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frontotemporal dementia; frontotemporal lobar degeneration; frontotemporal neurocognitive disorder (FTD, FTLD)

Includes Pick's disease, primary progressive aphasias, frontotemporal dementia with parkinsonism (FTDP-17) Epidemiology: 1) onset in 50's-70's 2) no known risk factors 3) 10-16% of cases of dementia Pathology: 1) atrophy of frontal & temporal lobes - exception: inferior frontal gyrus 2) deep gray matter & most white matter regions affected in later stages of disease [11] (stage 3) - exceptions: temporal-parietal junction* & parietal-occipital junction precuneus & entorhinal cortex* affected in stage 4 2) Pick bodies 3) tau inclusions in neurons & glia 4) tau-negative subtype with ubiquitin-positive inclusions confers poorer prognosis [10] 5) TDP-43 deposits in FTD associated with motor neuron disease [15] 6) FUS deposits in some cases [15] 7) ballooned neurons 8) amyloid deposition NOT a feature 9) ~10% of patients also have motor neuron disease [15] 10) appears to progress by spreading via brain connections * contrasts with selective vulnerability of neurons in Alzheimer's disease Genetics: 1) 50% of cases genetic a) 19 different mutations, most point mutations b) about 30% of mutations are autosomal dominant 2) microtubule-associated protein tau (MAPT) mutations in some cases a) see frontotemporal dementia with parkinsonism FTDP-17) b) mutations cluster in C-terminal region exon 10 (microtubule-binding-domain) or adjacent intron 3) associated with mutations in CHMP2b gene (FTD3) 4) associated with mutations in progranulin gene (GRN) [12,13] 5) hexanucleotide repeat expansion in C9ORF72 gene ~3-12% [16] Clinical manifestations: also see dementia for general features 1) clinical heterogeneity, despite apparently identical vgenetic aberrations [13] - 2 distinct clincal variants [15] - behavioral variant (frontotemporal neurocognitive disorder DSM5) - behavioral changes, personality changes - deficits in executive function - discordance between objective cognitive testing & degree of functional impairment early in the disease [15] - primary progressive aphasia - most patients perform worse than expected based on daily function because most cognitive tests are language-based [15] 2) behavioral disturbances (personality changes) occur 1st a) emotional blunting (67%), emotional lability, loss of empathy b) disinhibition, inappropriateness, impulsiveness c) obsessive compulsive behaviors [15] d) loss of social skills (98%) e) loss of insight (67%) f) perseveration g) diminished hygiene h) diminished speech (67%) i) diminished planning/executive function j) poor judgement k) self-injurious behavior l) apathy (67%) m) hyperorality - excessive intake of alcohol - binge eating or bizarre food preferences n) irritability o) aggressiveness p) depression, psychosis uncommon [15] 3) cognitive impairment - memory loss & visualspacial deficits are spared early# - performance on objective cognitive testing may be near normal - executive function & decision making affected early - lack of insight, poor judgement, thus functional impairment - lack of insight into impairment [15] - mental status examination - performance of MMSE may be near normal [15] - early manifestations - difficulty with set switching or sequencing - poor performance on clock drawing test [6] - variable language loss - preserved orientation - preserved visuospatial relations - late manifestations - language impairment - loss of memory & orientation - executive function (planning, organizing, performing complex sequence of tasks) is lost [4] - comprehension, sense of direction, copying skills & memory are relatively spared - word list learning, delayed recall & visuospatial deficits less pronounced with FTD than AD 4) signs, physical examination a) difficulty with motor sequences - muscle wasting [15] b) frontal release signs (primitive reflex) * also see diagnostic criteria for frontotemporal dementia # distinguishing feature from Alzheimer's disease Laboratory: - plasma neurofilament light chain (NfL) may inform disease progression in carriers of predisposing genetic mutations (see Genetics:) [24] - genetic testing appropriate for patients with a first degree relative with FTD [15] - GRN gene mutation Special laboratory: - EEG is normal [9] Radiology: - neuroimaging (CT or MRI) is helpful for confirmation - frontal or anterior temporal lobe abnormality [9] - FDG-PET scan if MRI does not distinguish from Alzheimer's disease [6] Differential diagnosis: 1) Alzheimer's disease - early behavioral changes & preserved visuospatial relations characterize Pick's disease 2) depression - inappropriateness & lack of awareness found in patients with FTD, but not in patients with depression [17] 3) progressive supranuclear palsy: supranuclear ophthalmoplegia 4) corticobasal degeneration: visual hallucinations 5) Lewy body dementia: visual hallucinations, parkinsonism, early falls Complications: - parkinsonism [15] - amyotrophic lateral sclerosis [15%] Management: 1) SSRI's can help compulsive behaviors & other behavioral disturbances 2) no role for cholinesterase inhibitors [6,15] - anecdotal report of cholinesterase worsening symptoms of FTD [29] - rivastigmine may improve behavioral symptoms [29] 3) memantine of no benefit [18] 4) siRNA holds therapeutic promise for treatment of disease resulting fron single nucleotide polymorphisms (SNP) in dominant genes [8] - repeated intrathecal antisense oligonucleotides that selectively blunt expression of G4C2 repeat-containing transcripts & effectively suppress CSF levels of poly(GP) dipeptides [25] (see C9ORF72) 5) progression faster & survival shorter than Alzheimer's disease [10] 6) genetic testing & genetic counseling is family members [15]

Interactions

disease interactions

Related

diagnostic criteria for frontotemporal dementia frontotemporal lobar degeneration (FTLD)

Specific

corticobasal syndrome (CBS) frontotemporal dementia 3 (FTD3, chromosome 3-linked FTD) frontotemporal dementia with parkinsonism (FTDP-17); multiple system tauopathy with presenile dementia (MSTD) Pick's disease

General

dementia; Alzheimer's disease & related dementias (ADRD) neurodegenerative disease

Properties

PATHOLOGY: atrophy ANATOMIC-STRUCTURE: frontal lobe temporal lobe

References

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  4. Miller B, UCSF Memory & Aging Center, 2001
  5. Geschwind, D. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  6. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004; 7th edition 2010 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  7. Martina Wiedau-Pazos, UCLA Brain Matters, June 23, 2003
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  11. Kril JJ et al Distribution of brain atrophy in behaviorally variant frontotemporal dementia J Neurol Sci 232:83, 2005 PMID: 15850587
  12. Baker M et al, Mutations in progranulin cause tau-negative frontotemporal dementa linked to chromosome 17. Nature 2006, 442:916 PMID: 16862116 - Crus M et al, Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature 2006, 442:920 PMID: 16862115
  13. Bruni AC et al, Heterogeneity within a large kindred with frontotemporal dementia: A novel progranulin mutation. Neurology 2007, 69:140 PMID: 17620546
  14. Piguet O et al. Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia. Neurology 2009 Feb 24; 72:732. PMID: 19237702
  15. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 19. American College of Physicians, Philadelphia 2009, 2012, 2015, 2021 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  16. DeJesus-Hernandez M et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011 Oct 20; 72:245. PMID: 21944778 - Renton AE et al A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-68. Epub 2011 Sep 21. PMID: 21944779
  17. Bertoux M et al. Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression. J Neurol Neurosurg Psychiatry 2012 Apr; 83:411 PMID: 22291219
  18. Boxer AL et al. Memantine in patients with frontotemporal lobar degeneration: A multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013 Feb; 12:149 PMID: 23290598
  19. Miller BL et al Case 9-2015 - A 31-Year-Old Man with Personality Changes and Progressive Neurologic Decline. N Engl J Med 2015; 372:1151-1162. March 19, 2015. PMID: 25785973 http://www.nejm.org/doi/full/10.1056/NEJMcpc1409839
  20. Rascovsky K, Hodges JR, Knopman D et al Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2456-77 PMID: 21810890
  21. Chare L, Hodges JR, Leyton CE et al New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications. J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):865-70. PMID: 24421286
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  23. Brown JA, Deng J, Neuhaus J et al Patient-Tailored, Connectivity-Based Forecasts of Spreading Brain Atrophy. Neuron. Oct 14, 2019 PMID: 31623919 https://www.cell.com/neuron/fulltext/S0896-6273(19)30743-3
  24. Rojas JC, Wang P, Staffaroni AM et al. Plasma neurofilament light for prediction of disease progression in familial frontotemporal lobar degeneration. Neurology. 2021 May 4;96(18):e2296-e2312 PMID: 33827960 Free PMC article.
  25. Tran H, Moazami MP, Yang H et al Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nature Medicine 2021. Dec 23 PMID: 34949835 https://www.nature.com/articles/s41591-021-01557-6
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  28. Friedberg A; Pasquini L, Diggs R et al Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia. JAMA Neurol. Published online February 27, 2023. PMID: 36848111 https://jamanetwork.com/journals/jamaneurology/fullarticle/2802050
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