Frontotemporal lobar degeneration

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Frontotemporal lobar degeneration
Frontotemporal degeneration.png
A human brain showing frontotemporal lobar degeneration causing frontotemporal dementia.
OMIM 600274
DiseasesDB 10034
MeSH D003704

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Synonyms and Keywords: Disinhibition-dementia-parkinsonism-amyotrophy complex; ddpac; frontotemporal dementia-amyotrophic lateral sclerosis; ftd-als pallidopontonigral degeneration; ppnd FTLD; frontotemporal lobar degeneration with tau inclusions; ftld with tau inclusions; frontotemporal dementia with parkinsonism; frontotemporal lobe dementia; fldem; ftdp17; multiple system tauopathy with presenile dementia; mstd;

Overview

Frontotemporal lobar degeneration (FTLD) is a pathologic process involving degeneration of gray matter in the frontal lobe and anterior portion of the temporal lobe of the cerebrum, with sparing of the parietal and occipital lobes.

Pathophysiology

The gross finding of frontotemporal lobar degeneration is likely produced by several etiologically distinct processes, with unique genetic and histopathological findings. Accordingly, there are a number of possible histopathological findings at post-mortem:

  • tau inclusions (either with Pick bodies or without)
  • ubiquitin positive (tau-negative) inclusions - in the majority of cases that have this type of pathology the ubiquitinated inclusions contain a protein called TDP-43. There are three subtypes of this type of pathology. Mackenzie et al (and subsequently Davidson et al) describe the following: type 1 with intranuclear inclusions; type 2 with neurites predominantly and type 3 with cytoplasmic inclusions predominantly. It should be noted that not all ubiquitin-positive, tau negative cases stain for TDP-43 e.g. the CHMP2B cases but also other cases.
  • Dementia lacking distinctive histology (DLDH) - A rare and controversial entity - new analyses have allowed many cases to be reclassified into one of the positively-defined subgroups.

Genetics

Many cases (possibly up to 50%) of FTLD are genetic rather than sporadic. Mutations in the Tau gene (on chromosome 17q21 - known as MAPT or Microtubule Associated Protein Tau) can cause FTLD and there are over 40 known mutations at present. A series of new mutations associated with FTLD has been recently described in the progranulin gene which is remarkably also on chromosome 17q21. Patients with progranulin mutations have type 1 TDP-43 positive, tau negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, whereas the mutations seen in the progranulin gene associated with FTLD suggests a deficit in progranulin may be the problem. There are currently 2 other known genes that can cause FTLD: CHMP2B (on chromosome 3) which is associated with a behavioural syndrome (mainly in a large Jutland cohort); and VCP (valosin-containing protein, on chromosome 9) which is associated with the IBMPFD syndrome (inclusion body myopathy, Paget's disease and frontotemporal dementia). These 2 genes only account for a tiny proportion of cases. A locus on chromosome 9 is associated with FTD-MND (or FTD-ALS) i.e. frontotemporal dementia associated with motor neurone disease (or amyotrophic lateral sclerosis) - the hunt for this gene is currently the focus of a number of research labs around the world.

Differential Diagnosis Of Major or Mild Frontotemporal Neurocognitive Disorder

  • Other neurocognitive disorders
  • Other neurological conditions
  • Other mental disorders and medical conditions
Cause of dementia Clinical features Associated features Nature of progression Histopathological findings
Cognitive impairment
Recall Recollection Cue requirement for recall Infirngement of thoughts Semantic memory Procedural memory Working memory Awareness Attention Executive functioning issues Visuo-spatial skills
Alzheimer's disease +++

(Slow cognitive and functional decline with early loss of awareness)

+++ Not helpful +++ ++ - ++ +++ ++ ++ ++ Has the following clinical stages:
Lewy body dementia ++ - Helpful +++ + + +++ + +++ +++ +++
Frontotemporal lobar degeneration +/- - Helpful +++ + - +++ +++ ++ +++ -
  • Onset in young age
Vascular dementia + (Dysexecutive syndrome) - Helpful + + + ++ - ++ +++ +


Epidemiology and Demographics Of Major or Mild Frontotemporal Neurocognitive Disorder

Prevalence

The prevalence of major or mild frontotemporal neurocognitive disorder is 2,000-10,000 per 100,000 (2%-10%) of the overall population.[1]

Age

In the over 65 age group, FTLD is probably the fourth most common cause of dementia after Alzheimer's disease, Dementia with Lewy bodies and vascular dementia. In the below 65 age group, it is the second most common cause after Alzheimer's disease. The process of FTLD is thought to be the main cause of three clinical syndromes: frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.

Risk Factors Of Major or Mild Frontotemporal Neurocognitive Disorder

Diagnosis

Symptoms

Physical Examination

Neuro

DSM-V Diagnostic Criteria for Major Or Mild Frontotemporal Neurocognitive Disorder[1]

  • A.The criteria are met for major or mild neurocognitive disorder.

AND

  • B.The disturbance has insidious onset and gradual progression.

AND

  • C.Either (1) or (2);
  • 1.Behavioral variant;
  • a.Three or more of the following behavioral symptoms:
  • i.Behavioral disinhibition.
  • ii.Apathy or inertia.
  • iii.Loss of sympathy or empathy.
  • iv.Perseverative, stereotyped or compulsive/ritualistic behavior.
  • v.Hyperorality and dietary changes.
  • b.Prominent decline in social cognition and/or executive abilities.
  • 2.Language variant:
  • a.Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension.

AND

  • D.Relative sparing of learning and memory and perceptual-motor function.

AND

  • E.The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder.

Probable frontotemporal neurocognitive disorderis diagnosed if either of the following is present; otherwise, possible frontotemporal neurocognitive disorder should be diagnosed:

  • 1.Evidence of a causative frontotemporal neurocognitive disorder genetic mutation, from either family history or genetic testing.
  • 2.Evidence of disproportionate frontal and/or temporal lobe involvement from neuro imaging.

Possible frontotemporal neurocognitive disorderis diagnosed if there is no evidence of a genetic mutation, and neuro imaging has not been performed.

References

  1. 1.0 1.1 1.2 1.3 Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.
  2. Jellinger KA (2008). "The pathology of "vascular dementia": a critical update". J. Alzheimers Dis. 14 (1): 107–23. PMID 18525132.
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  4. Hodges JR, Patterson K (1996). "Nonfluent progressive aphasia and semantic dementia: a comparative neuropsychological study". J Int Neuropsychol Soc. 2 (6): 511–24. PMID 9375155.
  5. Hodges JR, Patterson K, Oxbury S, Funnell E (1992). "Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy". Brain. 115 ( Pt 6): 1783–806. PMID 1486461.
  6. "Dementia, Globalization and Contemporary Art".
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  8. Weintraub S, Wicklund AH, Salmon DP (2012). "The neuropsychological profile of Alzheimer disease". Cold Spring Harb Perspect Med. 2 (4): a006171. doi:10.1101/cshperspect.a006171. PMC 3312395. PMID 22474609.
  9. Goldman JG, Williams-Gray C, Barker RA, Duda JE, Galvin JE (2014). "The spectrum of cognitive impairment in Lewy body diseases". Mov. Disord. 29 (5): 608–21. doi:10.1002/mds.25866. PMC 4126402. PMID 24757110.
  10. Metzler-Baddeley C (2007). "A review of cognitive impairments in dementia with Lewy bodies relative to Alzheimer's disease and Parkinson's disease with dementia". Cortex. 43 (5): 583–600. PMID 17715794.
  11. Uversky VN (2008). "Alpha-synuclein misfolding and neurodegenerative diseases". Curr. Protein Pept. Sci. 9 (5): 507–40. PMID 18855701.
  12. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE (2004). "Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function". Arch. Neurol. 61 (3): 378–84. doi:10.1001/archneur.61.3.378. PMID 15023815.
  13. Brion JP (1998). "Neurofibrillary tangles and Alzheimer's disease". Eur. Neurol. 40 (3): 130–40. PMID 9748670.
  14. Lee JS, Jung NY, Jang YK, Kim HJ, Seo SW, Lee J, Kim YJ, Lee JH, Kim BC, Park KW, Yoon SJ, Jeong JH, Kim SY, Kim SH, Kim EJ, Park KC, Knopman DS, Na DL (2017). "Prognosis of Patients with Behavioral Variant Frontotemporal Dementia Who have Focal Versus Diffuse Frontal Atrophy". J Clin Neurol. 13 (3): 234–242. doi:10.3988/jcn.2017.13.3.234. PMC 5532319. PMID 28748674.
  15. Pao WC, Dickson DW, Crook JE, Finch NA, Rademakers R, Graff-Radford NR (2011). "Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically". Alzheimer Dis Assoc Disord. 25 (4): 364–8. doi:10.1097/WAD.0b013e31820f8f50. PMC 3107353. PMID 21346515.
  16. Tsolaki M, Kokarida K, Iakovidou V, Stilopoulos E, Meimaris J, Kazis A (2001). "Extrapyramidal symptoms and signs in Alzheimer's disease: prevalence and correlation with the first symptom". Am J Alzheimers Dis Other Demen. 16 (5): 268–78. doi:10.1177/153331750101600512. PMID 11603162.
  17. McGuinness B, Barrett SL, Craig D, Lawson J, Passmore AP (2010). "Executive functioning in Alzheimer's disease and vascular dementia". Int J Geriatr Psychiatry. 25 (6): 562–8. doi:10.1002/gps.2375. PMID 19810010.

See also

sv:Frontallobsdemens



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