Total White Matter Hyperintensities Volume Research Articles

White Matter Hyperintensities and Microstructural Alterations in Contact Sport Athletes from Adolescence to Early Midlife.

Studies have demonstrated associations between cumulative concussion and repetitive head impact exposure (RHI) via contact sports with white matter (WM) alterations later in life. The course of WM changes associated with exposure earlier in the lifespan are unclear. This study investigated alterations in white matter (WM hyperintensity [WMH] volume and microstructural changes) associated with concussion and RHI exposure from adolescence to early midlife, as well as the interaction between exposure and age-cohort (i.e., adolescent/young adult compared to early midlife athlete cohorts) on WM outcomes. Participating football players included an adolescent/young adulthood cohort (n=82; Mage=18.41.7) and an early midlife cohort (37 former collegiate players approximately 15-years removed from sport; Mage=37.71.4). Years of football participation and number of prior concussions were exposures of interest. White matter outcomes included log-transformed manually segmented total WMH volume and neurite orientation dispersion and density imaging metrics of microstructure/organization (isotropic volume fraction[Viso], intra-cellular volume fraction[Vic], and orientation dispersion[OD]). Regression models were fit to test effects of concussion history, years of football participation, and age-cohort by years of football participation with WM outcomes. Spearman's correlations assessed associations between significant WM metrics and measures of cognitive and psychological function. A significant age-cohort by years of participation effect was observed for whole brain white matter OD, B=-0.002, SE=0.001, p=0.001. The interaction was driven by a negative association between years of participation and OD within the younger cohort, B=-0.001, SE=0.0004, p=0.008, whereas a positive association between participation and OD in the early midlife cohort, B=0.001, SE=0.0003, p=0.039, was observed. Follow-up ROI analyses showed significant interaction effects for OD in the body of the corpus callosum, genu of the corpus callosum, cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, posterior thalamic radiation (ps<0.05). Greater concussion history was significantly associated with greater Viso in the early midlife cohort, B=0.001, SE= 0.0002, p=0.010. Years of participation and concussion history were not associated with WMH volume, ps>0.05. Performance on a measure of executive function was significantly associated with years of participation, =.34, p=.04, and a trend was observed for OD, =.28, p=.09 in the early midlife cohort only. The global characterization of white matter changes associated with years of football participation were broadly similar and stable from adolescence through early midlife (i.e., microstructural alterations, but not macroscopic lesions). An inverse association between years of participation and orientation dispersion across age-cohorts may represent a process of initial recovery/reorganization proximal to sport, followed by later reduction of white matter coherence.

Strategic white matter hyperintensity locations associated with post-stroke cognitive impairment: a multicenter study in 1568 stroke patients.

Post-stroke cognitive impairment (PSCI) occurs in up to 50% of stroke survivors. Presence of pre-existing vascular brain injury, in particular the extent of white matter hyperintensities (WMH), is associated with worse cognitive outcome after stroke, but the role of WMH location in this association is unclear. We determined if WMH in strategic white matter tracts explain cognitive performance after stroke. Individual patient data from 9 ischemic stroke cohorts with MRI were harmonized through the Meta VCI Map consortium. The association between WMH volumes in strategic tracts and domain-specific cognitive functioning (attention and executive functioning, information processing speed, language and verbal memory) was assessed using linear mixed models and lasso regression. We used a hypothesis-driven design, primarily addressing four white matter tracts known to be strategic in memory clinic patients: the left and right anterior thalamic radiation, forceps major and left inferior fronto-occipital fasciculus. The total study sample consisted of 1568 patients (39.9% female, mean age: 67.3 years). Total WMH volume was strongly related to cognitive performance on all four cognitive domains. WMH volume in the left anterior thalamic radiation was significantly associated with cognitive performance on attention and executive functioning and information processing speed, and WMH volume in the forceps major with information processing speed. The multivariable lasso regression showed that these associations were independent of age, sex, education, and total infarct volume and had larger coefficients than total WMH volume. These results show tract-specific relations between WMH volume and cognitive performance after ischemic stroke, independent of total WMH volume. This implies that the concept of strategic lesions in PSCI extends beyond acute infarcts and also involves pre-existing WMH. The Meta VCI Map consortium is dedicated to data sharing, following our guidelines.

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.

The volume and the distribution of premorbid white matter hyperintensities: Impact on post-stroke aphasia.

White matter hyperintensities (WMH) are a radiological manifestation of progressive white matter integrity loss. The total volume and distribution of WMH within the corpus callosum have been associated with pathological cognitive ageing processes but have not been considered in relation to post-stroke aphasia outcomes. We investigated the contribution of both the total volume of WMH, and the extent of WMH lesion load in the corpus callosum to the recovery of language after first-ever stroke. Behavioural and neuroimaging data from individuals (N = 37) with a left-hemisphere stroke were included at the early subacute stage of recovery. Spoken language comprehension and production abilities were assessed using word and sentence-level tasks. Neuroimaging data was used to derive stroke lesion variables (volume and lesion load to language critical regions) and WMH variables (WMH volume and lesion load to three callosal segments). WMH volume did not predict variance in language measures, when considered together with stroke lesion and demographic variables. However, WMH lesion load in the forceps minor segment of the corpus callosum explained variance in early subacute comprehension abilities (t = -2.59, p = .01) together with corrected stroke lesion volume and socio-demographic variables. Premorbid WMH lesions in the forceps minor were negatively associated with early subacute language comprehension after aphasic stroke. This negative impact of callosal WMH on language is consistent with converging evidence from pathological ageing suggesting that callosal WMH disrupt the neural networks supporting a range of cognitive functions.

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.

Sleep apnea‐related hypoxemia, not sleep fragmentation, is associated with white matter hyperintensities in older adults

AbstractBackgroundSleep apnea is a type of sleep‐disordered breathing that increases risk for Alzheimer’s disease‐related pathology potentially through cerebrovascular pathology, likely exacerbated by two features of sleep apnea: intermittent hypoxia and sleep fragmentation. White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase in aging and in AD. Here, we tested the hypothesis that apnea‐related hypoxemia severity, and not sleep fragmentation, are associated with WMH volume in older adults.MethodsThirty‐two older adults (73.4±5.3 years, 19 female, AHI = 15.2±18.9) were evaluated with overnight polysomnography (PSG). Apnea severity was quantified using the Apnea‐Hypopnea Index (AHI), Respiratory Disturbance Index (RDI), and blood oxygen desaturation (Oxygen Desaturation Index (ODI), duration, frequency of ≥4% desaturations, and desaturation nadir) stratified by sleep stages. T1‐MPRAGE and T2‐FLAIR scans were acquired using a 3T Siemens scanner. Total WMH volumes were derived using a semi‐automated algorithm. Overnight memory retention was assessed using the change in the lure discrimination index (LDI) for the emotional version of the Mnemonic Discrimination Task.ResultsTraditional measures of apnea severity and sleep fragmentation were not significantly associated with global WMH volume. However, both max duration of oxygen desaturation events (r = 0.44, p = 0.011) and max oxygen desaturation percentage (in rapid‐eye movement (REM) and in total sleep: r = 0.48, p = 0.005, and r = 0.44, p = 0.01), were significantly associated with total WMH volume. Similar relationships were found with time spent below 90% and 80% oxygen saturation (Kendall’s tau = 0.33, p = 0.02 and tau = 0.275, p = 0.03). These relationships survived adjustment for sex, age, and hyperlipidemia and/or hypertension medication at time of PSG. Global WMH volume was also negatively associated with overnight memory retention (r = ‐0.38, p = 0.03).ConclusionsThese findings suggest that hypoxemia severity, compared to sleep fragmentation, are more strongly associated with global WMH volume. As WMH volume was associated with overnight memory retention, this may suggest a pathway in which OSA increases WMH, which is subsequently associated with tau burden, worsening sleep‐dependent memory.

Sleep apnea‐related hypoxemia, not sleep fragmentation, is associated with white matter hyperintensities in older adults

AbstractBackgroundSleep apnea is a type of sleep‐disordered breathing that increases risk for Alzheimer’s disease‐related pathology potentially through cerebrovascular pathology, likely exacerbated by two features of sleep apnea: intermittent hypoxia and sleep fragmentation. White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase in aging and in AD. Here, we tested the hypothesis that apnea‐related hypoxemia severity, and not sleep fragmentation, are associated with WMH volume in older adults.MethodThirty‐two older adults (73.4±5.3 years, 19 female, AHI = 15.2±18.9) were evaluated with overnight polysomnography (PSG). Apnea severity was quantified using the Apnea‐Hypopnea Index (AHI), Respiratory Disturbance Index (RDI), and blood oxygen desaturation (Oxygen Desaturation Index (ODI), duration, frequency of = 4% desaturations, and desaturation nadir) stratified by sleep stages. T1‐MPRAGE and T2‐FLAIR scans were acquired using a 3T Siemens scanner. Total WMH volumes were derived using a semi‐automated algorithm. Overnight memory retention was assessed using the change in the lure discrimination index (LDI) for the emotional version of the Mnemonic Discrimination Task.ResultTraditional measures of apnea severity and sleep fragmentation were not significantly associated with global WMH volume. However, both max duration of oxygen desaturation events (r = 0.44, p = 0.011) and max oxygen desaturation percentage (in rapid‐eye movement (REM) and in total sleep: r = 0.48, p = 0.005, and r = 0.44, p = 0.01), were significantly associated with total WMH volume. Similar relationships were found with time spent below 90% and 80% oxygen saturation (Kendall’s tau = 0.33, p = 0.02 and tau = 0.275, p = 0.03). These relationships survived adjustment for sex, age, and hyperlipidemia and/or hypertension medication at time of PSG. Global WMH volume was also negatively associated with overnight memory retention (r = ‐0.38, p = 0.03).ConclusionThese findings suggest that hypoxemia severity, compared to sleep fragmentation, are more strongly associated with global WMH volume. As WMH volume was associated with overnight memory retention, this may suggest a pathway in which OSA increases WMH, which is subsequently associated with tau burden, worsening sleep‐dependent memory.

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.

Genetic variants underlying the neuro‐anatomical signatures of hypertension measured on structural MRI

AbstractBackgroundHypertension (HTN) is associated with gray matter (GM) atrophy and increased white matter hyperintensity (WMH) burden, increasing their susceptibility to Alzheimer’s disease and related dementias. We developed a machine learning based model to quantify spatial patterns of abnormality recognizing HTN‐related brain changes (SPARE‐HTN) from structural magnetic resonance images (sMRI). We performed a genome wide association study (GWAS) to identify the genetic variants and associated biological traits that underlie the “expression” of HTN‐related brain changes, i.e., the individualized SPARE‐HTN index.MethodSPARE‐HTN model was trained on the large multi‐study iSTAGING dataset, with regional GM volumes from T1‐weighted images and lobar WMH volumes from T2‐weighted FLAIR images used as imaging features. GWAS was carried out in a subset of N = 7490 (46% Female, Age = 65.5±7 years) hypertensive participants from UK‐Biobank. A GWAS of SPARE‐HTN scores was run using linear regression with Plink, correcting for the top 40 genetic principal components, age, sex, and intracranial volume. Significant SNPs were identified and mapped to functional genes using the Functional Mapping and Annotation (FUMA) platform; and candidate SNPs were mapped to the GWAS catalog.ResultSPARE‐HTN was associated with regional atrophy most prominent in perisylvian and temporal cortex and increased WMH volumes, particularly in frontal white matter. SPARE‐HTN scores showed better discriminative power between normal and stage 1 participants (Cohen’s‐d effect size, d = 0.2) and stage 2 (d = 0.71) hypertensive participants when compared to total WMH volume (d = 0.04 and 0.38, respectively). GWAS identified N = 321 independently significant SNPs, of which a subset N = 46 candidate SNPs were mapped to 6 genes (ICA1L, CARF, WDR12, NBEAL1, KRT8P15, CYP20A1) in Chromosome 2 (Figure 2). These genes were previously reported to be associated with several cardiovascular conditions including coronary artery disease and stroke, and with increased WM damage on sMRI and diffusion MRI (Figure 3).ConclusionThe individualized imaging marker, SPARE‐HTN, was associated with genes relevant to HTN with traits including cardiovascular conditions and higher prevalence of WMH, and was more sensitive to HTN than total WMH volume. SPARE‐HTN is a useful tool to characterize HTN‐related brain changes and monitor treatment effects at an individual level.

Genetic variants underlying the neuro‐anatomical signatures of hypertension measured on structural MRI

AbstractBackgroundHypertension (HTN) is associated with gray matter (GM) atrophy and increased white matter hyperintensity (WMH) burden, increasing their susceptibility to Alzheimer’s disease and related dementias. We developed a machine learning based model to quantify spatial patterns of abnormality recognizing HTN‐related brain changes (SPARE‐HTN) from structural magnetic resonance images (sMRI). We performed a genome wide association study (GWAS) to identify the genetic variants and associated biological traits that underlie the “expression” of HTN‐related brain changes, i.e., the individualized SPARE‐HTN index.MethodSPARE‐HTN model was trained on the large multi‐study iSTAGING dataset, with regional GM volumes from T1‐weighted images and lobar WMH volumes from T2‐weighted FLAIR images used as imaging features. GWAS was carried out in a subset of N = 7490 (46% Female, Age = 65.5±7 years) hypertensive participants from UK‐Biobank. A GWAS of SPARE‐HTN scores was run using linear regression with Plink, correcting for the top 40 genetic principal components, age, sex, and intracranial volume. Significant SNPs were identified and mapped to functional genes using the Functional Mapping and Annotation (FUMA) platform; and candidate SNPs were mapped to the GWAS catalog.ResultSPARE‐HTN was associated with regional atrophy most prominent in perisylvian and temporal cortex and increased WMH volumes, particularly in frontal white matter. SPARE‐HTN scores showed better discriminative power between normal and stage 1 participants (Cohen’s‐d effect size, d = 0.2) and stage 2 (d = 0.71) hypertensive participants when compared to total WMH volume (d = 0.04 and 0.38, respectively). GWAS identified N = 321 independently significant SNPs, of which a subset N = 46 candidate SNPs were mapped to 6 genes (ICA1L, CARF, WDR12, NBEAL1, KRT8P15, CYP20A1) in Chromosome 2 (Figure 2). These genes were previously reported to be associated with several cardiovascular conditions including coronary artery disease and stroke, and with increased WM damage on sMRI and diffusion MRI (Figure 3).ConclusionThe individualized imaging marker, SPARE‐HTN, was associated with genes relevant to HTN with traits including cardiovascular conditions and higher prevalence of WMH, and was more sensitive to HTN than total WMH volume. SPARE‐HTN is a useful tool to characterize HTN‐related brain changes and monitor treatment effects at an individual level.

The Influence of White Matter Lesion Volume on Hippocampal Shape in Patients Along the Alzheimer’s Disease Continuum

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive neurocognitive disorder with irreversible hippocampal atrophy and degradation of cognitive function. Hippocampal atrophy can be assessed by volume and shape changes on MRI, and hippocampal volume is a sensitive marker for AD diagnosis and progression; however, it does not reflect regional changes within the hippocampus. Interest in shape analysis of the hippocampus is growing, as it provides more detailed assessment of morphological changes that highlight regional atrophic differences. Cerebral small vessel disease (CSVD) burden quantified as white matter lesion volume from MRI is strongly associated with hippocampal volume loss in AD and mild cognitive impairment (MCI). Our goal was to examine relationships between hippocampal morphometric features and white matter hyperintensity (WMH) volume, a measure of CSVD burden, across the AD continuum.MethodWe analyzed baseline data from 186 participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort whose cognitive diagnosis was adjudicated by an expert panel in accordance with NIA‐AA guidelines (without reference to AD biomarkers). Participants ranged from cognitively normal (CN) (n = 62, 72±8y), to MCI (n = 62, 73±7y), and dementia (n = 62, 73±9y). We focused on the left hippocampus and used T1‐weighted images from 3T brain MRI to generate left hippocampal segmentations and total intracranial volume estimates. Total WMH volume was estimated from FLAIR images using the lesion segmentation toolbox for SPM, it was then normalized to intracranial volume and log transformed to address skewness. Hippocampal shape analysis was performed using SlicerSALT, and a multivariate linear model was implemented to relate WMH volume to hippocampal shape features while adjusting for diagnosis, age, sex, and years of education.ResultOn the superior aspect of the hippocampus, greater WMH volume was associated with more surface contraction of the anterior portions of the CA1, CA2, CA3 and subiculum as shown in Figure 1A. Similar effects were seen on the inferior aspect as shown in Figure 1B.ConclusionThese finding suggest that higher WMH volume is associated with selective hippocampal subfield degeneration in the anterior portions of the hippocampus which may be more vulnerable to CSVD buildup.

Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)

AbstractBackgroundThe anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.MethodThis study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2). General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p&lt;0.05.ResultLinear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p&lt;0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p&lt;0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p&lt;0.05) (Fig.3B).ConclusionUsing graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.

Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)

AbstractBackgroundThe anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.MethodThis study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2).General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p&lt;0.05.ResultLinear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p&lt;0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p&lt;0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p&lt;0.05) (Fig.3B).ConclusionUsing graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.

Brain glutathione may be associated with white matter hyperintensities in patients with cardiovascular disease

AbstractBackgroundWhite matter hyperintensity (WMH) is a marker of age‐related cerebrovascular damage and is correlated with cognitive impairment; ischemia and inflammatory mechanisms have been proposed to be involved in its pathogenesis. These processes are associated with oxidative stress (OS), which may impair cellular function and affect antioxidant balance; however, the role of central antioxidant responses is still unclear.MethodPatients (age 55‐85) with ≥2 vascular risk factors or a previous vascular event were assessed at baseline for an exercise rehabilitation program. All participants completed the Montreal Cognitive Assessment (MoCA). Baseline WHM severity was determined using the standardized Canadian Dementia Imaging Protocol and semiautomatic protocols. Brain glutathione (GSH) at baseline was obtained in the anterior cingulate (AC) and occipital region (OC) using 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b).ResultOf 30 participants (mean age: 66.2 ± 7.42 SD; 80% male) currently enrolled, brain volumetric measurements were completed for 25 participants. Lower MoCA score was associated with greater total WMH volume, controlling for age (b[SE] = ‐0.017 [0.005], t(22) = ‐3.24, p = 0.004); this relationship remained significant when controlling for years of education separately (b[SE] = ‐0.016 [0.006], t(22) = ‐2.86, p = 0.01). Correcting for cerebrospinal fluid volume, lower AC‐GSH level was associated with higher deep WMH volume in the medial middle frontal (MMF) region of interest (b[SE] = ‐0.056 [0.023], t(23) = ‐2.38, p = 0.026), but not with MMF paraventricular WMH volume. After controlling for age, the model was no longer significant (F (2, 22) = 2.87, p = 0.078). No significant associations were found between OC‐GSH and occipital lobe WMH.ConclusionAs expected, total white matter hyperintensity volume was associated with poorer global cognition. In the medial middle frontal (MMF) region of interest, higher deep WMH was associated with lower GSH levels, suggesting altered brain antioxidant levels may be associated with the presence or formation of WMH. Recruitment is ongoing, and additional participants are needed to reinforce findings and to control for confounders in the analysis.

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.

Regional White Matter Hyperintensities are Associated with Diminished Blood Flow and Microstructure in Middle Age

AbstractBackgroundWhite matter hyperintensities (WMH) are areas of increased signal visualized on T2‐weighted FLAIR magnetic resonance imaging (MRI), thought to reflect macrostructural damage due to small vessel cerebrovascular disease. Previous work established an association of WMH severity, particularly in posterior regions, with risk and progression of AD in late onset and genetic forms of AD, suggesting a vascular component to disease pathogenesis and course. Examination of the emergence and correlates of cerebrovascular changes in middle age, a critical time when vascular risk appears to be most penetrant, can give insight into mechanisms linking vascular brain injury and risk for AD. In the current study, we examined the association of cerebral blood flow (CBF) and white matter microstructure with total and regional WMH volume in middle‐aged, community dwelling adults.MethodFour hundred and ninety‐two middle‐aged participants (55+/‐11 age = 28 ‐85 years) from the community‐based Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease received multi‐modal MRI scanning. Regional WMH volumes were derived with in‐house software that labeled clusters of voxels within a hyperintense intensity distribution. Pulsed arterial spin labeling (PASL) sequences were processed to quantify CBF. Fractional anisotropy (FA) maps were obtained from diffusion weighted data. Total and regional WMH volumes were used as predictors for whole brain voxel‐wise correlation analyses in separate models for CBF and FA.ResultThere were negative associations between WMH volume and CBF in frontal, parietal, and occipital regions. Higher white matter hyperintensity volume was associated with lower FA, particularly in the periventricular region.ConclusionWe found associations of increased WMH volume with diminished blood flow and white matter microstructure. Future studies are needed to explain the relationship between these changes and the risk of cognitive impairment in middle aged adults and risk for AD.

Cerebrovascular disease is associated with memory function in the Health and Aging in Africa Longitudinal Study of an INDEPTH community in rural South Africa

AbstractBackgroundHealth and Aging in Africa Longitudinal Study of an INDEPTH community in South Africa (HAALSI) is a sister study to the US‐based Health and Retirement Study. The purpose of HAALSI is to characterize the social, economic, biological, physical, and mental health factors in a population‐representative cohort of older adults in a rural community in Agincourt, South Africa. Beginning in 2020, as part of an Alzheimer’s disease and related disorders (ADRD) substudy, we conducted neuropsychological evaluations and structural magnetic resonance imaging (MRI) in a subset of HAALSI participants. Here, we report preliminary observations on the relationship of white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and hippocampal volume, a marker of neurodegeneration, on memory function in a group of substudy participants.MethodNinety‐nine HAALSI ADRD participants with available MRI scans and neuropsychological outcomes at time of analysis (mean ± SD; age = 70.3 ± 10.9, 87% with no formal education or some primary education) were included in these analyses. Participants received research‐grade, harmonized 1.5T MRI scanning at a private hospital and were evaluated with a battery of neuropsychological tests. Using in‐house developed software and FreeSurfer, respectively, we derived total WMH volume and total hippocampal volume. We examined the association of these variables with memory function, operationalized as the delayed recall score of the Logical Memory Test, adapted for context.ResultAdjusting for education level, increased WMH volume was associated with poorer performance on the Logical Memory Test (standardized β = ‐0.21, p&lt;0.05) but hippocampal volume was not (standardized β = 0.09, p = 0.41). Associations of these MRI markers with memory function did not interact with education level.ConclusionIn these preliminary analyses of older adults in a rural South African community, markers of small vessel cerebrovascular disease but not neurodegeneration are associated with poorer cognitive outcomes. Future work will examine the pathways that give rise to cognitive impairment and dementia in this rural South African population and track cognitive trajectories over time.

Total and posterior cerebral blood flow is associated with white matter hyperintensity volume and Alzheimer’s‐like patterns of brain atrophy in older adults

AbstractBackgroundSmall vessel cerebrovascular disease, often visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scans, contributes to risk, progression, and, possibly, pathogenesis of Alzheimer’s disease (AD). When considered in the context of previous neuroimaging biomarker work in AD, WMH appear to colocalize with other markers of disease risk and progression, including metabolic changes, atrophy, and tau pathology, in areas perfused by the posterior circulation. In the current study, we used a novel MR‐based method, termed phase contrast, to quantitate total cerebral blood flow in anterior and posterior circulations and test its relationship with WMH volume and an AD‐like pattern of brain atrophy in older, community‐dwelling adults.MethodTwo hundred forty‐five older adult participants (77±5.6 mean±SD age, 66% women, 42% Latinx, 30% Black, and 28% White individuals) in the Washington Heights Inwood Columbia Aging Project (WHICAP) received T1‐weighted, T2‐weighted (FLAIR), and phase contrast MR imaging. 2D phase contrast imaging can be used to quantify absolute blood flow rates with cross‐sectional velocity‐encoding of major vasculature leading into the brain. Blood flow rates in the anterior circulation (carotid arteries) and posterior circulation (vertebral arteries) were derived with Medis QFlow 4.0. WMH volume and cortical thickness in AD‐signature regions were derived with in‐house software and FreeSurfer v6.0, respectively. Separate general linear models tested the association of total, anterior, and posterior blood flow rates with WMH volumes and AD‐signature cortical thickness.ResultLower total cerebral blood flow was associated with increased total WMH volume (β = ‐0.14, p&lt;0.05, 95%CI [‐1.37E‐2, ‐7.32E‐4]), an effect that was stronger for posterior flow (β_posterior = ‐0.17, 95%CI [‐3.7E‐2, 2.5E3], β_anterior = ‐0.11, 95%CI [‐1.9E‐2, 5.4E3]). Lower posterior blood flow specifically was associated with lower AD‐signature cortical thickness, but only in older participants (age interaction term: β = ‐3.14, p&lt;0.01, 95%CI [‐2.0E‐4, ‐3.5E‐5]).ConclusionLower total cerebral blood flow, particularly in the posterior circulation, is associated with increased WMH volume and decreased cortical thickness, two neuroimaging markers that are implicated in risk and progression of AD. Future work that examines whether or how diminished total cerebral blood flow accounts for the colocalization of AD biomarkers across modalities will provide insight into the vascular contributions to AD.