1. Frontotemporal lobar degeneration: demographic and clinical characteristics in a Turkish dementia population Görsev G. Yener, M.D. Neurology, Dokuz Eylül University Neurology, Dokuz Eylül University Izmir, Turkey gorsev.yener@deu.edu.tr

2. Turkey- getting older WHO 1998

3. FTLD Prevalence Not clear (4-16%) Not clear (4-16%) Common cause pre-senile dementia Common cause pre-senile dementia 1:1 with AD 45-64 years 1:1 with AD 45-64 years (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)

4. FTLD in Izmir, Turkey Demographic data Genetics/Pathological Syndrome Neary Criteria – FTD, PA, SD MND association

5. 1994-2004 Izmir DEU Dementia Clinic 1994-2004 Izmir DEU Dementia ClinicN=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 %

6. FTLD Clinical Heterogeneity Genetic & sporadic cases Genetic & sporadic cases Histology varies Histology varies Motor overlap with PSP, CBD, ALS Motor overlap with PSP, CBD, ALS

8. Neary Criteria Frontotemporal Lobar Degeneration Frontotemporal Lobar Degeneration Frontotemporal Dementia Frontotemporal Dementia Progressive Non-Fluent Aphasia Progressive Non-Fluent Aphasia Semantic Dementia Semantic Dementia Neary et al. 1998, Neurology

9. Dokuz Eylül University Dementia and Movement Disorders Clinics 1994-2001 1994-2001 35 FTLD, 25 PSP, 5 CBD cases 35 FTLD, 25 PSP, 5 CBD cases Demographic and clinical features Demographic and clinical features Webster Webster MMSE (subitems) MMSE (subitems)

10. 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

11. 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

12. Presenile onset (%) -Turkish **

13. 40-60 % 40-60 % In Netherland series 38% In Netherland series 38% (15 million screened) (15 million screened) Family Hx (+), RR=3.5 Family Hx (+), RR=3.5 Family history

14. Family Hx (%)-Turkish population**

15. FTLD Pathological Syndrome Core Features Frontotemporal predominance Frontotemporal predominance Gliosis, spongiosus, neuronal loss Gliosis, spongiosus, neuronal loss

16. Variable Histological Features Neuronal inclusions with ubiquitin Neuronal inclusions with ubiquitin (Clinical: MND, ALS, Paget, Inclusion body myositis) (Clinical: MND, ALS, Paget, Inclusion body myositis) Neuronal inclusions with tau Neuronal inclusions with tau (Clinical: FTDP-17, PSP, CBD) (Clinical: FTDP-17, PSP, CBD) Other inclusions Other inclusions (Neuronal intermediate filament inclusion dementia) (Neuronal intermediate filament inclusion dementia) No inclusions (DLDH) No inclusions (DLDH) (Clinical: FTLD) (Clinical: FTLD)

17. Pick Bodies Cerebral cortex (Described by Alzheimer in 1911)

20. Time (minutes) Distance travelled by the tau species ( m) B.A. a b c d 0N4R-EGFP 0N4R-untagged Courtesy of Tim Hutton, Cambridge, UK

21. Tau mutations

22. 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

23. FTD with ubiquitinated neuronal inclusions and visuospatial impairment Meiner et al Neurology 2005;65:478–480

24. Ubiquitin and Tau Ubiquitin is a marker for a given protein to be sent to a proteasome for degradation 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 Ubiquitin proteins are also needed for the degradation of tau

25. FTD Neuropathology Subtypes FTD-Ub related to MND subtype FTD-Ub related to MND subtype CBD, PSP major tau subtype CBD, PSP major tau subtype DLDH less common with new staining techniques DLDH less common with new staining techniques

26. Clinical Features Subtypes Subtypes MND MND Parkinsonism Parkinsonism MMSE MMSE

27. 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

28. MND and FTD are associated FTD is associated with MND (15%) FTD is associated with MND (15%) Most ALS patients develop FTD Most ALS patients develop FTD FTLD-ALS chr 9 and 17 FTLD-ALS chr 9 and 17 Hypometabolism in frontal lobes in ALS Hypometabolism in frontal lobes in ALS

29. Chang et al, Neurology 2005;65:75–80 Brain atrophy in ALS and ALS/FTLD

30. Turkish FTLD and MND

31. Webster scores-Turkish FTLD subtypes Clinical Features-Parkinsonism **

32. Clinical Features Parkinsonism appears earlier in FTLD Parkinsonism appears earlier in FTLD MND - more often parkinsonism MND - more often parkinsonism No tau mutation was found in FTD- MND group. No tau mutation was found in FTD- MND group.

33. MMSE Scores in Turkish FTLD

34. MMSE Figure copying (%)

36. Clinical patterns PSP~CBD Both higher Webster and MMSE scores Both higher Webster and MMSE scores MMSE figure copy is discriminative MMSE figure copy is discriminative

37. Clinical patterns Webster scores Webster scores FTD-MND > FTLD FTD-MND > FTLD MMSE scores MMSE scores FTD-MND = FTLD FTD-MND = FTLD preserved figure copying preserved figure copying FTD-MND > FTLD FTD-MND > FTLD

38. Clinical patterns FTLD subtypes total MMSE PNFA < SD < FTD total MMSE PNFA < SD < FTD figure copySD < PNFA < FTD figure copySD < PNFA < FTD

39. Conclusions FTLD common in presenile ages FTLD common in presenile ages Turkish FTLD subtypes have similar profile to the US Turkish FTLD subtypes have similar profile to the US FTD> PNFA > SD FTD> PNFA > SD

40. Conclusions Higher family Hx than other dementias (54%) Higher family Hx than other dementias (54%) FTLD-MND association (22%) FTLD-MND association (22%) FTD-MND has higher parkinsonism scores FTD-MND has higher parkinsonism scores

41. Neary Criteria Frontotemporal Lobar Degeneration Frontotemporal Lobar Degeneration Frontotemporal Dementia Frontotemporal Dementia Progressive Non-Fluent Aphasia Progressive Non-Fluent Aphasia Semantic Dementia Semantic Dementia Neary et al. 1998, Neurology

42. Fv FTD M.Y. 52 y F Mute, childish, delusional, inappropriate behavior, stereotypic movements, incontinence (+) Family Hx

43. 1999 2000

44. Progressive Non-Fluent Aphasia (frontal variant) Non-fluent spontaneous speech with at least one of the following: Non-fluent spontaneous speech with at least one of the following: Agrammatism Agrammatism Phonemic paraphasias Phonemic paraphasias Anomia Anomia

45. Semantic Dementia (Temporal variant) Subtype of frontotemporal dementia Subtype of frontotemporal dementia Marked anomia Marked anomia Loss of meaning of words (semantics) Loss of meaning of words (semantics) Progressive perceptual disorder Progressive perceptual disorder Prosopagnosia or Prosopagnosia or Visual agnosia Visual agnosia

46. SEMANTIC DEMENTIA Raise your left arm Show me the door

47. Corticobasal degeneration

48. Conclusions FTLD common in presenile ages FTLD common in presenile ages Clinical syndromes depends on anatomical heterogeneity Clinical syndromes depends on anatomical heterogeneity Pathology- Tau, Ubiquitin, NIFID, DLDH Pathology- Tau, Ubiquitin, NIFID, DLDH

49. Conclusions Turkish FTLD subtypes have similar ratios to the US co-hort Turkish FTLD subtypes have similar ratios to the US co-hort FTD> PNFA > SD FTD> PNFA > SD Higher family Hx than other dementias (54%) Higher family Hx than other dementias (54%) FTLD-MND association (22%) FTLD-MND association (22%)

50. = Non-fluent PA FTD/CBD = Posterior PA AD = Semantic Dementia FTD Progressive Non-Fluent Aphasia (frontal variant)

52. Delusions 0 25 50 75 100 Percent HallucinationsAgitationDepressionAnxietyElation Apathy 0 25 50 75 100 Percent Disinhibition Irritability Aberrant MB Sleep DOEating DO FTD AD Frequency of Behavioral Disorders in AD and FTD (Neuropsychiatric inventory) [ * [ * [ * [ * Rosen et al. 2003 Neurology

53. Where and how does the brain represent knowledge? Where and how does the brain represent knowledge? Symbolic-linguistic function lost Symbolic-linguistic function lost Visual representation spared Visual representation spared Information represented in separate systems with distinctive anatomy Information represented in separate systems with distinctive anatomy Semantic Dementia

54. FTLD subtypes in Izmir, Turkey (n=35) 15 frontal variant (Fv) 15 frontal variant (Fv) 9 primary progressive aphasia (PPA) 9 primary progressive aphasia (PPA) 3 semantic dementia (Tv) 3 semantic dementia (Tv) 8 motor neuron signs (only 2 with MND) 8 motor neuron signs (only 2 with MND) as PPA and Fv as PPA and Fv

55. Family history is higher in FTLD than other neurodegenerative dementias Family history is higher in FTLD than other neurodegenerative dementias

56. Conclusions FTLD common presenile dementia FTLD common presenile dementia Clinical syndromes driven by anatomic heterogeneity Clinical syndromes driven by anatomic heterogeneity Linked to PSP, CBD, ALS Linked to PSP, CBD, ALS Pathology - Tau, Ubiquitin, DLDH Pathology - Tau, Ubiquitin, DLDH Window frontotemporal functions Window frontotemporal functions

57. Emotions and Temporal Damage Left amygdala Right amygdala

58. Florida Affect Battery Anger Fear Sadness Happiness

59. 100908070605040 2.5 2.0 1.5 1.0.5 Percent correct, negative emotions Volume right amygdala (cc 3 )

60. FTLD(n=35) % (+SD) PSP(n=25) CBD(n=5) Alzheimer (n=261 # ) % (+SD) Age of onset (yr) 58.7(16.7)63.5(7.2)58.0(4.5)68.5(8.4) Presenile onset (%)464810025.7 1 o relative (%) dementia/psychosis 54.3 54.3 25 * 20 24.1 & Gender (F %) 41286061 # not updated for n=390 * parkinsonism and tremor was also asked & family history was taken from 244 cases

61. FTLD subtypes Fv (n=15) Tv (n=3) PPA (n=9) Motor neuron involvement (n=8) Age of onset (yr) 60.8(7.8) 72.0 (1.0) 61.5(1.9) 67.2 (10.3) Websterscore (St dev) 0.5 (1.7) 1.0 (1.7) 0.6 (1.8) 4.4 (5.9) MMSE Mean (St dev) 15.1 (6.7) 4.3 (4.5) 2.5 (4.1) 14.1 (7.3) MMSE- Figure copy (%) 4702563

62. FTLD (fv/tv/ppa) (n=27) PSP(n=3)KBD(n=5) FTD + Motor neuron involvement (n=8) Age of onset (yr) 58.7 (16.7) 72.0 (1.0) 61.5(1.9) 67.2 (10.3) Websterscore (St dev) 4.9 (6.4) 11.4 (5.3) 9.2 (5.8) 4.4 (5.9) MMSE Mean (St dev) 14.1 (9.7) 24.3 (5.5) 23.6 (5.0) 14.1 (7.3) MMSE- Figure copy (%) 3369063

63. Florida Affect Battery Facial and prosodic subtests Facial and prosodic subtests Anger, happiness, sadness, fear and neutral Anger, happiness, sadness, fear and neutral Emotions

64. 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)

65. 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 * * *

66. Reduced Survival With Comorbid ALS Median Survival (Years) From: SubjectsDeathsOnsetPresentation + ALS 21194.91.4 - ALS 1345611.53.8 05101520 0 25 50 75 100 FTD + ALS AD - ALS Years From Onset Percent survival P<.0001 036912 0 25 50 75 100 FTD + ALS AD - ALS Years From Presentation Percent survival P<.0001 Roberson, et al. Neurology 2005

67. FTLD subtypes Fv (n=15) Tv (n=3) PPA (n=9) Motor neuron involvement (n=8) Age of onset (yr) 60.8(7.8) 72.0 (1.0) 61.5(1.9) 67.2 (10.3) Websterscore (St dev) 0.5 (1.7) 1.0 (1.7) 0.6 (1.8) 4.4 (5.9) MMSE Mean (St dev) 15.1 (6.7) 4.3 (4.5) 2.5 (4.1) 14.1 (7.3) MMSE- Figure copy (%) 4702563

68. FTLD (fv/tv/ppa) (n=27) PSP(n=3)KBD(n=5) FTD + Motor neuron involvement (n=8) Age of onset (yr) 58.7 (16.7) 72.0 (1.0) 61.5(1.9) 67.2 (10.3) Websterscore (St dev) 4.9 (6.4) 11.4 (5.3) 9.2 (5.8) 4.4 (5.9) MMSE Mean (St dev) 14.1 (9.7) 24.3 (5.5) 23.6 (5.0) 14.1 (7.3) MMSE- Figure copy (%) 3369063

69. FTLD(n=35) % (+SD) PSP(n=25) CBD(n=5) Alzheimer (n=390) % (+SD) Age of onset (yr) 58.7(16.7)63.5(7.2)58.0(4.5)68.5(8.4) Presenile onset (%) 464810025.7 Family Hx (%) 54.3 54.3 25 * 20 24.1 & Gender (F %) 41286061

70. Fv(n=15)Tv(n=3)PPA(n=9) + MN (n=8) Age of onset (yr) 60.8 (7.8) 72.0 (1.0) 61.5 (1.9) 67.2 (10.3) Webster 0.5 (1.7) 1.0 (1.7) 0.6 (1.8) 4.4 (5.9) MMSE 15.1 (6.7) 4.3 (4.5) 2.5 (4.1) 14.1 (7.3) Pentagons%336906333

71. Semantic Dementia vs Controls L Insula R Insula Ventromedial Frontal Anterior Cingulate Ventromedial Frontal L Amygdala R Amygdala Left Right

72. n = 148

73. 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