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{{for|the alternative medicine practice similar to homeopathy|tautopathy}}

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{{Infobox medical condition (new)
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'''Tauopathy''' belongs to a class of [[neurodegenerative disease]]s involving the aggregation of [[tau protein]] into neurofibrillary or gliofibrillary [[Neurofibrillary tangle|tangles]] ([[Nfts|NFTs]]) in the human brain. Tangles are formed by [[phosphorylation|hyperphosphorylation]] of the [[microtubule]] protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates.<ref name=":3">{{cite journal | vauthors = Goedert M, Spillantini MG | title = Propagation of Tau aggregates | journal = Molecular Brain | volume = 10 | issue = 1 | pages = 18 | date = May 2017 | pmid = 28558799 | pmc = 5450399 | doi = 10.1186/s13041-017-0298-7 }}</ref> (These aggregations are also called '''paired helical filaments'''.) The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of [[Alzheimer's disease]] or play a peripheral role is unknown.
'''Tauopathies''' are a class of [[neurodegenerative disease]]s characterized by the aggregation of abnormal [[tau protein]].<ref name=Kovacs2018>{{cite book |last1=Kovacs |first1=Gabor G. |title=Handbook of Clinical Neurology, volume 145 |chapter=Tauopathies |series=Handbook of Clinical Neurology |date=2018 |editor1=Gabor G. Kovacs|editor2=Irina Alafuzoff|pages=355–368 |doi=10.1016/B978-0-12-802395-2.00025-0|pmid=28987182 |isbn=978-0-12-802395-2 }}</ref> [[Hyperphosphorylation]] of tau proteins causes them to dissociate from [[microtubule]]s and form insoluble aggregates called [[neurofibrillary tangle]]s.<ref name=":3">{{cite journal | vauthors = Goedert M, Spillantini MG | title = Propagation of Tau aggregates | journal = Molecular Brain | volume = 10 | issue = 1 | page = 18 | date = May 2017 | pmid = 28558799 | pmc = 5450399 | doi = 10.1186/s13041-017-0298-7 | doi-access = free }}</ref> Various neuropathologic [[phenotype]]s have been described based on the anatomical regions and cell types involved as well as the unique tau [[isoforms]] making up these deposits. The designation 'primary tauopathy' is assigned to disorders where the predominant feature is the deposition of tau protein. Alternatively, diseases exhibiting tau pathologies attributed to different and varied underlying causes are termed 'secondary tauopathies'. Some neuropathologic phenotypes involving tau protein are [[Alzheimer's disease]], [[frontotemporal dementia]], [[progressive supranuclear palsy]], and [[corticobasal degeneration]].<ref name=Kovacs2018 />


==Tau protein==
==Detection and imaging==
[[Tau protein]], also called '''tubulin associated unit''' or '''microtubule-associated protein tau''' (MAPT), is a [[microtubule]]-associated protein that promotes polymerization and stabilization into microtubules by binding to tubulin. Variants of Tau [[Protein isoform|isoforms]], spanning from 352 to 441 amino acids, arise through the alternative splicing of exons 2,3 and 10 within the MAPT gene. The six isoforms are differentiated by the inclusion and exclusion of inserts of either 29 or 58 amino acids in the N-terminus domain. Furthermore, the isoforms are categorized based on the presence of either three (3R tau isoforms) or four (4R tau isoforms) tandem repeat sequences each consisting of 31 or 32 amino acids.<ref>{{cite journal |last1=Goedert |first1=M. |last2=Spillantini |first2=M.G. |last3=Jakes |first3=R. |last4=Rutherford |first4=D. |last5=Crowther |first5=R.A. |title=Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease |journal=Neuron |date=October 1989 |volume=3 |issue=4 |pages=519–526 |doi=10.1016/0896-6273(89)90210-9|pmid=2484340 }}</ref>
;Post-mortem: Tau tangles are seen microscopically in stained brain samples.{{cn|date=September 2021}}


==Biomarkers==
;Pre-mortem: In living patients tau tangle locations can be imaged with a [[PET scan]] using a suitable radio-emissive agent.<ref>[https://medicalxpress.com/news/2020-01-alzheimer-tau-protein-surpasses-amyloid.html ''Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue'']</ref>
===Neuroimaging===
[[Positron emission tomography]] (PET) is one type of [[biomarker]] capable of identifying elevated levels of tau in patients with Alzheimer's disease. PET is a great tool that can supplement information such as regions with higher neuropathologic burden than others. But it needs to be eligible, and have more positive outcomes than negative, such as exposure to radioactivity.<ref>{{cite journal |last1=Moloney |first1=Christina M. |last2=Labuzan |first2=Sydney A. |last3=Crook |first3=Julia E. |last4=Siddiqui |first4=Habeeba |last5=Castanedes-Casey |first5=Monica |last6=Lachner |first6=Christian |last7=Petersen |first7=Ronald C. |last8=Duara |first8=Ranjan |last9=Graff-Radford |first9=Neill R. |last10=Dickson |first10=Dennis W. |last11=Mielke |first11=Michelle M. |last12=Murray |first12=Melissa E. |author-link12 = Melissa E. Murray (neuropathologist)|title=Phosphorylated tau sites that are elevated in Alzheimer's disease fluid biomarkers are visualized in early neurofibrillary tangle maturity levels in the post mortem brain |journal=Alzheimer's & Dementia |date=March 2023 |volume=19 |issue=3 |pages=1029–1040 |doi=10.1002/alz.12749 |pmid=35920592 |language=en |issn=1552-5260|pmc=9895127 }}</ref>


===Biofluid===
⚫
== Alzheimer's disease ==
The analysis of [[cerebrospinal fluid]] (CSF) represents a potential avenue for the development of biomarkers in tauopathies. Substantial data on CSF biomarkers is available for Alzheimer's disease (AD), focusing on measures related to total and phosphorylated forms of tau and amyloid-beta (Aβ) protein. Elevated CSF tau and decreased Aβ levels constitute the characteristic CSF signature of AD, allowing differentiation from controls.<ref>{{cite journal |last1=Shaw |first1=Leslie M. |last2=Vanderstichele |first2=Hugo |last3=Knapik-Czajka |first3=Malgorzata |last4=Clark |first4=Christopher M. |last5=Aisen |first5=Paul S. |last6=Petersen |first6=Ronald C. |last7=Blennow |first7=Kaj |last8=Soares |first8=Holly |last9=Simon |first9=Adam |last10=Lewczuk |first10=Piotr |last11=Dean |first11=Robert |last12=Siemers |first12=Eric |last13=Potter |first13=William |last14=Lee |first14=Virginia M.-Y. |last15=Trojanowski |first15=John Q. |title=Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects |journal=Annals of Neurology |date=April 2009 |volume=65 |issue=4 |pages=403–413 |doi=10.1002/ana.21610|pmid=19296504 |pmc=2696350 }}</ref> This signature may also assist in distinguishing atypical forms of AD pathology associated with clinical frontotemporal dementia (FTD) from those with underlying frontotemporal lobar degeneration (FTLD)-Tau pathology.<ref>{{cite journal |last1=Irwin |first1=David J. |last2=McMillan |first2=Corey T. |last3=Toledo |first3=Jon B. |last4=Arnold |first4=Steven E. |last5=Shaw |first5=Leslie M. |last6=Wang |first6=Li-San |last7=Van Deerlin |first7=Vivianna |last8=Lee |first8=Virginia M.-Y. |last9=Trojanowski |first9=John Q. |last10=Grossman |first10=Murray |title=Comparison of Cerebrospinal Fluid Levels of Tau and Aβ 1-42 in Alzheimer Disease and Frontotemporal Degeneration Using 2 Analytical Platforms |url=https://jamanetwork.com/journals/jamaneurology/fullarticle/1151845 |journal=Archives of Neurology |pages=1018–1025 |doi=10.1001/archneurol.2012.26 |date=1 August 2012|volume=69 |issue=8 |pmid=22490326 |pmc=3528180 }}</ref>
[[File:Tauopathy in Alzheimer's disease.jpg|thumb|Abnormal accumulation of [[tau protein]] in [[neuron]]al cell bodies (arrow) and neuronal extensions (arrowhead) in the [[neocortex]] of a patient who died with Alzheimer's disease. The bar = 25 microns (0.025 millimeters).]]
Neurofibrillary tangles were first described by [[Alois Alzheimer]] in one of his patients suffering from [[Alzheimer's disease]] (AD). The tangles are considered a secondary tauopathy. AD is also classified as an [[amyloidosis]] because of the presence of [[senile plaques]].<ref name="ReferenceA">{{cite journal | vauthors = Dickson DW | title = Neuropathology of non-Alzheimer degenerative disorders | journal = International Journal of Clinical and Experimental Pathology | volume = 3 | issue = 1 | pages = 1–23 | date = August 2009 | pmid = 19918325 | pmc = 2776269 }}</ref>


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==Alzheimer's disease==
When tau becomes hyperphosphorylated, the protein dissociates from the microtubules in axons.<ref>{{cite journal | vauthors = Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K | title = Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration | journal = Journal of Alzheimer's Disease | volume = 33 Suppl 1 | pages = S123-39 | date = 2013 | pmid = 22710920 | doi = 10.3233/JAD-2012-129031 }}</ref> Then, tau becomes misfolded and the protein begins to aggregate, which eventually forms the neurofibrillary tangles seen in Alzheimer’s patients.<ref name=":3" /> Microtubules also destabilize when tau is dissociated. The combination of the neurofibrillary tangles and destabilized microtubules result in disruption of processes such as axonal transport and neural communication.<ref>{{cite journal | vauthors = Wang Y, Mandelkow E | title = Tau in physiology and pathology | journal = Nature Reviews. Neuroscience | volume = 17 | issue = 1 | pages = 5–21 | date = January 2016 | pmid = 26631930 | doi = 10.1038/nrn.2015.1 | s2cid = 30614958 }}</ref>
[[Alzheimer's disease]] (AD) is clinically characterized by a progressive decline in memory and cognitive functions, leading to severe dementia. Microscopically, AD is identified by the presence of two types of insoluble fibrous materials: (1) extracellular amyloid (Aβ) protein forming senile plaques and (2) intracellular neurofibrillary lesions (NFL) composed of abnormally and hyperphosphorylated tau protein. While AD is not strictly considered a prototypical tauopathy, as tau pathology coexists with Aβ protein deposition, the 'amyloid cascade hypothesis' posits that Aβ accumulation is the primary factor driving AD pathogenesis.<ref>{{cite journal |last1=Hardy |first1=John |last2=Selkoe |first2=Dennis J. |title=The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics |journal=Science |date=19 July 2002 |volume=297 |issue=5580 |pages=353–356 |doi=10.1126/science.1072994|pmid=12130773 }}</ref><ref>{{cite journal |last1=Nussbaum |first1=Robert L. |last2=Ellis |first2=Christopher E. |title=Alzheimer's Disease and Parkinson's Disease |journal=New England Journal of Medicine |date=3 April 2003 |volume=348 |issue=14 |pages=1356–1364 |doi=10.1056/NEJM2003ra020003|pmid=12672864 }}</ref> Nevertheless, AD neurofibrillary lesions were the first to undergo ultrastructural and biochemical analysis, thus laying the foundation for in-depth studies on tau protein deposition in various tauopathies.<ref>{{cite journal |last1=Tolnay |first1=Markus |last2=Probst |first2=Alphonse |title=The Neuropathological Spectrum of Neurodegenerative Tauopathies |journal=IUBMB Life |date=June 2003 |volume=55 |issue=6 |pages=299–305 |doi=10.1080/1521654032000114348|pmid=12938731 }}</ref>


==Neuropathologic phenotypes==
The degree of NFT involvement in AD is defined by [[Braak staging|Braak stages]]. Braak stages I and II are used when NFT involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there's also involvement of [[limbic]] regions such as the [[hippocampus]], and V and VI when there's extensive neocortical involvement. This should not be confused with the degree of [[senile plaque]] involvement, which progresses differently.<ref>{{cite journal | vauthors = Braak H, Braak E | title = Neuropathological stageing of Alzheimer-related changes | journal = Acta Neuropathologica | volume = 82 | issue = 4 | pages = 239–59 | year = 1991 | pmid = 1759558 | doi = 10.1007/BF00308809 | s2cid = 668690 }}</ref>
===Frontotemporal dementia===
[[Frontotemporal dementia]] is a part of a diverse spectrum of disorders clinically marked by dysfunction in the frontal and temporal lobes, collectively referred to as [[frontotemporal lobar degeneration]] (FTLD). The primary histological characteristics include profound neuronal loss, enlarged neurons, and distinctive spherical argyrophilic inclusions known as Pick bodies (PBs). These PBs primarily consist of hyperphosphorylated tau protein, with tau protein presenting as two major bands at 60 and 64 kDa and a variable, minor band at 69 kDa. Filamentous tau deposits in nerve cells are predominantly composed of 3R tau isoforms.<ref>{{cite journal |last1=Tolnay |first1=Markus |last2=Probst |first2=Alphonse |title=The Neuropathological Spectrum of Neurodegenerative Tauopathies |journal=IUBMB Life |date=June 2003 |volume=55 |issue=6 |pages=299–305 |doi=10.1080/1521654032000114348|pmid=12938731 }}</ref>

===Progressive supranuclear palsy===
[[Progressive supranuclear palsy]] (PSP) is a type of tauopathy, but the cause is not yet discovered. For PSP unusual phosphorylation for tau protein causes vital protein filaments in the nerve cells to destruct, a phenomenon called "neurofibrillary" degeneration. Typical symptoms of PSP would be abnormal speech, balance impairment and overcognitive and memory impairment. As CBD, PSP is also classified as a 4R tauopathy, and because of that PSP will often be selected for trials regarding anti-tau therapeutics.<ref>{{cite journal |last1=Coughlin |first1=David G. |last2=Litvan |first2=Irene |title=Progressive supranuclear palsy: Advances in diagnosis and management |journal=Parkinsonism & Related Disorders |date=April 2020 |volume=73 |pages=105–116 |doi=10.1016/j.parkreldis.2020.04.014|pmid=32487421 |pmc=7462164 }}</ref><ref>{{cite web |title=Progressive Supranuclear Palsy - Symptoms, Causes, Treatment {{!}} NORD |url=https://rarediseases.org/rare-diseases/progressive-supranuclear-palsy/ |website=rarediseases.org}}</ref>

⚫
===Corticobasal degeneration===
[[Corticobasal degeneration]] (CBD) is an increasingly acknowledged neurodegenerative disorder characterized by both motor and cognitive dysfunction. In affected regions, histological examination reveals pronounced neuronal loss accompanied by spongiosis and gliosis, cortical ballooned cells, and notable intracytoplasmic filamentous tau pathology in both glial and neuronal cells. Biochemically, the distinctive tau profile in CBD cases manifests as a prominent tau doublet at 64 and 68 kDa, which is variably identified. These bands predominantly consist of hyperphosphorylated 4R tau isoforms, leading to the classification of CBD as a 4R tauopathy.<ref>{{cite journal |last1=Tolnay |first1=Markus |last2=Probst |first2=Alphonse |title=The Neuropathological Spectrum of Neurodegenerative Tauopathies |journal=IUBMB Life |date=June 2003 |volume=55 |issue=6 |pages=299–305 |doi=10.1080/1521654032000114348|pmid=12938731 }}</ref>

==Tau therapeutics==
Currently, there are no specific treatments for tauopathies. Up till now, attempts have been made to target neurotransmitter disturbances to relieve disease symptoms. For AD a specific treatment is difficult because the pathological changes both early compared to the symptoms showing.<ref>{{cite journal |last1=Khan |first1=Sahil |last2=Barve |first2=Kalyani H. |last3=Kumar |first3=Maushmi S. |title=Recent Advancements in Pathogenesis, Diagnostics, and Treatment of Alzheimer's Disease |journal=Current Neuropharmacology |date=2020 |volume=18 |issue=11 |pages=1106–1125 |doi=10.2174/1570159X18666200528142429|pmid=32484110 |pmc=7709159 }}</ref>
Even though there is no current treatment for tauopathies, there are treatments that can relieve symptoms. Speech therapy can be beneficial for aphasia symptoms, symptoms such as depression and apathy frequently engaged with pharmaceuticals. For physical challenges, physical therapy has proven helpful in extending motor function for patients.<ref>{{cite journal |last1=Orr |first1=Miranda E. |last2=Sullivan |first2=A. Campbell |last3=Frost |first3=Bess |title=A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies |journal=Trends in Pharmacological Sciences |date=July 2017 |volume=38 |issue=7 |pages=637–648 |doi=10.1016/j.tips.2017.03.011|pmid=28455089 |pmc=5476494 }}</ref>


== Other diseases ==
== Other diseases ==
* [[Primary age-related tauopathy]] (PART) dementia, with NFTs similar to AD, but without [[amyloid plaques]].<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson PT, Dewar K, Clark LN, Crary JF | title = The MAPT H1 haplotype is associated with tangle-predominant dementia | journal = Acta Neuropathologica | volume = 124 | issue = 5 | pages = 693–704 | date = November 2012 | pmid = 22802095 | pmc = 3608475 | doi = 10.1007/s00401-012-1017-1 }}</ref><ref>{{cite journal | vauthors = Jellinger KA, Attems J | title = Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease | journal = Acta Neuropathologica | volume = 113 | issue = 2 | pages = 107–17 | date = February 2007 | pmid = 17089134 | doi = 10.1007/s00401-006-0156-7 | s2cid = 5655388 }}</ref>
* [[Primary age-related tauopathy]] (PART) dementia, with NFTs similar to AD, but without [[amyloid plaques]].<ref>{{cite journal | vauthors = Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson PT, Dewar K, Clark LN, Crary JF | title = The MAPT H1 haplotype is associated with tangle-predominant dementia | journal = Acta Neuropathologica | volume = 124 | issue = 5 | pages = 693–704 | date = November 2012 | pmid = 22802095 | pmc = 3608475 | doi = 10.1007/s00401-012-1017-1 }}</ref><ref>{{cite journal | vauthors = Jellinger KA, Attems J | title = Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease | journal = Acta Neuropathologica | volume = 113 | issue = 2 | pages = 107–17 | date = February 2007 | pmid = 17089134 | doi = 10.1007/s00401-006-0156-7 | s2cid = 5655388 }}</ref>
* [[Chronic traumatic encephalopathy]] (CTE)<ref>{{cite journal | vauthors = McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O'Connor K, Alvarez VE, Gordon WA | title = The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy | journal = Acta Neuropathologica | volume = 131 | issue = 1 | pages = 75–86 | date = January 2016 | pmid = 26667418 | pmc = 4698281 | doi = 10.1007/s00401-015-1515-z | url = http://eprints.gla.ac.uk/115891/1/115891.pdf }}</ref><ref>{{cite journal | vauthors = Roberts GW | title = Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis | journal = Lancet | volume = 2 | issue = 8626–8627 | pages = 1456–8 | year = 1988 | pmid = 2904573 | doi = 10.1016/S0140-6736(88)90934-8 | s2cid = 32662671 }}</ref>
* [[Chronic traumatic encephalopathy]] (CTE)<ref>{{cite journal | vauthors = McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I, Perl DP, Stein TD, Vonsattel JP, Stewart W, Tripodis Y, Crary JF, Bieniek KF, Dams-O'Connor K, Alvarez VE, Gordon WA | title = The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy | journal = Acta Neuropathologica | volume = 131 | issue = 1 | pages = 75–86 | date = January 2016 | pmid = 26667418 | pmc = 4698281 | doi = 10.1007/s00401-015-1515-z | url = http://eprints.gla.ac.uk/115891/1/115891.pdf }}</ref><ref>{{cite journal | vauthors = Roberts GW | title = Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis | journal = Lancet | volume = 2 | issue = 8626–8627 | pages = 1456–8 | year = 1988 | pmid = 2904573 | doi = 10.1016/S0140-6736(88)90934-8 | s2cid = 32662671 }}</ref>
* [[Progressive supranuclear palsy]] (PSP)<ref>{{cite journal | vauthors = Williams DR, Lees AJ | title = Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges | journal = The Lancet. Neurology | volume = 8 | issue = 3 | pages = 270–9 | date = March 2009 | pmid = 19233037 | doi = 10.1016/S1474-4422(09)70042-0 | s2cid = 1417930 }}</ref>
* [[Progressive supranuclear palsy]] (PSP)<ref>{{cite journal | vauthors = Williams DR, Lees AJ | title = Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges | journal = The Lancet. Neurology | volume = 8 | issue = 3 | pages = 270–9 | date = March 2009 | pmid = 19233037 | doi = 10.1016/S1474-4422(09)70042-0 | s2cid = 1417930 }}</ref>
* [[Corticobasal degeneration]] (CBD)<ref>{{cite journal |last1=Tolnay |first1=Markus |last2=Probst |first2=Alphonse |title=The Neuropathological Spectrum of Neurodegenerative Tauopathies |journal=IUBMB Life |date=June 2003 |volume=55 |issue=6 |pages=299–305 |doi=10.1080/1521654032000114348|pmid=12938731 }}</ref>
⚫
* [[Corticobasal degeneration]] (CBD)
* [[Frontotemporal dementia and parkinsonism linked to chromosome 17]] (FTDP-17)<ref>{{cite journal | vauthors = Selkoe DJ, Podlisny MB | title = Deciphering the genetic basis of Alzheimer's disease | journal = Annual Review of Genomics and Human Genetics | volume = 3 | pages = 67–99 | year = 2002 | pmid = 12142353 | doi = 10.1146/annurev.genom.3.022502.103022 }}</ref>
* [[Frontotemporal dementia and parkinsonism linked to chromosome 17]] (FTDP-17)<ref>{{cite journal | vauthors = Selkoe DJ, Podlisny MB | title = Deciphering the genetic basis of Alzheimer's disease | journal = Annual Review of Genomics and Human Genetics | volume = 3 | pages = 67–99 | year = 2002 | pmid = 12142353 | doi = 10.1146/annurev.genom.3.022502.103022 | doi-access = free }}</ref>
* Vacuolar tauopathy<ref>{{cite journal | vauthors = Darwich NF, Phan JM, et al. | title = Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau | journal = Science | volume = 370 | pages = eaay8826 | year = 2020 | pmid = 33004675 | doi = 10.1126/science.aay8826|pmc=7818661 }}</ref>
* Vacuolar tauopathy<ref>{{cite journal | vauthors = Darwich NF, Phan JM, et al. | title = Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau | journal = Science | volume = 370 | pages = eaay8826 | year = 2020 | issue = 6519 | pmid = 33004675 | doi = 10.1126/science.aay8826|pmc=7818661 }}</ref>
* [[Lytico-bodig disease]] (Parkinson-dementia complex of Guam)<ref>{{cite journal | vauthors = Hof PR, Nimchinsky EA, Buée-Scherrer V, Buée L, Nasrallah J, Hottinger AF, Purohit DP, Loerzel AJ, Steele JC, Delacourte A | title = Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders | journal = Acta Neuropathologica | volume = 88 | issue = 5 | pages = 397–404 | year = 1994 | pmid = 7847067 | doi = 10.1007/BF00389490 | s2cid = 2821768 }}</ref>
* [[Lytico-bodig disease]] (Parkinson-dementia complex of Guam)<ref>{{cite journal | vauthors = Hof PR, Nimchinsky EA, Buée-Scherrer V, Buée L, Nasrallah J, Hottinger AF, Purohit DP, Loerzel AJ, Steele JC, Delacourte A | title = Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders | journal = Acta Neuropathologica | volume = 88 | issue = 5 | pages = 397–404 | year = 1994 | pmid = 7847067 | doi = 10.1007/BF00389490 | s2cid = 2821768 }}</ref>
* [[Ganglioglioma]] and [[gangliocytoma]]<ref>{{cite journal | vauthors = Brat DJ, Gearing M, Goldthwaite PT, Wainer BH, Burger PC | title = Tau-associated neuropathology in ganglion cell tumours increases with patient age but appears unrelated to ApoE genotype | journal = Neuropathology and Applied Neurobiology | volume = 27 | issue = 3 | pages = 197–205 | date = June 2001 | pmid = 11489139 | doi = 10.1046/j.1365-2990.2001.00311.x | s2cid = 36482221 }}</ref>
* [[Ganglioglioma]] and [[gangliocytoma]]<ref>{{cite journal | vauthors = Brat DJ, Gearing M, Goldthwaite PT, Wainer BH, Burger PC | title = Tau-associated neuropathology in ganglion cell tumours increases with patient age but appears unrelated to ApoE genotype | journal = Neuropathology and Applied Neurobiology | volume = 27 | issue = 3 | pages = 197–205 | date = June 2001 | pmid = 11489139 | doi = 10.1046/j.1365-2990.2001.00311.x | s2cid = 36482221 }}</ref>
* [[Meningioangiomatosis]]<ref>{{cite journal | vauthors = Halper J, Scheithauer BW, Okazaki H, Laws ER | title = Meningio-angiomatosis: a report of six cases with special reference to the occurrence of neurofibrillary tangles | journal = Journal of Neuropathology and Experimental Neurology | volume = 45 | issue = 4 | pages = 426–46 | date = July 1986 | pmid = 3088216 | doi = 10.1097/00005072-198607000-00005 | s2cid = 663552 }}</ref>
* [[Meningioangiomatosis]]<ref>{{cite journal | vauthors = Halper J, Scheithauer BW, Okazaki H, Laws ER | title = Meningio-angiomatosis: a report of six cases with special reference to the occurrence of neurofibrillary tangles | journal = Journal of Neuropathology and Experimental Neurology | volume = 45 | issue = 4 | pages = 426–46 | date = July 1986 | pmid = 3088216 | doi = 10.1097/00005072-198607000-00005 | s2cid = 663552 }}</ref>
* [[Postencephalitic parkinsonism]]
* [[Subacute sclerosing panencephalitis]] (SSPE)<ref>{{cite journal | vauthors = Paula-Barbosa MM, Brito R, Silva CA, Faria R, Cruz C | title = Neurofibrillary changes in the cerebral cortex of a patient with subacute sclerosing panencephalitis (SSPE) | journal = Acta Neuropathologica | volume = 48 | issue = 2 | pages = 157–60 | date = November 1979 | pmid = 506699 | doi = 10.1007/BF00691159 | s2cid = 36105401 }}</ref>
* [[Subacute sclerosing panencephalitis]] (SSPE)<ref>{{cite journal | vauthors = Paula-Barbosa MM, Brito R, Silva CA, Faria R, Cruz C | title = Neurofibrillary changes in the cerebral cortex of a patient with subacute sclerosing panencephalitis (SSPE) | journal = Acta Neuropathologica | volume = 48 | issue = 2 | pages = 157–60 | date = November 1979 | pmid = 506699 | doi = 10.1007/BF00691159 | s2cid = 36105401 }}</ref>
* As well as [[Lead poisoning|lead encephalopathy]], [[tuberous sclerosis]], [[Pantothenate kinase-associated neurodegeneration]], and [[lipofuscinosis]]<ref>{{cite journal | vauthors = Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM | title = Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia | journal = Annals of Neurology | volume = 5 | issue = 3 | pages = 288–94 | date = March 1979 | pmid = 156000 | doi = 10.1002/ana.410050311 | s2cid = 25649751 }}</ref>
* As well as [[Lead poisoning|lead encephalopathy]], [[tuberous sclerosis]], [[pantothenate kinase-associated neurodegeneration]], and [[lipofuscinosis]]<ref>{{cite journal | vauthors = Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM | title = Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia | journal = Annals of Neurology | volume = 5 | issue = 3 | pages = 288–94 | date = March 1979 | pmid = 156000 | doi = 10.1002/ana.410050311 | s2cid = 25649751 }}</ref>

In both [[Pick's disease]] and [[corticobasal degeneration]], tau proteins are deposited as [[inclusion bodies]] within swollen or "ballooned" neurons.{{medcn|date=April 2018}}

Argyrophilic grain disease (AGD), another type of [[dementia]],<ref>{{cite journal | vauthors = Ferrer I, Santpere G, van Leeuwen FW | title = Argyrophilic grain disease | journal = Brain | volume = 131 | issue = Pt 6 | pages = 1416–32 | date = June 2008 | pmid = 18234698 | doi = 10.1093/brain/awm305 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Josephs KA, Whitwell JL, Parisi JE, Knopman DS, Boeve BF, Geda YE, Jack CR, Petersen RC, Dickson DW | title = Argyrophilic grains: a distinct disease or an additive pathology? | journal = Neurobiology of Aging | volume = 29 | issue = 4 | pages = 566–73 | date = April 2008 | pmid = 17188783 | pmc = 2727715 | doi = 10.1016/j.neurobiolaging.2006.10.032 }}</ref><ref>{{cite journal | vauthors = Wallon D, Sommervogel C, Laquerrière A, Martinaud O, Lecourtois M, Hannequin D | title = [Argyrophilic grain disease: synergistic component of dementia?] | language = French | journal = Revue Neurologique | volume = 166 | issue = 4 | pages = 428–32 | date = April 2010 | pmid = 19963233 | doi = 10.1016/j.neurol.2009.10.012 | trans-title = Argyrophilic grain disease: synergistic component of dementia? }}</ref> is marked by an abundance of argyrophilic grains and coiled bodies upon microscopic examination of brain tissue.<ref name=Ref99>{{cite journal | vauthors = Tolnay M, Monsch AU, Staehelin HB, Probst A | title = [Argyrophilic grain disease: differentiation from Alzheimer disease] | journal = Der Pathologe | volume = 20 | issue = 3 | pages = 159–68 | date = May 1999 | pmid = 10412175 | doi = 10.1007/s002920050339 | s2cid = 2026154 }}</ref> Some consider it to be a type of [[Alzheimer's disease]].<ref name=Ref99/> It may co-exist with other tauopathies such as progressive supranuclear palsy and corticobasal degeneration,<ref name="ReferenceA"/> and also Pick's disease.<ref>{{cite journal | vauthors = Jellinger KA | title = Dementia with grains (argyrophilic grain disease) | journal = Brain Pathology | volume = 8 | issue = 2 | pages = 377–86 | date = April 1998 | pmid = 9546294 | doi = 10.1111/j.1750-3639.1998.tb00161.x | s2cid = 22872309 | pmc = 8098394 }}</ref>

Tauopathies are often overlapped with [[synucleinopathies]], possibly due to interaction between the synuclein and tau proteins.<ref>{{cite journal | vauthors = Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ | title = Alpha-synuclein and tau: teammates in neurodegeneration? | journal = Molecular Neurodegeneration | volume = 9 | pages = 43 | date = October 2014 | pmid = 25352339 | pmc = 4230508 | doi = 10.1186/1750-1326-9-43 | name-list-style = amp }}</ref>

The non-Alzheimer's tauopathies are sometimes grouped together as "'''Pick's complex'''" due to their association with [[frontotemporal dementia]], or [[frontotemporal lobar degeneration]].<ref>{{cite journal | vauthors = Kertesz A, McMonagle P, Jesso S | title = Extrapyramidal syndromes in frontotemporal degeneration | journal = Journal of Molecular Neuroscience | volume = 45 | issue = 3 | pages = 336–42 | date = November 2011 | pmid = 21887521 | doi = 10.1007/s12031-011-9616-1 | s2cid = 13315112 }}</ref>


== See also ==
== See also ==
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== References ==
== References ==
{{Reflist}}
{{Reflist}}

== External links ==
== External links ==
{{Medical resources
{{Medical resources

Latest revision as of 01:03, 23 December 2024

Tauopathy
Diagram of a normal microtubule and one affected by tauopathy
SpecialtyNeurology Edit this on Wikidata

Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein.[1] Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary tangles.[2] Various neuropathologic phenotypes have been described based on the anatomical regions and cell types involved as well as the unique tau isoforms making up these deposits. The designation 'primary tauopathy' is assigned to disorders where the predominant feature is the deposition of tau protein. Alternatively, diseases exhibiting tau pathologies attributed to different and varied underlying causes are termed 'secondary tauopathies'. Some neuropathologic phenotypes involving tau protein are Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.[1]

Tau protein

[edit]

Tau protein, also called tubulin associated unit or microtubule-associated protein tau (MAPT), is a microtubule-associated protein that promotes polymerization and stabilization into microtubules by binding to tubulin. Variants of Tau isoforms, spanning from 352 to 441 amino acids, arise through the alternative splicing of exons 2,3 and 10 within the MAPT gene. The six isoforms are differentiated by the inclusion and exclusion of inserts of either 29 or 58 amino acids in the N-terminus domain. Furthermore, the isoforms are categorized based on the presence of either three (3R tau isoforms) or four (4R tau isoforms) tandem repeat sequences each consisting of 31 or 32 amino acids.[3]

Biomarkers

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Neuroimaging

[edit]

Positron emission tomography (PET) is one type of biomarker capable of identifying elevated levels of tau in patients with Alzheimer's disease. PET is a great tool that can supplement information such as regions with higher neuropathologic burden than others. But it needs to be eligible, and have more positive outcomes than negative, such as exposure to radioactivity.[4]

Biofluid

[edit]

The analysis of cerebrospinal fluid (CSF) represents a potential avenue for the development of biomarkers in tauopathies. Substantial data on CSF biomarkers is available for Alzheimer's disease (AD), focusing on measures related to total and phosphorylated forms of tau and amyloid-beta (Aβ) protein. Elevated CSF tau and decreased Aβ levels constitute the characteristic CSF signature of AD, allowing differentiation from controls.[5] This signature may also assist in distinguishing atypical forms of AD pathology associated with clinical frontotemporal dementia (FTD) from those with underlying frontotemporal lobar degeneration (FTLD)-Tau pathology.[6]

Alzheimer's disease

[edit]

Alzheimer's disease (AD) is clinically characterized by a progressive decline in memory and cognitive functions, leading to severe dementia. Microscopically, AD is identified by the presence of two types of insoluble fibrous materials: (1) extracellular amyloid (Aβ) protein forming senile plaques and (2) intracellular neurofibrillary lesions (NFL) composed of abnormally and hyperphosphorylated tau protein. While AD is not strictly considered a prototypical tauopathy, as tau pathology coexists with Aβ protein deposition, the 'amyloid cascade hypothesis' posits that Aβ accumulation is the primary factor driving AD pathogenesis.[7][8] Nevertheless, AD neurofibrillary lesions were the first to undergo ultrastructural and biochemical analysis, thus laying the foundation for in-depth studies on tau protein deposition in various tauopathies.[9]

Neuropathologic phenotypes

[edit]

Frontotemporal dementia

[edit]

Frontotemporal dementia is a part of a diverse spectrum of disorders clinically marked by dysfunction in the frontal and temporal lobes, collectively referred to as frontotemporal lobar degeneration (FTLD). The primary histological characteristics include profound neuronal loss, enlarged neurons, and distinctive spherical argyrophilic inclusions known as Pick bodies (PBs). These PBs primarily consist of hyperphosphorylated tau protein, with tau protein presenting as two major bands at 60 and 64 kDa and a variable, minor band at 69 kDa. Filamentous tau deposits in nerve cells are predominantly composed of 3R tau isoforms.[10]

Progressive supranuclear palsy

[edit]

Progressive supranuclear palsy (PSP) is a type of tauopathy, but the cause is not yet discovered. For PSP unusual phosphorylation for tau protein causes vital protein filaments in the nerve cells to destruct, a phenomenon called "neurofibrillary" degeneration. Typical symptoms of PSP would be abnormal speech, balance impairment and overcognitive and memory impairment. As CBD, PSP is also classified as a 4R tauopathy, and because of that PSP will often be selected for trials regarding anti-tau therapeutics.[11][12]

Corticobasal degeneration

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Corticobasal degeneration (CBD) is an increasingly acknowledged neurodegenerative disorder characterized by both motor and cognitive dysfunction. In affected regions, histological examination reveals pronounced neuronal loss accompanied by spongiosis and gliosis, cortical ballooned cells, and notable intracytoplasmic filamentous tau pathology in both glial and neuronal cells. Biochemically, the distinctive tau profile in CBD cases manifests as a prominent tau doublet at 64 and 68 kDa, which is variably identified. These bands predominantly consist of hyperphosphorylated 4R tau isoforms, leading to the classification of CBD as a 4R tauopathy.[13]

Tau therapeutics

[edit]

Currently, there are no specific treatments for tauopathies. Up till now, attempts have been made to target neurotransmitter disturbances to relieve disease symptoms. For AD a specific treatment is difficult because the pathological changes both early compared to the symptoms showing.[14] Even though there is no current treatment for tauopathies, there are treatments that can relieve symptoms. Speech therapy can be beneficial for aphasia symptoms, symptoms such as depression and apathy frequently engaged with pharmaceuticals. For physical challenges, physical therapy has proven helpful in extending motor function for patients.[15]

Other diseases

[edit]

See also

[edit]

References

[edit]
  1. ^ a b Kovacs, Gabor G. (2018). "Tauopathies". In Gabor G. Kovacs; Irina Alafuzoff (eds.). Handbook of Clinical Neurology, volume 145. Handbook of Clinical Neurology. pp. 355–368. doi:10.1016/B978-0-12-802395-2.00025-0. ISBN 978-0-12-802395-2. PMID 28987182.
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  28. ^ Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM (March 1979). "Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia". Annals of Neurology. 5 (3): 288–94. doi:10.1002/ana.410050311. PMID 156000. S2CID 25649751.
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