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The Frontotemporal Dementias
- 1. The Frontotemporal Dementias BrianS. Appleby, M.D. Associate Professor of Neurology University Hospitals-Case Medical Center
- 2. Disclosures • Co-PI: Memantinefor FTD • Co-PI: TauRx for FTD
- 3. Objectives 1. Provide anoverview 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 notDiagnosis) 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 MisfoldingDisorders (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 Overproductionof 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 FTDLexicon PGRN MAPT AGD Semantic dementia PPA C9ORF72 FTD FTD-MND FUS PSP NIFID CBD HSD IBMPFD
- 8. Timeline of FTDDiscoveries • 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) NearyCriteria (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, DementiGeriatr Cog Disord 2008
- 12. Papageorgiou S, etal. Alzheimer Dis Assoc Disord, 2009 AD FTLD
- 13. Survival Time Garcin B,Neurology 2009
- 14. Frontotemporal dementia (55%) Primaryprogressive aphasia Semantic dementia (25%) (20%)
- 15. Frontotemporal Dementia • Meanage 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 toleave 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
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- 19. Hemispheric Asymmetry (MRIand PET)
- 20. Primary Progressive Aphasia • • • • • Progressivenon-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 • • • • • • 60y.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
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- 23. Semantic Dementia CaseStudy • 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, butlacks 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 CaseStudy • 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 CaseStudy • 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
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- 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
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- 32. Cholinesterase Inhibitors Cholinesterase inhibitorsworsened cognition and behavior Irwin D, Am J Alzheimers Dis Other Disord 2010
- 33. Memantine • Increases brainFDG-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 usedbecause 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 reallywant to give a disinhibiting medication to a demented person with no frontal lobes?”
- 36. Antidepressants • Loss ofserotonergic 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
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- 40. CJD ZBI=Zarit Burden Interview FTD SD PPA AD CBD JohnsHopkins FTD/YOD
- 41. Neuropsychiatric Comorbidity Boutoleau-Bretonnière C,Dement Geriatr Cogn Disord 2008
- 42. Chow T, JAD2012
- 43. Chow T, JAD2012
- 44. Recommendations • FTD-specific supportgroup • “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 CenteredActivites • TauRx Clinical Trial for FTD • FTD Support Group (Alz Assoc/AFTD) • More to come…
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Editor's Notes
- #13 EOD<65