frontotemporal dementia; frontotemporal lobar degeneration; frontotemporal neurocognitive disorder (FTD, FTLD)
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Introduction
Includes Pick's disease, primary progressive aphasias, frontotemporal dementia with parkinsonism (FTDP-17)
Epidemiology
- onset in 50's-70's
- no known risk factors
- 10-16% of cases of dementia
Pathology
- atrophy of frontal & temporal lobes
- exception: inferior frontal gyrus
- 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
- Pick bodies
- tau inclusions in neurons & glia
- tau-negative subtype with ubiquitin-positive inclusions confers poorer prognosis[10]
- TDP-43 deposits in FTD associated with motor neuron disease[15]
- FUS deposits in some cases[15]
- ballooned neurons
- amyloid deposition NOT a feature
- ~10% of patients also have motor neuron disease[15]
- appears to progress by spreading via brain connections
* contrasts with selective vulnerability of neurons in Alzheimer's disease
Genetics
- 50% of cases genetic
- 19 different mutations, most point mutations
- about 30% of mutations are autosomal dominant
- microtubule-associated protein tau (MAPT) mutations in some cases
- see frontotemporal dementia with parkinsonism FTDP-17)
- mutations cluster in C-terminal region exon 10 (microtubule-binding-domain) or adjacent intron
- associated with mutations in CHMP2b gene (FTD3)
- associated with mutations in progranulin gene (GRN)[12][13]
- hexanucleotide repeat expansion in C9ORF72 gene ~3-12%[16]
Clinical manifestations
also see dementia for general features
- 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
- behavioral variant (frontotemporal neurocognitive disorder DSM5)
- 2 distinct clincal variants[15]
- behavioral disturbances (personality changes) occur 1st
- emotional blunting (67%), emotional lability, loss of empathy
- disinhibition, inappropriateness, impulsiveness
- obsessive compulsive behaviors[15]
- loss of social skills (98%)
- loss of insight (67%)
- perseveration
- diminished hygiene
- diminished speech (67%)
- diminished planning/executive function
- poor judgement
- self-injurious behavior
- apathy (67%)
- hyperorality
- excessive intake of alcohol
- binge eating or bizarre food preferences
- irritability
- aggressiveness
- depression, psychosis uncommon[15]
- 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
- 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
- memory loss & visualspacial deficits are spared early#
- signs, physical examination
- difficulty with motor sequences
- 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]
Diagnostic procedures
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]
Complications
Differential diagnosis
- Alzheimer's disease
- early behavioral changes & preserved visuospatial relations characterize Pick's disease
- depression
- inappropriateness & lack of awareness found in patients with FTD, but not in patients with depression[17]
- progressive supranuclear palsy: supranuclear ophthalmoplegia
- corticobasal degeneration: visual hallucinations
- Lewy body dementia: visual hallucinations, parkinsonism, early falls
Management
- SSRI's can help compulsive behaviors & other behavioral disturbances
- no role for cholinesterase inhibitors[6][15]
- anecdotal report of cholinesterase worsening symptoms of FTD[29]
- rivastigmine may improve behavioral symptoms[29]
- memantine of no benefit[18]
- 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)
- progression faster & survival shorter than Alzheimer's disease[10]
- genetic testing & genetic counseling is family members[15]
More general terms
More specific terms
- 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
Additional terms
References
- ↑ Brun A, Arch Gerontol Geriatr 6:193, 1987
- ↑ Brun A, Dementia, 4:126, 1993
- ↑ Brun et al, J Neurol Neurosurg Psychiatry 57:416, 1994
- ↑ 4.0 4.1 Miller B, UCSF Memory & Aging Center, 2001
- ↑ Geschwind, D. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ 6.0 6.1 6.2 6.3 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 - ↑ Martina Wiedau-Pazos, UCLA Brain Matters, June 23, 2003
- ↑ 8.0 8.1 Miller VM etl al, PNAS 100(12):7195, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12782788
- ↑ 9.0 9.1 9.2 Cummings JL, The Neuropsychiatry of Alzheimer's Disease and Related Dementias, Martin Dunitz, 2003
- ↑ 10.0 10.1 10.2 Rascovsky K, Salmon DP, Lipton AM, Leverenz JB, DeCarli C, Jagust WJ, Clark CM, Mendez MF, Tang-Wai DF, Graff-Radford NR, Galasko D. Rate of progression differs in frontotemporal dementia and Alzheimer disease. Neurology. 2005 Aug 9;65(3):397-403. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16087904
- ↑ 11.0 11.1 Kril JJ et al Distribution of brain atrophy in behaviorally variant frontotemporal dementia J Neurol Sci 232:83, 2005 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15850587
- ↑ 12.0 12.1 Baker M et al, Mutations in progranulin cause tau-negative frontotemporal dementa linked to chromosome 17. Nature 2006, 442:916 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16862116
Crus M et al, Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature 2006, 442:920 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16862115 - ↑ 13.0 13.1 13.2 Bruni AC et al, Heterogeneity within a large kindred with frontotemporal dementia: A novel progranulin mutation. Neurology 2007, 69:140 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17620546
- ↑ Piguet O et al. Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia. Neurology 2009 Feb 24; 72:732. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19237702
- ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 15.13 15.14 15.15 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 - ↑ 16.0 16.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/21944779 - ↑ 17.0 17.1 Bertoux M et al. Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression. J Neurol Neurosurg Psychiatry 2012 Apr; 83:411 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22291219
- ↑ 18.0 18.1 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: https://www.ncbi.nlm.nih.gov/pubmed/23290598
- ↑ 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. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25785973 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcpc1409839
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/21810890
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/24421286
- ↑ Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015 Oct 24;386(10004):1672-82. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26595641 Free PMC Article
- ↑ Brown JA, Deng J, Neuhaus J et al Patient-Tailored, Connectivity-Based Forecasts of Spreading Brain Atrophy. Neuron. Oct 14, 2019 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31623919 https://www.cell.com/neuron/fulltext/S0896-6273(19)30743-3
- ↑ 24.0 24.1 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: https://www.ncbi.nlm.nih.gov/pubmed/33827960 Free PMC article.
- ↑ 25.0 25.1 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: https://www.ncbi.nlm.nih.gov/pubmed/34949835 https://www.nature.com/articles/s41591-021-01557-6
- ↑ Sivasathiaseelan H, Marshall CR, Agustus JL et al. Frontotemporal dementia: a clinical review. Semin Neurol. 2019;39(2):251-263 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30925617 https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0039-1683379
- ↑ Toller G et al. Sensitivity of the Social Behavior Observer Checklist to early symptoms of patients with frontotemporal dementia. Neurology 2022 May 18; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35584922 https://n.neurology.org/content/99/5/e488
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/36848111 https://jamanetwork.com/journals/jamaneurology/fullarticle/2802050
- ↑ 29.0 29.1 29.2 Huey ED, Putnam KT, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology. 2006 Jan 10;66(1):17-22. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16401839 PMCID: PMC4499854 Free PMC article. Review.