographic and clinical characteristics

in a Turkish dementia populationin a Turkish dementia population

Görsev G. YenerGörsev G. Yener, M.D., M.D.

NeurologyNeurology, Dokuz Eylül University, Dokuz Eylül University

Izmir, TurkeyIzmir, Turkey

gorsev.yener@deu.edu.trgorsev.yener@deu.edu.tr

FTLD FTLD Prevalence Prevalence

Not clearNot clear ( (4-4-16%)16%)

Common cause pre-senile dementiaCommon cause pre-senile dementia

1:1 with AD 45-64 year1:1 with AD 45-64 yearss (Ratnavalli Neurology 2002)(Ratnavalli Neurology 2002)

more common than AD below 60 years more common than AD below 60 years (Knopman Neurology 2004)(Knopman Neurology 2004)

FTLDFTLD in Izmir, Turkey in Izmir, Turkey

Demographic Demographic datadata

GeneticsGenetics//Pathological Syndrome Pathological Syndrome

Neary Criteria – FTD, PA, SDNeary Criteria – FTD, PA, SD

MND associationMND association

1994-2004 Izmir DEU Dementia Clinic1994-2004 Izmir DEU Dementia Clinic

N=1169 N=1169

Demented= 66 % Demented= 66 %

AD (possible / probable) 67 % AD (possible / probable) 67 %

Vascular dementia 15 % Vascular dementia 15 %

Fronto-temporal dementia 4 %Fronto-temporal dementia 4 %

Lewy body dementia 9 %Lewy body dementia 9 %

FTLD Clinical Heterogeneity

Genetic & sporadic casesGenetic & sporadic cases

Histology variesHistology varies

Motor overlap with PSP, CBD, ALSMotor overlap with PSP, CBD, ALS

Neary CriteriaNeary Criteria Frontotemporal Lobar DegenerationFrontotemporal Lobar Degeneration

Frontotemporal DementiaFrontotemporal Dementia

Progressive Non-Fluent AphasiaProgressive Non-Fluent Aphasia

Semantic DementiaSemantic Dementia

Neary et al. 1998, NeurologyNeary et al. 1998, Neurology

Dokuz Eylül University Dokuz Eylül University Dementia and Movement Disorders ClinicsDementia and Movement Disorders Clinics

1994-20011994-2001

35 FTLD, 25 PSP, 5 CBD cases35 FTLD, 25 PSP, 5 CBD cases

Demographic and clinical featuresDemographic and clinical features

WebsterWebster

MMSE (subitems)MMSE (subitems)

FTLD: GenderFTLD: Gender

****

TurkishTurkish (N=35) (N=35) (% male)(% male)

Ag

e (

Years

)A

ge (

Years

) ****

39%40%

72%

59%

0

20

40

60

80

FTD SD PNFA MND

40%

67%64%

0

20

40

60

80

FTD SD PNFA

USUS (N=353) (N=353) (% male)(% male)

Johnson et al. Johnson et al. Arch NeurolArch Neurol. 2005;62:925-930.. 2005;62:925-930. Yener et al 2002Yener et al 2002

FTLD: Age at OnsetFTLD: Age at Onset

****

5859

63

50

55

60

65

FTD SD PNFA

US (N=353US (N=353))

Ag

e (

Years

)A

ge (

Years

)

Johnson et al. Johnson et al. Arch NeurolArch Neurol. 2005;62:925-930.. 2005;62:925-930.

61

72

61

50

55

60

65

70

75

FTD SD PNFA

Turkish (N=35)Turkish (N=35)

?

Yener et al 2002Yener et al 2002

Presenile onset (%) -TurkishPresenile onset (%) -Turkish

26%

100%

48%46%

0

20

40

60

80

100

**

40-60 %40-60 %

In Netherland series 38% In Netherland series 38%

(15 million screened) (15 million screened)

Family Hx (+) , RR=3.5Family Hx (+) , RR=3.5

Family historyFamily history

Family Hx (%)-Turkish population

10%

24%20%25%

54%

0

0

0

0

0

1

1

FTLD

(N=35

)

PSP (N

=25)

CBD

(N=5)

AD (N

=390)

VAD

(N=65

)

****

FTFTLLD D PathologicalPathological Syndrome SyndromeCore FeaturesCore Features

Frontotemporal predominanceFrontotemporal predominance

Gliosis, spongiosus, neuronal lossGliosis, spongiosus, neuronal loss

Variable Histological FeaturesVariable Histological FeaturesNeuronal inclusions with ubiquitinNeuronal inclusions with ubiquitin

(Clinical: MND, ALS, Paget, Inclusion body myositis)(Clinical: MND, ALS, Paget, Inclusion body myositis)

Neuronal inclusions Neuronal inclusions with tauwith tau (Clinical: FTDP-17, PSP, CBD)(Clinical: FTDP-17, PSP, CBD)

Other inclusionsOther inclusions (Neuronal intermediate filament inclusion dementia)(Neuronal intermediate filament inclusion dementia)

No inclusionsNo inclusions (DLDH) (DLDH) (Clinical: FTLD)(Clinical: FTLD)

Pick Bodies Cerebral cortex(Described by Alzheimer in 1911)

Time (minutes)

Dis

tanc

e tr

avel

led

by th

e ta

u sp

ecie

s (

m)

B.A.

c d

0

20

40

60

80

100

150 175 200 225 250

0N4R-EGFP0N4RpCIneo

0N4R-EGFP0N4R-untagged

Courtesy of Tim Hutton, Cambridge, UK

Tau mutations

Bigio, et al, 2004, J Neuropath Exp Neurol, 63(8): 801 811

Neuronal ubiquitinated intranuclear inclusions in familial and non-familial

FTD-MND associated with ALS

FTD with ubiquitinated neuronal inclusions and visuospatial impairment

Meiner et al Neurology 2005;65:478–480

Ubiquitin and TauUbiquitin and Tau

Ubiquitin is a marker for a given protein to Ubiquitin is a marker for a given protein to be sent to a proteasome for degradationbe sent to a proteasome for degradation

Ubiquitin proteins are also needed for the Ubiquitin proteins are also needed for the degradation of taudegradation of tau

FTD Neuropathology SubtypesFTD Neuropathology Subtypes

FTD-Ub FTD-Ub related to MND subtyperelated to MND subtype

CBD, PSP major tau subtypeCBD, PSP major tau subtype

DLDH DLDH less common withless common with new stain new staining ing techniquestechniques

Clinical FeaturesClinical Features

SubtypesSubtypes

MNDMND

ParkinsonismParkinsonism

MMSEMMSE

FTLD subtypes in the US and TurkeyFTLD subtypes in the US and Turkey

PNFA (n=11)31%

SD (n=3)9%

FTD (n=21)60%

PNFA (n=87)25%

SD (n=66)19%FTD

(n=200)56%

Johnson et al. Johnson et al. Arch NeurolArch Neurol. 2005;62:925-930.. 2005;62:925-930.

3 sites (N=353)3 sites (N=353)

1 site (N=35)1 site (N=35)Yener et al 2002Yener et al 2002

MND and FTDMND and FTD are associatedare associated

FTD is associated with MND (15%)FTD is associated with MND (15%)

Most Most ALS ALS patients developpatients develop FTD FTD

FTLD-ALSFTLD-ALS chr chr 9 9 andand 17 17

Hypometabolism in fHypometabolism in frontal rontal lobes in ALSlobes in ALS

Chang et al, Neurology 2005;65:75–80

Brain atrophy in ALS and ALS/FTLD

FTLD ; 78%

FTD_MND; 22%

0%

10%

20%

30%

40%

50%

60%

70%

80%

FTLD FTD_MND

Turkish FTLD and MND

Webster scores-Turkish FTLD subtypesWebster scores-Turkish FTLD subtypes

4,4

0,51

0,6

0,00

1,00

2,00

3,00

4,00

5,00

6,00

7,00

8,00

FTD SD PNFA FTD-MND

Clinical Features-ParkinsonismClinical Features-Parkinsonism

**

Clinical FeaturesClinical Features

Parkinsonism appears earlier in FTLDParkinsonism appears earlier in FTLD

MND - more often parkinsonismMND - more often parkinsonism

No tau mutation was found in FTD-MND group.No tau mutation was found in FTD-MND group.

MMSE Scores in Turkish FTLDMMSE Scores in Turkish FTLD

14,1014,10

24,30 23,60

0

20

FTLD PSP CBD MND-FTD

MMSE Figure copying (%)MMSE Figure copying (%)

63%

0%

69%

33%

0

20

40

60

80

Clinical patternsClinical patterns

PSP~CBD PSP~CBD

Both higher Webster and MMSE Both higher Webster and MMSE scoresscores

MMSE figure copy is discriminativeMMSE figure copy is discriminative

Clinical patternsClinical patterns

Webster scores Webster scores FTD-MND > FTLDFTD-MND > FTLD

MMSE scoresMMSE scores FTD-MND = FTLDFTD-MND = FTLD

preserved figure copying preserved figure copying FTD-MND > FTLDFTD-MND > FTLD

Clinical patternsClinical patterns

FTLD subtypes FTLD subtypes

total MMSE total MMSE PNFA < PNFA < SDSD < FTD < FTD

figure copyfigure copy SDSD < PNFA < FTD < PNFA < FTD

ConclusionsConclusions FTLDFTLD common in presenile ages common in presenile ages

Turkish Turkish FTLD FTLD subtypes have similar subtypes have similar profile to the USprofile to the US

FTD> PNFA > SD FTD> PNFA > SD

ConclusionsConclusions Higher family Hx than other dementias Higher family Hx than other dementias

(54%)(54%)

FTLD-MND association (22%)FTLD-MND association (22%)

FTD-MND has higher parkinsonism FTD-MND has higher parkinsonism scores scores