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Background: Relatively little is known about how white matter hyperintensity (WMH) changes relate to well‐characterised markers of disease progression such as brain atrophy rates in autosomal dominant familial AD (ADAD). Such analyses may improve models of disease progression and indicate whether WMH accrual and brain atrophy are associated features over the disease course. Methods: We investigated WMH accrual in the Dominantly Inherited Alzheimer Network (DIAN) cohort. Participants included 72 controls, 95 PSEN1, 7 PSEN2 and 27 APP mutation carriers, with longitudinal multi‐modal imaging. WMH were segmented using a semi‐automated protocol. Brain atrophy rate was calculated using the boundary shift integral (BSI). Three statistical models were used: Model 1 used mixed‐effect linear regression to assess WMH accrual by mutation presence or type, adjusting for evidence of cognitive impairment (symptomatic status as defined using CDR). Model 2 assessed the effect of estimated years to onset (EYO) on WMH accrual. Model 3 estimated correlations between residual rates of change after allowing mean rates of change in WMH and brain volume to depend on proximity to expected onset. All models (1‐3) were allowed to depend upon total intracranial volume. Results: The table shows summary statistics and rates of change including annualised rates of WMH accrual and brain atrophy. Results from Model 1 showed differences in WMH accrual between mutation groups after adjustment for symptom status (p<0.001), with APP having higher rates of accrual than all other groups. Model 2 demonstrated WMH increases were associated with EYO in PSEN1 and APP groups (p≤0.001, both tests), with an accelerating rate of accrual observed approaching and passing estimated onset in the PSEN1 and PSEN2 groups (p≤0.005, both tests). Model 3 demonstrated associations between residual rates of change in WMH and brain volume in the PSEN1 (r 0.76, p<0.001) and APP (r 0.55, p=0.03) groups (the figure shows crude rates). Conclusion: Mutation type has an impact on WMH accrual, with APP mutation carriers in this cohort gaining more WMH over time. WMH changes are an important biomarker in ADAD with burden increasing with EYO. WMH and brain atrophy changes track together across the AD disease course. [ABSTRACT FROM AUTHOR]

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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Accurate, automated white matter hyperintensity (WMH) segmentations are needed for large-scale studies to understand contributions of WMH to neurological diseases. We evaluated Bayesian Model Selection (BaMoS), a hierarchical fully-unsupervised model selection framework for WMH segmentation. We compared BaMoS segmentations to semi-automated segmentations, and assessed whether they predicted longitudinal cognitive change in control, early Mild Cognitive Impairment (EMCI), late Mild Cognitive Impairment (LMCI), subjective/significant memory concern (SMC) and Alzheimer's (AD) participants. Data were downloaded from the Alzheimer's disease Neuroimaging Initiative (ADNI). Magnetic resonance images from 30 control and 30 AD participants were selected to incorporate multiple scanners, and were semi-automatically segmented by 4 raters and BaMoS. Segmentations were assessed using volume correlation, Dice score, and other spatial metrics. Linear mixed-effect models were fitted to 180 control, 107 SMC, 320 EMCI, 171 LMCI and 151 AD participants separately in each group, with the outcomes being cognitive change (e.g. mini-mental state examination; MMSE), and BaMoS WMH, age, sex, race and education used as predictors. There was a high level of agreement between BaMoS' WMH segmentation volumes and a consensus of rater segmentations, with a median Dice score of 0.74 and correlation coefficient of 0.96. BaMoS WMH predicted cognitive change in: control, EMCI, and SMC groups using MMSE; LMCI using clinical dementia rating scale; and EMCI using Alzheimer's disease assessment scale-cognitive subscale (p < 0.05, all tests). BaMoS compares well to semi-automated segmentation, is robust to different WMH loads and scanners, and can generate volumes which predict decline. BaMoS can be applicable to further large-scale studies.

Introduction: Understanding relationships among blood pressure (BP), cognition, and brain volume could inform Alzheimer's disease (AD) management., Methods: We investigated Alzheimer's Disease Neuroimaging Initiative (ADNI) participants: 200 controls, 346 mild cognitive impairment (MCI), and 154 AD. National Alzheimer's Co-ordinating Center (NACC) participants were separately analyzed: 1098 controls, 2297 MCI, and 4845 AD. Relationships between cognition and BP were assessed in both cohorts and BP and atrophy rates in ADNI. Multivariate mixed linear-regression models were fitted with joint outcomes of BP (systolic, diastolic, and pulse pressure), cognition (Mini-Mental State Examination, Logical Memory, and Digit Symbol) and atrophy rate (whole-brain, hippocampus)., Results: ADNI MCI and AD patients with greater baseline systolic BP had higher hippocampal atrophy rates ([r, P value]; 0.2, 0.005 and 0.2, 0.04, respectively). NACC AD patients with lower systolic BP had lower cognitive scores (0.1, 0.0003)., Discussion: Higher late-life BP may be associated with faster decline in cognitively impaired elders., Competing Interests: There are no reported conflicts apart from a note that Christopher Lane is now employed by Eisai Europe Ltd., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5-T MRI. CSF Aβ 42 and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ 42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc., (© 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.)