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The Frontotemporal Dementias
- 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 strain Dementia • Reversible causes – Vitamin deficiency – Depression • Progressive brain diseases – Alzheimer’s disease – Frontotemporal dementia – Dementia with Lewy bodies
- 5. Neurodegenerative Dementias Protein Misfolding Disorders (PMD) Disease Protein Alzheimer’s disease A-beta (plaques) Phosphorylated tau (tangles) Parkinson’s disease Alpha-synuclein (Lewy bodies) Prion disease Prion protein Frontotemporal dementias Various - Phosphorylated tau - Ubiquinated inclusions (TDP-43)
- 6. PMD Origins Root Causes Example Overproduction of proteins Trisomy 21, AD Inefficient protein metabolism Presenilin mutations in AD Impaired protein clearance Tauopathies-impaired transport Neurotoxicity Protein oligomers in most PMD Exictotoxicity “Working overtime”-glutamate toxicity Unfolded protein response Stop making the normal proteins AD=Alzheimer’s disease; PMD=protein misfolding disorders
- 7. The Crazy FTD Lexicon PGRN MAPT AGD Semantic dementia PPA C9ORF72 FTD FTD-MND FUS PSP NIFID CBD HSD IBMPFD
- 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, 2009 AD FTLD
- 13. Survival Time Garcin 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
- 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 degeneration Josephs 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
- 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
- 30. Cohort n C9ORF72 PGRN SOD1 TARDBP FUS fFTLD-TDP 66 25 (38%) 13 (20%) n/a n/a n/a sFTLD-TDP 53 8 (15%) 8 (15%) n/a n/a n/a fALS 34 8 (24%) n/a 4 (12%) 1 (3%) 1 (3%) sALS 195 8 (4%) n/a 0 (0%) 2 (1%) 3 (1.5%) f=familial, s=sporadic Other mutations: MAPT, VCP, CHMP2B Adapted from: DeJesus-Hernandez M, Neuron 2011
- 32. Cholinesterase Inhibitors Cholinesterase 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 “Parkinson’sPlus” 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/day Herrmann N, Am J Geriatr Psychiatry 2012
- 38. Brain 2011
- 40. CJD ZBI=Zarit Burden Interview FTD SD PPA AD CBD Johns Hopkins FTD/YOD
- 41. Neuropsychiatric Comorbidity Boutoleau-Bretonnière 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 isn’t Alzheimer’s?” by Lisa Radin • At least ½ 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 • Alzheimer’s 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
Editor's Notes
- EOD<65