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Hyperphosphorylated tau in young and middle-aged subjects
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
2012 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, no 1, 97-104 p.Article in journal (Refereed) Published
Abstract [en]

The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HP tau) and beta-amyloid (A beta) pathology in predilection neuroanatomical areas. HP tau pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter the microtubule-associated protein. HP tau pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical A beta or transentorhinal HP tau pathology. This observation was present even when assessing only one routine section of 7 mu m thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HP tau pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted.

Place, publisher, year, edition, pages
2012. Vol. 123, no 1, 97-104 p.
Keyword [en]
Locus coeruleus, Hyperphosphorylated tau, Immunohistochemistry, Post-mortem study, Middle-aged, Cognitively unimpaired
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-168118DOI: 10.1007/s00401-011-0906-zISI: 000298643400008OAI: oai:DiVA.org:uu-168118DiVA: diva2:491749
Available from: 2012-02-07 Created: 2012-02-06 Last updated: 2016-04-04Bibliographically approved
In thesis
1. Altered proteins in the aging brain
Open this publication in new window or tab >>Altered proteins in the aging brain
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The classification of neurodegenerative disorders is based on the major component of the protein aggregates in the brain. The most common altered proteins associated with neurodegeneration are Hyperphosphorylated tau (HPt), beta amyloid (Aβ), alpha-synclein (αS) and transactive response DNA binding protein 43 (TDP43). In this study we assessed the incidence and the neuroanatomical distribution of proteins associated with neurodegeneration in the brain tissue of cognitively unimpaired subjects.

We demonstrated the early involvement of the Locus Coeruleus (LC) with HPt pathology in cognitively unimpaired mid aged subjects, a finding which supports the notion that LC is an initiation site of HPt pathology. This may suggest that development of clinical assessment techniques and radiological investigations reflecting early LC alterations may help in identifying subjects with early stages of neurodegeneration.

Furthermore, we studied a large cohort of cognitively unimpaired subjects with age at death ≥50 years and we applied the National Institute on Aging –Alzheimer’s disease (AD) Association (NIA-AA) guidelines for the assessment of AD related neuropathological changes. Interestingly, a considerable percentage of the subjects were classified as having an intermediate level of AD pathology. We also showed that the altered proteins;  HPt , Aβ, αS, and TDP43 are frequently seen in the brain of cognitively unimpaired subjects with age at death ≥50 years, the incidence of these proteins increased significantly with age. This finding suggests that neurodegeneration has to be extensive to cause functional disturbance and clinical symptoms.

Moreover, we investigated the correlation between AD related pathology in cortical biopsies, the AD / cerebrospinal fluid (CSF) biomarkers and the Mini Mental State examination (MMSE) scores in a cohort of idiopathic Normal Pressure Hydrocephalus (iNPH) patients. We demonstrated that AD/ CSF biomarkers and MMSE scores reflect AD pathology in the cortical biopsies obtained from iNPH patients. 

In conclusion, this study shows that the altered proteins associated with neurodegeneration are frequently seen in the brain tissue of cognitively unimpaired aged subjects. This fact should be considered while developing diagnostic biomarkers for identification of subjects at early stages of the disease, in order to introduce therapeutic intervention prior to the occurrence of significant cognitive impairment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1182
Cognitively unimpaired subjects, Hyperphosphorylated tau, Beta amyloid, Alpha-synclein, Transactive response DNA binding protein 43
National Category
Medical and Health Sciences
Research subject
urn:nbn:se:uu:diva-277214 (URN)978-91-554-9482-7 (ISBN)
Public defence
2016-04-08, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2016-03-18 Created: 2016-02-18 Last updated: 2016-04-04

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