Tauopathy

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Tauopathy
Taupathy.svg
Diagram of a normal microtubule and one affected by tauopathy
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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]

Contents

Tau protein

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

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. [4]

Biofluid

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

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

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. [10]

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. [11] [12]

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. [13]

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. [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

See also

Related Research Articles

<span class="mw-page-title-main">Lewy body</span> Spherical inclusion commonly found in damaged neurons

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside neurons affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

<span class="mw-page-title-main">Frontotemporal dementia</span> Types of dementia involving the frontal or temporal lobes

Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. Men and women appear to be equally affected. FTD generally presents as a behavioral or language disorder with gradual onset. Signs and symptoms tend to appear in late adulthood, typically between the ages of 45 and 65, although it can affect people younger or older than this. Currently, no cure or approved symptomatic treatment for FTD exists, although some off-label drugs and behavioral methods are prescribed.

<span class="mw-page-title-main">Progressive supranuclear palsy</span> Medical condition of the brain

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain. The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and cognitive impairment. PSP may be mistaken for other types of neurodegeneration such as Parkinson's disease, frontotemporal dementia and Alzheimer's disease. The cause of the condition is uncertain, but involves the accumulation of tau protein within the brain. Medications such as levodopa and amantadine may be useful in some cases.

<span class="mw-page-title-main">Tau protein</span> Group of six protein isoforms produced from the MAPT gene

The tau proteins form a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve, with an average plaque area of 400-450 square micrometers (μm2). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

<span class="mw-page-title-main">Frontotemporal lobar degeneration</span> Atrophy of the brains frontal and temporal lobes

Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

<span class="mw-page-title-main">Neurofibrillary tangle</span> Aggregates of tau protein known as a biomarker of Alzheimers disease

Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is known about their exact relationship to the different pathologies.

<span class="mw-page-title-main">Hippocampal sclerosis</span> Medical condition

Hippocampal sclerosis (HS) or mesial temporal sclerosis (MTS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus. Neuroimaging tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may identify individuals with hippocampal sclerosis. Hippocampal sclerosis occurs in 3 distinct settings: mesial temporal lobe epilepsy, adult neurodegenerative disease and acute brain injury.

Parkinson-plus syndromes (PPS) are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease with additional features that distinguish them from simple idiopathic Parkinson's disease (PD). Parkinson-plus syndromes are either inherited genetically or occur sporadically.

<span class="mw-page-title-main">Corticobasal degeneration</span> Rare neurodegenerative disease

Corticobasal degeneration (CBD) is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia. CBD symptoms typically begin in people from 50 to 70 years of age, and typical survival before death is eight years. It is characterized by marked disorders in movement and cognition, and is classified as one of the Parkinson plus syndromes. Diagnosis is difficult, as symptoms are often similar to those of other disorders, such as Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and a definitive diagnosis of CBD can only be made upon neuropathologic examination.

<span class="mw-page-title-main">Frontotemporal dementia and parkinsonism linked to chromosome 17</span> Medical condition

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative tauopathy and Parkinson plus syndrome. FTDP-17 is caused by mutations in the MAPT gene located on the q arm of chromosome 17, and has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">Chronic traumatic encephalopathy</span> Neurodegenerative disease caused by head injury

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated trauma to the head. The encephalopathy symptoms can include behavioral problems, mood problems, and problems with thinking. The disease often gets worse over time and can result in dementia.

<span class="mw-page-title-main">Proteinopathy</span> Diseases caused by abnormal protein structure

In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body.

<span class="mw-page-title-main">TMEM106B</span> Protein-coding gene in humans

Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.

Primary age-related tauopathy (PART) is a neuropathological designation introduced in 2014 to describe the neurofibrillary tangles (NFT) that are commonly observed in the brains of normally aged and cognitively impaired individuals that can occur independently of the amyloid plaques of Alzheimer's disease (AD). The term and diagnostic criteria for PART were developed by a large group of neuropathologists, spearheaded by Drs. John F. Crary and Peter T. Nelson. Despite some controversy, the term PART has been widely adopted, with the consensus criteria cited over 1130 times as of April 2023 according to Google Scholar.

Corticobasal syndrome (CBS) is a rare, progressive atypical Parkinsonism syndrome and is a tauopathy related to frontotemporal dementia. CBS is typically caused by the deposit of tau proteins forming in different areas of the brain.

<span class="mw-page-title-main">Limbic-predominant age-related TDP-43 encephalopathy</span> (LATE) -- a form of dementia

LATE is a term that describes a prevalent medical condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome. In other words, the symptoms of LATE are similar to those of Alzheimer's disease. 

Semorinemab is a monoclonal antibody against tau which was under development for the treatment of Alzheimer's disease but was discontinued. It binds to the N-terminus of all six isoforms of tau. The drug was ineffective in the treatment of Alzheimer's disease in two phase 2 clinical trials. Clinical development of semorinemab for Alzheimer's disease was discontinued in February 2024.

References

  1. 1 2 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.
  2. ↑ Goedert M, Spillantini MG (May 2017). "Propagation of Tau aggregates". Molecular Brain. 10 (1): 18. doi: 10.1186/s13041-017-0298-7 . PMC   5450399 . PMID   28558799.
  3. ↑ Goedert, M.; Spillantini, M.G.; Jakes, R.; Rutherford, D.; Crowther, R.A. (October 1989). "Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease". Neuron. 3 (4): 519–526. doi:10.1016/0896-6273(89)90210-9. PMID   2484340.
  4. ↑ Moloney, Christina M.; Labuzan, Sydney A.; Crook, Julia E.; Siddiqui, Habeeba; Castanedes-Casey, Monica; Lachner, Christian; Petersen, Ronald C.; Duara, Ranjan; Graff-Radford, Neill R.; Dickson, Dennis W.; Mielke, Michelle M.; Murray, Melissa E. (March 2023). "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". Alzheimer's & Dementia. 19 (3): 1029–1040. doi:10.1002/alz.12749. ISSN   1552-5260. PMC   9895127 . PMID   35920592.
  5. ↑ Shaw, Leslie M.; Vanderstichele, Hugo; Knapik-Czajka, Malgorzata; Clark, Christopher M.; Aisen, Paul S.; Petersen, Ronald C.; Blennow, Kaj; Soares, Holly; Simon, Adam; Lewczuk, Piotr; Dean, Robert; Siemers, Eric; Potter, William; Lee, Virginia M.-Y.; Trojanowski, John Q. (April 2009). "Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects". Annals of Neurology. 65 (4): 403–413. doi:10.1002/ana.21610. PMC   2696350 . PMID   19296504.
  6. ↑ Irwin, David J.; McMillan, Corey T.; Toledo, Jon B.; Arnold, Steven E.; Shaw, Leslie M.; Wang, Li-San; Van Deerlin, Vivianna; Lee, Virginia M.-Y.; Trojanowski, John Q.; Grossman, Murray (1 August 2012). "Comparison of Cerebrospinal Fluid Levels of Tau and Aβ 1-42 in Alzheimer Disease and Frontotemporal Degeneration Using 2 Analytical Platforms". Archives of Neurology. 69 (8): 1018–1025. doi:10.1001/archneurol.2012.26. PMC   3528180 . PMID   22490326.
  7. ↑ Hardy, John; Selkoe, Dennis J. (19 July 2002). "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics". Science. 297 (5580): 353–356. doi:10.1126/science.1072994. PMID   12130773.
  8. ↑ Nussbaum, Robert L.; Ellis, Christopher E. (3 April 2003). "Alzheimer's Disease and Parkinson's Disease". New England Journal of Medicine. 348 (14): 1356–1364. doi:10.1056/NEJM2003ra020003. PMID   12672864.
  9. ↑ Tolnay, Markus; Probst, Alphonse (June 2003). "The Neuropathological Spectrum of Neurodegenerative Tauopathies". IUBMB Life. 55 (6): 299–305. doi:10.1080/1521654032000114348. PMID   12938731.
  10. ↑ Tolnay, Markus; Probst, Alphonse (June 2003). "The Neuropathological Spectrum of Neurodegenerative Tauopathies". IUBMB Life. 55 (6): 299–305. doi:10.1080/1521654032000114348. PMID   12938731.
  11. ↑ Coughlin, David G.; Litvan, Irene (April 2020). "Progressive supranuclear palsy: Advances in diagnosis and management". Parkinsonism & Related Disorders. 73: 105–116. doi:10.1016/j.parkreldis.2020.04.014. PMC   7462164 . PMID   32487421.
  12. ↑ "Progressive Supranuclear Palsy - Symptoms, Causes, Treatment | NORD". rarediseases.org.
  13. ↑ Tolnay, Markus; Probst, Alphonse (June 2003). "The Neuropathological Spectrum of Neurodegenerative Tauopathies". IUBMB Life. 55 (6): 299–305. doi:10.1080/1521654032000114348. PMID   12938731.
  14. ↑ Khan, Sahil; Barve, Kalyani H.; Kumar, Maushmi S. (2020). "Recent Advancements in Pathogenesis, Diagnostics, and Treatment of Alzheimer's Disease". Current Neuropharmacology. 18 (11): 1106–1125. doi:10.2174/1570159X18666200528142429. PMC   7709159 . PMID   32484110.
  15. ↑ Orr, Miranda E.; Sullivan, A. Campbell; Frost, Bess (July 2017). "A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies". Trends in Pharmacological Sciences. 38 (7): 637–648. doi:10.1016/j.tips.2017.03.011. PMC   5476494 . PMID   28455089.
  16. ↑ Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson PT, Dewar K, Clark LN, Crary JF (November 2012). "The MAPT H1 haplotype is associated with tangle-predominant dementia". Acta Neuropathologica. 124 (5): 693–704. doi:10.1007/s00401-012-1017-1. PMC   3608475 . PMID   22802095.
  17. ↑ Jellinger KA, Attems J (February 2007). "Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease". Acta Neuropathologica. 113 (2): 107–17. doi:10.1007/s00401-006-0156-7. PMID   17089134. S2CID   5655388.
  18. ↑ 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 (January 2016). "The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy" (PDF). Acta Neuropathologica. 131 (1): 75–86. doi:10.1007/s00401-015-1515-z. PMC   4698281 . PMID   26667418.
  19. ↑ Roberts GW (1988). "Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis". Lancet. 2 (8626–8627): 1456–8. doi:10.1016/S0140-6736(88)90934-8. PMID   2904573. S2CID   32662671.
  20. ↑ Williams DR, Lees AJ (March 2009). "Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges". The Lancet. Neurology. 8 (3): 270–9. doi:10.1016/S1474-4422(09)70042-0. PMID   19233037. S2CID   1417930.
  21. ↑ Tolnay, Markus; Probst, Alphonse (June 2003). "The Neuropathological Spectrum of Neurodegenerative Tauopathies". IUBMB Life. 55 (6): 299–305. doi:10.1080/1521654032000114348. PMID   12938731.
  22. ↑ Selkoe DJ, Podlisny MB (2002). "Deciphering the genetic basis of Alzheimer's disease". Annual Review of Genomics and Human Genetics. 3: 67–99. doi: 10.1146/annurev.genom.3.022502.103022 . PMID   12142353.
  23. ↑ Darwich NF, Phan JM, et al. (2020). "Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau". Science. 370 (6519): eaay8826. doi:10.1126/science.aay8826. PMC   7818661 . PMID   33004675.
  24. ↑ Hof PR, Nimchinsky EA, Buée-Scherrer V, Buée L, Nasrallah J, Hottinger AF, Purohit DP, Loerzel AJ, Steele JC, Delacourte A (1994). "Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders". Acta Neuropathologica. 88 (5): 397–404. doi:10.1007/BF00389490. PMID   7847067. S2CID   2821768.
  25. ↑ Brat DJ, Gearing M, Goldthwaite PT, Wainer BH, Burger PC (June 2001). "Tau-associated neuropathology in ganglion cell tumours increases with patient age but appears unrelated to ApoE genotype". Neuropathology and Applied Neurobiology. 27 (3): 197–205. doi:10.1046/j.1365-2990.2001.00311.x. PMID   11489139. S2CID   36482221.
  26. ↑ Halper J, Scheithauer BW, Okazaki H, Laws ER (July 1986). "Meningio-angiomatosis: a report of six cases with special reference to the occurrence of neurofibrillary tangles". Journal of Neuropathology and Experimental Neurology. 45 (4): 426–46. doi:10.1097/00005072-198607000-00005. PMID   3088216. S2CID   663552.
  27. ↑ Paula-Barbosa MM, Brito R, Silva CA, Faria R, Cruz C (November 1979). "Neurofibrillary changes in the cerebral cortex of a patient with subacute sclerosing panencephalitis (SSPE)". Acta Neuropathologica. 48 (2): 157–60. doi:10.1007/BF00691159. PMID   506699. S2CID   36105401.
  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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