Burke, Anna

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

BackgroundAdvanced diffusion‐based MRI biomarkers may provide insight into microstructural and perfusion changes associated with neurodegeneration and cognitive decline.PurposeTo assess longitudinal microstructural and perfusion changes using apparent diffusion coefficient (ADC) and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) parameters in cognitively impaired (CI) and healthy control (HC) groups.Study TypeProspective/longitudinal.PopulationTwelve CI patients (75% female) and 13 HC subjects (69% female).Field Strength/Sequence3 T; Spin‐Echo‐IVIM‐DWI.AssessmentTwo MRI scans were performed with a 12‐month interval. ADC and IVIM‐DWI metrics (diffusion coefficient [D] and perfusion fraction [f]) were generated from monoexponential and biexponential fits, respectively. Additionally, voxel‐based correlations were evaluated between change in Montreal Cognitive Assessment (ΔMoCA) and baseline imaging parameters.Statistical TestsAnalysis of covariance with sex and age as covariates was performed for main effects of group and time (false discovery rate [FDR] corrected) with post hoc comparisons using Bonferroni correction. Partial‐η2 and Hedges' g were used for effect‐size analysis. Spearman's correlations (FDR corrected) were used for the relationship between ΔMoCA score and imaging. P < 0.05 was considered statistically significant.ResultsSignificant differences were found for the main effects of group (HC vs. CI) and time. For group effects, higher ADC, IVIM‐D, and IVIM‐f were observed in the CI group compared to HC (ADC: 1.23 ± 0.08.10−3 vs. 1.09 ± 0.07.10−3 mm2/sec; IVIM‐D: 0.82 ± 0.01.10−3 vs. 0.73 ± 0.01.10−3 mm2/sec; and IVIM‐f: 0.317 ± 0.008 vs. 0.253 ± 0.009). Significantly higher ADC, IVIM‐D, and IVIM‐f values were observed in the CI group after 12 months (ADC: 1.45 ± 0.05.10−3 vs. 1.50 ± 0.07.10−3 mm2/sec; IVIM‐D: 0.87 ± 0.01.10−3 vs. 0.94 ± 0.02.10−3 mm2/sec; and IVIM‐f: 0.303 ± 0.007 vs. 0.332 ± 0.008), but not in the HC group at large effect size. ADC, IVIM‐D, and IVIM‐f negatively correlated with ΔMoCA score (ρ = −0.49, −0.51, and −0.50, respectively).Data ConclusionThese findings demonstrate that longitudinal differences between CI and HC cohorts can be measured using IVIM‐based metrics.Level of Evidence2Technical Efficacy Stage2

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease that affects aging populations. Current MRI techniques are often limited in their sensitivity to underlying neuropathological changes.PurposeTo characterize differences in voxel‐based morphometry (VBM), apparent diffusion coefficient (ADC), and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) metrics in aging populations. Additionally, to investigate the connection between cognitive assessments and neuroimaging metrics.Study TypeProspective/cross‐sectional.PopulationIn all, 49 subjects, including 13 with AD dementia, 12 with mild cognitive impairment (MCI), and 24 healthy controls (HC).Field Strength/Sequence3T/magnetization‐prepared rapid acquisition gradient echo (MP‐RAGE) and IVIM‐DWIAssessmentAll participants completed a cognitive screening battery prior to MRI. IVIM‐DWI maps (pure diffusion coefficient [D], pseudodiffusion coefficient [D*], and perfusion fraction [f]) were generated from a biexponential fit of diffusion MRI data. VBM was performed on the standard T1‐weighted MP‐RAGE structural images. Group‐wise templates were used to compare across groups.Statistical TestsAnalysis of covariance (ANCOVA) with gender and age as covariates (familywise error [FWE] corrected, post‐hoc comparisons using Bonferroni correction) for group comparisons. Partial‐η2 and Hedges' g were used for effect‐size analysis. Spearman's correlations (false discovery rate [FDR]‐corrected) for the relationship between cognitive scores and imaging.ResultsClusters of significant group‐wise differences were found mainly in the temporal lobe, hippocampus, and amygdala using all VBM and IVIM methods (P < 0.05 FWE). While VBM showed significant changes between MCI and AD groups and between HC and AD groups, no significant clusters were observed between HC and MCI using VBM. ADC and IVIM‐D demonstrated significant changes, at P < 0.05 FWE, between HC and MCI, notably in the amygdala and hippocampus. Several voxel‐based correlations were observed between neuroimaging metrics and cognitive tests within the cognitively impaired groups (P < 0.05 FDR).Data ConclusionThese findings suggest that IVIM‐DWI metrics may be earlier biomarkers for AD‐related changes than VBM. The use of these techniques may provide novel insight into subvoxel neurodegenerative processes.Level of Evidence2Technical Efficacy Stage2 J. MAGN. RESON. IMAGING 2020;52:1811–1826.

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain‐only donations and currently has banked more than 1600 brains. More than 430 whole‐body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0‐hour median post‐mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant‐funded projects.