White Matter Hyperintensities Burden Research Articles

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.

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

Short Sleep Duration and Hypertension: A Double Hit for the Brain.

Short sleep duration has been associated with an increased risk of cognitive impairment and dementia. Short sleep is associated with elevated blood pressure, yet the combined insult of short sleep and hypertension on brain health remains unclear. We assessed whether the association of sleep duration with cognition and vascular brain injury was moderated by hypertensive status. A total of 682 dementia-free participants (mean age, 62±9 years; 53% women) from the Framingham Heart Study completed assessments of cognition, office blood pressure, and self-reported habitual and polysomnography-derived sleep duration; 637 underwent brain magnetic resonance imaging. Linear regressions were performed to assess effect modification by hypertensive status on total sleep time (coded in hours) and cognitive and magnetic resonance imaging outcomes. There was a significant interaction between sleep duration and hypertensive status when predicting executive function/processing speed (Trail Making B-A) and white matter hyperintensities. When results were stratified by hypertensive status, longer sleep duration was associated with better executive functioning/processing speed scores in the hypertensive group (meaning that shorter sleep duration was associated with poorer executive function/processing speed scores) (self-report sleep: β=0.041 [95% CI, 0.012-0.069], P=0.005; polysomnography sleep: β=0.045 [95% CI, 0.002-0.087], P=0.038), but no association was observed for the normotensive group. Similarly, shorter subjective sleep duration was associated with higher white matter hyperintensity burden in the hypertensive group (β=-0.115 [95% CI, -0.227 to -0.004], P=0.042), but not in the normotensive group. In individuals with hypertension, shorter sleep duration was associated with worse cognitive performance and greater brain injury.

Automated quantification of cerebral microbleeds in susceptibility-weighted MRI: association with vascular risk factors, white matter hyperintensity burden, and cognitive function.

To train and validate a deep learning (DL)-based segmentation model for cerebral microbleeds (CMB) on susceptibility-weighted MRI; and to find associations between CMB, cognitive impairment, and vascular risk factors. Participants in this single-institution retrospective study underwent brain MRI to evaluate cognitive impairment between January-September 2023. For training the DL model, the nnU-Net framework was used without modifications. The DL model's performance was evaluated on independent internal and external validation datasets. Linear regression analysis was used to find associations between log-transformed CMB numbers, cognitive function (mini-mental status examination [MMSE]), white matter hyperintensity (WMH) burden, and clinical vascular risk factors (age, sex, hypertension, diabetes, lipid profiles, and body mass index). Training of the DL model (n = 287) resulted in a robust segmentation performance with an average dice score of 0.73 (95% CI, 0.67-0.79) in an internal validation set, (n = 67) and modest performance in an external validation set (dice score = 0.46, 95% CI, 0.33-0.59, n = 68). In a temporally independent clinical dataset (n = 448), older age, hypertension, and WMH burden were significantly associated with CMB numbers in all distributions (total, lobar, deep, and cerebellar; all P <.01). MMSE was significantly associated with hyperlipidemia (β = 1.88, 95% CI, 0.96-2.81, P <.001), WMH burden (β = -0.17 per 1% WMH burden, 95% CI, -0.27-0.08, P <.001), and total CMB number (β = -0.01 per 1 CMB, 95% CI, -0.02-0.001, P = .04) after adjusting for age and sex. The DL model showed a robust segmentation performance for CMB. In all distributions, CMB had significant positive associations with WMH burden. Increased WMH burden and CMB numbers were associated with decreased cognitive function. CMB = cerebral microbleed; DL = deep learning, DSC = dice similarity coefficient; MMSE = mini-mental status examination; SVD = small vessel disease; SWI = susceptibility-weighted image; WMH = white matter hyperintensity.

Assessing the Diagnostic Value of Brain White Matter Hyperintensities and Clinical Symptoms in Predicting the Detection of CSF Venous Fistula in Patients with Suspected Spontaneous Intracranial Hypotension.

Spontaneous intracranial hypotension (SIH) due to CSF venous fistula (CVF) is increasingly recognized as a secondary cause of headaches, with symptoms often overlapping with primary headache syndromes such as migraine. While brain MRI studies have focused on features indicative of SIH, findings that support an alternate headache etiology, such as the bifrontal white matter hyperintensities (WMH) often seen in migraines, have not been explored in this context. This study assesses 1) the quantity and distribution of WMH and 2) the presenting clinical features in patients with and without CVF found on dynamic decubitus CT myelography (dCTM). 72 consecutive patients underwent clinical workup for SIH due to suspected CVF, including pre-procedural brain and spine MRI followed by dCTM. Brain imaging features were analyzed, including Bern score, quantitative WMH burden, and WMH distribution. Demographics and clinical symptoms present at the time of presentation were recorded. Imaging features were compared between groups with and without CVF using parametric or nonparametric comparisons according to variable normality. Multivariate logistic regression explored the relationships between imaging features, clinical symptoms, and the presence of CVF. The cohort included 40 patients with (CVF+) and 32 patients without (CVF-), with no significant age or sex differences. CVF+ patients had significantly higher Bern scores and significantly fewer WMH. There were significant differences in the frequencies of WMH patterns between groups, with a migrainous pattern observed most frequently in CVF-patients. Logistic regression combining Bern score, WMH burden, and WMH pattern demonstrated a better fit for predicting CVF than using Bern score or WMH features alone. Fourteen clinical symptoms showed the greatest differences between CVF+ and CVF-groups. Logistic regression demonstrated a positive association between CVF detection and a pressure/throbbing headache quality, and negative associations for neck pain, facial pain, phonophobia, and anhedonia/depression. These findings suggest a negative association between CVF detection, increased burden of WMH, and a migrainous WMH pattern. Symptom analysis describes distinct clinical phenotypes, challenging orthostatic headache as a defining characteristic. These results support a comprehensive assessment of imaging and clinical presentations in the workup of suspected SIH. SIH = spontaneous intracranial hypotension; CVF = CSF venous fistula; WMH = white matter hyperintensities; dCTM = dynamic CT myelography; dDSM = dynamic digital subtraction myelography; PPV = positive predictive value; NPV = negative predictive value Received month day, year; accepted after revision month day, year.

Systolic blood pressure variability in late-life predicts cognitive trajectory and risk of Alzheimer's disease.

The relationship of systolic blood pressure variability (SBPV) with Alzheimer's disease (AD) remains controversial. We aimed to explore the roles of SBPV in predicting AD incidence and to test the pathways that mediated the relationship of SBPV with cognitive functions. Longitudinal data across 96 months (T0 to T4) were derived from the Alzheimer's disease Neuroimaging Initiative cohort. SBPV for each participant was calculated based on the four measurements of SBP across 24 months (T0 to T3). At T3, logistic regression models were used to test the SBPV difference between 86 new-onset AD and 743 controls. Linear regression models were used to test the associations of SBPV with cognition and AD imaging endophenotypes for 743 non-demented participants (median age = 77.0, female = 42%). Causal mediation analyses were conducted to explore the effects of imaging endophenotypes in mediating the relationships of SBPV with cognitive function. Finally, Cox proportional hazard model was utilized to explore the association of SBPV with incident risk of AD (T3 to T4, mean follow-up = 3.5 years). Participants with new-onset AD at T3 had significantly higher SBPV compared to their controls (p = 0.018). Higher SBPV was associated with lower scores of cognitive function (p = 0.005 for general cognition, p = 0.029 for memory, and p = 0.016 for executive function), higher cerebral burden of amyloid deposition by AV45 PET (p = 0.044), lower brain metabolism by FDG PET (p = 0.052), and higher burden of white matter hyperintensities (WMH) (p = 0.012). Amyloid pathology, brain metabolism, and WMH partially (ranging from 17.44% to 36.10%) mediated the associations of SBPV with cognition. Higher SBPV was significantly associated with elevated risk of developing AD (hazard ratio = 1.29, 95% confidence interval = 1.07 to 1.57, p = 0.008). These findings supported that maintaining stable SBP in late life helped lower the risk of AD, partially by modulating amyloid pathology, cerebral metabolism, and cerebrovascular health.

Quantification of white matter hyperintensities in type 1 diabetes and its relation to neuropathy and clinical characteristics

AimsThe aims were to quantify periventricular and deep white matter hyperintensities (WMHs) in adults with type 1 diabetes with different neuropathic phenotypes and to correlate WMH measurements to explanatory factors in diabetes. MethodsWMH measurements were obtained from brain magnetic resonance imaging of 56 adults with type 1 diabetes in subgroups including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN and 20 healthy controls using Fazekas scale and automatic segmentation analysis. ResultsNo differences in Fazekas assessed WMHs were found (individuals with periventricular lesions: diabetes 66 % vs. controls 40 %,p = 0.063, deep lesions: diabetes 52 % vs. controls 50 %,p = 1.0). Using automatic detection, there were no significant differences in count of periventricular (p = 0.30) or deep (p = 0.31) WMHs. Higher periventricular lesion burden was present in diabetes compared with controls (0.21 % vs. 0.06 %,p = 0.048), which was associated with more severe DPN, increased age, decreased cognitive function, and reduced volumetric and metabolic brain measures (all p < 0.05). ConclusionsOur findings indicate increased burden of periventricular WMHs in diabetes which were associated to DPN severity and measures reflecting neurodegeneration. Deep WMHs, often considered as chronic ischemic, were not significantly different. Mechanisms reflecting neurodegeneration and accelerated brain aging could be an overlooked aspect of peripheral and central neuropathy.

Associations between structural neuroimaging markers of Alzheimer's risk and scam susceptibility.

Older adults with greater scam susceptibility are at greater risk for mild cognitive impairment and incident Alzheimer's dementia, regardless of baseline cognition. This, combined with documented associations between scam susceptibility and beta amyloid at death suggests that scam susceptibility may be an earlier indicator of pathological aging than cognition. Little, however, is known about whether in vivo neuroimaging markers of early-stage risk for Alzheimer's dementia are also related to scam susceptibility; such knowledge will inform upon the associations of neurodegenerative processes with scam susceptibility and may help identify vulnerable individuals. Participants were 472 community-based adults without dementia (age ~ 81y; 75% women) from the Rush Memory and Aging Project. Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess the cortical thickness 'signature' of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden, respectively. Scam susceptibility was measured using a questionnaire that assessed behaviors associated with vulnerability to fraud and scams. Demographically-adjusted linear effects regression models determined the relationship of each neuroimaging measure, first separately and then combined, with scam susceptibility. Reduced AD-CT was associated with higher levels of scam susceptibility (estimate=-0.10, standard error = 0.03, p = 0.002). WMH burden was not associated with scam susceptibility either alone or when combined in the same model as AD-CT (p-values ≥ 0.14). Results for AD-CT persisted after the inclusion of WMH burden. AD-CT was associated with scam susceptibility in older adults without dementia possibly signaling an in vivo profile of this behavior.

Effects of white matter hyperintensity burden on functional outcome after mild versus moderate-to-severe ischemic stroke

It is uncertain whether the prognostic power of white matter hyperintensity (WMH) on post-stroke outcomes is modulated as a function of initial neurological severity, a critical determinant of outcome after stroke. This multi-center MRI study tested if higher WMH quintiles were associated with 3-month poor functional outcome (modified Rankin Scale ≥ 3) for mild versus moderate-to-severe ischemic stroke. Mild and moderate-to-severe stroke were defined as admission National Institute of Health Stroke Scale scores of 1–4 and ≥ 5, respectively. Mean age of the enrolled patients (n = 8918) was 67.2 ± 12.6 years and 60.1% male. The association between WMH quintiles and poor functional outcome was modified by stroke severity (p-for-interaction = 0.008). In mild stroke (n = 4994), WMH quintiles associated with the 3-month outcome in a dose-dependent manner for the 2nd to 5th quintile versus the 1st quintile, with adjusted-odds-ratios (aOR [95% confidence interval]) being 1.29 [0.96–1.73], 1.37 [1.02–1.82], 1.60 [1.19–2.13], and 1.89 [1.41–2.53], respectively. In moderate-to-severe stroke (n = 3924), however, there seemed to be a threshold effect: only the highest versus the lowest WMH quintile was significantly associated with poor functional outcome (aOR 1.69 [1.29–2.21]). WMH burden aggravates 3-month functional outcome after mild stroke, but has a lesser modulatory effect for moderate-to-severe stroke, likely due to saturation effects.

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.

Orthostatic hypotension and cerebral small vessel disease: A systematic review.

Orthostatic hypotension(OH) is highly prevalent in ageing populations and may contribute to cognitive decline through cerebral small vessel disease(CSVD). Research on the association between OH and CSVD is fragmented and inconsistent. We systematically reviewed the literature for studies assessing the association between OH and CSVD, published until December 1st 2023 in MEDLINE, PubMed or Web of Science. We included studies with populations aged ≥60, that assessed OH in relation to CSVD including white matter hyperintensities(WMH), lacunes and cerebral microbleeds. Modified JBI checklist was used to assess risk of bias. A narrative synthesis of the results was presented. Of 3180 identified studies, eighteen were included. Fifteen studies reported on WMH, four on lacunes, seven on microbleeds. Six of fifteen studies on WMH found that OH was related to an increased burden of WMH, neither longitudinal studies found associations with WMH progression. Findings were inconsistent across studies concerning lacunes and microbleeds. Across outcomes, adequate adjustment for systolic blood pressure tended to coincide with smaller effect estimates. Current evidence on the OH-CSVD association originates mostly from cross-sectional studies, providing inconsistent and inconclusive results. Longitudinal studies using standardized and fine-grained assessment of OH and CSVD and adequate adjustment for supine blood pressure are warranted.

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.

Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities).

Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors. The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Alterations in the Glymphatic System and Association with Brain Structure and Cognitive Function in Moyamoya Disease.

The glymphatic system is crucial for clearing metabolic waste from the brain, maintaining neural health and cognitive function. This study explores the glymphatic system's role in Moyamoya disease (MMD), characterized by progressive cerebral artery stenosis and brain structural lesions. We assessed 33 MMD patients and 21 healthy controls using diffusion tensor imaging along the perivascular space (DTI-ALPS) and global cortical gray matter-cerebrospinal fluid (CSF) coupling indices (gBOLD-CSF), which are indirect measurements of the glymphatic system. Cerebral perfusion in patients was evaluated via computed tomography perfusion imaging. We also measured the peak width of skeletonized mean diffusivity (PSMD), white matter hyperintensity (WMH) burden, and cognitive function. MMD patients exhibited lower ALPS and gBOLD-CSF coupling indices compared to controls (P < 0.01), indicating disrupted glymphatic function. Significant cognitive impairment was also observed in MMD patients (P < 0.01). ALPS indices varied with cerebral perfusion stages, being higher in earlier ischemic stages (P < 0.05). Analysis of brain structure showed increased CSF volume, PSMD index, and higher WMH burden in MMD patients (P < 0.01). The ALPS index positively correlated with white matter volume and cognitive scores, and negatively correlated with CSF volume, PSMD, and WMH burden (P < 0.05). Mediation analysis revealed the number of periventricular WMH significantly mediated the relationship between glymphatic dysfunction and cognitive impairment. In summary, MMD patients exhibit significant glymphatic system impairments, associated with brain structural changes and cognitive deficits.

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.

Effects of strategic white matter hyperintensities of cholinergic pathways on basal forebrain volume in patients with amyloid-negative neurocognitive disorders

BackgroundThe cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer’s disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood.MethodsWe enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson’s dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores.ResultsA total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [βstd] = -0.25, P = 0.01), female (βstd = 0.20, P = 0.04), and diabetes mellitus (βstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity.ConclusionsWe identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.

Association of cortical morphology, white matter hyperintensity, and glymphatic function in frontotemporal dementia variants.

Frontotemporal dementia (FTD) can be phenotypically divided into behavioral variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). However, the neural underpinnings of this phenotypic heterogeneity remain elusive. Cortical morphology, white matter hyperintensities (WMH), diffusion tensor image analysis along the perivascular space (DTI-ALPS), and their interrelationships were assessed in subtypes of FTD. Neuroimaging-transcriptional analyses on the regional cortical morphological deviances among subtypes were also performed. Changes in cortical thickness, surface area, gyrification, WMH, and DTI-ALPS were subtype-specific in FTD. The three morphologic indices are related to whole-brain WMH volume and cognitive performance, while cortical thickness is related to DTI-ALPS. Neuroimaging-transcriptional analyses identified key biological pathways linked to the formation and/or spread of TDP-43/tau pathologies. We found subtype-specific changes in cortical morphology, WMH, and glymphatic function in FTD. Our findings have the potential to contribute to the development of personalized predictions and treatment strategies for this disorder. Cortical morphologic changes, white matter hyperintensities (WMH), and glymphatic dysfunction are subtype-specific. Cortical morphologic changes, WMH, and glymphatic dysfunction are inter-correlated. Cortical morphologic changes and WMH burden contribute to cognitive impairments.

Cortical lobar volume reductions associated with homocysteine-related subcortical brain atrophy and poorer cognition in healthy aging.

Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging.

Optical Coherence Tomography Angiography Retinal Imaging Associations With Burden of Small Vessel Disease and Amyloid Positivity in the Brain.

Alzheimer disease (AD) and other dementias are associated with vascular changes and amyloid deposition, which may be reflected as density changes in the retinal capillaries. These changes may can be directly visualized and quantified with optical coherence tomography angiography (OCTA), making OCTA a potential noninvasive preclinical biomarker of small vessel disease and amyloid positivity. Our objective was to investigate the feasibility of retinal imaging metrics as noninvasive biomarkers of small vessel disease and amyloid positivity in the brain. We investigated associations between OCTA and neuroimaging and cognitive metrics in 41 participants without dementia from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center. OCTA metrics included superficial, deep, and full retina capillary density of the fovea, parafovea, and macula as well as the area of the foveal avascular zone (FAZ). Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds (CMB), lacunar infarcts, and amyloid positivity as evidenced on positron emission tomography (PET), whereas cognitive metrics included mini-mental status examination (MMSE) score. We performed generalized estimating equations to account for measurements in each eye while controlling for age and sex to estimate associations between OCTA metrics and neuroimaging and cognitive scores. Associations between OCTA and neuroimaging metrics were restricted to the fovea. OCTA showed decreased capillary density with high burden of WMH in both the superficial (P = 0.003), deep (P = 0.004), and full retina (P = 0.01) in the fovea but not the parafovea or whole macula. Similarly, participants with amyloid PET positivity had significantly decreased capillary density in the superficial fovea (P = 0.027) and deep fovea (P = 0.03) but higher density in the superficial parafovea (P = 0.038). Participants with amyloid PET positivity also had a significantly larger FAZ (P = 0.031), whereas in those with high WMH burden the difference did not reach statistical significance (P = 0.075). There was also a positive association between MMSE and capillary density of the full retina within the fovea (P = 0.037) and in the superficial parafovea (P = 0.046). No associations were found between OCTA metrics and presence of CMB or presence of lacunar infarcts. The associations of lower foveal capillary density with cerebral WMH and amyloid positivity suggest that further research is warranted to evaluate for shared mechanisms of disease between small vessel disease and AD pathologies.