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Altered proteins in the aging brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Neuropathology research group)
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1182
Keyword [en]
Cognitively unimpaired subjects, Hyperphosphorylated tau, Beta amyloid, Alpha-synclein, Transactive response DNA binding protein 43
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-277214ISBN: 978-91-554-9482-7 (print)OAI: oai:DiVA.org:uu-277214DiVA: diva2:904441
Public defence
2016-04-08, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-03-18 Created: 2016-02-18 Last updated: 2016-04-04
List of papers
1. Hyperphosphorylated tau in young and middle-aged subjects
Open this publication in new window or tab >>Hyperphosphorylated tau in young and middle-aged subjects
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.

Keyword
Locus coeruleus, Hyperphosphorylated tau, Immunohistochemistry, Post-mortem study, Middle-aged, Cognitively unimpaired
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168118 (URN)10.1007/s00401-011-0906-z (DOI)000298643400008 ()
Available from: 2012-02-07 Created: 2012-02-06 Last updated: 2017-12-08Bibliographically approved
2. Alzheimer's disease-related plaques in nondemented subjects
Open this publication in new window or tab >>Alzheimer's disease-related plaques in nondemented subjects
2014 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 10, no 5, 522-529 p.Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) pathology was assessed in 587 nondemented subjects, with age at death at or more than 50 years. In 307 subjects, amyloid-beta (A beta) immunoreactive (IR) plaques were seen; in 192 subjects, neuritic plaques (NPs) stained with modified Bielschowsky silver stain (mBky) were observed. In 20% of the whole cohort and in 62% of the 192 subjects with NPs in mBky, hyperphosphorylated tau (HPtau) IR NPs were seen. In most cases in this nondemented cohort, the HPtau IR NPs were observed either sparsely or to a moderate extent. The correlation between the NP score and Braak stage was best (r = 0.6, P < .001) when HPtau immunohistochemistry was used. Eighty-three percent of the subjects could not be categorized following the 1997 National Institute on Aging and the Reagan Institute (NIA-RI) recommendations, whereas the 2012 National Institute on Aging Alzheimer's Association (NIA-AA) guidelines were applicable for all study subjects. Twenty-eight subjects had an intermediate level of AD neuropathological change according to the 2012 NIA-AA guidelines, and 25 of these 28 subjects displayed HPtau IR NPs in the temporal cortex. It is noteworthy, however, that as many as 119 out of the 192 subjects with NPs in mBky displayed HPtau IR NPs in the temporal cortex. Ninety-four of these 119 subjects with neocortical HPtau IR NPs had a low level of neuropathological AD change according to the 2012 NIA-AA guidelines because they were in Braak stages I and II. Thus, 94 subjects were not acknowledged as being at risk for AD when applying the 2012 NIA-AA guidelines. We suggest that to identify all subjects with cortical HPtau pathology and, consequently, probably being at risk for developing AD, in addition to the level of AD neuropathological change as recommended by the 2012 NIA-AA guidelines, assessment of HPtau IR NPs in the neocortex should be carried out.

Keyword
Neuritic plaques, National Institute on Aging Alzheimer's Association, Hyperphosphorylated tau, Nondemented aged subjects
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-234158 (URN)10.1016/j.jalz.2012.12.009 (DOI)000341543600002 ()
Available from: 2014-10-15 Created: 2014-10-14 Last updated: 2017-12-05Bibliographically approved
3. Correlations Between Mini-Mental State Examination Score, Cerebrospinal Fluid Biomarkers, and Pathology Observed in Brain Biopsies of Patients With Normal-Pressure Hydrocephalus
Open this publication in new window or tab >>Correlations Between Mini-Mental State Examination Score, Cerebrospinal Fluid Biomarkers, and Pathology Observed in Brain Biopsies of Patients With Normal-Pressure Hydrocephalus
2015 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 74, no 5, 470-479 p.Article in journal (Refereed) Published
Abstract [en]

Alzheimer disease (AD)-related pathology was assessed in cortical biopsy samples of 111 patients with idiopathic normal-pressure hydrocephalus. Alzheimer disease hallmark lesions-beta-amyloid (A beta) and hyperphosphorylated tau (HPtau)-were observed in 47% of subjects, a percentage consistent with that for whole-brain assessment reported postmortem in unselected cohorts. Higher-immunostained area fraction of AD pathology corresponded with lower preoperative mini-mental state examination scores. Concomitant A beta and HPtau pathology, reminiscent of that observed in patients with AD, was observed in 22% of study subjects. There was a significant correlation between A beta-immunostained area fraction in tissue and A beta 42 (42-amino-acid form of A beta) in cerebrospinal fluid (CSF). Levels of A beta 42 were significantly lower in CSF in subjects with concomitant A beta and HPtau pathology compared with subjects lacking pathology. Moreover, a significant correlation between HPtau-immunostained area fraction and HPtau in CSF was noted. Both HPtau and total tau were significantly higher in CSF in subjects with concomitant A beta and HPtau pathology compared with subjects lacking pathology. The 42-amino-acid form of A beta (A beta 42) and HPtau in CSF were the most significant predictors of the presence of AD pathology in cortical biopsies. Long-term follow-up studies are warranted to assess whether all patients with idiopathic normal-pressure hydrocephalus with AD pathology progress to AD and to determine the pathologic substrate of idiopathic normal-pressure hydrocephalus.

Keyword
Amyloid beta, Cerebrospinal fluid biomarkers, Cognitive status, Hyperphosphorylated tau, Normal-pressure hydrocephalus
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-252677 (URN)10.1097/NEN.0000000000000191 (DOI)000353056400008 ()25868149 (PubMedID)
Available from: 2015-05-26 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
4. Altered proteins in the aging brain
Open this publication in new window or tab >>Altered proteins in the aging brain
Show others...
2016 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 4, 316-325 p.Article in journal (Refereed) Published
Abstract [en]

We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-tau (HP tau), beta-amyloid, alpha-synuclein (alpha S), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HP tau-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. beta-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HP tau Braak stage and age. Intermediate Alzheimer disease-related pathology (ADRP) was seen in 12%; 52% of the subjects with HP tau-IR fulfilled criteria for definite primary age-related tauopathy (PART). The incidence of concomitant pathology (alpha S, TDP43) did not differ between those with PART and those with ADRP but the former were younger. TDP43-IR was observed in 36%; the most frequently affected region was the medulla; alpha S-IR was observed in 19% of subjects. In 41% of the subjects from 80 to 89 years at death, 3 altered proteins were seen in the brain. Thus, altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases.

Place, publisher, year, edition, pages
Oxford University Press, 2016
Keyword
alpha-Synuclein; beta-Amyloid; Aging; Cognition; Hyperphosphorylated-tau; Immunohistochemistry; Transactive response DNA binding protein 43
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-277213 (URN)10.1093/jnen/nlw002 (DOI)000375797000004 ()26979082 (PubMedID)
Available from: 2016-02-18 Created: 2016-02-18 Last updated: 2017-11-30Bibliographically approved

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