Frontotemporal lobar degeneration: Difference between revisions

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(/* DSM-V Diagnostic Criteria for Major Or Mild Frontotemporal Neurocognitive Disorder{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year ...)
 
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{{SI}}
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{{CMG}}; {{AE}} {{KS}}
{{CMG}}; {{AE}}[[User:Qasim Khurshid|Qasim Khurshid, M.B.B.S [1]]]. {{KS}}


{{SK}} 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,
{{SK}}
disinhibition-dementia-parkinsonism-amyotrophy complex, ddpac, frontotemporal dementia-amyotrophic lateral sclerosis, ftd-als
 
pallidopontonigral degeneration, ppnd
Frontotemporal lobar degeneration, FTD, FTLD, Frontotemporal dementia, Pick’s disease


==Overview==
==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 lobe|parietal]] and [[occipital lobe]]s.
'''Frontotemporal lobar degeneration (FTLD)''' is an umbrella term that refers to a group of progressive [[brain]] [[diseases]], which are heterogeneous concerning [[neuropathology]] and [[etiology]] but share [[atrophy]] of the [[frontal]] and/or [[temporal]] cortex as a morphological feature. The clinical manifestations of the [[disorder]] depend on the primary site of [[atrophy]] and dominated by [[behavior]] alterations and language impairment.  The mean survival after [[diagnosis]] is from 3 to 10 years.
 
== Historical Perspective ==
Historically, patients having [[symptoms]] of frontotemporal lobe [[degeneration]] were diagnosed as  [[Pick's disease|Pick disease]] after Arnold Pick described a 71-year-old man with [[dementia]] with behavioral symptoms and [[sensory aphasia]] for the first time in 1892. This patient demonstrated severe atrophy of frontotemporal [[lobes]] on [[autopsy]].[[Histopathology|Histopathologic]] examination of [[tissue]] samples showed “ballooned” achromatic [[neurons]], which was referred to as Pick cells and argyrophilic [[inclusions]] within frontal neurons that were referred to as [[Pick bodies]]( composed of insoluble filaments of the microtubule-associated [[protein]] tau). Later on, [[autosomal dominant]] forms of Pick disease were reported, and the mutations in the gene encoding the [[microtubule]]-associated protein tau (''MAPT'') located at 17q21 were identified. At present, 42 [[Mutation|mutations]] in ''MAPT'' have been described in 119 families with FTLD or related [[disorders]]. However, in an estimated 60% to 70% of all patients with FTLD undergoing [[autopsy]], no tau [[Pathological|pathologic]] characteristics can be demonstrated. This autopy finding suggets that insoluble tau is not necessary for the clinical phenotype to develop..<ref>Pick A. Uber die [https://ci.nii.ac.jp/naid/10021235320/ Beziehungen der senilen Hirnatrophie zur Aphasie]. Prag Med Wochenschr. 1892;17:165-7.</ref><ref>Hutton M, Lendon CL, Rizzu P, et al. [https://doi.org/10.1038/31508 Association of missense and 5'-splice-site mutations in tau with the inherited dementia] FTDP-17. ''Nature''. 1998;393(6686):702-705. doi:10.1038/31508</ref>
 
== Classification ==
Frontotemporal lobe degeneration [[patients]] can be classified into three different clinical syndromes depending on the early and predominant [[symptoms]]. The overlap between these clinical [[syndromes]] can occur as the disease progresses to involve both [[temporal]] and [[frontal lobes]] more diffusely.<ref>Rabinovici GD, Miller BL. [https://doi.org/10.2165/11533100-000000000-00000 Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management]. ''CNS Drugs''. 2010;24(5):375-398. doi:10.2165/11533100-000000000-00000</ref>
 
# Behavioural-Variant Frontotemporal [[Dementia]] (bvFTD)


# Semantic [[Dementia]] (SD)
# Progressive Nonfluent Aphasia (PNFA)
=== Behavioural-Variant Frontotemporal Dementia (bvFTD) ===
[[Behavioral]] variant frontotemporal [[dementia]] is characterized by a progressive decline in executive and [[interpersonal skills]], with altered [[emotions]] and the emergence of a variety of abnormal behaviors including [[disinhibition]], [[obsessions]], [[apathy]], and stereotypes. The bvFTD can develop indolently, and early detection may depend on small changes of social circumstances, reduced [[libido]], idiosyncratic lapses of [[taste]] or social awareness, and altered dietary or musical preferences.<ref>Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, Van Swieten JC, Seelaar H, Dopper EG, Onyike CU, Hillis AE. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011 Sep 1;134(9):2456-77.</ref>
=== Semantic Dementia (SD) ===
Semantic dementia is also known as semantic variant primary progressive [[aphasia]] (svPPA) is a highly characteristic syndrome led by the progressive breakdown of [[semantic memory]]—a type of long term memory system that stores knowledge about concepts and objects based on the individual’s accumulated experience of the world. Typically, semantic [[dementia]] initially presents with progressive loss of semantic knowledge about words, concepts and objects.<ref>Hodges JR, Patterson K. [https://doi.org/10.1016/s1474-4422(07)70266-1 Semantic dementia: a unique clinicopathological syndrome]. ''Lancet Neurol''. 2007;6(11):1004-1014. doi:10.1016/S1474-4422(07)70266-1</ref>
=== Progressive Nonfluent Aphasia (PNFA) ===
Progressive Nonfluent [[Aphasia]] (PNFA) is characterized by a progressive breakdown in language output with slow, impaired production, effortful [[speech]], and comprehension of grammar, and motor speech deficits. [[Apraxia]] of speech is highly characteristic of PNFA, and [[dysarthria]] is more variably present. Some patients have expressive agrammatism with terse telegraphic phrases as the [[dominant]] feature of the [[disease]], whereas, in others, the syndrome is dominated by speech sound (phonemic) or [[Articulatory phonology|articulatory]] (phonetic, speech [[apraxic]]) errors.<ref>Rohrer JD, Rossor MN, Warren JD. Syndromes of nonfluent primary progressive aphasia: a clinical and neurolinguistic analysis. Neurology. 2010 Aug 17;75(7):603-10.</ref>
=== Frontotemporal Lobar Degeneration (FTLD) Overlap Syndromes ===
The frontotemporal [[degeneration]] spectrum overlaps with the syndromes of [[Corticobasal degeneration|corticobasal]] degeneration(CBD), [[progressive supranuclear palsy]](PSP), and FTD with motor neuron [[disease]]. CBD patients present with dystonia, limb [[apraxia]], postural instability, [[Axial]], and limb rigidity, [[myoclonus]], [[supranuclear gaze palsies]], the ‘alien limb phenomenon,’ and cortical [[sensory]] loss. The progressive [[supranuclear palsy syndrome]](PSP) is characterized by impairment of [[Vertical gaze center|vertical gaze]], frontal behavioral changes with marked [[cognitive]] slowing, and early postural instability with falls.<ref>Litvan I, Bhatia KP, Burn DJ, et al. [https://doi.org/10.1002/mds.10459 Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders]. ''Mov Disord''. 2003;18(5):467-486. doi:10.1002/mds.10459</ref><ref>Kertesz A, McMonagle P. Behavior and cognition in corticobasal degeneration and progressive supranuclear palsy. Journal of the neurological sciences. 2010 Feb 15;289(1-2):138-43.</ref><br />
==Pathophysiology==
==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:
FTLD is strongly [[familial]], with up to 40% of [[patients]] having a history of a similar disorder within their family, indicating that [[genetic]] factors play a significant role in its etiology. An [[autosomal dominant]] pattern of [[inheritance]] is documented in about 10%. Three significant causal [[genes]] have been identified. [[Mutations]] in MAPT on [[chromosome]] 17 (71,160), not unexpectedly, drive FTLD-tau [[pathology]]. FTLD-TDP pathology, by contrast, is not, or perhaps only rarely, associated with [[mutations]] in the TDP-43 gene, TARDBP. Instead, it is represented by [[Mutation|mutations]] in the progranulin gene (GRN) on [[chromosome 17]] (9,34) or expansions in C9orf72 on [[chromosome 9]] (40,134). Mutations in other [[genes]] have also, less commonly, been associated with FTLD. Of these, most notable are CHMP2B [[mutations]] on [[chromosome 3]] (20,56,148) occurring almost exclusively within a single pedigree within the Jutland region of Denmark (20,56,74). NCI is present in such [[cases]], and although these are ubiquitinated, the target [[protein]] remains to be identified. The classification, FTLD-UPS, has been applied in recognition of the involvement of the ubiquitin-proteasome system in the disease. The vast majority of cases with FTLD-FUS pathology appear to be sporadic. Other rare genetic forms of FTLD involve mutations in valosin containing protein (VCP) (174), SQSTMI (also known as p62), optineurin (OPTN) (104), [[ubiquitin 2]] (UBQLN2) and TANK binding-kinase 1 (TBK1. Although collectively, such cases are numerically few, they do provide essential clues to [[pathogenesis]] since all involve TDP-43 proteinopathy, and all have functioned within the cell’s protein [[degradation]] systems. <ref>Holm IE, Englund E, Mackenzie IR, Johannsen P, Isaacs AM. [https://doi.org/10.1097/nen.0b013e3181567f02 A reassessment of the neuropathology of frontotemporal dementia linked to chromosome] 3. ''J Neuropathol Exp Neurol''. 2007;66(10):884-891. doi:10.1097/nen.0b013e3181567f02</ref><ref>Rohrer JD, Guerreiro R, Vandrovcova J, et al. T[https://doi.org/10.1212/wnl.0b013e3181bf997a he heritability and genetics of frontotemporal lobar degeneration]. ''Neurology''. 2009;73(18):1451-1456. doi:10.1212/WNL.0b013e3181bf997a</ref>
*[[Tau protein|tau]] inclusions (either with [[Pick bodies]] or without)
== Causes ==
*[[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.
FTD [[patients]] have an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain, the [[tau protein]], and the transactive response [[DNA-binding domain|DNA binding]] protein-43 (TDP-43) are commonly involved. The specific functions of these [[Protein|proteins]] are not entirely known, but these proteins are critical for the proper function of neurons. In patients with FTD, these [[proteins]] are misfolded, clumped, or aggregate together, leading to atrophy of frontal and [[temporal lobes]].
*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===
* Almost 60% of [[patients]] have sporadic or non familial form of disease
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.
* Almost 40% of patients have family history of [[Neurodegenerative disease|neurodegenerative]] disorder
* Almost 10-25% of patients following major gene [[mutations]] have been identified.
**''MAPT''
** ''GRN''
** ''C9ORF72''
*Following [[gene]] [[mutations]] are rare causes of FTD.
**''VCP''
**''TARDBP,''
**''FUS''
**''CHMP2B''
**''TBK1''


==Differential Diagnosis Of Major or Mild Frontotemporal Neurocognitive Disorder==
==Differential Diagnosis ==
*Other neurocognitive disorders
*Other neurocognitive disorders
:*[[Alzheimer's disease]]
:*[[Alzheimer's disease]]
Line 42: Line 74:
:*[[Progressive supranuclear palsy]]
:*[[Progressive supranuclear palsy]]
*Other mental disorders and medical conditions
*Other mental disorders and medical conditions
:*[[Bipolar disorder]]s
:*[[Bipolar disorder]]s
:*[[Major depression]]
:*[[Major depression]]
:*[[Schizophrenia]]<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
:*[[Schizophrenia]]<ref name="DSMV">{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
* The following table outlines the main findings of the diseases which must be differentiated from dementia with frontotemporal lobar degeneration as they may share common characteristics of [[cognitive impairment]]:<ref name="pmid18525132">{{cite journal |vauthors=Jellinger KA |title=The pathology of "vascular dementia": a critical update |journal=J. Alzheimers Dis. |volume=14 |issue=1 |pages=107–23 |year=2008 |pmid=18525132 |doi= |url=}}</ref><ref name="pmid19198143">{{cite journal |vauthors=Murayama S |title=[Neuropathology of frontotemporal dementia] |language=Japanese |journal=Rinsho Shinkeigaku |volume=48 |issue=11 |pages=998 |year=2008 |pmid=19198143 |doi= |url=}}</ref><ref name="pmid9375155">{{cite journal |vauthors=Hodges JR, Patterson K |title=Nonfluent progressive aphasia and semantic dementia: a comparative neuropsychological study |journal=J Int Neuropsychol Soc |volume=2 |issue=6 |pages=511–24 |year=1996 |pmid=9375155 |doi= |url=}}</ref><ref name="pmid1486461">{{cite journal |vauthors=Hodges JR, Patterson K, Oxbury S, Funnell E |title=Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy |journal=Brain |volume=115 ( Pt 6) |issue= |pages=1783–806 |year=1992 |pmid=1486461 |doi= |url=}}</ref><ref name="urlDementia, Globalization and Contemporary Art">{{cite web |url=https://kohlibri.e-bookshelf.de/products/reading-epub/product-id/4033550/title/Dementia.html |title=Dementia, Globalization and Contemporary Art |format= |work= |accessdate=}}</ref><ref name="pmid3178177">{{cite journal |vauthors=Helkala EL, Laulumaa V, Soininen H, Riekkinen PJ |title=Recall and recognition memory in patients with Alzheimer's and Parkinson's diseases |journal=Ann. Neurol. |volume=24 |issue=2 |pages=214–7 |year=1988 |pmid=3178177 |doi=10.1002/ana.410240207 |url=}}</ref><ref name="pmid22474609">{{cite journal |vauthors=Weintraub S, Wicklund AH, Salmon DP |title=The neuropsychological profile of Alzheimer disease |journal=Cold Spring Harb Perspect Med |volume=2 |issue=4 |pages=a006171 |year=2012 |pmid=22474609 |pmc=3312395 |doi=10.1101/cshperspect.a006171 |url=}}</ref><ref name="pmid24757110">{{cite journal |vauthors=Goldman JG, Williams-Gray C, Barker RA, Duda JE, Galvin JE |title=The spectrum of cognitive impairment in Lewy body diseases |journal=Mov. Disord. |volume=29 |issue=5 |pages=608–21 |year=2014 |pmid=24757110 |pmc=4126402 |doi=10.1002/mds.25866 |url=}}</ref><ref name="pmid17715794">{{cite journal |vauthors=Metzler-Baddeley C |title=A review of cognitive impairments in dementia with Lewy bodies relative to Alzheimer's disease and Parkinson's disease with dementia |journal=Cortex |volume=43 |issue=5 |pages=583–600 |year=2007 |pmid=17715794 |doi= |url=}}</ref><ref name="pmid18855701">{{cite journal |vauthors=Uversky VN |title=Alpha-synuclein misfolding and neurodegenerative diseases |journal=Curr. Protein Pept. Sci. |volume=9 |issue=5 |pages=507–40 |year=2008 |pmid=18855701 |doi= |url=}}</ref><ref name="pmid15023815">{{cite journal |vauthors=Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE |title=Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function |journal=Arch. Neurol. |volume=61 |issue=3 |pages=378–84 |year=2004 |pmid=15023815 |doi=10.1001/archneur.61.3.378 |url=}}</ref><ref name="pmid9748670">{{cite journal |vauthors=Brion JP |title=Neurofibrillary tangles and Alzheimer's disease |journal=Eur. Neurol. |volume=40 |issue=3 |pages=130–40 |year=1998 |pmid=9748670 |doi= |url=}}</ref><ref name="pmid28748674">{{cite journal |vauthors=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 |title=Prognosis of Patients with Behavioral Variant Frontotemporal Dementia Who have Focal Versus Diffuse Frontal Atrophy |journal=J Clin Neurol |volume=13 |issue=3 |pages=234–242 |year=2017 |pmid=28748674 |pmc=5532319 |doi=10.3988/jcn.2017.13.3.234 |url=}}</ref><ref name="pmid21346515">{{cite journal |vauthors=Pao WC, Dickson DW, Crook JE, Finch NA, Rademakers R, Graff-Radford NR |title=Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically |journal=Alzheimer Dis Assoc Disord |volume=25 |issue=4 |pages=364–8 |year=2011 |pmid=21346515 |pmc=3107353 |doi=10.1097/WAD.0b013e31820f8f50 |url=}}</ref><ref name="pmid11603162">{{cite journal |vauthors=Tsolaki M, Kokarida K, Iakovidou V, Stilopoulos E, Meimaris J, Kazis A |title=Extrapyramidal symptoms and signs in Alzheimer's disease: prevalence and correlation with the first symptom |journal=Am J Alzheimers Dis Other Demen |volume=16 |issue=5 |pages=268–78 |year=2001 |pmid=11603162 |doi=10.1177/153331750101600512 |url=}}</ref><ref name="pmid19810010">{{cite journal |vauthors=McGuinness B, Barrett SL, Craig D, Lawson J, Passmore AP |title=Executive functioning in Alzheimer's disease and vascular dementia |journal=Int J Geriatr Psychiatry |volume=25 |issue=6 |pages=562–8 |year=2010 |pmid=19810010 |doi=10.1002/gps.2375 |url=}}</ref>


==Epidemiology and Demographics Of Major or Mild Frontotemporal Neurocognitive Disorder==
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"


===Prevalence===
|+
The prevalence of major or mild frontotemporal neurocognitive disorder is 2,000-10,000 per 100,000 (2%-10%) of the overall population.<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
! rowspan="2" style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Cause of dementia}}
! colspan="11" align="center" style="background:#4479BA; color: #FFFFFF; width: 400px;" + | Clinical features
! rowspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" + |Associated features
! rowspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" + |Nature of progression
! rowspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" + |Histopathological findings
|-
! colspan="11" align="center" style="background:#4479BA; color: #FFFFFF;" + |Cognitive impairment
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Recall
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Recollection
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Cue requirement for recall
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Infirngement of thoughts
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Semantic memory
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Procedural memory
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Working memory
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Awareness
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Attention
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Executive functioning issues
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Visuo-spatial skills
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Alzheimer's disease]]
| style="padding: 5px 5px; background: #F5F5F5;" | +++


===Age===
(Slow [[cognitive]] and functional decline with early loss of awareness)
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]].
|<nowiki>+++</nowiki>
|Not helpful
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|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|<nowiki>++</nowiki>
|
* [[Focal neurologic signs|Focal neurological signs]] absent during early stage (may develop later)
* Mild [[extrapyramidal]] signs
|Has the following clinical stages:
* Pre-clinical
* [[Mild cognitive impairment]]
* Advanced [[dementia]] (full blown dementia)
|
* [[Neurofibrillary tangle|Neurofibrillary tangles]]
* [[Senile plaques|Senile (neuritic) plaques]]
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[Lewy body dementia]]
| style="padding: 5px 5px; background: #F5F5F5;" | ++  
|<nowiki>-</nowiki>
|Helpful
|<nowiki>+++</nowiki>
|<nowiki>+</nowiki>
|<nowiki>+</nowiki>
|<nowiki>+++</nowiki>
|<nowiki>+</nowiki>
|<nowiki>+++</nowiki>
|<nowiki>+++</nowiki>
|<nowiki>+++</nowiki>
|
* Focal neurological signs present in majority
* Strongly associated with [[extrapyramidal]] signs
* [[Autonomic]] changes
|
* Early [[visual hallucinations]]
* [[Muscle rigidity]]
* [[Sleep disturbance]]
|
* [[Alpha-synuclein|α-synuclein]] deposits present in [[Neuron|neurons]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |[[Frontotemporal lobar degeneration]]
| style="padding: 5px 5px; background: #F5F5F5;" | +/-
|<nowiki>-</nowiki>
|Helpful
|<nowiki>+++</nowiki>
|<nowiki>+</nowiki>
|<nowiki>-</nowiki>
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|<nowiki>-</nowiki>
|
* [[Focal neurologic signs|Focal neurological signs]] present ([[motor neuron disease]])
* [[Extrapyramidal|Extrapyramidal signs]] present (familial [[Frontotemporal lobar degenerations|frontotemporal lobar degeneration]])


==Risk Factors Of Major or Mild Frontotemporal Neurocognitive Disorder==
* Onset in young age
*Genetic predisposition
*[[Motor neuron disease]]<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>


* Strong [[familial]] association
* Focal [[atrophy]] of [[Frontal lobe|frontal]] and [[temporal lobes]]
* Knife-edge [[atrophy]] noted on [[Magnetic resonance imaging|MRI]]
* [[Personality changes|Personality]] and behavioral changes
* Language impairment
|
* Two major variants:
** Progressive nonfluent [[aphasia]]
** [[Semantic Dementia|Semantic]] variant
* [[Progressive supranuclear palsy]]
|
* [[Pick bodies]]
* [[Corticobasal degeneration]]
* [[Ubiquitination|Ubiquitinated]] inclusions
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |[[Vascular dementia]]
| style="padding: 5px 5px; background: #F5F5F5;" | + (Dysexecutive syndrome)
|<nowiki>-</nowiki>
|Helpful
|<nowiki>+</nowiki>
|<nowiki>+</nowiki>
|<nowiki>+</nowiki>
|<nowiki>++</nowiki>
|<nowiki>-</nowiki>
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|<nowiki>+++</nowiki>
|<nowiki>+</nowiki>
|
* [[Focal neurologic signs|Focal neurological signs]] present typically
* Mild [[extrapyramidal]] signs
* [[Depression]]
* Mild [[Motor disorders|motor signs]] in subcortical [[vascular dementia]]
* Slowed processing speed
* Presentation might be similar to Alzheimer's disease
|
* Stepwise progression and focal neurologic signs (also known as [[multi-infarct dementia]] or poststroke [[dementia]])
|
* Multifocal and/or diffuse lesions (lacunes and microinfarcts)
* The following [[brain]] areas may be involved:
** [[Subcortical|Subcortical area]]
** [[Thalamus]]
** Frontobasal[[limbic system]]
** [[White matter]] lesions
** [[Hippocampal sclerosis]]
** Diffuse post-ischemic lesions
|}
==Epidemiology and Demographics==
The [[prevalence]] of FTD in [[population]]-based studies varied from 2.7/100,00 to 9.4 /100,000 in the 60-69-year-old group in the Zuid-Holland district, Netherlands. Two studies reported a similar [[incidence]] of  FLD in adults with early-onset [[dementia]] in Cambridge, UK( 3.5/100,000 person-years in 45-64 years old group), and Rochester, USA( 3.3/100,000 person-years in 50-59 age group).<ref>Rosso SM, Donker Kaat L, Baks T, et al. [https://doi.org/10.1093/brain/awg204 Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study]. ''Brain''. 2003;126(Pt 9):2016-2022. doi:10.1093/brain/awg204</ref><ref>Ratnavalli E, Brayne C, Dawson K, Hodges JR. [https://doi.org/10.1212/wnl.58.11.1615 The prevalence of frontotemporal dementia. ''Neurology'']. 2002;58(11):1615-1621. doi:10.1212/wnl.58.11.1615</ref>
The majority of the patients manifest the [[disease]] in the sixth decade of life, but the age of onset can vary widely from the third to the ninth decade. Although FTLD is generally considered presenile [[dementia]], individuals over the age of 65 years account for almost 20–25% of all cases.
==Risk Factors ==
*[[Genetic]] predisposition
*There are no other [[risk factors]].
== Screening ==
There is insufficient [[evidence]] to recommend routine screening for FTLD.
== Natural History, Complications, and Prognosis ==
The clinical course of  FTLD [[syndromes]] is steadily progressive, with declining function in everyday life, and patients are dependent for activities of daily living. With time they have [[cognitive]], social, and [[neurological disabilities]] leading to complete dependency requiring institutional care. Based on a [[meta-analysis]], the survival duration is highly variable among the FTD [[syndromes]]. The FTD associated with [[motor neuron]] disease is most aggressive and leads to death within three to five years of [[symptoms]] onset. However, patients with semantic [[dementia]] can survive for over a decade. There tends to be a convergence of [[syndromes]] with time, and the precise clinical trajectory is difficult to predict in individual [[cases]]. Wandering and intrusive behaviors, incontinence, apathy [[dysphagia]], and mutism are common issues toward the end of life, and important sources of caregiver distress. Compared with other [[Neurodegenerative disease|neurodegenerative diseases]], caregivers of patients with FTD suffer from more burden.<ref>Brodaty H, Seeher K, Gibson L. [https://doi.org/10.1017/s1041610211002924 Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia]. ''Int Psychogeriatr''. 2012;24(7):1034-1045. doi:10.1017/S1041610211002924</ref><ref>Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain. 2005 Sep 1;128(9):1996-2005.</ref><ref>Seltman RE, Matthews BR. Frontotemporal lobar degeneration. CNS drugs. 2012 Oct 1;26(10):841-70.</ref>
==Diagnosis==
==Diagnosis==
===Symptoms===
*[[Parkinson's disease|Parkinsonism]] with [[dystonia]]
*[[Dementia]]
*[[Urinary incontinence]]
*[[Neck stiffness]]
*[[Memory loss]]


=== Diagnostic Study of Choice ===
There is no single [[Gold standard (test)|gold standard]] test to [[Diagnosis|diagnose]] frontotemporal degeneration. The [[diagnosis]] of this disorder generally involves the following.
* Medical history and detailed [[neurological examination]]
* Neuropsychological examination to assess language, memory,[[behavior]], visual-spatial, and executive functions.
*[[Neuroimaging]] to determine [[brain atrophy]].
*[[Lumbar puncture]]  and blood tests to rule out other [[diseases]] that can mimic FTLD
=== History and Symptoms ===
[[Behavior|Behavioral]] variant FTD  is the most common clinical [[subtype]] and comprise approximately half of all cases of FTD. The main clinical feature of bvFTD is a progressive change in [[personality]] and behavior. The following are the first behavioral changes in bvFTD.
*[[Disinhibition]] – Examples of disinhibition or socially inappropriate behavior include public [[urination]] without concern, and [[touching]] or kissing strangers.
*[[Hyperorality]] – [[Hyperorality]]  manifest as altered food preferences. For example, [[carbohydrate]] cravings, particularly for sweet foods, and [[binge eating]].
*[[Apathy]]  – Apathy manifests as losing interest in activities and social relationships. [[Patients]] may participate less in conversations and grow passive.
*[[Compulsive behaviors]] – Stereotyped, [[perseverative]], or compulsive ritualistic behaviors include stereotyped [[speech]] and complex ritualistic behaviors such as cleaning, [[Hoarding disorder|hoarding]], or checking.
*[[Agitation]]
*Frequent [[mood changes]]
Most patients of FTLD lack insight into their behavioral changes and the distress experienced by family members.
===Physical Examination===
===Physical Examination===
====Neuro====
*Ocular motility abnormalities
*Pyramidal tract dysfunction
*Frontal lobe release signs
*Perseverative vocalizations
*[[Bradykinesia]]
*[[Postural instability]]


==DSM-V Diagnostic Criteria for Major Or Mild Frontotemporal Neurocognitive Disorder<ref name=DSMV>{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>==
*[[Patients]] with initial stages of disease generally lack [[Cranial nerves|cranial nerve]], [[cerebellar]], [[sensory]], pyramidal, and [[extrapyramidal]] motor findings.
{{cquote|
* Front release signs may be seen, but these findings are not specific to this disease.
* Parkinsonism may also emerge in advanced stages of the disease. and patients may have following physical findings.
**[[Rigidity]]
**[[Bradykinesia]]
** Resting [[tremor]]
** Mask like face
**[[Magnetic gate]]
* Almost 10-15 % of patients with bvFTD may develop concomitant motor neuron disease.
 
=== Laboratory Findings ===
Following tests may be  done to exclude other causes that can mimic the FTD.
 
*[[Thyroid function tests]]
*[[Vitamin B12]]
*[[HIV]]
*[[Syphilis]]
*[[CSF analysis]]
 
=== Electrocardiogram ===
There are no [[ECG]] findings associated with FTLD.
 
=== X-ray ===
There are no [[X-rays|X ray]] findings associated with FTD.
 
=== Echocardiography or Ultrasound ===
There are no echocardiography/[[ultrasound]] findings associated with FTLD.
 
=== Neuroimaging with CT and MRI ===
Routine brain imaging with [[MRI]] or computed tomography ([[Computed tomography|CT)]] is used to rule out other diseases mimicking FTD and usually remarkable only for cerebral atrophy. Some patients may show variable regional [[atrophy]] depending on the [[genetic]] and clinical phenotype.
 
In the majority of the patients, the following dominant patterns of regional loss are demonstrated.
 
* bv FTD: [[bilateral]] frontal [[atrophy]], especially the medial [[Frontal lobe|frontal cortex]] and sometimes with anterior [[temporal lobe]] atrophy.
* sv PPA: [[Temporal lobe|left temporal lobe]]
* non-fluent variant of PPA: left [[insula]] and frontal [[Operculum (brain)|operculum]]
* FTLD-FUS: bilateral [[Caudate nucleus|caudate nuclei]]
* FTLD-TDP : right frontal, lateral [[temporal]] and [[parietal lobe]]<nowiki/>s
* FTLD-TDP due to C9orf72 [[mutation]]: bilateral [[hemispheres]]
* FTLD-tau: due to MAPT mutation: bilateral [[temporal lobe]]<nowiki/>s
* PNFA: mostly have perisylvian, left hemisphere [[atrophy]], involving the frontal lobe and insula, extending into the temporal lobe
 
=== Other Imaging Findings ===
A fluorodeoxyglucose positron emission tomography ([[FDG-PET]]) scan or [[Single photon emission computed tomography|SPECT]] (single photon emission CT) can help to differentiate between FTD and [[Alzheimer's disease|Alzheimer's]] disease. FDG-PET scans show functional changes in glucose metabolism of the brain and are often positive earlier than MRI.  [[SPECT]] reflects blood flow more than metabolic change; therefore, it is less sensitive to diagnose FTD. The FDA has approved three different versions of a PET tracer for [[amyloid]] – currently valuable to FTD diagnosis as a negative scan ruling out [[Alzheimer's disease|Alzheimer’s diseas]]<nowiki/>e.<ref>Norman L. Foster, Judith L. Heidebrink, Christopher M. et al., [https://doi.org/10.1093/brain/awm177 FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease,] ''Brain'', Volume 130, Issue 10, October 2007, Pages 2616–2635</ref>
=== Other Diagnostic Studies ===
[[Electrophysiologic Testing|Electrophysiologic]] testing is sometimes used to rule out nonspecific [[Seizure|seizures]] in patients with  FTD.
 
== '''Diagnostic criteria for bvFTD''' ==
The International Behavioral Variant FTD Criteria Consortium (FTDC) published new criteria for bvFTD in 2011. The FTDC criteria synthesize [[clinical features]], [[Neuroimaging|neuroimaging,]] [[Neuropathology|neuropathology,]] and genetic testing . The FTDC criteria are structured as a diagnostic hierarchy. A diagnosis of possible bvFTD is based solely on the [[Syndrome|clinical syndrome]] and aims to identify patients at the mildest stages of the disease.
 
Possible bvFTD requires a combination of three of six clinical features:
 
●[[Disinhibition]]
 
●[[Apathy]]/inertia
 
●Loss of sympathy/empathy
 
●Perseverative/compulsive behaviors
 
●Hyperorality
 
●Dysexecutive neuropsychologic profile
 
Probable FTD requires the same clinical criteria, plus demonstrable functional decline and imaging findings that reflect the principal anatomic location of neurodegeneration in bvFTD (i.e., frontal and/or temporal lobe atrophy, hypometabolism, or [[hypoperfusion]]).
 
== Treatment ==


*A.The criteria are met for major or mild neurocognitive disorder.
=== Medical Therapy ===


'''''AND'''''
==== Non Pharmacological Intervention ====
First-line therapy for [[Behavior|behavioral]] disturbances in FTLD should be nonpharmacological. The current [[drug]] therapies are modestly effective and have serious adverse effects. A management plan that does not include a nonpharmacological intervention will not be successful. The main goals of nonpharmacological [[treatment]] include family and caregiver education, behavioral, and physical interventions to minimize the occurrence and consequences of undesired behaviors. Additional helpful interventions include physical and [[speech therapy]], home safety evaluations, and the implementation of augmentative communication devices. A frank discussion about [[End-of-life (medical treatment)|end-of-life]] decisions and goals of care is imperative.<ref>Merrilees J. [https://doi.org/10.1097/wad.0b013e31815bf774 A model for management of behavioral symptoms in frontotemporal lobar degeneration]. ''Alzheimer Dis Assoc Disord''. 2007;21(4):S64-S69. doi:10.1097/WAD.0b013e31815bf774</ref>


*B.The disturbance has insidious onset and gradual progression.
==== Behavioural and Cognitive Symptoms ====
There is no [[cure]] for FTLD, and current [[pharmacotherapy]] focuses primarily on [[symptomatic]], [[neurotransmitter]] base treatments. There is no drug developed for these patients, and the rationale for the use of [[medications]] is their efficacy in treating similar [[Neurodegenerative disorder|neurodegenerative]] disorders. Most of the FLTD [[treatments]] reported in the literature are based on single case reports or small series.


'''''AND'''''
Drugs affecting the [[Serotonin|serotonin level]] have the most robust rationale since there is strong evidence of [[serotonin]] deficiency in these patients. Patients with FTD have alterations of serotonin metabolites in CSF and significant neural loss in the serotonergic [[Dorsal raphe nucleus|dorsal raphe]] nuclei.  Many behavioral symptoms of FTLD, such as depression, [[disinhibition]], [[compulsions]], stereotypical movements, repetitive behaviors, and dysregulated eating, respond to selective serotonin reuptake inhibitors ([[Selective serotonin reuptake inhibitor|SSRIs]]).<ref>Huey ED, Putnam KT, Grafman J. [https://doi.org/10.1212/01.wnl.0000191304.55196.4d A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia]. ''Neurology''. 2006;66(1):17-22. doi:10.1212/01.wnl.0000191304.55196.4d</ref><ref>Perry RJ, Miller BL. [https://doi.org/10.1212/wnl.56.suppl_4.s46 Behavior and treatment in frontotemporal dementia]. ''Neurology''. 2001;56(11 Suppl 4):S46-S51. doi:10.1212/wnl.56.suppl_4.s46</ref>


*C.Either (1) or (2);
FLD patients with severe behavioral disturbances ([[agitation]], [[psychosis]]) should be treated with atypical [[Antipsychotics|antipsychotic]] medications. This class of [[medications]] should be used with great caution, mainly due to two reasons. First, antipsychotic medications are associated with increased mortality in elderly patients with [[dementia]], and secondly, these patients are susceptible to [[extrapyramidal]] side effects. Increased mortality appears to be related to infections and an increase in [[cardiovascular]] events. Furthermore, these medications may also reflect a nonspecific effect of sedation in this vulnerable population. Often, atypical antipsychotics are necessary only as a temporizing measure and can be tapered as patients become more apathetic as the disease progresses.
:*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'''''
Patients with parkinsonism should be treated with a trail of levodopa/carbidopa. However the response to these medications is inadequate in [[CBD]] and PSP. Patients not responding to levodopa should receive dopamine agonists such as [[pramipexole]] or [[ropinirole]].
*D.Relative sparing of learning and memory and perceptual-motor function.


'''''AND'''''
[[Urinary incontinence]] is common in FLD patients and may occur due to multiple mechanisms.  For optimal treatment of bladder dysfunction, these patients should be referred for [[Urodynamics|urodynamic]] studies to determine the underlying cause. [[Upper motor neuron]] dysfunction can be treated with [[anticholinergic]] drugs. However, anticholinergic drugs should be used with caution as they can exacerbate the cognitive and [[Neuropsychiatry|neuropsychiatric]] deficits. When necessary, [[trospium]] chloride or [[darifenacin]] are preferred medications due to lower [[CNS]] penetration. Intermittent [[catheterization]] should be considered for patients with lower motor neuron dysfunction.  [[Constipation]] is common in these patients and responds in most cases to a daily bowel regimen.<ref>van Balken I, Litvan I. [https://doi.org/10.1007/s11940-006-0012-z Current and future treatments in progressive supranuclear palsy. ''Curr Treat Options''] ''Neurol''. 2006;8(3):211-223. doi:10.1007/s11940-006-0012-z</ref><ref>Perry RJ, Miller BL. [https://doi.org/10.1212/wnl.56.suppl_4.s46 Behavior and treatment in frontotemporal dementia. ''Neurology'']. 2001;56(11 Suppl 4):S46-S51. doi:10.1212/wnl.56.suppl_4.s46</ref>


*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.
== Surgery ==
'''''Probable frontotemporal neurocognitive disorder'''''is diagnosed if either of the following is present; otherwise, possible frontotemporal neurocognitive disorder should be diagnosed:
[[Surgery]] is not recommended for FLD patinets.
*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.
== Primary prevention ==
There are no established measures for the [[primary prevention]] of FTLD.


'''''Possible frontotemporal neurocognitive disorder'''''is diagnosed if there is no evidence
== Secondary Prevention ==
of a genetic mutation, and neuro imaging has not been performed.
There are no established measures for the [[secondary prevention]] of FTLD.
}}


== References ==
== References ==

Latest revision as of 15:14, 19 July 2020

Frontotemporal lobar degeneration
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: Qasim Khurshid, M.B.B.S [1]. Kiran Singh, M.D. [2]

Synonyms and keywords:

Frontotemporal lobar degeneration, FTD, FTLD, Frontotemporal dementia, Pick’s disease

Overview

Frontotemporal lobar degeneration (FTLD) is an umbrella term that refers to a group of progressive brain diseases, which are heterogeneous concerning neuropathology and etiology but share atrophy of the frontal and/or temporal cortex as a morphological feature. The clinical manifestations of the disorder depend on the primary site of atrophy and dominated by behavior alterations and language impairment. The mean survival after diagnosis is from 3 to 10 years.

Historical Perspective

Historically, patients having symptoms of frontotemporal lobe degeneration were diagnosed as Pick disease after Arnold Pick described a 71-year-old man with dementia with behavioral symptoms and sensory aphasia for the first time in 1892. This patient demonstrated severe atrophy of frontotemporal lobes on autopsy.Histopathologic examination of tissue samples showed “ballooned” achromatic neurons, which was referred to as Pick cells and argyrophilic inclusions within frontal neurons that were referred to as Pick bodies( composed of insoluble filaments of the microtubule-associated protein tau). Later on, autosomal dominant forms of Pick disease were reported, and the mutations in the gene encoding the microtubule-associated protein tau (MAPT) located at 17q21 were identified. At present, 42 mutations in MAPT have been described in 119 families with FTLD or related disorders. However, in an estimated 60% to 70% of all patients with FTLD undergoing autopsy, no tau pathologic characteristics can be demonstrated. This autopy finding suggets that insoluble tau is not necessary for the clinical phenotype to develop..[1][2]

Classification

Frontotemporal lobe degeneration patients can be classified into three different clinical syndromes depending on the early and predominant symptoms. The overlap between these clinical syndromes can occur as the disease progresses to involve both temporal and frontal lobes more diffusely.[3]

  1. Behavioural-Variant Frontotemporal Dementia (bvFTD)
  1. Semantic Dementia (SD)
  2. Progressive Nonfluent Aphasia (PNFA)

Behavioural-Variant Frontotemporal Dementia (bvFTD)

Behavioral variant frontotemporal dementia is characterized by a progressive decline in executive and interpersonal skills, with altered emotions and the emergence of a variety of abnormal behaviors including disinhibition, obsessions, apathy, and stereotypes. The bvFTD can develop indolently, and early detection may depend on small changes of social circumstances, reduced libido, idiosyncratic lapses of taste or social awareness, and altered dietary or musical preferences.[4]

Semantic Dementia (SD)

Semantic dementia is also known as semantic variant primary progressive aphasia (svPPA) is a highly characteristic syndrome led by the progressive breakdown of semantic memory—a type of long term memory system that stores knowledge about concepts and objects based on the individual’s accumulated experience of the world. Typically, semantic dementia initially presents with progressive loss of semantic knowledge about words, concepts and objects.[5]

Progressive Nonfluent Aphasia (PNFA)

Progressive Nonfluent Aphasia (PNFA) is characterized by a progressive breakdown in language output with slow, impaired production, effortful speech, and comprehension of grammar, and motor speech deficits. Apraxia of speech is highly characteristic of PNFA, and dysarthria is more variably present. Some patients have expressive agrammatism with terse telegraphic phrases as the dominant feature of the disease, whereas, in others, the syndrome is dominated by speech sound (phonemic) or articulatory (phonetic, speech apraxic) errors.[6]

Frontotemporal Lobar Degeneration (FTLD) Overlap Syndromes

The frontotemporal degeneration spectrum overlaps with the syndromes of corticobasal degeneration(CBD), progressive supranuclear palsy(PSP), and FTD with motor neuron disease. CBD patients present with dystonia, limb apraxia, postural instability, Axial, and limb rigidity, myoclonus, supranuclear gaze palsies, the ‘alien limb phenomenon,’ and cortical sensory loss. The progressive supranuclear palsy syndrome(PSP) is characterized by impairment of vertical gaze, frontal behavioral changes with marked cognitive slowing, and early postural instability with falls.[7][8]

Pathophysiology

FTLD is strongly familial, with up to 40% of patients having a history of a similar disorder within their family, indicating that genetic factors play a significant role in its etiology. An autosomal dominant pattern of inheritance is documented in about 10%. Three significant causal genes have been identified. Mutations in MAPT on chromosome 17 (71,160), not unexpectedly, drive FTLD-tau pathology. FTLD-TDP pathology, by contrast, is not, or perhaps only rarely, associated with mutations in the TDP-43 gene, TARDBP. Instead, it is represented by mutations in the progranulin gene (GRN) on chromosome 17 (9,34) or expansions in C9orf72 on chromosome 9 (40,134). Mutations in other genes have also, less commonly, been associated with FTLD. Of these, most notable are CHMP2B mutations on chromosome 3 (20,56,148) occurring almost exclusively within a single pedigree within the Jutland region of Denmark (20,56,74). NCI is present in such cases, and although these are ubiquitinated, the target protein remains to be identified. The classification, FTLD-UPS, has been applied in recognition of the involvement of the ubiquitin-proteasome system in the disease. The vast majority of cases with FTLD-FUS pathology appear to be sporadic. Other rare genetic forms of FTLD involve mutations in valosin containing protein (VCP) (174), SQSTMI (also known as p62), optineurin (OPTN) (104), ubiquitin 2 (UBQLN2) and TANK binding-kinase 1 (TBK1. Although collectively, such cases are numerically few, they do provide essential clues to pathogenesis since all involve TDP-43 proteinopathy, and all have functioned within the cell’s protein degradation systems. [9][10]

Causes

FTD patients have an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain, the tau protein, and the transactive response DNA binding protein-43 (TDP-43) are commonly involved. The specific functions of these proteins are not entirely known, but these proteins are critical for the proper function of neurons. In patients with FTD, these proteins are misfolded, clumped, or aggregate together, leading to atrophy of frontal and temporal lobes.

  • Almost 60% of patients have sporadic or non familial form of disease
  • Almost 40% of patients have family history of neurodegenerative disorder
  • Almost 10-25% of patients following major gene mutations have been identified.
    • MAPT
    • GRN
    • C9ORF72
  • Following gene mutations are rare causes of FTD.
    • VCP
    • TARDBP,
    • FUS
    • CHMP2B
    • TBK1

Differential Diagnosis

  • 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

The prevalence of FTD in population-based studies varied from 2.7/100,00 to 9.4 /100,000 in the 60-69-year-old group in the Zuid-Holland district, Netherlands. Two studies reported a similar incidence of FLD in adults with early-onset dementia in Cambridge, UK( 3.5/100,000 person-years in 45-64 years old group), and Rochester, USA( 3.3/100,000 person-years in 50-59 age group).[28][29]

The majority of the patients manifest the disease in the sixth decade of life, but the age of onset can vary widely from the third to the ninth decade. Although FTLD is generally considered presenile dementia, individuals over the age of 65 years account for almost 20–25% of all cases.

Risk Factors

Screening

There is insufficient evidence to recommend routine screening for FTLD.

Natural History, Complications, and Prognosis

The clinical course of FTLD syndromes is steadily progressive, with declining function in everyday life, and patients are dependent for activities of daily living. With time they have cognitive, social, and neurological disabilities leading to complete dependency requiring institutional care. Based on a meta-analysis, the survival duration is highly variable among the FTD syndromes. The FTD associated with motor neuron disease is most aggressive and leads to death within three to five years of symptoms onset. However, patients with semantic dementia can survive for over a decade. There tends to be a convergence of syndromes with time, and the precise clinical trajectory is difficult to predict in individual cases. Wandering and intrusive behaviors, incontinence, apathy dysphagia, and mutism are common issues toward the end of life, and important sources of caregiver distress. Compared with other neurodegenerative diseases, caregivers of patients with FTD suffer from more burden.[30][31][32]

Diagnosis

Diagnostic Study of Choice

There is no single gold standard test to diagnose frontotemporal degeneration. The diagnosis of this disorder generally involves the following.

History and Symptoms

Behavioral variant FTD is the most common clinical subtype and comprise approximately half of all cases of FTD. The main clinical feature of bvFTD is a progressive change in personality and behavior. The following are the first behavioral changes in bvFTD.

Most patients of FTLD lack insight into their behavioral changes and the distress experienced by family members.

Physical Examination

  • Patients with initial stages of disease generally lack cranial nerve, cerebellar, sensory, pyramidal, and extrapyramidal motor findings.
  • Front release signs may be seen, but these findings are not specific to this disease.
  • Parkinsonism may also emerge in advanced stages of the disease. and patients may have following physical findings.
  • Almost 10-15 % of patients with bvFTD may develop concomitant motor neuron disease.

Laboratory Findings

Following tests may be done to exclude other causes that can mimic the FTD.

Electrocardiogram

There are no ECG findings associated with FTLD.

X-ray

There are no X ray findings associated with FTD.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with FTLD.

Neuroimaging with CT and MRI

Routine brain imaging with MRI or computed tomography (CT) is used to rule out other diseases mimicking FTD and usually remarkable only for cerebral atrophy. Some patients may show variable regional atrophy depending on the genetic and clinical phenotype.

In the majority of the patients, the following dominant patterns of regional loss are demonstrated.

Other Imaging Findings

A fluorodeoxyglucose positron emission tomography (FDG-PET) scan or SPECT (single photon emission CT) can help to differentiate between FTD and Alzheimer's disease. FDG-PET scans show functional changes in glucose metabolism of the brain and are often positive earlier than MRI. SPECT reflects blood flow more than metabolic change; therefore, it is less sensitive to diagnose FTD. The FDA has approved three different versions of a PET tracer for amyloid – currently valuable to FTD diagnosis as a negative scan ruling out Alzheimer’s disease.[33]

Other Diagnostic Studies

Electrophysiologic testing is sometimes used to rule out nonspecific seizures in patients with FTD.

Diagnostic criteria for bvFTD

The International Behavioral Variant FTD Criteria Consortium (FTDC) published new criteria for bvFTD in 2011. The FTDC criteria synthesize clinical features, neuroimaging, neuropathology, and genetic testing . The FTDC criteria are structured as a diagnostic hierarchy. A diagnosis of possible bvFTD is based solely on the clinical syndrome and aims to identify patients at the mildest stages of the disease.

Possible bvFTD requires a combination of three of six clinical features:

●Disinhibition

●Apathy/inertia

●Loss of sympathy/empathy

●Perseverative/compulsive behaviors

●Hyperorality

●Dysexecutive neuropsychologic profile

Probable FTD requires the same clinical criteria, plus demonstrable functional decline and imaging findings that reflect the principal anatomic location of neurodegeneration in bvFTD (i.e., frontal and/or temporal lobe atrophy, hypometabolism, or hypoperfusion).

Treatment

Medical Therapy

Non Pharmacological Intervention

First-line therapy for behavioral disturbances in FTLD should be nonpharmacological. The current drug therapies are modestly effective and have serious adverse effects. A management plan that does not include a nonpharmacological intervention will not be successful. The main goals of nonpharmacological treatment include family and caregiver education, behavioral, and physical interventions to minimize the occurrence and consequences of undesired behaviors. Additional helpful interventions include physical and speech therapy, home safety evaluations, and the implementation of augmentative communication devices. A frank discussion about end-of-life decisions and goals of care is imperative.[34]

Behavioural and Cognitive Symptoms

There is no cure for FTLD, and current pharmacotherapy focuses primarily on symptomatic, neurotransmitter base treatments. There is no drug developed for these patients, and the rationale for the use of medications is their efficacy in treating similar neurodegenerative disorders. Most of the FLTD treatments reported in the literature are based on single case reports or small series.

Drugs affecting the serotonin level have the most robust rationale since there is strong evidence of serotonin deficiency in these patients. Patients with FTD have alterations of serotonin metabolites in CSF and significant neural loss in the serotonergic dorsal raphe nuclei. Many behavioral symptoms of FTLD, such as depression, disinhibition, compulsions, stereotypical movements, repetitive behaviors, and dysregulated eating, respond to selective serotonin reuptake inhibitors (SSRIs).[35][36]

FLD patients with severe behavioral disturbances (agitation, psychosis) should be treated with atypical antipsychotic medications. This class of medications should be used with great caution, mainly due to two reasons. First, antipsychotic medications are associated with increased mortality in elderly patients with dementia, and secondly, these patients are susceptible to extrapyramidal side effects. Increased mortality appears to be related to infections and an increase in cardiovascular events. Furthermore, these medications may also reflect a nonspecific effect of sedation in this vulnerable population. Often, atypical antipsychotics are necessary only as a temporizing measure and can be tapered as patients become more apathetic as the disease progresses.

Patients with parkinsonism should be treated with a trail of levodopa/carbidopa. However the response to these medications is inadequate in CBD and PSP. Patients not responding to levodopa should receive dopamine agonists such as pramipexole or ropinirole.

Urinary incontinence is common in FLD patients and may occur due to multiple mechanisms. For optimal treatment of bladder dysfunction, these patients should be referred for urodynamic studies to determine the underlying cause. Upper motor neuron dysfunction can be treated with anticholinergic drugs. However, anticholinergic drugs should be used with caution as they can exacerbate the cognitive and neuropsychiatric deficits. When necessary, trospium chloride or darifenacin are preferred medications due to lower CNS penetration. Intermittent catheterization should be considered for patients with lower motor neuron dysfunction. Constipation is common in these patients and responds in most cases to a daily bowel regimen.[37][38]

Surgery

Surgery is not recommended for FLD patinets.

Primary prevention

There are no established measures for the primary prevention of FTLD.

Secondary Prevention

There are no established measures for the secondary prevention of FTLD.

References

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  7. ↑ Litvan I, Bhatia KP, Burn DJ, et al. Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord. 2003;18(5):467-486. doi:10.1002/mds.10459
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  20. ↑ 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.
  21. ↑ Uversky VN (2008). "Alpha-synuclein misfolding and neurodegenerative diseases". Curr. Protein Pept. Sci. 9 (5): 507–40. PMID 18855701.
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  23. ↑ Brion JP (1998). "Neurofibrillary tangles and Alzheimer's disease". Eur. Neurol. 40 (3): 130–40. PMID 9748670.
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  25. ↑ 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.
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See also

sv:Frontallobsdemens


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