1.The Frontotemporal Dementias Brian S. Appleby, M.D. Associate Professor of Neurology University Hospitals-Case Medical Center

2. Disclosures Co-PI: Memantine for FTD Co-PI: TauRx for FTD 3. Objectives 1. Provide an overview of the cause underlying frontotemporal dementia (FTD) 2. Provide an overview of the clinical symptoms and diagnosis of FTD 3. Explore caregiver burdens of caring for individuals with FTD and subsequent management options 4. Dementia (Symptom not Diagnosis) Chest Pain Heart attack Pneumonia Muscle strainDementia Reversible causes Vitamin deficiency Depression Progressive brain diseases Alzheimers disease Frontotemporal dementia Dementia with Lewy bodies 5. Neurodegenerative Dementias Protein Misfolding Disorders (PMD) DiseaseProteinAlzheimers diseaseA-beta (plaques) Phosphorylated tau (tangles)Parkinsons diseaseAlpha-synuclein (Lewy bodies)Prion diseasePrion proteinFrontotemporal dementiasVarious - Phosphorylated tau - Ubiquinated inclusions (TDP-43) 6. PMD Origins Root CausesExampleOverproduction of proteinsTrisomy 21, ADInefficient protein metabolismPresenilin mutations in ADImpaired protein clearanceTauopathies-impaired transportNeurotoxicityProtein oligomers in most PMDExictotoxicityWorking overtime-glutamate toxicityUnfolded protein responseStop making the normal proteinsAD=Alzheimers disease; PMD=protein misfolding disorders 7. The Crazy FTD Lexicon PGRN MAPTAGDSemantic dementiaPPA C9ORF72FTD FTD-MNDFUSPSPNIFIDCBD HSDIBMPFD 8. Timeline of FTD Discoveries Frontal and temporal atrophy in dementia (Pick 1892) Pick bodies (Alzheimer & Pick 1911) Pathology criteria (3 types) (Brun 1994) Clinical criteria (3 types) (Neary 1998)Brun A, J Mol Neurosci 2011 9. Frontotemporal Lobar Degeneration (FTLD) Neary Criteria (1998) Frontotemporal dementia Primary progressive aphasia (PPA) Semantic dementia (SD)Other Family Members Progressive non-fluent aphasia (PNFA) Logopenic aphasia Progressive supranuclear palsy (PSP) Cortical basal degeneration (CBD) FTD-motor neuron disease 10. Causes Sporadic Familial (~25%) Environmental Risk Factors (?) Traumatic brain injury Pathology of chronic traumatic encephalopathy is similar to FTD with some important differences 11. Appleby BS, Dementi Geriatr Cog Disord 2008 12. Papageorgiou S, et al. Alzheimer Dis Assoc Disord, 2009ADFTLD 13. Survival TimeGarcin B, Neurology 2009 14. Frontotemporal dementia (55%)Primary progressive aphasia Semantic dementia (25%) (20%) 15. Frontotemporal Dementia Mean age of onset: 55-65 years-of-age Male>Female Prominent frontal lobe symptoms Disinhibition Poor insight/judgment Loss of social graces Perseverative behaviors Apathy 16. FTD Case Study 58 y.o. AAM attorney with h/o dyslexia with a 2 yr h/o cognitive decline and personality change Distracted, poor concentration, low mood, fatigued Only reads comic books and watches cartoons, often the same ones repeatedly 17. Exam General: Asked to leave room several times to walk around. Buccal stereotypies (i.e., blowing) Speech: Sparse, poverty of content Affect: Flat, no brightening MMSE: 19/30 Brain MRI: Mild generalized atrophy 18. Further Work-upBrain SPECT 19. Hemispheric Asymmetry (MRI and PET) 20. Primary Progressive Aphasia Progressive non-fluent aphasia Decreased speech output Speech apraxia Changes in grammar use Neuropathology is often progressive supranuclear palsy or corticobasal degenerationJosephs KA, Brain 2006 21. PPA Case Study 60 y.o. WM with no past neuropsych hx Initial complaint is stuttering/stammering Phonemic paraphrasic errors on exam MoCA=28/30 f=2 words, animals=18 At next visit, has complaints of poor concentration and distractibility 22. Semantic Dementia AnimalBird 23. Semantic Dementia Case Study 77 y.o. WF with a 2 year history of losing words Initial symptom was forgetting the essence of and word for furnace filter Calls everyone honey-child More frontal behaviors/personality changes Obsessed with puzzles 24. Exam Speech: fluent, but lacks content and is vague with generalization of word usage Verbal fluency: f=12 words, animals=1 Behaviors: Some perseverative picking Memory and visuospatial skills were completely intact 25. Progressive Supranuclear Palsy Case Study 60 y.o. WF with h/o rheumatic fever, GERD, vit D def, osteopenia, and liver/brain hemangiomas 1 yr h/o progressive strabismus with diplopia (repaired with return 1 mo later), parkinsonism, dysarthria, and shortterm amnesia, fatigue, anxiety, panic attacks 26. Exam Speech: hypophonic, sparse, dysarthric Thought Process: bradyphrenic Affect: stable, flat without brightening MMSE: 7/30 UPDRS II: 43 Neuro: vertical gaze impairment, choppy saccades, hypomimia, axial rigidity 27. Cortical Basal Degeneration Case Study 50 y.o. female from Spain with 4 yr h/o gradual executive dysfxn, short-term amnesia, progressive non-fluent aphasia, parkinsonism, and myoclonus Paces frequently, apathetic, crying when frustrated, seen responding to internal stimuli, and sometimes thinks others are stealing from her 28. Exam (1/2) Gait: slow, shuffling, leans to left Speech: Effortful, paraphrasic errors MMSE: 5/30 3MS: 17/100 Clock: 1/5 UPDRS II: 44 Myoclonus with speech and action Left-sided neglect, finger agnosia 29. Exam (2/2) PentagonsClock 30. CohortnC9ORF72PGRNSOD1TARDBPFUSfFTLD-TDP6625 (38%)13 (20%)n/an/an/asFTLD-TDP538 (15%)8 (15%)n/an/an/afALS348 (24%)n/a4 (12%)1 (3%)1 (3%)sALS1958 (4%)n/a0 (0%)2 (1%)3 (1.5%)f=familial, s=sporadicOther mutations: MAPT, VCP, CHMP2B Adapted from: DeJesus-Hernandez M, Neuron 2011 31. Treatment/Management 32. Cholinesterase InhibitorsCholinesterase inhibitors worsened cognition and behavior Irwin D, Am J Alzheimers Dis Other Disord 2010 33. Memantine Increases brain FDG-PET metabolism in FTD and SD (Chow 2011, 2012) No improvement in behavior/cognition (DiehlSchmid 2008, Vercelletto 2011) Transient improvement in neuropsych symptoms in FTD and PPA (Swanberg 2007, Boxer 2009) Large double-blind, RCT, no effects (Boxer A, Lancet Neurol 2013) 34. Antipsychotics Often used because of behavioral symptoms Mounting evidence of hypersensitivity to EPS in FTD (Mendez 2001, Pijnenburg 2003, Czarnecki 2008) Think of overlap of FTLD with ParkinsonsPlus disorders 35. Benzodiazepines Do you really want to give a disinhibiting medication to a demented person with no frontal lobes? 36. Antidepressants Loss of serotonergic neurons->replete with serotonergic drugs Trazodone (Lebert 2004) SSRIs (Swartz 1997, Moretti 2003, Herrmann 2011) Paroxetine: no effect, worsened cognition (Deakin 2004) 37. Citalopram 40mg/dayHerrmann N, Am J Geriatr Psychiatry 2012 38. Brain 2011 39. The Other PatientCAREGIVERS 40. CJD ZBI=Zarit Burden InterviewFTDSDPPAADCBDJohns Hopkins FTD/YOD 41. Neuropsychiatric ComorbidityBoutoleau-Bretonnire C, Dement Geriatr Cogn Disord 2008 42. Chow T, JAD 2012 43. Chow T, JAD 2012 44. Recommendations FTD-specific support group What if it isnt Alzheimers? by Lisa Radin At least day per week of personal time for caregivers Speak to children early and often Social Security Disability Insurance (SSDI) Compassionate Allowances (fast track) 45. Resources Alzheimers Association (www.alz.org) Association for Frontotemporal Dementia (AFTD) (www.theaftd.org) FTD specific support groups (Alz Assoc/AFTD) (Columbus, Akron, Cleveland) 46. Frontotemporal Dementia Centered Activites TauRx Clinical Trial for FTD FTD Support Group (Alz Assoc/AFTD) More to come 47. Thank You