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    FTD Turkish characte.. FTD Turkish characte.. Presentation Transcript

    • Frontotemporal lobar degeneration: demographic and clinical characteristics in a Turkish dementia population
      • Görsev G. Yener , M.D.
      • Neurology , Dokuz Eylül University
      • Izmir, Turkey
      • [email_address]
    • Turkey- getting older WHO 1998
    • FTLD Prevalence
      • Not clear ( 4- 16%)
      • Common cause pre-senile dementia
        • 1:1 with AD 45-64 year s
              • (Ratnavalli Neurology 2002)
        • more common than AD below 60 years
              • (Knopman Neurology 2004)
    • FTLD in Izmir, Turkey
      • Demographic data
      • Genetics / Pathological Syndrome
      • Neary Criteria – FTD, PA, SD
      • MND association
      • 1994-2004 Izmir DEU Dementia Clinic
      • N=1169
      • Demented= 66 %
        • AD (possible / probable) 67 %
        • Vascular dementia 15 %
        • Fronto-temporal dementia 4 %
        • Lewy body dementia 9 %
    • FTLD Clinical Heterogeneity
      • Genetic & sporadic cases
      • Histology varies
      • Motor overlap with PSP, CBD, ALS
    •  
    • Neary Criteria
      • Frontotemporal Lobar Degeneration
        • Frontotemporal Dementia
        • Progressive Non-Fluent Aphasia
        • Semantic Dementia
          • Neary et al. 1998, Neurology
    • Dokuz Eylül University Dementia and Movement Disorders Clinics
      • 1994-2001
      • 35 FTLD, 25 PSP, 5 CBD cases
        • Demographic and clinical features
        • Webster
        • MMSE (subitems)
    • FTLD: Gender ** Turkish (N=35) (% male) Age (Years) ** US (N=353) (% male) Johnson et al. Arch Neurol . 2005;62:925-930. Yener et al 2002
    • FTLD: Age at Onset ** US (N=353) Age (Years) Johnson et al. Arch Neurol . 2005;62:925-930. Turkish (N=35) ? Yener et al 2002
    • Presenile onset (%) -Turkish **
        • 40-60 %
        • In Netherland series 38%
          • (15 million screened)
        • Family Hx (+) , RR=3.5
      Family history
    • Family Hx (%)-Turkish population **
    • FT L D Pathological Syndrome Core Features
        • Frontotemporal predominance
        • Gliosis, spongiosus, neuronal loss
    • Variable Histological Features
        • Neuronal inclusions with ubiquitin
          • (Clinical: MND, ALS, Paget, Inclusion body myositis)
        • Neuronal inclusions with tau
          • (Clinical: FTDP-17, PSP, CBD)
        • Other inclusions
          • (Neuronal intermediate filament inclusion dementia)
        • No inclusions (DLDH)
          • (Clinical: FTLD)
    • Pick Bodies Cerebral cortex (Described by Alzheimer in 1911)
    •  
    •  
    • Time (minutes) Distance travelled by the tau species (  m) B. A. 0N4R-EGFP 0N4R-untagged Courtesy of Tim Hutton, Cambridge, UK a b c d
    • 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 Tau
      • Ubiquitin is a marker for a given protein to be sent to a proteasome for degradation
      • Ubiquitin proteins are also needed for the degradation of tau
    • FTD Neuropathology Subtypes
      • FTD-Ub related to MND subtype
      • CBD, PSP major tau subtype
      • DLDH less common with new stain ing techniques
    • Clinical Features
      • Subtypes
      • MND
      • Parkinsonism
      • MMSE
    • FTLD subtypes in the US and Turkey Johnson et al. Arch Neurol . 2005;62:925-930. 3 sites (N=353) 1 site (N=35) Yener et al 2002
    • MND and FTD are associated
      • FTD is associated with MND (15%)
      • Most ALS patients develop FTD
      • FTLD-ALS chr 9 and 17
      • Hypometabolism in f rontal lobes in ALS
    • Chang et al, Neurology 2005;65:75–80 Brain atrophy in ALS and ALS/FTLD
    • Turkish FTLD and MND
    • Webster scores-Turkish FTLD subtypes Clinical Features-Parkinsonism **
    • Clinical Features
      • Parkinsonism appears earlier in FTLD
      • MND - more often parkinsonism
      • No tau mutation was found in FTD-MND group.
    • MMSE Scores in Turkish FTLD
    • MMSE Figure copying (%)
    •  
    • Clinical patterns
        • PSP~CBD
        • Both higher Webster and MMSE scores
        • MMSE figure copy is discriminative
    • Clinical patterns
        • Webster scores
            • FTD-MND > FTLD
        • MMSE scores
            • FTD-MND = FTLD
        • preserved figure copying
            • FTD-MND > FTLD
    • Clinical patterns
        • FTLD subtypes
      • total MMSE PNFA < SD < FTD
      • figure copy SD < PNFA < FTD
    • Conclusions
      • FTLD common in presenile ages
      • Turkish FTLD subtypes have similar profile to the US
          • FTD> PNFA > SD
    • Conclusions
      • Higher family Hx than other dementias (54%)
      • FTLD-MND association (22%)
      • FTD-MND has higher parkinsonism scores
    • Neary Criteria
      • Frontotemporal Lobar Degeneration
        • Frontotemporal Dementia
        • Progressive Non-Fluent Aphasia
        • Semantic Dementia
          • Neary et al. 1998, Neurology
    • Fv FTD
      • M.Y. 52 y F
      • Mute, childish, delusional, inappropriate behavior, stereotypic movements, incontinence
      • (+) Family Hx
    • 1999 2000
    • Progressive Non-Fluent Aphasia (frontal variant)
      • Non-fluent spontaneous speech with at least one of the following:
        • Agrammatism
        • Phonemic paraphasias
        • Anomia
    • Semantic Dementia ( Temporal variant)
      • Subtype of frontotemporal dementia
      • Marked anomia
      • Loss of meaning of words (semanti cs )
      • Progressive perceptual disorder
        • Prosopagnosia or
        • Visual agnosia
    • SEMANTIC DEMENTIA Raise your left arm Show me the door
    • Corticobasal degeneration
    • Conclusions
      • FTLD common in presenile ages
      • Clinical syndromes depends on anatomical heterogeneity
      • Pat h olo gy - Tau, Ubi q uitin, NIFID, DLDH
    • Conclusions
      • Turkish FTLD subtypes have similar ratios to the US co-hort
          • FTD> PNFA > SD
      • Higher family Hx than other dementias (54%)
      • FTLD-MND association (22%)
    • Progressive Non-Fluent Aphasia (frontal variant) = Non-fluent PA FTD/CBD = Posterior PA AD = Semantic Dementia FTD
    • PSP
    • Delusions 0 25 50 75 100 Percent Hallucinations Agitation Depression Anxiety Elation Apathy 0 25 50 75 100 Percent Disinhibition Irritability Aberrant MB Sleep DO Eating DO FTD AD Frequency of Behavioral Disorders in AD and FTD (Neuropsychiatric inventory) Rosen et al. 2003 Neurology [ * [ * [ * [ *
      • Where and how does the brain represent knowledge?
      • Symbolic-linguistic function lost
      • Visual representation spared
      • Information represented in separate systems with distinctive anatomy
      Semantic Dementia
    • FTLD subtypes in Izmir, Turkey (n=35)
        • 15 frontal variant (Fv)
        • 9 primary progressive aphasia (PPA)
        • 3 semantic dementia (Tv)
        • 8 motor neuron signs (only 2 with MND)
          • as PPA and Fv
      • Family history is higher in FTLD than other neurodegenerative dementias
    • Conclusions
      • FTLD common presenile dementia
      • Clinical syndromes driven by anatomic heterogeneity
      • Linked to PSP, CBD, ALS
      • Pathology - Tau, Ubiquitin, DLDH
      • Window frontotemporal functions
    • Emotions and Temporal Damage Left amygdala Right amygdala
    • Florida Affect Battery Anger Fear Sadness Happiness
    • 100 90 80 70 60 50 40 2.5 2.0 1.5 1.0 .5 Percent correct, negative emotions Volume right amygdala (cc 3 )
    • # not updated for n=390 * parkinsonism and tremor was also asked & family history was taken from 244 cases 28 25 * 48 63.5 (7.2) PSP (n=25) % ( + SD) 60 20 100 58.0 (4.5) CBD (n=5) % ( + SD) 61 41 Gender (F %) 24.1 & 54.3 1 o relative (%) dementia/psychosis 25.7 46 Presenile onset (%) 68.5 (8.4) 58.7 (16.7) Age of onset (yr) Alzheimer (n=261 # ) % ( + SD) FTLD (n=35) % ( + SD)
    • 25 2.5 (4.1) 0.6 (1.8) 61.5(1.9) PPA (n=9) 0 4.3 (4.5) 1.0 (1.7) 72.0 (1.0) Tv (n=3) 63 47 MMSE-Figure copy (%) 14.1 (7.3) 15.1 (6.7) MMSE Mean (St dev) 4.4 (5.9) 0.5 (1.7) Webster score (St dev) 67.2 (10.3) 60.8(7.8) Age of onset (yr) Motor neuron involvement (n=8) Fv (n=15) FTLD subtypes
    • 0 23.6 (5.0) 9.2 (5.8) 61.5(1.9) KBD (n=5) 69 24.3 (5.5) 11.4 (5.3) 72.0 (1.0) PSP (n=3) 63 33 MMSE-Figure copy (%) 14.1 (7.3) 14.1 (9.7) MMSE Mean (St dev) 4.4 (5.9) 4.9 (6.4) Webster score (St dev) 67.2 (10.3) 58.7 (16.7) Age of onset (yr) FTD + Motor neuron involvement (n=8) FTLD (fv/tv/ppa) (n=27)
    • Florida Affect Battery
      • Facial and prosodic subtests
      • Anger, happiness, sadness, fear and neutral
      Emotions
    • 0.00 25.00 50.00 75.00 percent correct Happiness Sadness Anger Fear * * * 100.00 * = p<0.05 (corrected) compared with controls Controls (n=10) tvFTD (n=9)
    • 0.00 25.00 50.00 75.00 100.00 Controls (n=10) tvFTD (n=9) Identity Discrimination Emotion Discrimination Emotion Naming Emotion Selection Emotion Matching * = p<0.05 (corrected) compared with controls percent correct * * *
    • Reduced Survival With Comorbid ALS 0 5 10 15 20 0 25 50 75 100 FTD + ALS AD - ALS Years From Onset Percent survival P <.0001 0 3 6 9 12 0 25 50 75 100 FTD + ALS AD - ALS Years From Presentation Percent survival P <.0001 Roberson, et al. Neurology 2005 Median Survival (Years) From: 11.5 4.9 Onset 1.4 19 21 + ALS 3.8 56 134 - ALS Presentation Deaths Subjects
    • 25 2.5 (4.1) 0.6 (1.8) 61.5(1.9) PPA (n=9) 0 4.3 (4.5) 1.0 (1.7) 72.0 (1.0) Tv (n=3) 63 47 MMSE-Figure copy (%) 14.1 (7.3) 15.1 (6.7) MMSE Mean (St dev) 4.4 (5.9) 0.5 (1.7) Webster score (St dev) 67.2 (10.3) 60.8(7.8) Age of onset (yr) Motor neuron involvement (n=8) Fv (n=15) FTLD subtypes
    • 0 23.6 (5.0) 9.2 (5.8) 61.5(1.9) KBD (n=5) 69 24.3 (5.5) 11.4 (5.3) 72.0 (1.0) PSP (n=3) 63 33 MMSE-Figure copy (%) 14.1 (7.3) 14.1 (9.7) MMSE Mean (St dev) 4.4 (5.9) 4.9 (6.4) Webster score (St dev) 67.2 (10.3) 58.7 (16.7) Age of onset (yr) FTD + Motor neuron involvement (n=8) FTLD (fv/tv/ppa) (n=27)
    • 28 25 * 48 63.5 (7.2) PSP (n=25) % ( + SD) 60 20 100 58.0 (4.5) CBD (n=5) % ( + SD) 61 41 Gender (F %) 24.1 & 54.3 Family Hx (%) 25.7 46 Presenile onset (%) 68.5 (8.4) 58.7 (16.7) Age of onset (yr) Alzheimer (n=390) % ( + SD) FTLD (n=35) % ( + SD)
    • 0 14.1 (7.3) 2.5 (4.1) 4.3 (4.5) 15.1 (6.7) MMSE 63 0.6 (1.8) 61.5 (1.9) PPA (n=9) 69 1.0 (1.7) 72.0 (1.0) Tv (n=3) 33 33 Pentagons % 4.4 (5.9) 0.5 (1.7) Webster 67.2 (10.3) 60.8 (7.8) Age of onset (yr) + MN (n=8) Fv (n=15)
    • Semantic Dementia vs Controls L Insula R Insula Ventromedial Frontal Anterior Cingulate Ventromedial Frontal L Amygdala R Amygdala Left Right
    • n = 148
    • Findings in Behavior
      • FTD-like behaviors equal FTD and SD > NFPA
      • Functional impairment FTD > AD or SD for given MMSE (behavior driven?)
      • Behavioral dysfunction correlates with right medial frontal disease
      • Specific behavioral abnormalities have unique anatomical associations