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Biomarkers as Monitors of Drug Effect, Diagnostic Tools and Predictors of Deterioration Rate in Alzheimer’s Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Decreased amyloid-ß42 (Aß42), increased total tau (t-tau) and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) reflect histopathological core changes in the most common dementia disorder, Alzheimer’s disease (AD). They discriminate AD from healthy controls and predict conversion to AD with a relatively high accuracy. Memantine, an uncompetitive NMDA-receptor antagonist, is indicated for symptomatic treatment of AD. The first aim of this thesis was to investigate effects of memantine on CSF concentrations of Aβ42, tau and p-tau. Secondly, the aim was to explore the relation between these CSF biomarkers and retention of the amyloid biomarker Pittsburgh compound B using positron emission tomography (PIB PET), regional glucose metabolism measured with 18Fluoro-2-deoxy-d-glucose (FDG) PET and neuropsychological test performance. The third aim was to investigate their possible utility as predictors of future rate of AD dementia deterioration. All patients in the studies were recruited from the Memory Clinic, Uppsala University Hospital. In study I CSF p-tau concentrations in 11 AD patients were reduced after twelve months treatment with memantine, indicating that this compound may affect a key pathological process in AD. Results from study II showed that the concentrations of CSF Aß42 are lower in PIB+ patients than in PIB- patients, and that the PIB retention was stable during 12 months. In study III 10 patients with the diagnoses AD (6 PIB+/4 PIB-) and 8 subjects (1 PIB+/7 PIB-) with frontotemporal dementia were included. PIB+ patients had lower psychomotor speed measured by performance on the Trail Making Test A and impaired visual episodic memory compared to the PIB- patients. The initial clinical diagnoses were changed in 33% of the patients (6/18) during follow-up. Study IV is the first-ever report of an association between high CSF tau and dying in severe dementia. These 196 AD patients were followed up to nine years after baseline lumbar puncture. Moreover, CSF t-tau concentrations above median was associated with an increased risk of rapid cognitive decline (OR 3.31 (95% CI 1.53-7.16), independently of baseline functional stage. Thus, a clear association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease was shown.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 881
Keyword [en]
Alzheimer's disease, biomarkers, CSF, PIB PET, amyloid-beta, tau, rapid cognitive decline, dying in severe dementia, mortality, neuropsychological tests
National Category
Geriatrics
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-196965ISBN: 978-91-554-8629-7 (print)OAI: oai:DiVA.org:uu-196965DiVA: diva2:611277
Public defence
2013-05-16, Enghoffsalen, Ingång 50, bv, Akademiska sjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-24 Created: 2013-03-15 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Reduction of Phosphorylated Tau during Memantine Treatment of Alzheimer's Disease
Open this publication in new window or tab >>Reduction of Phosphorylated Tau during Memantine Treatment of Alzheimer's Disease
2007 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 24, no 4, 247-252 p.Article in journal (Refereed) Published
Abstract [en]

Background: Memantine is a moderate affinity N-methyl-D-aspartate receptor antagonist approved for treatment of Alzheimer's disease (AD). In AD, tau is abnormally hyperphosphorylated. However, no significant changes of phosphorylated tau levels in CSF are found at follow-up in studies with AD patients. It has been shown in vitro that memantine reverse induced abnormal hyperphosphorylation of tau in hippocampal neurons of rats. Methods: Eleven AD patients were examined with cognitive tests and interviews of relatives. CSF analyses were performed before starting treatment with memantine as well as after 1 year. Results: A statistically significant reduction of CSF phosphorylated tau at the 1-year follow-up was seen, from median 126 (interquartile range 107-153) to 108 (88-133) ng/l (p = 0.018). No statistically significant differences of total tau or A42 were found. Conclusion: The results may reflect effects of memantine on a key pathological feature in AD in line with previous in vitro findings.

Keyword
Alzheimer's disease, Memantine, Phosphorylated tau, Cerebrospinal fluid
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11724 (URN)10.1159/000107099 (DOI)000249536700002 ()17700020 (PubMedID)
Available from: 2007-10-15 Created: 2007-10-15 Last updated: 2017-12-11Bibliographically approved
2. Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study
Open this publication in new window or tab >>Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study
Show others...
2010 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 29, no 3, 204-212 p.Article in journal (Refereed) Published
Abstract [en]

Background:

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring β-amyloid (Aβ) load. Associations between PET PIB and cerebrospinal fluid (CSF) Aβ1–42 and apolipoprotein E ε4 (APOE ε4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer’s disease (AD) are less investigated.

Method:

PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD.

Results:

PIB retention was constant over 1 year, inversely related to low CSF Aβ1–42 (p = 0.01) and correlated positively to the numbers of the APOE ε4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = –0.59, p = 0.07), and plasma cystatin C (r = –0.56, p = 0.09).

Conclusion:

PIB retention is strongly related to CSF Aβ1–42, and to the numbers of the APOE ε4 allele.

National Category
Medical and Health Sciences Geriatrics
Identifiers
urn:nbn:se:uu:diva-132548 (URN)10.1159/000281832 (DOI)000276783100003 ()20332638 (PubMedID)
Available from: 2010-10-21 Created: 2010-10-21 Last updated: 2017-12-12Bibliographically approved
3. Re-evaluation of clinical dementia diagnoses with PET-PIB
Open this publication in new window or tab >>Re-evaluation of clinical dementia diagnoses with PET-PIB
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives: There is an overlap regarding Pittsburgh Compound-B (PIB) retention in patients clinically diagnosed as Alzheimer’s disease (AD) and non-AD dementia.  The aim of the present study was to investigate whether there are any differences between PIB+ and PIB PIB- patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with 18 Fluoro-2-deoxy-d-glucose (FDG) PET.

Methods: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with  PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.

Results:  The PIB+ patients (7/18) had slower psychomotor speed and more impaired visual episodic memory than the PIB- patients, otherwise performance did not differ between groups. The initial clinical diagnoses were changed in one third of the patients (6/18) during follow-up.  

Conclusions: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need of amyloid biomarkers and readiness to re-evaluate the initial diagnosis.

Keyword
Alzheimer’s disease, PIB PET, Dementia with Lewy Bodies, Frontotemporal dementia, ß-amyloid, amyloid biomarker, FDG PET, neuropsychological tests, TMT A, episodic memory
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-196962 (URN)
Available from: 2013-03-15 Created: 2013-03-15 Last updated: 2013-08-30
4. High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer's Disease
Open this publication in new window or tab >>High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer's Disease
Show others...
2014 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 37, no 3-4, 196-206 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Cerebrospinal fluid (CSF) amyloid beta(42) (A beta(42)), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. Methods: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2-9 years' duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. Results: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of = 4 points/year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53-7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21-5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16-18.82). Conclusions: In this large AD cohort, we found an association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive decline and a higher risk of dying in severe dementia.

Keyword
Alzheimer’s disease, tau, p-tau, beta-amyloid, CSF, rapid cognitive decline, dying in severe dementia, mortality
National Category
Geriatrics Gerontology, specializing in Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-196964 (URN)10.1159/000355556 (DOI)000335227300006 ()
Available from: 2013-03-15 Created: 2013-03-15 Last updated: 2017-12-06Bibliographically approved

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