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Correlations Between Mini-Mental State Examination Score, Cerebrospinal Fluid Biomarkers, and Pathology Observed in Brain Biopsies of Patients With Normal-Pressure Hydrocephalus
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
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.

Place, publisher, year, edition, pages
2015. Vol. 74, no 5, 470-479 p.
Keyword [en]
Amyloid beta, Cerebrospinal fluid biomarkers, Cognitive status, Hyperphosphorylated tau, Normal-pressure hydrocephalus
National Category
Neurosciences Neurology
Identifiers
URN: urn:nbn:se:uu:diva-252677DOI: 10.1097/NEN.0000000000000191ISI: 000353056400008PubMedID: 25868149OAI: oai:DiVA.org:uu-252677DiVA: diva2:814271
Available from: 2015-05-26 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1182
Keyword
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: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)
Opponent
Supervisors
Available from: 2016-03-18 Created: 2016-02-18 Last updated: 2016-04-04

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Elobeid, AdilaCesarini, Kristina GiulianaAlafuzoff, Irina

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