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      No evidence for amyloid pathology as a key mediator of neurodegeneration post-stroke - a seven-year follow-up study

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          Abstract

          Background

          Cognitive impairment (CI) with mixed vascular and neurodegenerative pathologies after stroke is common. The role of amyloid pathology in post-stroke CI is unclear. We hypothesize that amyloid deposition, measured with Flutemetamol ( 18F-Flut) positron emission tomography (PET), is common in seven-year stroke survivors diagnosed with CI and, further, that quantitatively assessed 18F-Flut-PET uptake after 7 years correlates with amyloid-β peptide (Aβ 42) levels in cerebrospinal fluid (CSF) at 1 year, and with measures of neurodegeneration and cognition at 7 years post-stroke.

          Methods

          208 patients with first-ever stroke or transient Ischemic Attack (TIA) without pre-existing CI were included during 2007 and 2008. At one- and seven-years post-stroke, cognitive status was assessed, and categorized into dementia, mild cognitive impairment or normal. Etiologic sub-classification was based on magnetic resonance imaging (MRI) findings, CSF biomarkers and clinical cognitive profile. At 7 years, patients were offered 18F-Flut-PET, and amyloid-positivity was assessed visually and semi-quantitatively. The associations between 18F-Flut-PET standardized uptake value ratios (SUVr) and measures of neurodegeneration (medial temporal lobe atrophy (MTLA), global cortical atrophy (GCA)) and cognition (Mini-Mental State Exam (MMSE), Trail-making test A (TMT-A)) and CSF Aβ 42 levels were assessed using linear regression.

          Results

          In total, 111 patients completed 7-year follow-up, and 26 patients agreed to PET imaging, of whom 13 had CSF biomarkers from 1 year. Thirteen out of 26 patients were diagnosed with CI 7 years post-stroke, but only one had visually assessed amyloid positivity. CSF Aβ 42 levels at 1 year, MTA grade, GCA scale, MMSE score or TMT-A at 7 years did not correlate with 18F-Flut-PET SUVr in this cohort.

          Conclusions

          Amyloid binding was not common in 7-year stroke survivors diagnosed with CI. Quantitatively assessed, cortical amyloid deposition did not correlate with other measures related to neurodegeneration or cognition. Therefore, amyloid pathology may not be a key mediator of neurodegeneration 7 years post-stroke.

          Trial registration

          Clinicaltrials.gov ( NCT00506818). July 23, 2007. Inclusion from February 2007, randomization and intervention from May 2007 and trial registration in July 2007.

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          Most cited references33

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          The role of apolipoprotein E in Alzheimer's disease.

          The epsilon4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Abeta aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE epsilon4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.
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            Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).

            The incidence of stroke is predicted to rise because of the rapidly ageing population. However, over the past two decades, findings of randomised trials have identified several interventions that are effective in prevention of stroke. Reliable data on time-trends in stroke incidence, major risk factors, and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence. We aimed to obtain these data. We ascertained changes in incidence of transient ischaemic attack and stroke, risk factors, and premorbid use of preventive treatments from 1981-84 (Oxford Community Stroke Project; OCSP) to 2002-04 (Oxford Vascular Study; OXVASC). Of 476 patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and 93 transient ischaemic attacks were incident events. Despite more complete case-ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29% (relative incidence 0.71, 95% CI 0.61-0.83, p=0.0002). Incidence declined by more than 50% for primary intracerebral haemorrhage (0.47, 0.27-0.83, p=0.01) but was unchanged for subarachnoid haemorrhage (0.83, 0.44-1.57, p=0.57). Thus, although 28% more incident strokes (366 vs 286) were expected in OXVASC due to demographic change alone (33% increase in those aged 75 or older), the observed number fell (262 vs 286). Major reductions were recorded in mortality rates for incident stroke (0.63, 0.44-0.90, p=0.02) and in incidence of disabling or fatal stroke (0.60, 0.50-0.73, p<0.0001), but no change was seen in case-fatality due to incident stroke (17.2% vs 17.8%; age and sex adjusted relative risk 0.85, 95% CI 0.57-1.28, p=0.45). Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers, mean total cholesterol, and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure lowering drugs (all p<0.0001). The age-specific incidence of major stroke in Oxfordshire has fallen by 40% over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors.
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              Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition.

              Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood.
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                Author and article information

                Contributors
                guri.hagberg@gmail.com
                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central (London )
                1471-2377
                8 May 2020
                8 May 2020
                2020
                : 20
                : 174
                Affiliations
                [1 ]GRID grid.414168.e, ISNI 0000 0004 0627 3595, Bærum Hospital, Vestre Viken Hospital Trust, ; N-3004 Drammen, Norway
                [2 ]GRID grid.5510.1, ISNI 0000 0004 1936 8921, Institute of Clinical Medicine, , University of Oslo, ; Oslo, Norway
                [3 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Geriatric Medicine, , Oslo University Hospital, ; Oslo, Norway
                [4 ]GRID grid.15895.30, ISNI 0000 0001 0738 8966, Department of Neurology, Department of Internal Medicine, Central Hospital Karlstad and Faculty of Medicine, , Örebro University, ; Örebro, Sweden
                [5 ]GRID grid.411279.8, ISNI 0000 0000 9637 455X, Department of Neurology, , Akershus University Hospital, ; Oslo, Norway
                [6 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Division of Radiology, , Nuclear Medicine Oslo University Hospital, ; Oslo, Norway
                [7 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Nuclear Medicine, , Oslo University Hospital, ; Oslo, Norway
                [8 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, , University of Oxford, ; Oxford, UK
                [9 ]GRID grid.8348.7, ISNI 0000 0001 2306 7492, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, ; Oxford, UK
                Author information
                http://orcid.org/0000-0003-2822-7701
                Article
                1753
                10.1186/s12883-020-01753-w
                7206753
                32384876
                4b5f4d81-58aa-49ba-ba23-ce82fdd96da5
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 17 December 2019
                : 29 April 2020
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Neurology
                stroke,cognitive impairment,cerebrospinal fluid,positron emission tomography,prognosis
                Neurology
                stroke, cognitive impairment, cerebrospinal fluid, positron emission tomography, prognosis

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