White Matter Hyperintensity Volume Research Articles

Sex-Specific Vulnerabilities to Subclinical Vascular Brain Injury in Early Late-Life: The Framingham Heart Study.

Subclinical vascular brain injury is an increasingly recognized risk factor for stroke and dementia. Despite well-established sex differences in vascular risk and disease prevalence, the impact of sex on drivers of subclinical vascular brain injury remains unclear, presenting a barrier to developing sex-specific prevention guidelines. We aimed to establish the extent to which sex moderates associations between vascular risk factors and magnetic resonance imaging (MRI) measures of subclinical brain injury in stroke-free older adults. We leveraged cross-sectional data from 1,579 stroke- and dementia-free Framingham Heart Study Offspring participants at exam 8 (age 65.7 ± 8.8 years, 53% women). Vascular risks were assessed using components of the Framingham Stroke Risk Profile (FSRP) and diastolic blood pressure (DBP). White matter hyperintensity volume (WMH), total cerebral brain volume (TBV), and covert brain infarcts were quantified using MRI. We examined whether vascular risk factors were associated with MRI measures across the combined cohort, and then determined whether sex modified these associations. Higher FSRP and specifically systolic blood pressure (SBP) were associated with greater WMH. These associations were stronger in women and remained after adjusting for menopause age and hormone therapy use. By contrast, diabetes and lower DBP were associated with smaller TBV primarily in men. The DBP-atrophy relationship was only observed in men with declining DBP or prior hypertension. Our findings highlight differential vulnerability to the impact of vascular risk factors on white matter health in women and global atrophy in men, supporting the development of sex-specific guidelines to better preserve vascular brain health in aging. ANN NEUROL 2024.

Cerebrovascular markers of WMH and infarcts in ADNI: A historical perspective and future directions.

White matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers. HIGHLIGHTS: White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

White Matter Hyperintensities and Cognitive Functions in People With the R544C Variant of the NOTCH3 Gene Without Stroke or Dementia.

NOTCH3 pathologic variants cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which presents with stroke and dementia and is characterized by white matter hyperintensities (WMHs) on brain MRI. The R544C variant is a common pathologic variant in Taiwan, but not all carriers exhibit significant symptoms. We investigated whether WMHs occur before clinical symptoms in carriers with pathogenic variants, examined factors associated with WMHs, and explored their relationship with cognitive functions. We enrolled 63 R544C carriers without overt clinical disease (WOCD) and 37 age-matched and sex-matched noncarriers as controls from the Taiwan Precision Medicine Initiative data set. All participants underwent clinical interviews, comprehensive neuropsychological assessments, and brain MRI. We calculated total and regional WMH volumes, determined the age at which WMHs began increasing in carriers, and examined the relationship between WMHs and neuropsychological performance. Factors associated with WMH volumes were analyzed using multivariable linear regression models. Compared with controls, R544C carriers WOCD had increased WMH volume, except in the occipital and midbrain areas, and showed a rapid increase in WMHs starting at age 48. They scored lower on the Mini-Mental State Examination (median = 28.4 vs 29.0, p = 0.048), Montreal Cognitive Assessment (MoCA) (median = 28.3 vs 29.0, p = 0.013), and memory and executive function tests than controls. After adjusting for age, sex, and education, MoCA scores were associated with whole-brain (r = -0.387, padj = 0.008) and regional WMHs (all padj < 0.05) except in the midbrain area. Age (β = 0.034, 95% CI 0.021-0.046, p < 0.001), hypercholesterolemia (β = 0.375, 95% CI 0.097-0.653, p = 0.009), and the vascular risk factor (VRF) index (β = 0.132, 95% CI 0.032-0.242, p = 0.019) were associated with the WMH severity in carriers. Our study revealed that WMHs are extensively distributed in R544C carriers WOCD. They exhibited a rapid increase in WMHs beginning at age 48, approximately 7 years earlier than the reported age at symptomatic onset. Age was the strongest predictive factor of WMHs, and VRF, particularly hypercholesterolemia, might be modifying factors of WMHs.

Neuropathological Correlates of White Matter Hyperintensities in Cerebral Amyloid Angiopathy.

White matter hyperintensities (WMHs) are frequently observed on magnetic resonance imaging (MRI) in patients with cerebral amyloid angiopathy (CAA). The neuropathological substrates that underlie WMHs in CAA are unclear, and it remains largely unexplored whether the different WMH distribution patterns associated with CAA (posterior confluent and subcortical multispot) reflect alternative pathophysiological mechanisms. We performed a combined invivo MRI-ex vivo MRI-neuropathological study in patients with definite CAA. Formalin-fixed hemispheres from 19 patients with CAA, most of whom also had invivo MRI available, underwent 3T MRI, followed by standard neuropathological examination of the hemispheres and targeted neuropathological assessment of WMH patterns. Exvivo WMH volume was independently associated with CAA severity (P=0.046) but not with arteriolosclerosis (P=0.743). In targeted neuropathological examination, compared with normal-appearing white matter, posterior confluent WMHs were associated with activated microglia (P=0.043) and clasmatodendrosis (P=0.031), a form of astrocytic injury. Trends were found for an association with white matter rarefaction (P=0.074) and arteriolosclerosis (P=0.094). An exploratory descriptive analysis suggested that the histopathological correlates of WMH multispots were similar to those underlying posterior confluent WMHs. This study confirmed that vascular amyloid β severity in the cortex is significantly associated with WMH volume in patients with definite CAA. The histopathological substrates of both posterior confluent and WMH multispots were comparable, suggesting overlapping pathophysiological mechanisms, although these exploratory observations require confirmation in larger studies.

Associations of Circulating Platelet Endothelial Cell Adhesion Molecule-1 Levels With Progression of Cerebral Small-Vessel Disease, Cognitive Decline, and Incident Dementia.

The association between platelet endothelial cell adhesion molecule-1 (PECAM-1) with cerebral small-vessel disease and cognition in dementia-free subjects remains uninvestigated. A prospective cohort of dementia-free subjects was recruited from memory clinics and followed up for 5 years. Annual neurocognitive assessments and twice-yearly brain magnetic resonance imaging scans were performed. Associations of baseline plasma PECAM-1 levels with cerebral small-vessel disease, cognitive decline (Montreal Cognitive Assessment scores and executive function Z scores), and incident dementia were evaluated. Of 213 subjects (aged 70.2±7.7 years, 51.2% men), median PECAM-1 levels were 0.790 (interquartile range, 0.645-0.955 ng/mL). Compared with the highest tertile, subjects within the lowest PECAM-1 tertile had greater cross-sectional white matter hyperintensity volume (β=4.84 [95% CI, 0.67-9.01]; P=0.023), age-related white matter change scores (β=1.39 [95% CI, 0.12-2.67]; P=0.033), and cerebral microbleeds (Adjusted risk ratio, 2.59 [95% CI, 1.19-5.62]; P=0.016). Of the 204 participants with follow-up data (median, 60.0 [interquartile range, 60.0-60.0] months), 24 (11.8%) developed incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM-1 had a higher risk of incident dementia (first tertile: adjusted hazard ratio [AHR], 4.52 [95% CI, 1.35-15.13]; P=0.024; second tertile: AHR, 3.28 [95% CI, 1.02-10.60]; P=0.047). The lowest PECAM-1 tertile was associated with greater progression of white matter hyperintensity volume (β=4.15 [95% CI, 0.06-8.24]; P=0.047), cerebral microbleeds (incident relative risk [IRR], 2.21 [95% CI, 1.05-4.65]; P=0.036), and decline in executive function (β=-0.45 [95% CI, -0.76 to -0.14]; P=0.004), and Montreal Cognitive Assessment (β=-1.32 [95% CI, -2.30 to -0.35]; P=0.008) scores. In dementia-free subjects, lower circulating PECAM-1 levels are associated with greater cerebral small-vessel disease progression and cognitive decline, thus warranting future study as a potential therapeutic target.

Role of Cardiovascular Risk in Associations of Brain-Derived Neurotrophic Factor with Longitudinal Brain and Cognitive Trajectories in Older Adults

ABSTRACT Background Higher levels of brain-derived neurotrophic factor (BDNF) have been associated with better neurocognitive outcomes. BDNF is present in cardiovascular tissue, and some evidence suggests it may benefit cardiovascular function. The current study assessed whether there is a mediating and/or moderating role of cardiovascular health in the relationship between BDNF and brain and cognitive outcomes. Method We examined longitudinal data from 397 older adults (aged 54–89;164 females, 233 males) enrolled in the Alzheimer’s Disease Neuroimaging Initiative with available plasma BDNF, medical, neuroimaging, and cognitive assessments. We used path analysis and linear regression to estimate the mediating and moderating roles of two measures of cardiovascular health, the Framingham Risk Score (FRS) and pulse pressure, in the relationships between BDNF and longitudinal changes in brain structure (white matter hyperintensity volume, hippocampal volume, and primary visual cortex volume) and cognitive function (executive function, episodic memory, and language). Results There was no significant association of plasma BDNF with FRS or pulse pressure (ps > 0.31), precluding mediation. There were no robust associations between BDNF and longitudinal change in any brain structural or cognitive measures (ps > .12). Higher FRS was significantly associated with greater increases in WMH volume (ps < .01). FRS and pulse pressure were not associated with any other brain structural or cognitive outcomes (ps > .07). Conclusion These results suggest that cardiovascular health may not play an important role in the influence of BDNF on neurocognitive health in older adults.

Cortico-limbic volume abnormalities in late life depression are distinct from β amyloid and white matter pathologies.

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUCVol = 0.71, AUCWMH, Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

Unveiling connections between venous disruption and cerebral small vessel disease using diffusion tensor image analysis along perivascular space (DTI-ALPS): A 7-T MRI study.

Cerebral venous disruption is one of the characteristic findings in cerebral small vessel disease (CSVD), and its disruption may impede perivascular glymphatic drainage. And lower diffusivity along perivascular space (DTI-ALPS) index has been suggested to be with the presence and severity of CSVD. However, the relationships between venous disruption, DTI-ALPS index, and CSVD neuroimaging features remain unclear. To investigate the association between venous integrity and perivascular diffusion activity, and explore the mediating role of DTI-ALPS index between venous disruption and CSVD imaging features. In this cross-sectional study, 31 patients (mean age, 59.0 ± 9.9 years) were prospectively enrolled and underwent 7-T magnetic resonance (MR) imaging. DTI-ALPS index was measured to quantify the perivascular diffusivity. The visibility and continuity of deep medullary veins (DMVs) were evaluated based on a brain region-based visual score on high-resolution susceptibility-weighted imaging. White matter hyperintensity (WMH) and perivascular space (PVS) were assessed using qualitative and quantitative methods. Linear regression and mediation analysis were performed to analyze the relationships among DMV scores, DTI-ALPS index, and CSVD features. The DTI-ALPS index was significantly associated with the parietal DMV score (β = -0.573, p corrected = 0.004). Parietal DMV score was associated with WMH volume (β = 0.463, p corrected = 0.013) and PVS volume in basal ganglia (β = 0.415, p corrected = 0.028). Mediation analyses showed that DTI-ALPS index manifested a full mediating effect on the association between parietal DMV score and WMH (indirect effect = 0.115, Pm = 43.1%), as well as between parietal DMV score and PVS volume in basal ganglia (indirect effect = 0.161, Pm = 42.8%). Cerebral venous disruption is associated with glymphatic activity, and with WMH and PVS volumes. Our results suggest cerebral venous integrity may play a critical role in preserving perivascular glymphatic activity; while disruption of small veins may impair the perivascular diffusivity, thereby contributing to the development of WMH and PVS enlargement.

Childhood Community Disadvantage and MRI-Derived Structural Brain Integrity After Age 65 Years

Prior studies associate late-life community disadvantage with worse brain health. It is relatively unknown if childhood community disadvantage associates with late-life brain health. To test associations between childhood residence in an economically disadvantaged community, individual income and education, and late-life cortical brain volumes and white matter integrity. This cohort study was conducted in the ongoing harmonized cohorts KHANDLE (Kaiser Healthy Aging and Diverse Life Experiences Study; initiated 2017) and STAR (Study of Healthy Aging in African Americans; initiated 2018) using all available data collected out of a regional integrated health care delivery network in California between cohort initiation and analysis initiation in June 2023. Eligible participants were Kaiser Permanente Northern California member ages 65 years or older. Data were analyzed between June and November 2023. Residence at birth was geocoded and linked to historical Area Deprivation Indices (ADI). ADI is a nationally ranked percentile; community disadvantage was defined as ADI of 80 or higher. Regional brain volumes and white matter integrity measures were derived from a random subset of participants who underwent 3T magnetic resonance imaging. Models adjusted for race and ethnicity, sex, and parental education. Of a total 2161 individuals in the combined cohort, 443 individuals were eligible for imaging (mean [SD] age, 76.3 [6.5] years; 253 female [57.1%]; 56 Asian [12.6%], 212 Black [47.9%], 67 Latino [15.1%], 109 White [24.6%]). Imaging participants had a mean (SD) 15.0 (2.5) years of education, and 183 (41.3%) earned $55 000 to $99 999 annually. Fifty-four participants (12.2%) resided in a disadvantaged childhood community. Childhood community disadvantage was associated with smaller gray matter volumes overall (-0.39 cm3; 95% CI, -0.65 to -0.10 cm3) and in the cerebellum (-0.39 cm3; 95% CI, -0.66 to -0.09 cm3), hippocampus (-0.37 cm3; 95% CI, -0.68 to -0.04 cm3), and parietal cortex (-0.25 cm3; 95% CI, -0.46 to -0.04 cm3) and larger mean lateral ventricle (0.44 cm3; 95% CI, 0.12 to 0.74 cm3), third ventricle (0.28 cm3; 95% CI, 0.03 to 0.55 cm3), and white matter hyperintensity volume (0.31 cm3; 95% CI, 0.06 to 0.56 cm3). Educational attainment and late-life income did not mediate these associations. In this cohort study of racially and ethnically diverse health plan members, childhood community disadvantage was associated with worse late-life brain health independent of individual socioeconomic status. Future work should explore alternative pathways (eg, cardiovascular health) that may explain observed associations.

Genetic risk factors underlying white matter hyperintensities and cortical atrophy

White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer’s disease neuropathology

Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD). Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n=291), resilient in both (n=260) or advanced in one/resilient in the other (n=163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.

Perivascular space enlargement accelerates in ageing and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

BackgroundPerivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD.MethodsWe studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre “DZNE Longitudinal Cognitive Impairment and Dementia Study” (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39).ResultsPVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant’s age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρspearman = -0.17, pFDR = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T + > A-T-, pFDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, pFDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, pFDR = 0.021).ConclusionOur longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies.Trial registrationGerman Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966.

Executive functions and processing speed in covert cerebral small vessel disease.

Executive dysfunction and slowed processing speed are central cognitive impairments in cerebral small vessel disease (cSVD). It is unclear whether the subcomponents of executive functions become equally affected and whether computerized tests are more sensitive in detecting early cognitive changes over traditional tests. The associations of specific executive abilities (cognitive flexibility, inhibitory control, working memory) and processing speed with white matter hyperintensities (WMHs) and Instrumental Activities of Daily Living (IADL) were examined. In the Helsinki Small Vessel Disease Study, 152 older individuals without stroke or dementia were assessed with brain magnetic resonance imaging and comprehensive neuropsychological evaluation. WMH volumes were obtained with automated segmentation. Executive functions and processing speed measures included established paper-and-pencil tests and the computer-based Flexible Attention Test (FAT), Simon task and Sustained Attention to Response Task. White matter hyperintensity volume and IADL were associated with multiple cognitive measures across subdomains independently of demographic factors. The highest effect sizes were observed for FAT numbers and number-letter tasks (tablet modifications from the Trail Making Test), FAT visuospatial span, Simon task and semantic verbal fluency. Some of the widely used tests such as Stroop inhibition, phonemic fluency and digit span were not significantly associated with either WMHs or IADL. Processing speed and executive function subcomponents are broadly related to functional abilities and WMH severity in covert cSVD, but the strength of associations within subdomains is heavily dependent on the assessment method. Digital tests providing precise measures of reaction times and response accuracy seem to outperform many of the conventional paper-and-pencil tests.

Large sample size MRI measurements to assess the relation between cardiac function and structure and white matter hyperintensity volumes

Abstract Background People with established cardiovascular disease (CVD) are at risk of early cognitive decline, and neurological diseases such as dementia. CVD and neurological diseases share common risk factors, such as blood pressure, sedentary lifestyle, as well as genomic risk factors such as mutations in APOE4 [1]. It's unclear to what extent the co-occurrence of CVD and neurological diseases is explained by these risk factors, or whether there is a direct association where CVD is a first step towards poorer neurological health. White matter hyperintensities (WMH) of presumed vascular origin are damaged areas in the brain observed through magnetic resonance imaging (MRI). These lesions are associated with progressive neurological disease such as vascular dementia, as well with risk factors for CVD [2]. Purpose We set out to determine to what extent CMR measurements associated with WMH independent of known cerebrovascular risk factors. Methods Cardiac and brain MRI images were analysed for 23,963 UK biobank (UKB) participants. WMH analysis included 5 brain regions (Frontal[F], Parietal[P], Temporal[T], Occipital[O], Basal Ganglia and Thalami [BGT]) and total brain WMH volume. Cardiac traits included stroke volumes, atrial volumes, ejection fractions of right and left chambers, left ventricular (LV) strain, LV wall thickness and aortic areas. Multivariable regression analysis was carried out, where each cardiac trait was regressed on each brain region and adjusted for: age, difference between age at initial visit and imaging visit, sex, systolic and diastolic blood pressure, Hba1c, household income, educational status, Townsend score and family history of disease (Alzheimer’s, Parkinson's, high blood pressure, stroke, heart disease) . Results were evaluated against a multiple testing correct p-value threshold of 0.05, reflecting the number of principle components(n=10) necessary to explain 90% of the cardiac trait variability. Results For 5 cardiac traits (right ventricular stroke volume, left atrial stroke volume, left ventricular stroke volume, left ventricular ejection fraction and right ventricular end diastolic volume) higher values were associated with lower WMH volumes in all brain regions. Additionally, some cardiac traits such as LV cardiac output associated with specific brain regions (T, O, BGT). Additionally, APOE- ε4 stratified analyses indicated, homozygous carriers show a greater association between higher minimum LA and RA volumes and higher WMH volumes in the occipital lobe. Conclusions This study gives an insight into the WMH burden in a large population of adults. It highlights the associations of cardiac traits with white matter hyperintensity volumes in different brain regions independent of known risk factors. Using cardiac traits as surrogate markers of different cardiac disease could explain how cardiac functionality defines WMH volume distribution and subsequently the wider relationship between CVD and cerebrovascular disease.Figure 1Graphical Abstract

Sex differences in association between dietary sodium intake and white matter hyperintensity volume

Abstract Background There is limited evidence on the relationship between dietary sodium intake (dNa) and brain health, and very little on sex differences in associations. Purpose To study the relationship between dNa and imaging measures of brain health in men and women from the INSIGHT 46 substudy of the MRC National Survey of Health and Development (British 1946 birth cohort). Methods Participants had measurements (dNa using 5-day food diary, anthropometrics, blood pressure (BP) body mass index (BMI)) at 60-64years. Whole-brain and hippocampal volumes, white matter hyperintensity volume (WMHV) and florbetapir amyloid-β positivity were measured using MRI-PET imaging at 69-71years. Associations (β (95% confidence intervals)) were estimated separately in men and women using generalized linear models with robust standard errors adjusted for potential confounders (age, diet quality, energy intake, socioeconomic status) or potential mediators (BMI, BP). Results Participants’ characteristics are shown in Table 1. In women but not men dNa was positively associated with higher WMHV (β[women]=32(1, 72) %/g; p=0.043; β[men]=-10(-27, 11)%/g; p=0.342); this relationship in women was independent of BMI (β = 32(1, 72)%/g; p = 0.043) or systolic BP (β = 31(1, 70)%/g; p=0.041). dNa was not associated with total brain volume, hippocampal volume or amyloid-β positivity in either sex. Conclusions Elevated sodium consumption in the diet is associated with cerebral small vessel disease in older age women but not men. This association was independent of BMI or BP.Table 1

Identification of new instances of white matter hyperintensities in patients following TAVI (from the CAPITA study)

Abstract A third of patients diagnosed with symptomatic severe aortic valve stenosis and scheduled for transcatheter aortic valve implantation (TAVI) exhibit some level of cognitive impairment. The prospective CAPITA study aimed to systematically evaluate the impact of TAVI on cerebral and cognitive outcomes in patients undergoing the procedure. In this report, we focus on the identification of new incidence of white matter hyperintensities (WMH) and the correlation with changes in cognitive functioning. The CAPITA (CArdiac OutPut, Cerebral Blood Flow and Cognition In Patients With Severe Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation) study is a prospective study of cerebral and cognitive outcomes following TAVI. Patients underwent magnetic resonance imaging (MRI) and extensive neuropsychological testing at baseline and three month follow-up. New cerebral infarcts were defined according to NeuroARC criteria. We examined the incidence of new WMH in terms of volume (Δ mL) and number on FLAIR MRI, and explored the correlation between new WMH and cognitive functioning. A total of 148 patients were included who underwent TAVI between August 2020 and October 2022. Mean age was 80.5±5.7 years, of whom 43% female with a median STS-PROM of 2.0% (IQR 1.4%-2.9%). Median baseline WMH comprised 127 (IQR 32-216) lesions, with a total volume of 13.1 (IQR 7.0-24.6) mL. At 3 months follow-up, the number of lesions increased to 164 (IQR 121-301) lesions, with a total volume of 13.3 (IQR 5.8-21.5) mL. Median WMH volume increase was 0.1 (IQR 0.0-0.3) ml (p=0.02). A total of 9 patients (9.5%) had an increase of 1 mL of WMH or more. At follow-up, 12% of patients exhibited cognitive decline of &amp;gt;0.5SD. These patient tended to have a greater increase in white matter hyperintensity volume (1.26±2.96 ml), compared to the 53% of patients with stable cognition (0.29±0.45 ml) and the 36% of patients with improved cognition (0.31±0.91 ml), (p=0.06). WMH lesions did not exhibit distribution patterns across various locations within the groups characterized by declined, stable, or improved cognition (Figure 1). WMH volumes were higher in patients who experienced postprocedural delirium than in patients without delirium (27.1±14.0 vs 15.0±12.5 mL, p&amp;lt;0.001). In this study, patients with severe symptomatic aortic valve stenosis undergoing TAVI, there was an overall increase of white matter hyperintensity volume between baseline and 3-month follow-up. Up to 12% of patients had cognitive decline, which was associated with new white matter hyperintensities on MRI.

Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults

BackgroundFor over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce.MethodsWe applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk.ResultsOur findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P < 0.001). Second, individuals with higher WMH volumes experienced more rapid cortical thinning (σ = -0.226, SE = 0.093, Z = -2.443, P = 0.007), particularly in temporal, cingulate, and insular regions. Similarly, those with lower initial cortical thickness had faster WMH progression (σ = -0.141, SE = 0.060, Z = -2.336, P = 0.009), with this effect being most pronounced in temporal, cingulate, and insular cortices. Third, faster WMH progression was associated with accelerated cortical thinning (σ = -0.239, SE = 0.139, Z = -1.710, P = 0.044), particularly in frontal, occipital, and insular cortical regions.ConclusionsOur study suggests that cortical thinning and WMH progression could be mutually reinforcing rather than parallel, unrelated processes, which become entangled before cognitive deficits are detectable.Trial registrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015).

Multidomain cognitive improvement in patients with severe aortic valve stenosis undergoing transcatheter aortic valve implantation

Abstract Background Cognitive impairment is prevalent in one third of patients with symptomatic severe aortic valve stenosis scheduled for transcatheter aortic valve implantation (TAVI). How TAVI affects cognitive functioning in these patients remains unknown. Purpose The CAPITA study (CArdiac outPut, cerebral blood flow and cognition In patients with severe aortic valve stenosis undergoing Transcatheter Aortic valve implantation) assessed the effects of TAVI on cerebral lesions and cognitive functioning. Methods CAPITA is a prospective study of cerebral and cognitive outcomes in 148 patients undergoing TAVI. One day before and three months after TAVI, patients underwent a standardized multidomain neuropsychological assessment, and simultaneous brain magnetic resonance imaging. The primary outcome was change in global cognitive functioning as measured with z-scores. Also, we assessed the cognitive subdomains of attention/psychomotor speed, memory, language, and executive functioning. Z-scores for each cognitive domain were constructed as: (test score - mean baseline score) / standard deviation. Global cognitive function was calculated as the mean from the four domain scores. Results Mean age was 80.5±5.7 years, 43% was female and median STS-PROM (Society for Thoracic Surgeons Predicted Risk for 30-day Mortality) was 2.0% (IQR 1.4%-2.9%). MoCA scores improved from 23.3±3.7 to 24.4±3.3, (p&amp;lt;0.001) and MMSE scores from 26.4±2.6 to 26.9±2.4 (p=0.01). There was an overall increase in global cognitive z-scores (0.02±0.52 to 0.15±0.48, p&amp;lt;0.001). Cognitive domains of memory (0.03±0.77 to 0.18±0.80, p=0.003) and language (-0.07±1.07 to 0.20±0.80, p=0.02) significantly improved, whereas executive function (0.01±0.70 to 0.06±0.76, p=0.42) and attention (0.10±0.69 to 0.17±0.69, p=0.06) did not significantly change. Quality of life on the visual analogue scale improved from 66.4±15.9 to 72.9±12.8, (p&amp;lt;0.001). Patients in the lowest tertile of baseline cognitive functioning (i.e., those with worst baseline cognitive functioning), had the largest increase in cognitive functioning, compared with patients in the intermediate or highest tertile of baseline cognitive functioning (0.30±0.55 vs 0.09±0.27 vs 0.01±0.16, p=0.002). Patients with &amp;gt;0.5 SD decline in cognitive functioning (12%), had a higher volume of new white matter hyperintensities on follow-up MRI than patients with stable or improved cognitive functioning (1.26±2.96, vs 0.29±0.45 vs 0.31±0.91 mL, p=0.06). Conclusions In 148 patients who underwent TAVI, there was an overall improvement in cognitive functioning at three months follow-up. This improvement was consistent through different cognitive domains and most prominent in patient with lowest baseline cognitive functioning.Change in cognitive functionin

Degree of joint risk factor control and incident all cause dementia in hypertensive patients

Abstract Background Hypertension (HT) is a known modifiable risk factor for dementia. This study evaluates the impact of effectively controlling multiple modifiable risk factors in HT patients on the incidence of dementia. Methods Data from the UK Biobank (2006-2010) were used in this longitudinal study, including essential HT patients and non-HT participants, excluding those with pre-existing dementia or less than two years of follow-up. The study focused on seven risk factors: physical activity, smoking status, blood pressure, body mass index, glycosylated hemoglobin levels, lipids, and urinary Albumin-to-Creatinine Ratio. The Cox model evaluated the association between the degree of risk factor control and the incidence of dementia, while linear regression models analyzed the brain abnormalities among different risk factor control groups. Results Of 291,720 participants, 86,675 had HT. Over a median follow-up of 14.3 years, dementia developed in 2,002 HT and 1,379 non-HT participants. Compared with non-HT individuals, a gradual decrease in dementia risk in HT patients with the number of well-controlled risk factors was observed (hazard ratio: 2.01 [95% confidence interval (CI) 1.73-2.34] to 1.25 [95% CI 1.13-1.40]). While within HT patients, with the highest level of control lowering the risk to 0.63 (95% CI [0.54-0.73]). Moreover, HT patients with better well-controlled risk factors had lower geometric mean for white matter hyperintensity volume and increased total brain parenchymal volume, gradually narrowing the gap with non-HT individuals. Conclusion In HT patients, a higher degree of well-controlled risk factors seemed to be associated with progressively lower risks of dementia and brain abnormalities.HRs of all-cause dementia in patientsGMRs of different risk factors on target

Sleep apnea physiological burdens and markers of white matter injury: the Multi-Ethnic Study of Atherosclerosis.

Obstructive sleep apnea (OSA) is associated with cognitive impairment; however, the underlying mechanisms remain incompletely understood. OSA is characterized by periods of interrupted ventilation ("ventilatory burden (VB)"), leading to hypoxemia ("hypoxic burden (HB)") and/or arousal ("arousal burden (AB)") from sleep. While hypoxemia is considered a key mechanism underlying white matter injury, its measurement has been limited. In our primary analysis, we assessed the association of HB, a quantitative measure of hypoxemia, with white matter hyperintensity volume (WMHv), a marker of small vessel disease, and compared with that of VB and AB (quantitative measures of ventilatory deficit and arousals). Data from participants in the Multi-Ethnic Study of Atherosclerosis with full polysomnograms (PSG) and brain MRI were analyzed. HB was defined as the total area under the oxygen desaturation curve per hour of sleep, while VB was defined as the event-specific area under the ventilation signal and AB was defined as the normalized cumulative duration of all arousals. The primary outcome was WMHv, with other MRI measures considered secondary outcomes. The analysis included PSGs from 587 participants (age: 65.5±8.2 years). In the fully adjusted model, each 1 standard deviation (SD) increase in HB was associated with a 0.09 SD increase in WMHv (p=0.023), after adjusting for demographics, study site, and comorbidities. In contrast, VB, AB, and conventional OSA measures were not associated with outcomes. Hypoxic burden was associated with white matter hyperintensity volume in a racially/ethnically diverse cohort of older individuals with a high prevalence of OSA.