Total White Matter Hyperintensities Research Articles

Association of Cognitive Reserve Indicator with Cognitive Decline and Structural Brain Differences in Middle and Older Age: Findings from the UK Biobank

BackgroundCognitive reserve (CR) contributes to preserving cognition when facing brain aging and damage. CR has been linked to dementia risk in late life. However, the association between CR and cognitive changes and brain imaging measures, especially in midlife, is unclear.ObjectiveWe aimed to explore the association of CR with cognitive decline and structural brain differences in middle and older age.DesignThis longitudinal study was from the UK Biobank project where participants completed baseline surveys between 2006 to 2010 and were followed (mean follow-up: 9 years).SettingA population-based study.ParticipantsA total of 42,301 dementia-free participants aged 40–70 were followed-up to detect cognitive changes. A subsample (n=34,041) underwent brain magnetic resonance imaging scans.MeasurementsWe used latent class analysis to generate a CR indicator (categorized as high, moderate, and low) based on education, occupation, and multiple cognitively stimulating activities. Cognitive tests for global and domain-specific cognition were administrated at baseline and follow-up. Total brain, white matter, grey matter, hippocampal, and white matter hyperintensity volumes (TBV, WMV, GMV, HV, and WMHV) were assessed at the follow-up examination. Data were analyzed using mixed-effects models and analysis of covariance.ResultsAt baseline, 16,032 (37.9%), 10,709 (25.3%), and 15,560 (36.8%) participants had low, moderate, and high levels of CR, respectively. Compared with low CR, high CR was associated with slower declines in global cognition (β [95% confidence interval]: 0.10 [0.08, 0.11]), prospective memory (0.10 [0.06, 0.15]), fluid intelligence (0.07 [0.04, 0.10]), and reaction time (0.04 [0.02, 0.06]). Participants with high CR had lower TBV, WMV, GMV, and WMHV, but higher HV when controlling for global cognition (corrected P <0.01 for all). The significant relationships between CR and cognition and TBV were present among both middle-aged (<60 years) and older (≥60 years) participants. The CR-cognition association remained significant despite reductions in brain structural properties.ConclusionsHigher CR is associated with slower cognitive decline, higher HV, and lower microvascular burden, especially in middle age. Individuals with high CR could tolerate smaller brain volumes while maintaining cognition. The benefit of CR for cognition is independent of structural brain differences. Our findings highlight the contribution of enhancing CR to helping compensate for neuroimaging alterations and ultimately prevent cognitive decline.

Abstract 01: Childhood Socioeconomic Position is Associated With Accelerated Brain Aging in U.S Hispanic/Latino Population. Findings From the Hispanic Community Health Study/Study of Latinos

Introduction: Low childhood socioeconomic position (SEP) may have a long-lasting influence on functional and structural brain development. However, little is known about whether early-life SEP is associated with a steeper age-related reduction in measures of brain structure, previously linked to Alzheimer’s Disease and Related Dementias (ADRD) vulnerability. Hypothesis: Low childhood SEP measured by parental education modifies the association between age and magnetic resonance imaging (MRI)-derived brain volumes, with worse age-related brain volumes among adults with low early-life SEP. Methods: We used data from adults (age range 50-85) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL-INCA-MRI), a population-based cohort study conducted in four major U.S cities. Measures of brain structure (e.g., total brain volume-TBV, total gray matter volume-TGMV, total cortical gray volume-TCGV, hippocampus volume-HV, and white matter hyperintensity volume-WMHV were quantified using MRI in 2400 adults with normal and impaired cognitive function. We used participants' self-reports of the highest education attained by either their father or mother as a proxy for childhood SEP (&lt; high school and ≥ high school). We conducted survey linear regression models of age on brain volumes adjusting for participant’s sex, Hispanic/Latino background, field center, nativity, and age at immigration. We then included interaction terms between age and childhood SEP. Results: In multivariable regression models, older age was associated with smaller brain volumes (β, and 95% confidence interval-CI for TBV for each year increment in age: -3.22, 95% CI: -3.73, -2.71), while older age was associated with larger log-transformed WMHV (β: 0.90, 95% CI: 0.08, 0.10). Childhood SEP modifies the association between age and brain volumes, with significant smaller age-related brain volumes among adults whose parents have less than high school (β for TBV:-3.65, 95% CI: -4.25, -3.04; and TGMV: -1.29, 95% CI: -1.62, -0.95) as compared with those with high school or more (β for TBV: -2.32, 95% CI: -3.17, -1.45; p-value for interaction: 0.024; and TGMV: -0.54, 95% CI: -0.98, -0.10; p-value for interaction: 0.017). These smaller age-related volumes persisted after accounting for participant’s education and income. In contrast, higher childhood SEP was associated with a slightly larger age-related WMHV (β for interaction term: 0.03, 95% CI: 0.01, 0.05, p-value: 0.016). Conclusions: This study highlights the unique contributions of childhood SEP to accelerated brain aging. The age by childhood SEP interaction suggests that childhood socioeconomic disadvantage has a long-lasting influence in accelerated disparities in brain aging as indexed by bran MRI.

Regional covariance of white matter hyperintensity volume patterns associated with hippocampal volume in healthy aging.

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Comparison of brain imaging and physical health between research and clinical neuroimaging cohorts of ageing.

To compare brain MRI measures between Adult Changes in Thought (ACT) participants who underwent research, clinical, or both MRI scans, and clinical health measures across the groups and non-MRI subjects. Retrospective cohort study leveraging MRI, clinical, demographic, and medication data from ACT. Three neuroradiologists reviewed MRI scans using NIH Neuroimaging Common Data Elements (CDEs). Total brain and white matter hyperintensity (WMH) volumes, clinical characteristics, and outcome measures of brain and overall health were compared between groups. 1166 MRIs were included (77 research, 1043 clinical, and 46 both) and an additional 3146 participants with no MRI were compared. Compared to the group with research MRI only, the clinical MRI group had higher prevalence of the following: acute infarcts, chronic haematoma, subarachnoid haemorrhage, subdural haemorrhage, haemorrhagic transformation, and hydrocephalus (each P < .001). Quantitative WMH burden was significantly lower (P < .001) and total brain volume significantly higher (P < .001) in research MRI participants compared to other MRI groups. Prevalence of hypertension, self-reported cerebrovascular disease, congestive heart failure, dementia, and recent hospitalization (all P < .001) and diabetes (P = .002) differed significantly across groups, with smaller proportions in the research MRI group. In ageing populations, significant differences were observed in MRI metrics between research MRI and clinical MRI groups, and clinical health metric differences between research MRI, clinical MRI, and no-MRI groups. This questions whether research cohorts can adequately represent the greater ageing population undergoing imaging. These findings may also be useful to radiologists when interpreting neuroimaging of ageing.

Comprehensive allostatic load risk index is associated with increased frontal and left parietal white matter hyperintensities in mid-life cognitively healthy adults

To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.

Association of mild and complex multimorbidity with structural brain changes in older adults: A population-based study.

We quantified the association of mild (ie, involving one or two body systems) and complex (ie, involving ≥3 systems) multimorbidity with structural brain changes in older adults. We included 390 dementia-free participants aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen who underwent brain magnetic resonance imaging at baseline and after 3 and/or 6 years. Using linear mixed models, we estimated the association between multimorbidity and changes in total brain tissue, ventricular, hippocampal, and white matter hyperintensities volumes. Compared to non-multimorbid participants, those with complex multimorbidity showed the steepest reduction in total brain (β*time -0.03, 95% CI -0.05, -0.01) and hippocampal (β*time -0.05, 95% CI -0.08, -0.03) volumes, the greatest ventricular enlargement (β*time 0.03, 95% CI 0.01, 0.05), and the fastest white matter hyperintensities accumulation (β*time 0.04, 95% CI 0.01, 0.07). Multimorbidity, particularly when involving multiple body systems, is associated with accelerated structural brain changes, involving both neurodegeneration and vascular pathology. Multimorbidity accelerates structural brain changes in cognitively intact older adults These brain changes encompass both neurodegeneration and cerebrovascular pathology The complexity of multimorbidity is associated with the rate of brain changes' progression.

Ophthalmic Artery Morphology and Hemodynamics Associated with White Matter Hyperintensity.

Purpose: To investigate morphological and hemodynamic characteristics of the ophthalmic artery (OA) in patients with white matter hyperintensity (WMH), and the association of the presence and severity of WMH with OA characteristics. Methods: This cross-sectional study included 44 eyes of 25 patients with WMH and 38 eyes of 19 controls. The Fazekas scale was adopted as criteria for evaluating the severity of white matter hyperintensities. The morphological characteristics of the OA were measured on the basis of three-dimensional reconstruction. The hemodynamic parameters of the OA were calculated using computational fluid dynamics simulations. Results: Compared with the control group, the diameter (16.0±0.27 mm vs. 1.71±0.18 mm, P=0.029), median blood flow velocity (0.12 m/s vs. 0.22 m/s, P<0.001), mass flow ratio (2.16% vs. 3.94%, P=0.012) and wall shear stress (2.65 Pa vs. 9.31 Pa, P<0.001) of the OA in patients with WMH were significantly decreased. After adjusting for confounding factors, the diameter, blood flow velocity, wall shear stress, and mass flow ratio of the OA were significantly associated with the presence of WMH. Male sex and high low-density protein level were associated with moderate-to-severe total WMH, and smoking was associated with the moderate-to-severe periventricular WMH. Conclusions: The diameter, blood flow velocity, mass flow ratio, and wall shear stress of the OA were independently associated with the presence of WMH. Atherosclerosis might be involved in the common mechanism of the occurrence of WMH and the OA changes.

Association of white matter hyperintensities and clinical vascular burden with depressive symptoms in Black older adults.

Black older adults have a higher vascular burden compared to non-Hispanic White (NHW) older adults, which may put them at risk for a form of depression known as vascular depression (VaDep). The literature examining VaDep in Black older adults is sparse. The current study addressed this important gap by examining whether vascular burden was associated with depressive symptoms in Black older adults. Participants included 113 Black older adults from the Healthy Brain Project, a substudy of the Health, Aging, and Body Composition Study. In multiple regression analyses, clinical vascular burden (sum of vascular conditions) and white matter hyperintensity (WMH) volume predicted depressive symptoms as measured by the Center for Epidemiologic Studies Depression Scale, controlling for demographic variables. Follow-up analyses compared the associations in the Black subsample and in 179 NHW older adults. Higher total WMH volume, but not clinically-defined vascular burden, predicted higher concurrent depressive symptoms and higher average depressive symptoms over 4years. Similar associations were found between uncinate fasciculus (UF) WMHs and concurrent depressive symptoms and between superior longitudinal fasciculus WMHs and average depressive symptoms. The association between depressive symptoms and UF WMH was stronger in Black compared to NHW individuals. This research is consistent with the VaDep hypothesis and extends it to Black older adults, a group that has historically been underrepresented in the literature. Results highlight WMH in the UF as particularly relevant to depressive symptoms in Black older adults and suggest this group may be particularly vulnerable to the negative effects of WMH.

UNDERSTANDING THE INTERPLAY OF BRAIN HEALTH, COGNITION, AND AUTONOMIC FUNCTION

Abstract Research in clinical populations focused on various age-related diseases report multi-system difficulties in autonomic regulation, motor performance, cognition, and brain health. My research investigated the relationship between brain health, chronological age, and cognition. To assess these domains, I cross analyzed Compass 31, MoCA, and Brain Age Technology. The study population included 158 participants, both healthy and unhealthy. The collected data evaluated the relationship between brain age disparity, chronological age, and autonomic function. Correlation analysis, regression modeling, and subgroup comparisons were employed to explore potential associations, age-related patterns, and autonomic function variations. The findings from this research study contributes to a deeper understanding of the complex interplay between brain health, chronological age, and autonomic function. Age, White Matter Hyperintensities, Brain Age Gap, and Brain Age Variance demonstrate high significance when correlated with the MoCA total score. MoCA and all Compass 31 domains were found to be predictive of total white matter hyperintensity volume. This finding highlights a strong relationship between all three domains and suggests that when participants score high on both assessments, they should follow up with neuroimaging to discover potential brain damage. Future studies should identify risk factors for cognitive impairment and brain health that are also symptoms for autonomic dysregulation.

Correlation between white matter hyperintensity and delusional symptoms in Alzheimer’s disease

BackgroundPatients with Alzheimer’s disease (AD) often exhibit neuropsychiatric symptoms (NPS), particularly delusions. Previous studies have shown an association between white matter hyperintensities (WMH) and specific NPS. This study aims to explore the relationship between WMH volume and delusions in AD patients by comparing the WMH volumes of delusional and non-delusional subgroups.Methods80 AD patients were divided into a delusion group (n = 36) and a non-delusion group (n = 44) based on the Neuropsychiatric Inventory (NPI). The brain cortical volume and WMH volume were quantitatively calculated for all 80 patients, including total WMH volume, periventricular WMH (PVWMH) volume, deep WMH volume, as well as bilateral frontal lobe, temporal lobe, parietal lobe, and occipital lobe WMH volumes. Firstly, we compared the differences in WMH volumes between the delusion group and non-delusion group. Then, within the delusion group, we further categorized patients based on severity scores of their delusional symptoms into mild (1 point), moderate (2 points), or severe groups (3 points). We compared the WMH volumes among these three groups to investigate the role of WMH volume in delusional symptoms.ResultsThere was a significant difference in left occipital lobe WMH volume between the delusion group and non-delusion group(P < 0.05). Within the delusion group itself, there were significant differences in overall WMH volume as well as PVWMH volume among patients with mild or severe levels of delusions(P < 0.05).ConclusionLeft occipital lobe WMH volume may be associated with the occurrence of delusional AD patients, and the total volume of whole-brain WMH and PVWMH volume may affect the degree of severity of delusional symptoms.

Sex‐specific associations of cerebrospinal fluid YKL‐40 with white matter hyperintensities over a 7‐year follow‐up period

AbstractBackgroundWomen have a higher prevalence of Alzheimer’s disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction.ResultIn main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values&gt;0.20) or longitudinal WMH progression (p‐values&gt;0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values&lt;0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003).ConclusionHigher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline.FundingIIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082

Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs&lt;.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs&lt;.2, p&gt;.05 for all) or VKC completion time (r&lt;.1, p&gt;05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.

Association between retinal layer thickness and cerebral white matter hyperintensities in older adults

AbstractBackgroundThe brain and retina may share pathophysiological mechanisms in various central nervous system disorders, suggesting the potential associations between retinal layer thickness and cerebral white matter hyperintensities (WMH).MethodA total of 149 participants without dementia aged over 65 years (mean age: 75.4, SD: 5.4, range: 65‐91; male: 90 [60.4%]) from the randomly sampled community‐dwelling prospective cohort were included in the analysis. Using spectral‐domain optical coherence tomography, we assessed the thickness of 6 retinal layers in the macular region, the peripapillary retinal nerve fiber layers, and the subfoveal choroid. We classified WMH into 3 groups using the distance from the ventricle surface: juxtaventricular (JVWMH, &lt; 4mm), periventricular (PVWMH, &gt;4mm, &lt;14mm), and deep WMH (DWMH &gt; = 14mm). The associations between retinal layer thickness and WMH volume were examined using linear regression models adjusting age, sex, comorbid hypertension, and diabetes.ResultThe thicknesses of superior outer, inferior outer ganglion cell layers (GCL) and superior outer, inferior outer, total outer inner plexiform layers (IPL) were negatively associated with the total WMH, PVWMH, and DWMH volumes. Reduced thicknesses of total outer GCL and temporal outer inner nuclear layer (INL) were associated with higher total WMH and PVWMH volumes. Center GCL thickness was positively associated with JVWMH volume, and nasal outer GCL thickness was negatively associated with DWMH volume.ConclusionOuter GCL and IPL thicknesses may be associated with WMH volume in older adults. This study may also suggest differential associations based on etiology between retinal layer subfields and WMH subgroups.

Relationship between a novel virtual reality test of mild functional difficulties and cerebrovascular disease

AbstractBackgroundIt is well known that mild cognitive impairment (MCI) is associated with subtle functional decline. However, standardized and cost‐effective methods for the objective quantification of mild functional difficulties are lacking. Here we report preliminary validity data for a novel, non‐immersive virtual‐reality task (Virtual Kitchen Challenge [VKC]) against brain markers of cerebrovascular disease and in contrast to a conventional, self‐report measure of function.MethodTwenty (n = 14 healthy control, n = 6 MCI) community‐dwelling older adults aged 60+ completed neuropsychological testing, including the Functional Activities Questionnaire (FAQ), and the VKC, which requires completion of simulated breakfast and lunch tasks on a touch‐screen computer. White matter hyperintensity (WMH) volumes from Fluid Attenuation Inversion Recovery (FLAIR) MRI sequences were derived using the UBO detector, a cluster‐based WMH extraction pipeline based on k‐nearest neighbors (k‐NN) algorithm. WMH volumes were calculated in SPM’s DARTEL space, precluding the need to adjust for intracranial volume (ICV).ResultMCI participants reported significantly more functional difficulties than healthy controls (FAQ U = 76.50 p = .002) and obtained marginally slower completion times on the VKC (U = 60.00, p = .138). VKC completion time was moderately associated with age (r = .441, p = .059) but relations with sex, race, and IQ were weak and not significant (all rs&lt;.195). VKC completion time significantly and strongly correlated with all WMH measures, even after controlling for age, sex, race, and IQ (total WMH r = .649, p = .031; deep WMH r = .615, p = .044; periventricular WMH r = .623, p = .041). By contrast, FAQ was not associated with WMH (rs&lt;.2, p&gt;.05 for all) or VKC completion time (r&lt;.1, p&gt;05) after controlling for age, sex, race, and IQ.ConclusionOur naturalistic, performance‐based measure of function (VKC) was not associated with race, sex, or premorbid IQ, but was strongly associated with neuroimaging markers of cerebrovascular disease (WMH). By contrast, a conventional self‐report measure of everyday functioning (FAQ) was not associated with neuroimaging measures (WMH). These results offer preliminary support for the VKC as a valid measure of early, subtle functional difficulties associated with cerebrovascular pathology that is not vulnerable to bias associated with race, sex, or premorbid IQ.

The structural integrity of anterior‐temporal and posterior‐medial brain regions in Alzheimer’s disease and Parkinson’s disease: Effects of APOEε4, p‐tau181 and Aβ42

AbstractBackgroundAlzheimer’s disease (AD) and Parkinson’s disease (PD) are two distinct neurodegenerative brain conditions associated with varying degrees of cognitive impairment, including an overlapping amnestic phenotype. At autopsy, APOEe4 and AD proteinopathies are associated with dementia severity in both AD and PD. The extent to which in‐vivo AD biomarkers are associated with memory and underlying regional brain volume in AD and PD patients is under‐investigation. Here, we focused on plasma biomarker associations with anterior‐temporal and posterior‐medial regions that are known to accumulate tau and Aß in AD.MethodNeuroimaging, biomarker, genetic and cognitive data were collected from 244 patients through the Ontario Neurodegenerative Disease Research Initiative (MeanAge = 68.96; 41% women; 35%APOE‐e4‐carriers). Based on clinical diagnostic criteria, three groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 120), ii)PD with MCI or dementia(PDMCI/PDD;N = 76) and iii)PD with normal cognition(PD‐NC;N = 48). Linear regressions assessed clinical diagnosis differences in the volumetric integrity of a priori regions: anterior‐temporal(ATN; including amygdala, fusiform gyrus, and ITG) and posterior‐medial(PMN; including PCC, parahippocampal cortex and precuneus;Fig1). Differences on related item recognition memory and associative memory was examined via the FaceName Association Task. APOE(e4‐/e4+), p‐tau181‐UGOT and Aß42 associations between ATN/PMN and item recognition/associative memory outcomes were estimated. Diagnostic*APOEe4*ptau181 interactions were tested. Age, sex, education and ICV were covaried.ResultBackground characteristics showed that the ADMCI/ADD group exhibited the oldest age and the highest frequency of female sex and e4‐carriership. ADMCI/ADD and PDMCI/PDD, but not PD‐NC, exhibited elevated ptau181 and Aß42 relative to a healthy control group. Both ADMCI/ADD and PDMCI/PDD groups exhibited PMN and ATN degradation, as well as memory impairment, relative to the PD‐NC(Fig2A‐B). Plasma p‐tau181 was associated with ATN and PMN, as well as associative memory(Fig3A). APOEe4 was associated with PMN only, as well as item recognition(Fig3B). Diagnostic*APOEe4*ptau181 interactions were not significant. Post‐hoc analysis showed significant p‐tau181xAPOEe4 interactions on item recognition and total white matter hyperintensity(WMH;Fig3C). Aß42 was not associated with outcomes.ConclusionVolumes of the ATN and PMN are lower in cognitively impaired AD and PD patients with higher p‐tau and/or APOEe4‐carriership. P‐tau and APOEe4 may work synergistically to promote domain‐specific memory impairment and WMH burden in both AD and PD.

Comparison of white matter hyperintensities between Latin American and American individuals with Alzheimer’s disease and cognitively normal older adults

AbstractBackgroundWhite matter hyperintensities (WMH) are Flair signal abnormalities frequently seen in periventricular and subcortical brain regions in the elderly. They are presumed to be, at least in part, a sign of cardiovascular disease (CVD). WMHs are associated with stroke, cognitive decline, and dementia. Given that most of the literature on dementia comes from high‐income countries, little is known about dementia in Latin American countries (LAC), which have an increased risk of dementia and CVD due to unique demographic, socioeconomic, cultural and ethnic factors. Our study aims to characterize the effects of white matter hyperintensities (WMH) in patients with AD within LAC and to compare these findings with a sample from the USA.MethodA total of 491 latin american subjects (235 cognitively normal (CN), 256 AD) and 271 american subjects (165 CN, 106 AD), underwent a brain MRI. WMH were extracted from T2‐FLAIR images using the Lesion Segmentation Toolbox and were divided into periventricular (pWMH) or deep (dWMH) depending on their distance from the ventricles. Linear mixed‐effects were used to model the volumes of WMH as a function of age, gender, years of education, intracranial volume, average cortical thickness, and region (LAC or USA).ResultAD groups from both regions showed larger total, dWMH and pWMH volumes compared to HC. Higher pWMH from AD and HC was associated with age, female sex and inversely associated with years of education. On the other hand, the increase in dWMH was found to be associated with female sex for the HC group and with age for AD. Cortical thinning was associated with an increase in total, subcortical and periventricular WMH for both groups. No statistically significant association was found between the region (USA or LAC) and WMH.ConclusionAD showed higher WMH compared to HC. Our findings suggest that pWMH and dWMH have different clinical correlates. No associations between region and WMH load or distribution were found. Future studies need to elucidate if there is an increase in other signs of CVD (such as cerebral microbleeds, brain lacunae, enlarged perivascular spaces) in Latin America and if they are linked to cognition and social determinants of health.

Social Networks and MRI measures of Brain Injury in Racially and Ethnically Diverse Populations

AbstractBackgroundSocial networks may influence late‐life cognition directly via affecting brain structures or indirectly through enhancing cognitive resilience – i.e., the ability to maintain cognitive function in the presence of neurodegeneration. This study assesses the associations of social networks with markers of neurodegeneration, and determines whether social networks modify the associations between these markers and cognitive function.MethodWe pooled data from three harmonized cohorts of Kaiser Permanente Northern California members: the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE)study, the Study of Healthy Aging in African Americans (STAR), and the LifeAfter90 (LA90) Study. Social network sizes were calculated by summing the number of living children, spouse, and close relatives and friends. Neuroimaging markers included total brain volume (TBV), hippocampal volume (HCV), and white matter hyperintensity volume (WMH). Volumetric measures were normalized using a residual approach, which regressed intracranial volume (ICV) on volumetric measures to predict the ICV‐adjusted volume. Executive function and verbal episodic memory were measured by the Spanish and English Neuropsychological Assessment Scales and were z‐standardized. Linear regression models estimated the associations between social network size and each neuroimaging marker, adjusting for age, sex, race and ethnicity, education, cohort, and Activities of Daily Living (ADLs). We included an interaction term between social networks and neuroimaging markers to evaluate whether the relationships between imaging markers and cognitive function differed by social networks.ResultThe pooled sample’s average age was 76 (SD 11) years (59% female; 47% Black) (Table 1). In the fully adjusted models, the mean differences in injury markers did not differ by social network size (Figure 1). However, the associations of HCV and WMH with executive function (βsocial network*WMH = 0.09, 95% CI 0.01,0.18; βsocial network*HCV = ‐0.08, 95% CI ‐0.15, ‐0.01) were stronger among participants with smaller social networks (Figure 2).ConclusionIn this cross‐sectional study of racially and ethnically diverse older adults, larger social networks attenuated the associations between neurodegeneration markers and executive function. These findings suggest that larger social networks may promote cognitive resilience.

A multi‐center pooled analysis of individual imaging data of 14,876 non‐demented participants to create normative data for total and regional white matter hyperintensity volumes to support dementia diagnosis.

AbstractBackgroundWhite matter hyperintensities (WMH) are a common manifestation of cerebral small vessel disease and a major cause of cognitive decline and dementia. Recent studies show that the cognitive impact of WMH depends on their location in strategic white matter regions. WMH are highly prevalent among asymptomatic individuals and increase with age. For dementia diagnosis, identifying patients with excessive total and regional (strategic) WMH therefore requires age‐ and sex specific norms, which are currently lacking. We aimed to obtain normative data for both total and regional WMH volumes in non‐demented community‐dwelling individuals.MethodWe harmonized individual person data from 15 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Cohorts were eligible for inclusion if participants were recruited from the population, underwent brain MRI (with availability of FLAIR and T1 sequences) and cognitive testing. Cohorts that recruited patients based on the presence of cognitive symptoms were not eligible for inclusion. Individuals fulfilling criteria for dementia were excluded. WMH were segmented and registered to the MNI‐152 template. WMH maps were used to calculate total WMH volume and regional WMH volumes in 20 pre‐specified white matter tracts. Normative data on WMH volumes were derived from observed values in 5‐years age bands and reported as cut‐off values for percentiles. All volumes are normalized WMH volumes (i.e. calculated on the MNI‐152 template).ResultWe analyzed 14,876 individuals with a mean age of 63.9 years (SD 11.9), 52% of whom were female. Median WMH volume was 2.0 mL (normalized, IQR 3.9) for the total sample. Median WMH volume increased with age, from 0.25 mL (&lt;45 years) to 7.3 and 12.8 mL (&gt;85 years) for men and women respectively. The table shows total WMH volume cut‐off values for percentiles, stratified for age and sex (cut‐off values for regional WMH volumes not shown due to abstract size constraints).ConclusionThis study provides age‐ and sex‐specific normative data on total and regional WMH volumes. This enables an individualized approach to interpreting total and regional WMH burden to support diagnosis in clinical practice.

Influence of lung function on macro‐ and micro‐structural brain changes in mid‐ and late‐ life: a large population‐based cohort study in the UK Biobank

AbstractBackgroundLung function has been associated with cognitive decline and dementia, but the extent to which lung function impacts brain structural changes remains unclear. We aimed to investigate the association of lung function with structural macro‐ and micro‐ brain changes across mid‐ and late‐ life in a large population‐based cohort study.MethodThe study included a total of 37,590 neurologic disorder‐free participants aged 40‐70 years from the UK Biobank, who underwent brain magnetic resonance imaging (MRI) scans 9 years after baseline. After 2.5 years, a subsample (n = 3,941) underwent a second MRI scan. Lung function was assessed using a composite score based on forced expiratory volume in 1 second, forced vital capacity, and peak expiratory flow, and divided into tertiles (i.e., low, moderate, and high). Regional brain volumes (including total brain, gray matter, white matter, hippocampus, and white matter hyperintensities) and diffusion markers (fractional anisotropy [FA] and mean diffusivity [MD]) were assessed. Data were analyzed using linear regression and mixed‐effects models.ResultAt baseline, lung function ranged from ‐3.43 to 22.91 among all participants. In multi‐adjusted linear regression, low lung function was dose‐dependently related to smaller brain volumes and lower white matter integrity. Compared to high lung function, low lung function was associated with smaller total brain (β [95% CI]: ‐0.083 [‐0.097, ‐0.070], gray matter ‐0.145 [‐0.161, ‐0.130], white matter ‐0.017 [‐0.031, ‐0.004], and hippocampal ‐0.102 [‐0.128, ‐0.075]) volume, as well as poor white matter health (FA ‐0.165 [‐0.195, ‐0.135] for lower, WMH 0.269 [0.242, 0.295] and MD 0.168 [0.140, 0.196] for higher). Over the 2.5 years follow‐up, low PF was associated with reduced white matter (‐0.021 [‐0.041, ‐0.002]) and hippocampal (‐0.078 [‐0.110, ‐0.046]) volume, reduced FA (‐0.063 [‐0.091, ‐0.035]), and increased WMH volume (0.065 [0.016, 0.114]) and MD (0.121 [0.089, 0.154]). After stratification by age, the associations remained significant among adults aged 40‐60 years and 60+ years.ConclusionLow lung function is associated with macro‐ and micro‐ structural brain changes involving both neurodegenerative and vascular pathologies. This association is significant in both mid‐ and late‐ life.