White Matter Hyperintensity Volume Research Articles

Interactions between muscle volume and body mass index on brain structure in the UK Biobank.

Low skeletal muscle volume may increase dementia risk through mechanisms affecting brain structure. However, it is unclear whether this relationship exists outside of sarcopenia and/or varies by other factors. We aimed to study the interplay between skeletal muscle volume and factors, such as age, sex, and body mass index (BMI), in explaining brain structure at midlife in a cohort without sarcopenia. We used abdominal and brain magnetic resonance imaging (MRI) data from a population-based cohort enrolled in the UK Biobank. The following measures were derived: thigh fat-free muscle volume (FFMV), total brain volume (TBV), gray matter volume (GMV), white matter volume (WMV), total hippocampal volume (THV), and white matter hyperintensity volume (WMHV). Participants below sex-based grip strength thresholds suggesting probable sarcopenia were excluded. Linear regression analysis was used to study the interaction or mediation effects of age, sex, and BMI on the associations between FFMV and brain volumes. Data were available for 20,353 participants (median age 64 years, 53% female). We found interactions between thigh FFMV, BMI, and age (all p < 0.05). Greater thigh FFMV was associated with better brain volumes in those aged <64 years with normal (TBV: β = 2.0 ml/L, p = 0.004; GMV: β = 0.8 ml/L, p = 0.04; WMV: β = 1.1 ml/L, p = 0.006; WMHV: β = -0.2 ml/L, p = 3.7 × 10-5) or low BMI (TBV: β = 21.2 ml/L, p = 0.003; WMV: β = 13.3 ml/L, p = 0.002, WMHV: β = -1.1 ml/L, p = 0.04). Greater thigh muscle volume correlates with better brain volumes at midlife in people without sarcopenia, but this relationship weakens with greater age and BMI. Further study is required to investigate the underlying mechanisms to understand which components of body composition are potentially modifiable risk factors for dementia.

Increased extracellular free water is related to white matter hyperintensity burden.

Extracellular free water (FW) has important roles in the occurrence and development of white matter hyperintensity (WMH). To explore the correlations between FW and WMH burden. A prospective analysis was conducted using magnetic resonance imaging (MRI) data from 126 individuals. WMH burden was determined based on WMH volumes and Fazekas scores from deep and periventricular white matter hyperintensity (DWMH and PWMH, respectively) in fluid-attenuated inversion recovery (FLAIR) images. FW values were taken from diffusion tensor imaging (DTI). Univariate analysis showed that FW values were correlated with WMH burden, including WMH volumes and DWMH and PWMH Fazekas scores (P < 0.05). After multivariate analysis, FW values were correlated with WMH volumes and DWMH and PWMH Fazekas scores when adjusted for age and hypertension (P < 0.05). Using MRI, increasing extracellular FW was related to WMH burden.

Structural brain correlates of sustained attention in healthy ageing: Cross-sectional findings from the LEISURE study

Sustained attention is important for maintaining cognitive function and autonomy during ageing, yet older people often show reductions in this domain. The role of the underlying neurobiology is not yet well understood, with most neuroimaging studies primarily focused on fMRI. Here, we utilise sMRI to investigate the relationships between age, structural brain volumes and sustained attention performance. Eighty-nine healthy older adults (50–84 years, Mage 65.5 (SD=8.4) years, 74 f) underwent MRI brain scanning and completed two sustained attention tasks: a rapid visual information processing (RVP) task and sustained attention to response task (SART). Independent hierarchical linear regressions demonstrated that greater volumes of white matter hyperintensities (WMH) were associated with worse RVP_A’ performance, whereas greater grey matter volumes were associated with better RVP_A’ performance. Further, greater cerebral white matter volumes were associated with better SART_d’ performance. Importantly, mediation analyses revealed that both grey and white matter volumes completely mediated the relationship between ageing and sustained attention. These results explain disparate attentional findings in older adults, highlighting the intervening role of brain structure.

Correspondence between white matter hyperintensities and regional grey matter volumes in Alzheimer's disease.

White matter hyperintensities (WMH) are the most common neuroimaging manifestation of cerebral small vessel disease, and is frequently observed in Alzheimer's disease (AD). This study aimed to investigate the relationship between WMH and cognition and to verify the mediation of grey matter atrophy in this relationship. The diffusion tensor imaging (DTI) technique analyses white matter fiber tract to assess white matter integrity. Voxel-based morphometry was applied to measure the grey matter volume (GMV). A linear regression model was applied to examine the associations between WMH and GMV, and mediation analyses was performed to determine the mediating role of regional GMV in the effect of WMH on cognitive function. Compared to the HC group, AD group have 8 fiber tract fractional anisotropy (FA) decreased and 16 fiber tract mean diffusivity (MD) increased. Compared to AD without WMH, AD with high WMH had 9 fiber tracts FA decreased and 13 fiber tracts MD increased. High WMH volume was negatively correlated with GMV in the frontal-parietal region. Low WMH volume was also negatively correlated with GMV except for the three regions (right angular gyrus, right superior frontal gyrus and right middle/inferior parietal gyrus), where GMV was positively correlated. Mediation analysis showed that the association between WMH and executive function or episodic memory were mediated by GMV in the frontal-parietal region. Damage to white matter integrity was more severe in AD with WMH. Differential changes in DTI metrics may be caused by progressive myelin and axonal damage. There was a negative correlation between WMH and grey matter atrophy in frontal-parietal regions in a volume-dependent manner. This study indicates the correspondence between WMH volume and GMV in cognition, and GMV being a key modulator between WMH and cognition in AD. This result will contribute to understanding the progression of the disease process and applying targeted therapeutic intervention in the earlier stage to delay neurodegenerative changes in frontal-parietal regions to achieve better treatment outcomes and affordability.

Subthreshold amyloid deposition, cerebral small vessel disease, and functional brain network disruption in delayed cognitive decline after stroke.

Although its incidence is relatively low, delayed-onset post-stroke cognitive decline (PSCD) may offer valuable insights into the "vascular contributions to cognitive impairment and dementia," particularly concerning the roles of vascular and neurodegenerative mechanisms. We postulated that the functional segregation observed during post-stroke compensation could be disrupted by underlying amyloid pathology or cerebral small vessel disease (cSVD), leading to delayed-onset PSCD. Using a prospective stroke registry, we identified patients who displayed normal cognitive function at baseline evaluation within a year post-stroke and received at least one subsequent assessment. Patients suspected of pre-stroke cognitive decline were excluded. Decliners [defined by a decrease of ≥3 Mini-Mental State Examination (MMSE) points annually or an absolute drop of ≥5 points between evaluations, confirmed with detailed neuropsychological tests] were compared with age- and stroke severity-matched non-decliners. Index-stroke MRI, resting-state functional MRI, and 18F-florbetaben PET were used to identify cSVD, functional network attributes, and amyloid deposits, respectively. PET data from age-, sex-, education-, and apolipoprotein E-matched stroke-free controls within a community-dwelling cohort were used to benchmark amyloid deposition. Among 208 eligible patients, 11 decliners and 10 matched non-decliners were identified over an average follow-up of 5.7 years. No significant differences in cSVD markers were noted between the groups, except for white matter hyperintensities (WMHs), which were strongly linked with MMSE scores among decliners (rho = -0.85, p < 0.01). Only one decliner was amyloid-positive, yet subthreshold PET standardized uptake value ratios (SUVR) in amyloid-negative decliners inversely correlated with final MMSE scores (rho = -0.67, p = 0.04). Decliners exhibited disrupted modular structures and more intermingled canonical networks compared to non-decliners. Notably, the somato-motor network's system segregation corresponded with the decliners' final MMSE (rho = 0.67, p = 0.03) and was associated with WMH volume and amyloid SUVR. Disruptions in modular structures, system segregation, and inter-network communication in the brain may be the pathophysiological underpinnings of delayed-onset PSCD. WMHs and subthreshold amyloid deposition could contribute to these disruptions in functional brain networks. Given the limited number of patients and potential residual confounding, our results should be considered hypothesis-generating and need replication in larger cohorts in the future.

Impact of amyloid and cardiometabolic risk factors on prognostic capacity of plasma neurofilament light chain for neurodegeneration

BackgroundPlasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer’s disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer’s Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL.MethodsNon-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity.ResultsOver a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores (p-value 0.005) and hippocampal volumes (p-value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p-values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores (p-value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p-value 0.026).ConclusionThis study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults.

Obstructive sleep apnea and cerebral small vessel disease in community-based older people: an aspirin in reducing events in the elderly imaging substudy

Abstract Study Objectives Obstructive sleep apnea (OSA) may increase the risk of dementia. A potential pathway for this risk is through cerebral small vessel disease (CSVD). In the context of an existing randomized trial of aspirin for primary prevention, we aimed to investigate OSA’s impact on CSVD imaging measures and explore whether aspirin effects these measures over 3 years that differ in the presence or absence of OSA. Methods A substudy of the aspirin in reducing events in the elderly (ASPREE) randomized placebo-controlled trial of low-dose aspirin. Community-dwelling participants aged 70 years and above, without cognitive impairment, cardiovascular disease, or known OSA completed an unattended limited-channel sleep study that calculated the oxygen desaturation index and apnea–hypopnea index. At baseline and 3 years later, volumes of white matter hyperintensities (WMH) and silent brain infarctions (SBI) were measured on 1.5 Tesla brain magnetic resonance imaging, and retinal vessel calibers were calculated from retinal vascular imaging. Results Mild and moderate/severe OSA was detected in 48.9% and 29.9%, respectively, of the 311 participants, who had a mean age of 73.7 years (SD 3.4 years), 38.6% female. OSA of any severity was not associated with WMH volumes, SBI, nor retinal vessel calibers at baseline, nor with change in these measures in the 277 participants with repeated measures acquired after 3 years. OSA of any severity did not interact with aspirin on change in these measures over 3 years. Conclusions In healthy older adults undiagnosed OSA was not associated with retinal vascular calibers and neuroimaging measures of CSVD. Clinical Trial Information ASPREE trial has registration with the International Standard Randomized Controlled Trial Number (ISRCTN) www.isrctn.com, ISRCTN83772183 and with www.clinicaltrials.gov, NCT01038583. SNORE-ASA has registration with the Australian New Zealand Clinical Trials Registry (ANZCTR) at www.anzctr.org.au, ACTRN12612000891820.

Predictive value of white matter hyperintensity burden combined with collateral circulation in mechanical thrombectomy for acute anterior circulation large vessel occlusion

ObjectiveTo investigate the correlation and predictive value of white matter hyperintensity (WMH) burden in conjunction with collateral circulation during mechanical thrombectomy (MT) for acute anterior circulation occlusion. MethodsA database comprising consecutive registrations of patients who underwent mechanical thrombectomy for acute anterior circulation large vessel occlusive cerebral infarction at Nanjing Drum Tower Hospital from January 2018 to December 2021 was analyzed. Collateral circulation was assessed using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scoring criteria. The good collateral group included ASITN/SIR grades 3 and 4, while the poor collateral group included grades 1 and 2. Additionally, white matter hyperintensity burden was evaluated using white matter hyperintensity volume and the Fazekas scoring system. A favorable functional outcome was defined as a modified Rankin scale (mRS) of 0–2 at 90 days. Multivariable logistic regression analyses and Spearman correlation analysis were employed to assess the correlation between white matter hyperintensity burden and unfavorable outcomes in mechanical thrombectomy. ResultsA total of 123 patients who underwent mechanical thrombectomy for acute anterior circulation occlusion were included (56.9 % male). Favorable outcomes were observed in 45.5 % (56/123) of cases. Those with a low ASITN/SIR scale (r = -1.33, 95 % CI: 0.26 (0.09–0.78), P=0.01; cutoff value = 2.5), low low-density lipoprotein cholesterol (LDL-C) level (r = -1.00, 95 % CI: 0.37 (0.15–0.92), P=0.03; cutoff value = 2.26), and high white matter hyperintense volume (r = 0.28, 95 % CI: 1.33 (1.03–1.71), P=0.03; cutoff value = 10.03) were more likely to experience unfavorable outcomes. Moreover, when compared to ASITN/SIR scale (AUC=89.6, 95 % CI: 0.09–0.78) and LDL level (AUC=62.8, 95 % CI: 0.15–0.92), white matter hyperintense volume demonstrated greater accuracy in predicting poor outcomes (AUC=94.4, 95 % CI: 1.03–1.71). Importantly, white matter hyperintense volume showed a positive correlation with the modified Rankin Scale (mRS) Score (r = 0.8289, P<0.0001). In brief, the burden of white matter hyperintensity is negatively correlated with collateral circulation in mechanical thrombectomy for acute anterior circulation occlusion. ConclusionsThe higher the burden of white matter hyperintensity, the worse the collateral circulation in mechanical thrombectomy for acute anterior circulation occlusion. The combination of high white matter hyperintensity volume and poor collateral circulation enhances might predict a worse clinical outcome of mechanical thrombectomy with acute anterior circulation occlusion.

Hypertension and cerebral blood flow in the development of Alzheimer's disease.

We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n=138) or Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n=78; ADNI: n=89). The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau.

Cerebrovascular hemodynamics association with brain structure and function in Multiple Sclerosis

BackgroundVascular risk factors seem to contribute to disease progression in Multiple Sclerosis (MS), but the mechanistic connection between vascular risk and MS is unknown. Understanding cerebrovascular hemodynamics (CVH) in MS may help advance our understanding of the link between vascular risk and MS. ObjectivesExamine the relationship between CVH [dynamic cerebral autoregulation (dCA) and vasoreactivity (VR)] and brain structure (MRI) and function (cognition, and gait) in individuals with MS. MethodsTranscranial Doppler ultrasound (TCD) was utilized to assess two key markers of CVH: dCA and VR. dCA (reported as phase and gain) is calculated from the spontaneous blood pressure and flow velocity oscillations. VR is calculated as the slope of change in cerebral blood flow velocity in response to end-tidal CO2. Global gray matter (GM), white matter (WM), WM hyperintensity (WMH) volumes and WM lesion counts were measured from brain MRI. All participants underwent detailed cognitive and gait assessments. ResultsEighty participants were included (age 44 ± 11, 26 % male); 75 had relapsing-remitting MS (94 %), with disease duration of 8 (11) years [median (IQR)] since MS diagnosis and an Expanded Disability Status Scale (EDSS) of 2.0 (4.0). Higher phase (better dCA) was associated with greater GM volume, lower WHM burden and higher cognitive scores in the memory and global cognitive domains (all P values <0.05). There was no relationship between CVH and gait speed in our study participants. There was no relationship between VR and any measures of brain structure and function. ConclusionsMore efficient cerebral autoregulation is associated with better brain structure (larger GM and lower WMH volumes) and function (cognition, but not gait) in patients with MS.

Association between surgical admissions, cognition, and neurodegeneration in older people: a population-based study from the UK Biobank

Previous studies have shown that major surgical and medical hospital admissions are associated with cognitive decline in older people (aged 40-69years at recruitment), which is concerning for patients and caregivers. We aimed to validate these findings in a large cohort and investigate associations with neurodegeneration using MRI. For this population-based study, we analysed data from the UK Biobank collected from March 13, 2006, to July 16, 2023, linked to the National Health Service Hospital Episode Statistics database, excluding participants with dementia diagnoses. We constructed fully adjusted models that included age, time, sex, Lancet Commission dementia risk factors, stroke, and hospital admissions with a participant random effect. Primary outcomes were hippocampal volume and white matter hyperintensities, both of which are established markers of neurodegeneration, and exploratory analyses investigated the cortical thickness of Desikan-Killiany-Tourville atlas regions. The main cognitive outcomes were reaction time, fluid intelligence, and prospective and numeric memory. Surgeries were calculated cumulatively starting from 8years before the baseline evaluation. Of 502 412participants in the UK Biobank study, 492 802participants were eligible for inclusion in this study, of whom 46 706underwent MRI. Small adverse associations with cognition were found per surgery: reaction time increased by 0·273ms, fluid intelligence score decreased by 0·057correct responses, prospective memory (scored as correct at first attempt) decreased (odds ratio 0·96 [95% CI 0·95to 0·97]), and numeric memory maximum correct matches decreased by 0·025in fully adjusted models. Surgeries were associated with smaller hippocampal volume (β=-5·76mm³ [-7·89to-3·64]) and greater white matter hyperintensities volume (β=100·02 mm³ [66·17to 133·87]) in fully adjusted models. Surgeries were also associated with neurodegeneration of the insula and superior temporal cortex. This population-based study corroborates that surgeries are generally safe but cumulatively are associated with cognitive decline and neurodegeneration. Perioperative brain health should be prioritised for older and vulnerable patients, particularly those who have multiple surgical procedures. The Australian and New Zealand College of Anaesthetists (ANZCA) Foundation and the University of Sydney.

Predictors of white matter hyperintensities in the elderly Congolese population.

White matter hyperintensities (WMHs) are strongly linked to cardiovascular risk factors and other health conditions such as Alzheimer's disease. However, there is a dearth of research on this topic in low-income countries and underserved populations, especially in the Democratic Republic of Congo (DRC) where the population is aging rapidly with increasing cardiovascular risk factors and dementia-related diseases. This study evaluates health factors associated with WMH in the elderly Sub-Saharan Africa (SSA), specifically Congolese adults. In a cross-sectional study of 77 people from the DRC, participants underwent neuroimaging to analyze WMH volume and completed clinical evaluation, laboratory-based blood exams, self-reported questionnaires, and interviews. A simple linear regression model was conducted to test the association between WMH and potential predictors (neurological status, age, sex, hypertension, diabetes, tobacco abuse, stroke, high cholesterol, cardiovascular medication, and alcohol abuse). Stepwise selection and backward elimination analyses were performed to obtain the final model. Finally, a multiple linear regression model was conducted to assess the association between WMH and variables retained in the final model (neurological status, sex, and age). Of the 77 individuals, 47 (61%) had dementia, 40 (52.6%) were males, and the mean age was 73 years (± 8.0 years standard deviation). In simple linear regression models, WMH was significantly associated with dementia (expβ1=1.75, 95% CI=1.14 - 2.71, p-value=0.01) though it had a weak association with age (expβ1=1.03, 95% CI=1.00 - 1.05, p-value=0.05) and sex (male) (expβ1=0.66, 95% CI=0.43 - 1.01, p-value=0.05). In multiple linear regression models, WMH was statistically significantly associated with dementia (expβ1=1.97, 95% CI=1.31 - 2.95, p-value =0.001), male sex (expβ2=0.54, 95% CI=0.36 - 0.80, p-value=0.003), and age (expβ3=1.03, 95% CI=1.00 - 1.06, p-value=0.03). However, WMH was not significantly associated with common cardiovascular risk factors, such as high blood pressure, diabetes, tobacco use, obesity, and high cholesterol levels. WMH is significantly associated with neurological status, sex, and age in the Congolese population. Understanding these predictors may improve our ability to diagnose, assess, and develop preventative treatments for white matter disease in SSA/DRC populations, where neuroimaging is difficult to obtain.

Cortical surface-based morphometry in cognitive impairment in sporadic cerebral small vessel disease

Background: Analysis of structural MR images plays a key role in assessing the underlying substrate of cognitive impairment (CI) in sporadic age-related cerebral small vessel disease (SVD), leading to up to 45% of all cases of dementia. The variety of MR-morphometry results in SVD requires extensive research and comparisons with clinical data. Aims: to assess the characteristics of brain atrophy in cognitive impairment in patients with SVD using surface-based morphometry (SBM). Materials and methods: A prospective study was conducted assessing patients with SVD and CI of varying severity (subjective - subCI, moderate - MCI and dementia) and a group of volunteers matched by gender and age. MRI was performed with subsequent analysis of MRI signs of SVD and calculation of the general SVD index and processing of T1mpr images using the SBM method with general and regional quantitative assessment of the brain, including the thickness of the cerebral cortex. Results: the main group with SVD consisted of 173 patients, the control group included 47 healthy volunteers. As the severity of structural changes in the brain and the severity of CI increased, there was a significant (p0.05) decrease in the thickness of the cortex of certain regions according to a similar pattern: the cingulate gyri, mainly their posterior sections; medial and middle sections of the frontal lobes, various parts of the insular cortex, temporo-parietal areas (especially the supramarginal gyri). The volume of the brain itself (total volume, gray and white matter) in SVD had significant differences only with controls, but not between groups of patients with different severity of CI. The volume of white matter hyperintensities was significantly different between the groups with dementia and MCI, dementia and sub-CI (p 0.0001). Conclusions: The data obtained during the study confirm the secondary/mixed nature of atrophy in SVD. The wide variety of regions with significant thinning of the cortex limits the specification of the progression of CI in SVD based on their atrophy. This allows the quantitative measurement of the cortex to be used only as an auxiliary method in assessing the prediction of SVD progression.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Association of hemoglobin with plasma neurofilament light and white matter hyperintensities in Alzheimer's disease continuum

ObjectiveThis study aimed to investigate the association of hemoglobin (Hb) with axonal injury marker plasma neurofilament light (PNFL) and brain structure measurements in the Alzheimer's disease (AD) continuum. MethodsThe data used in this study were collected from the Alzheimer's Disease Neuroimaging Initiative database. Participants with cognitively normal, mild cognitive impairment, and mild dementia were included in the data analyses. All participants had available data on blood tests, PNFL levels, neuropsychological assessments, brain structure measurements (including volumes of white matter hyperintensities [WMH], hippocampus, gray matter, and total brain), and Aβ positron emission tomography standardized uptake value ratio (SUVR) at baseline. Aβ-positive was defined as SUVR threshold value > 1.11. Linear regression, restricted cubic spline, and causal mediation analyses were conducted to investigate the association of Hb concentration with PNFL levels and brain structure measurements. Stratified analyses were also employed to evaluate the association between Hb concentration and PNFL levels across different APOE genotypes and sex. ResultsIn the Aβ-positive group, Hb concentration was associated with PNFL levels (β = −0.022, p = 0.002). Stratified analyses suggested an association between Hb concentration and PNFL in APOE ɛ4 carriers (β = −0.031, p < 0.001) and males (β = −0.030, p < 0.001) but not in non-carriers and females (p > 0.05). Hb concentration was also associated with WMH volume (β = −0.04, p = 0.028), especially in APOE ɛ4 carriers, with mediation analysis revealing that PNFL mediated the association between Hb concentration and WMH volume. The association of Hb concentration with other brain structure measurements was minimal. ConclusionIn the AD continuum, Hb was associated with axonal injury marker PNFL and WMH volume, particularly in APOE ɛ4 carriers.

Effects and Thresholds of Young to Midlife Vascular Risks on Brain Health.

Vascular risk factors, particularly hypertension, are important contributors to accelerated brain aging. We sought to quantify vascular risk factor risks over adulthood and assess the empirical evidence for risk thresholds. We used SBP (systolic blood pressure) and diastolic blood pressure, total cholesterol, fasting blood glucose, and body mass index measurements collected from participants in the CARDIA study (Coronary Artery Risk Development in Young Adults) at 2- to 5-year intervals through year 30. The Montreal Cognitive Assessment and domain-specific cognitive tests were performed at year 30. White matter hyperintensity volume was measured by magnetic resonance imaging. We used a 2-step method to fit longitudinal vascular risk factor exposures to optimized spline functions with mixed-effects models, then used the participant-specific random effects that characterized individual exposures over time in cross-sectional models adjusted for sex, race, age, and education to study effects on midlife brain health. Change in SBP up to 33 years of age was negatively associated with Montreal Cognitive Assessment scores (-0.29 Montreal Cognitive Assessment Z score per mm Hg/y change [95% CI, -0.49 to -0.09]; P=0.005), with similar effects for SBP changes from 33 to 49 years of age (-0.08 [95% CI, -0.16 to 0.01]; P=0.08). We observed comparable, significant associations between SBP exposure during those ages, midlife performance on specific cognitive domains, and volume of white matter hyperintensity (all P<0.05). SBP ≤111 mm Hg was the estimated threshold below which no harmful association with midlife cognitive performance was identified. SBP in early adulthood is the vascular risk factor most strongly associated with midlife cognitive performance and white matter hyperintensity burden, with SBP 111 mm Hg suggested as a harm threshold.

P030 EFFECTS OF GENDER-RELATED FACTORS ON THE HYPERTENSION-WHITE MATTER HYPERINTENSITIES ASSOCIATION: A SEX-STRATIFIED ANALYSIS

Background: Hypertension (HTN) is a global health issue affecting various vascular beds, including the brain. There is a gap in understanding how gender-related factors, such as roles, identity, relationships, and institutionalized gender, contribute to sex differences in the relationship between HTN and brain structure changes. This study aims to investigate the role of gender-related factors in the relationship between HTN and white matter hyperintensities (WMH) in both males and females. Methods: This cohort study used MRI data from 41,300 UK Biobank participants. HTN status was determined through hospital records and self-report, and WMH volumes were measured using MRI. Eight gender-related factors, including unpaid work, caregiving, unemployment, risk-taking behavior, living alone, education, income, and material deprivation, were examined. Generalized linear models were used to evaluate the interactions between each gender-related factor and HTN in males and females. Effect modification was evaluated using the Z-test to compare the beta coefficients of the HTN-WMH association across strata. Results: The study included 19,260 males and 22,040 females aged 40-69 years at baseline, with 27.3% hypertensive. Hypertensive males (7.7±9.2 mL) and females (7.2±8.8 mL) exhibited greater WMH volumes compared to their normotensive counterparts (males: 4.7±5.9 mL; females: 3.9±5.2 mL). The main effects model revealed that low income was significantly associated with greater WMHs in females, while no gender-related factors were linked to WMHs in males after adjusting for clinical, behavioral, and gender-related variables. No significant interactions between HTN and gender-related factors were found in either males or females after adjustment. In the stratified analysis, females with lower material deprivation showed a significantly greater increase in WMHs compared to those with higher material deprivation. No other gender-related factors in either group interacted with HTN to amplify the association with WMHs. Discussion: Socioeconomic factors, particularly in females, were associated with WMH. These findings highlight the importance of considering biological and social determinants to address hypertension risks effectively.

Analysis of white matter hyperintensities in Alzheimer’s disease and vascular dementia with magnetic resonance imaging

Objectives: The study aimed to analyze the brain white matter hyperintensities (WMHs) of patients with vascular dementia (VaD) and Alzheimer’s disease (AD) using magnetic resonance imaging to determine whether white matter lesions in the brain could be detected by a computer using image processing methods. Patients and methods: In this retrospective observational study, a unimodal, unsupervised, and automatic method was developed, and magnetic resonance imaging of 35 patients were examined. Of the 35 patients, 19 (14 males, 5 females; mean age: 73.2±6.7 years; range, 56 to 83 years) were picked from patients with AD or VaD who were admitted to a neurology clinic between January 2016 and December 2022 (Group 1). The remaining 16 patients (10 females, 5 males; mean age: 80.4±5.4 years; range, 69 to 92 years) were included from the ABVIB (Aging Brain: Vasculature, Ischemia, and Behavior) study from the ADNI (Alzheimer’s Disease Neuroimaging Initiative) database (Group 2). To calculate the volume of WMHs, a detailed analysis was conducted. Initially, skull stripping was performed, and then the brain was segmented. Afterward, two types of masks (Mask1 and Mask-2) were obtained by applying painting, decreasing, and blurring processes to the segmented white matter. These masks limited the region that was searched for WMHs. With this limitation, false positives that could arise from gray matter intensities were tried to be prevented. To evaluate the accuracy of WMH detection, a user interface was developed, and manual marking was conducted by an expert neurologist. After WMH detection, WMH volumes were calculated. Results: For Group 1, the similarity index was found to be 0.76 for Mask-1 and 0.80 for Mask-2, while for Group 2, the similarity index was 0.71 for Mask-1 and 0.87 for Mask-2. In patients with AD, the mean WMH lesion load (LL) was 15.16±16.59 mL. In patients with VaD, who were expected to suffer more from WMHs, the mean WMH LL was 29.22±11.40 mL. In Group 2, the mean WMH LL was 17.77±12.26 mL. Conclusion: This study may contribute to the literature since it is an automatic, unimodal, and unsupervised method that was applied to both a completely unique data set with many different scanning parameters and an open database data set.

Framingham Stroke Risk Profile Score and White Matter Disease Progression.

To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm 3 /year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm 3 (IQR: 3.3-28.4 cm 3 ), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm 3 /year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P <0.001). This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

Improved Dementia Prediction in Cerebral Small Vessel Disease Using Deep Learning-Derived Diffusion Scalar Maps From T1.

Cerebral small vessel disease is the most common pathology underlying vascular dementia. In small vessel disease, diffusion tensor imaging is more sensitive to white matter damage and better predicts dementia risk than conventional magnetic resonance imaging sequences, such as T1 and fluid attenuation inversion recovery, but diffusion tensor imaging takes longer to acquire and is not routinely available in clinical practice. As diffusion tensor imaging-derived scalar maps-fractional anisotropy (FA) and mean diffusivity (MD)-are frequently used in clinical settings, one solution is to synthesize FA/MD from T1 images. We developed a deep learning model to synthesize FA/MD from T1. The training data set consisted of 4998 participants with the highest white matter hyperintensity volumes in the UK Biobank. Four external validations data sets with small vessel disease were included: SCANS (St George's Cognition and Neuroimaging in Stroke; n=120), RUN DMC (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort; n=502), PRESERVE (Blood Pressure in Established Cerebral Small Vessel Disease; n=105), and NETWORKS (n=26), along with 1000 normal controls from the UK Biobank. The synthetic maps resembled ground-truth maps (structural similarity index >0.89 for MD maps and >0.80 for FA maps across all external validation data sets except for SCANS). The prediction accuracy of dementia using whole-brain median MD from the synthetic maps is comparable to the ground truth (SCANS ground-truth c-index, 0.822 and synthetic, 0.821; RUN DMC ground truth, 0.816 and synthetic, 0.812) and better than white matter hyperintensity volume (SCANS, 0.534; RUN DMC, 0.710). We have developed a fast and generalizable method to synthesize FA/MD maps from T1 to improve the prediction accuracy of dementia in small vessel disease when diffusion tensor imaging data have not been acquired.