Primary age-related tauopathy
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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).[1][2] The term and diagnostic criteria for PART were developed by a large group of neuropathologists, spearheaded by Drs. John F. Crary (then at Columbia University Medical Center) and Peter T. Nelson (University of Kentucky).[3] Despite some controversy,[4][5] the term PART has been widely adopted, with the consensus criteria cited over 1130 times as of April 2023 according to Google Scholar.
At autopsy, the hallmark of PART is the presence of Alzheimer-type neurofibrillary tangles (NFTs) composed of abnormal tau protein in neurons in the medial temporal lobe, but no amyloid-beta (Aβ42) peptide accumulation in plaques.[2] This ultimately leads to neuronal death and brain atrophy.[6] 18% of Alzheimer neuropathological changes in cognitively normal and 5% of cognitively impaired elderly cases have been shown to display this pattern of degeneration.[7] Patients with severe PART typically exhibit mild cognitive impairment or an amnestic dementia.[2]
Neuropathological features
Patients with PART display neurofibrillary tangles that are essentially identical to those occurring in mild to moderate-stage Alzheimer's disease and other tauopathies.[8] Amyloid pathology is sparse or absent in patients with PART.[2][7] If few senile plaques are found, Thal phase grading can be implemented to differentiate the pathology as either PART or AD.[7]
Clinical features
Patients with PART can be cognitively normal, mildly cognitively impaired, or demented.[9][7] Specifically, higher stages of tangle burden (i.e. Braak III or IV) in PART have been found to be associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention.[9] Braak state 0 is restricted to the cortex, state l-ll bound by transentorhinal region and it can progress into limbic region of the brain (stage lll-lV).[10] PART can be further categorized as symptomatic (cognitive impairment and dementia) and asymptomatic (no signs of dementia).[7][6] One current hypothesis suggests that PART related dementia could be infrequent in younger populations, but may show symptomatic onset within oldest old (people greater than 90 years old).[11] Given that the elderly represent a fast growing segment of the population worldwide, further research is needed to understand how PART related pathological process can manifest in specific clinical symptoms.
Furthermore, serological testing cannot be used to identify PART patients and MRI scans are the only current available diagnostic tools.[12]
Relationship to Alzheimer's disease
Given the similarities in the pattern of neurofibrillary tangles in PART, some scientists have argued that they represent the same phenomenon.[13][14] However, others have argued that sufficient evidence exists to conclude that PART represents a pathological process.[15] Further more, Aβ42 presence in AD contributes to tau hyper phosphorylation and consequently its development into NFTs.[16][17] Aβ42 is absent in PART and due to several mechanisms underlying tau formation and maintenance, it would be necessary to separate PART from AD due to implications with respect to developing diagnostics and therapeutics.[2][18][19]
Genetics
PART has been associated with microtubule association tau protein (MAPT) H1 haplotype and no association has been seen with APOE ε4, a gene strongly linked to AD.[2][8][19] Thus another piece of evidence supporting the hypothesis that PART represents a novel diagnostic category. Also transformation as a result of tau mutation into isoforms (3R and 4R) on chromosome 17 has been linked to Parkinson and frontotemporal dementia.[18] Transformation in tau gene on chromosome 17 can be linked to PART due to the fact that the tau protein analyzed from PART NFTs consist of 3R and 4R isoforms.[12] MAPT gene results in different tau protein isoforms due to splicing patterns of exon 10.[10]