1. Memory and Aging Center What FTD is teaching us about the brain Joel Kramer Memory and Aging Center UCSF

2. Memory and Aging Center Arnold Pick: 1892 71-year-old male with 2-yr hx of decline Behavior change –Threatened wife with knife –Childish Language disturbance –Marked aphasia; overtalkative with words in wrong order and nonsensical words –Impaired naming Post-mortem: –Pronounced atrophy on left, particularly temporal lobe

3. Memory and Aging Center Alzheimer: 1911 56-yo with poor language and memory, apathy, hyperorality, echolalia Argyrophilic inclusions (Pick bodies) and swollen achromatic cells (Pick cells) in frontal and temporal lobes. Binder lab, NWU

4. Memory and Aging Center Frontotemporal dementia Behavioral variant Primary progressive aphasia –Semantic –Non-fluent

5. Memory and Aging Center Prevalence Common cause pre-senile dementia –Ratnavalli 1:1 with AD 45-64 years (Neurology 2002) –Knopman more common than AD below 60 years (Neurology 2004) –Broader spectrum even more common (PSP, CBD, ALS) Less common after 70?

6. Rates of Psychiatric Diagnosis Woolley et. al. J Clin Psych. 2011.

7. BvFTD Diagnosis♂♀ Depression13 (65%)*8 (50%)* Bipolar affective4 (20%)*4 (25%)* Schizophrenia1 (5%)1 (6%) Anxiety-1 (6%) Adj. Disorder-- * p<0.01; (–) denotes a value of zero; percent listed is in comparison to ND group Psychiatric Diagnoses

8. Memory and Aging Center Neurodegenerative diseases ProteinDisease/Clinical syndrome Amyloid and tauAlzheimer’s disease Alpha-synucleinParkinson’s disease HuntingtonHuntington’s disease Insidious onset; gradual decline Accumulation of abnormally folded proteins Focal vulnerability: regions, networks and function

9. Memory and Aging Center Primary Progressive Aphasia Introduced by Mesalum in 1982 Most prominent clinical feature is difficulty with language (word-finding deficits, paraphasias, effortful speech, grammatical and/or comprehension deficits) These deficits are the principal cause of impaired daily living activities (e.g., problems with communication activity related to speech and language, such as using the telephone) Aphasia should be the most prominent deficit for approximately two years since symptom onset.

10. Memory and Aging Center Semantic Variant PPA (sv-PPA) Poor confrontation naming (of pictures or objects), particularly for low familiarity or low frequency items Impaired single-word comprehension Poor object and/or person knowledge, particularly for low frequency or low familiarity items At least 3 of the following: –Poor object knowledge –Surface dyslexia and/or dysgraphia –Spared repetition –Spared motor speech Predominant anterior temporal lobe atrophy or anterior temporal hypoperfusion or hypometabolism

11. Memory and Aging Center SV-PPA

12. Memory and Aging Center Lessons for neuropsychology Organization of semantic information

13. Neural Network Model of Conceptualisation (Rogers et al., Psych. Rev., 2004) Verbal descriptors Visual features Modality-Invariant Hub Sounds OlfactionPraxis Somatosensory Ovals = Modality-specific association cortices, processing non-semantic perceptual info HUB = Hetero-modal cortex performing higher-order abstraction, away from specific modalities N.B – NO SEMANTIC FEATURES

14. Memory and Aging Center WAIS-3 Info and anterior temporal lobe

15. Memory and Aging Center Surface dyslexia Text Phonological Processor Semantic memory direct lexical access Grapheme-phoneme conversion rules

16. Memory and Aging Center Lessons for neuropsychology Role of anterior temporal lobe in emotion and social behavior

17. Memory and Aging Center Non-fluent variant (NFV-PPA) Grammatical errors and simplification in language production Effortful, halting speech with inconsistent distortions, deletions, substitutions, insertions, or transpositions of speech sounds, particularly in polysyllabic words (often considered to reflect "apraxia of speech") Two of the following: –Impaired comprehension of syntactically complex sentences, with relatively spared comprehension of syntactically simpler sentences –Spared content, single word comprehension –Spared object knowledge Predominant left posterior fronto-insular atrophy or hypometabolism

18. Memory and Aging Center Nonfluent PPA Scan at Presentation Scan after 15 months

19. Memory and Aging Center Lessons for neuropsychology Anatomy of syntax

20. Memory and Aging Center Logopenic Varient PPA (lvPPA) 1. Impaired single-word retrieval in spontaneous speech (speech fluency interrupted by word finding pauses) and confrontational naming 2. Impaired repetition of sentences and phrases At least three of the following other features must be present: 1. Speech sound (phonological) errors in spontaneous speech and naming 2. Spared single word comprehension and object knowledge 3. Spared motor speech (no distortions)4. Absence of frank agrammatism predominant left posterior perisylvian or parietal atrophy

21. Memory and Aging Center Distinguishing Progressive Aphasias SemanticNon-fluentLogopenic Spontaneous speech FluentNon-fluentMixed RepetitionSparedImpaired NamingSevereMildModerate Motor speechSparedImpairedSpared SyntaxSparedImpairedspared 1 0 deficitSemanticsSyntax; motor Lexical access; phonology

22. Memory and Aging Center (Gorno-Tempini et al., 2004)

23. Memory and Aging Center Behavioral variant FTD (bvFTD) Clinical presentation Neuropsychology Neuroanatomy Brain-behavior relationships

24. Memory and Aging Center New diagnostic criteria: bvFTD Possible bvFTD (3 of 6; early and prominent sx) –Behavior disinhibition –Apathy or inertia –Loss of sympathy or empathy –Perseverative, stereotyped or compulsive/ritualistic behavior –Hyperorality and dietary changes –Executive/generation deficits with relative sparing of memory and visuospatial Probable: possible bvFTD plus –Frontal and/or anterior temporal atrophy or –Frontal hypoperfusion or hypometabolism Rascovsky et al 2011

25. Memory and Aging Center Executive/generation deficits with relative sparing of memory and visuospatial

26. Memory and Aging Center Sample Case 58 y.o. RH Caucasian man, previously worked as a computer programmer, referred for progressive changes in behavior and cognition over the last few years

27. Memory and Aging Center Early Symptoms per patient: misplacing objects X 1 year new compulsive habits (shampoo, check temp); new obsession with television buying urges (videos, swords, shields) apathy about hobbies and friends eating more sweets, gained 30 lbs in 2 years less attention to dress & hygiene socially-inappropriate; less discriminating in conversations

28. Memory and Aging Center 2003 2005

29. Memory and Aging Center Patient’s neuropsych MMSE=30 DKEFS Trails=66” (average) Stroop interference=56/min (average) Backward dig span=7 D-word generation=14 (average) Animal generation=16 (low) BNT=15/15 CVLT-SF: 6-8-7-8; 10’=2; recog=7H,3FP

30. Memory and Aging Center The Neuropsychology of bvFTD Episodic memory Spatial cognition Language Working memory Executive functioning Executive / generation deficits with relative sparing of memory and visuospatial functions

31. Memory and Aging Center Consolidation: AD vs bvFTD path/Pib confirmed cases Mansoor et al., 2012

32. Memory and Aging Center Neuropsychology: AD v. bvFTD Controls n=115 AD n=50 bvFTD n=57 Age63.263.958.8 Educ17.016.516.4 MMSE29.626.026.3

33. Memory and Aging Center Group Differences: Spatial and Language ControlsADbvFTD Rey copy 15.513.614.8 Spatial location 9.27.38.1 BNT 14.512.612.8

34. Memory and Aging Center Working memory and fluency ControlsADbvFTD Dig back 5.54.14.2 VF (d-words) 16.210.79.9 Categ fluency 22.411.912.3 Design fluency 11.35.35.7

35. Memory and Aging Center Group differences: Executive ControlsADbvFTD Trails 3.42.12.4 Stroop Int 54.322.231.7

36. Memory and Aging Center Stroop (Heflin et al., 2011) 112 MAC patients Color naming accounted for 73% of the variance Parietal lobes were the best predictor of interference condition performance No relationship to behavioral disinhibition (as measured by NPI)

37. FTD atrophy by clinical stage (Seeley et al.) Early symptomatic N = 15 Symptomatic N = 15 Severe dementia N = 15

38. Memory and Aging Center Behavior and EF are anatomically dissociable Only OFC significantly predicts disinhibition. Only MFG predicts executive functioning. Krueger et al., 2011

39. Memory and Aging Center Lessons for neuropsychology The old brain-behavior rules don’t apply. Edith was right! We cannot automatically infer anatomy from test performance. We must first infer the underlying cognitive constructs involved.

40. Memory and Aging Center –Neuroanatomical substrates AD: R parietal bvFTD: R DLPFC –Cognitive mechanisms AD: spatial perception and attention (“bottom-up”) bvFTD: spatial planning and working memory (“top-down”) AD and bvFTD patients may fail figure copy for different reasons Possin et al., 2011

41. Memory and Aging Center Figure Copy has different anatomical correlates in AD and bvFTD rPLrDLPFC AD r=.54**r=.20 bvFTD r=.26r=.45* **p<.001, *p<.01 controlling ICV, MMSE, sex, age

42. Memory and Aging Center Figure Copy has different cognitive correlates in AD and bvFTD Spatial Perception Spatial Planning Spatial working memory Spatial attention AD.58*.42.25.60* bvFTD.38.67*.51*.35 controlling MMSE, sex, age

43. Memory and Aging Center Ex. 1: spatial distortions and misplacements AD patient, MMSE = 20, Figure copy = 10/17

44. Memory and Aging Center Ex 2: planning and perseverative errors bvFTD, MMSE = 22, Figure copy = 10/17

45. Memory and Aging Center Carey et al. (2008) –Participants: 44 bvFTD, 30 AD, and 27 healthy controls (HC) –Cognitive outcome measures: D-KEFS Tower Test Neuropsychologia, 46, 1081-1087

46. Memory and Aging Center Results Achievement Rule violations

47. Memory and Aging Center Executive Function in AD and bvFTD: The NIH EXAMINER Executive function tasks traditionally not successful at differentiating AD from bvFTD Battery measuring multiple facets of executive functioning, some with a more focal medial or lateral frontal anatomy, and some associated with a dorsal frontal-parietal network 22 bvFTD, 26 AD, and 31 NC

48. Memory and Aging Center EXAMINER scores by Dx after adjusting for MMSE Discriminant function classified the bvFTDs and ADs with 75% accuracy

49. Memory and Aging Center Neuropsychology of FTD Relative preservation of spatial cognition and memory consolidation Comparable to AD on most tasks, including working memory and executive functioning Impaired fluency, but relatively more impaired on phonemic Significantly more prone to rule violations and perseverative errors

50. Memory and Aging Center Lessons for neuropsychology Sometimes we need to think outside the cognitive box

51. Memory and Aging Center Working model of behavioral regulation

52. Memory and Aging Center Motivational and cognitive factors in behavioral regulation

53. Interaction: p<.05 Monetary Incentive Delay

54. Delay Discounting in AD and bvFTD

55. Betting thresholds by dx

56. Memory and Aging Center Lessons for neuropsychology The anatomy of behavior is very interesting

57. The Insula

58. Memory and Aging Center Overeating in bvFTD Orbitofrontal-insular-striatal circuits have been implicated in high-level regulation of feeding. 18 healthy control subjects and 32 patients (13 with FTD) with neurodegenerative disease. The subjects were given as many sandwiches as they wished until either they were full or 1 hour had passed. Woolley et al., 2007

59. Memory and Aging Center Overeating in bvFTD 6 patients (4 men and 2 women), all of them with FTD, each consumed enough sandwiches to be at least 1.5 SD above the mean consumption for all subjects –greater than 17.5 quarter sandwiches for men and 14 quarter sandwiches for women). The overeating patients had significantly more atrophy in the right ventral insula, striatum, and anterior orbitofrontal cortex (OFC).

60. Memory and Aging Center Overeating in bvFTD Right Insular and Ventral Frontal Atrophy Woolley, et al, 2006

61. Memory and Aging Center Lessons for neuropsychology Phrenology is dead. t’s all about networks

62. Network-based Neurodegeneration Time (sec) “Resting” BOLD amplitude Single subject Gray matter volume S1 S2S3S4 S5 S6 S7

63. Executive Functions are Robust and Independent Predictors of White Matter 115 community dwelling older adults FreeSurfer 5.1 and DTI Analysis of the relationship between executive functions and white matter integrity Covariates: Age, Gender, Education, Frontal-Parietal Grey Matter, Processing Speed Result: White Matter is strongly associated with executive functions, and independent of grey matter contribution Bettcher et al., 2012

64. Memory and Aging Center Lessons from bvFTD bvFTD is a behavioral phenotype with possible multiple pathologies It is a medial frontal disorder hitting a frontal insula, ACC and OFC network Dorsolateral PFC can be relatively spared early on The contribution of cognitive neuropsychology is modest –Fluency patterns –Errors and rule monitoring

65. Memory and Aging Center Lessons from bvFTD Right hemisphere rules! –Major role in emotion, personality, behavioral, and attention Importance of studying social cognition –Right amygdala, insula, temporal pole, OFC