eprintid: 10137088 rev_number: 17 eprint_status: archive userid: 608 dir: disk0/10/13/70/88 datestamp: 2021-10-28 12:02:36 lastmod: 2021-11-06 00:12:18 status_changed: 2021-10-28 12:02:36 type: article metadata_visibility: show creators_name: Fiford, CM creators_name: Sudre, CH creators_name: Young, AL creators_name: Macdougall, A creators_name: Nicholas, J creators_name: Manning, EN creators_name: Malone, IB creators_name: Walsh, P creators_name: Goodkin, O creators_name: Pemberton, HG creators_name: Barkhof, F creators_name: Alexander, DC creators_name: Cardoso, MJ creators_name: Biessels, GJ creators_name: Barnes, J creators_name: Alzheimer’s Disease Neuroimaging Initiative, . title: Presumed small vessel disease, imaging and cognition markers in the Alzheimer's Disease Neuroimaging Initiative ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F82 divisions: F86 divisions: B04 divisions: C05 divisions: F48 divisions: F42 keywords: Alzheimer’s, biomarkers, cerebrovascular disease, microbleeds, white matter hyperintensities note: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract: MRI-derived features of presumed cerebral small vessel disease are frequently found in Alzheimer’s disease. Influences of such markers on disease-progression measures are poorly understood. We measured markers of presumed small vessel disease (white matter hyperintensity volumes; cerebral microbleeds) on baseline images of newly enrolled individuals in the Alzheimer’s Disease Neuroimaging Initiative cohort (GO and 2) and used linear mixed models to relate these to subsequent atrophy and neuropsychological score change. We also assessed heterogeneity in white matter hyperintensity positioning within biomarker abnormality sequences, driven by the data, using the Subtype and Stage Inference algorithm. This study recruited both sexes and included: controls: [n = 159, mean(SD) age = 74(6) years]; early and late mild cognitive impairment [ns = 265 and 139, respectively, mean(SD) ages =71(7) and 72(8) years, respectively]; Alzheimer’s disease [n = 103, mean(SD) age = 75(8)] and significant memory concern [n = 72, mean(SD) age = 72(6) years]. Baseline demographic and vascular risk-factor data, and longitudinal cognitive scores (Mini-Mental State Examination; logical memory; and Trails A and B) were collected. Whole-brain and hippocampal volume change metrics were calculated. White matter hyperintensity volumes were associated with greater whole-brain and hippocampal volume changes independently of cerebral microbleeds (a doubling of baseline white matter hyperintensity was associated with an increase in atrophy rate of 0.3 ml/year for brain and 0.013 ml/year for hippocampus). Cerebral microbleeds were found in 15% of individuals and the presence of a microbleed, as opposed to none, was associated with increases in atrophy rate of 1.4 ml/year for whole brain and 0.021 ml/year for hippocampus. White matter hyperintensities were predictive of greater decline in all neuropsychological scores, while cerebral microbleeds were predictive of decline in logical memory (immediate recall) and Mini-Mental State Examination scores. We identified distinct groups with specific sequences of biomarker abnormality using continuous baseline measures and brain volume change. Four clusters were found; Group 1 showed early Alzheimer’s pathology; Group 2 showed early neurodegeneration; Group 3 had early mixed Alzheimer’s and cerebrovascular pathology; Group 4 had early neuropsychological score abnormalities. White matter hyperintensity volumes becoming abnormal was a late event for Groups 1 and 4 and an early event for 2 and 3. In summary, white matter hyperintensities and microbleeds were independently associated with progressive neurodegeneration (brain atrophy rates) and cognitive decline (change in neuropsychological scores). Mechanisms involving white matter hyperintensities and progression and microbleeds and progression may be partially separate. Distinct sequences of biomarker progression were found. White matter hyperintensity development was an early event in two sequences. date: 2021-10-07 date_type: published official_url: https://doi.org/10.1093/braincomms/fcab226 oa_status: green full_text_type: pub pmcid: PMC8514859 language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1895055 doi: 10.1093/braincomms/fcab226 pii: fcab226 lyricists_name: Alexander, Daniel lyricists_name: Barkhof, Frederik lyricists_name: Barnes, Josephine lyricists_name: Goodkin, Olivia lyricists_name: Malone, Ian lyricists_name: Manning, Emily lyricists_name: Pemberton, Hugh lyricists_name: Young, Alexandra lyricists_id: DALEX06 lyricists_id: FBARK32 lyricists_id: JASHL10 lyricists_id: OGOOD06 lyricists_id: IBMAL93 lyricists_id: EMMAN90 lyricists_id: HGBPE46 lyricists_id: YOUNG96 actors_name: Kalinowski, Damian actors_id: DKALI47 actors_role: owner full_text_status: public publication: Brain Communications volume: 3 number: 4 article_number: fcab226 event_location: England issn: 2632-1297 citation: Fiford, CM; Sudre, CH; Young, AL; Macdougall, A; Nicholas, J; Manning, EN; Malone, IB; ... Alzheimer’s Disease Neuroimaging Initiative, .; + view all <#> Fiford, CM; Sudre, CH; Young, AL; Macdougall, A; Nicholas, J; Manning, EN; Malone, IB; Walsh, P; Goodkin, O; Pemberton, HG; Barkhof, F; Alexander, DC; Cardoso, MJ; Biessels, GJ; Barnes, J; Alzheimer’s Disease Neuroimaging Initiative, .; - view fewer <#> (2021) Presumed small vessel disease, imaging and cognition markers in the Alzheimer's Disease Neuroimaging Initiative. Brain Communications , 3 (4) , Article fcab226. 10.1093/braincomms/fcab226 <https://doi.org/10.1093/braincomms%2Ffcab226>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10137088/1/Barnes_Presumed%20small%20vessel%20disease%2C%20imaging%20and%20cognition%20markers%20in%20the%20Alzheimer%27s%20Disease%20Neuroimaging%20Initiative_VoR.pdf