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IntroductionWhite matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.MethodsIndividual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.ResultsVRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimers Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

As the United States' (US) elderly population becomes increasingly diverse, it is imperative that research studies address cognitive health in diverse populations of older Americans. White Matter Hyperintensities (WMH) are useful imaging findings that can be studied in elderly individuals and have been linked to an increased risk of neurological conditions, such as stroke, cognitive impairment, and dementia. We performed a systematic review of literature using PubMed sources to compile all the studies that investigated the prevalence of ethnic and racial differences of WMH burden amongst diverse groups in the US. We identified 23 unique articles that utilized 16 distinct cohorts of which 94 % were prospective, longitudinal studies that included community-based and family-based populations. The overall results were heterogenous in all aspects of data collection and analysis, limiting our ability to run meta-analyses and draw definitive conclusions. General observations suggest increased vascular risk on African American populations, contributing to greater WMH burden in that population. Overall, the findings of this study indicate a need for a standardized approach to investigating WMH in efforts to measure its clinical impact on diverse populations.

Background: For 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. Methods: We 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. Results: Our 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. Conclusions: Our 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 registration: German Clinical Trials Register (DRKS00007966, 04/05/2015). [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) observed in T2 fluidattenuated inversion recovery (FLAIR) images have emerged as potential markers of neurodegenerative diseases like Multiple Sclerosis (MS). Lacking comprehensive automated WMH classification systems in current research, there is a need to develop accurate detection and classification methods for WMH that will benefit the diagnosis and monitoring of brain diseases. Objective: Juxtacortical WMH (JCWMH) is a less explored subtype of WMH, primarily due to the hard definition of the cortex in FLAIR images, which is escalated by the presence of lesions to obtain appropriate gray matter (GM) masks. Methods: In this study, we present a method to perform a specialized GM segmentation developed for the classification of WMH, especially JCWMH. Using T1 and FLAIR images, we propose a pipeline to integrate masks of white matter, cerebrospinal fluid, ventricles, and WMH to create a unique mask to refine the primary GM map. Subsequently, we utilize this pipeline to generate paired data for training a conditional generative adversarial network (cGAN) to substitute the pipeline and reduce the inputs to only FLAIR images. The classification of WMH is then based on the distances between WMH and ventricular and GM masks. Due to the lack of multi-class labeled WMH datasets and the need for extensive data for training deep learning models, we attempted to collect a large local dataset and manually segment and label some data for WMH and ventricles. Results: In JCWMH classification, the proposed method exhibited a Dice similarity coefficient, precision, and sensitivity of 0.76, 0.69, and 0.84, respectively. With values of 0.66, 0.55, and 0.81, the proposed method clearly outperformed the approach commonly used in the literature, which uses extracted GM masks from registered T1 images on FLAIR. Conclusion: After training, the method proves its efficiency by providing results in less than one second. In contrast, the usual approach would require at least two minutes for registration and segmentation alone. The proposed method is automated and fast and requires no initialization as it works exclusively with FLAIR images. Such innovative methods will undoubtedly facilitate accurate and meaningful analysis of WMH in clinical practice by reducing complexity and increasing efficiency. [ABSTRACT FROM AUTHOR]

Studies have demonstrated associations between cumulative concussion and repetitive head impact exposure (RHI) through contact sports with white matter (WM) alterations later in life. The course of WM changes associated with exposure earlier in the lifespan is unclear. This study investigated alterations in white matter (WM hyperintensity [WMH] volume and microstructural changes) associated with concussion and RHI exposure from adolescence to early midlife, as well as the interaction between exposure and age cohort (i.e., adolescent/young adult compared with early midlife athlete cohorts) on WM outcomes. Participating football players included an adolescent/young adulthood cohort (n = 82; Mage = 18.4 ± 1.7) and an early midlife cohort (37 former collegiate players approximately 15 years removed from sport; Mage = 37.7 ± 1.4). Years of football participation and number of prior concussions were exposures of interest. White matter outcomes included log-transformed manually segmented total WMH volume and neurite orientation dispersion and density imaging metrics of microstructure/organization (isotropic volume fraction [Viso], intracellular volume fraction [Vic], and orientation dispersion [OD]). Regression models were fit to test the effects of concussion history, years of football participation, and age cohort by years of football participation with WM outcomes. Spearman's correlations assessed associations between significant WM metrics and measures of cognitive and psychological function. A significant age cohort by years of participation effect was observed for whole brain white matter OD, B = −0.002, SE = 0.001, p = 0.001. The interaction was driven by a negative association between years of participation and OD within the younger cohort, B = −0.001, SE = 0.0004, p = 0.008, whereas a positive association between participation and OD in the early midlife cohort, B = 0.001, SE = 0.0003, p = 0.039, was observed. Follow-up ROI analyses showed significant interaction effects for OD in the body of the corpus callosum, genu of the corpus callosum, cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and posterior thalamic radiation (p values <0.05). Greater concussion history was significantly associated with greater Viso in the early midlife cohort, B = 0.001, SE = 0.0002, p = 0.010. Years of participation and concussion history were not associated with WMH volume, p values >0.05. Performance on a measure of executive function was significantly associated with years of participation, ρ = 0.34, p = 0.04, and a trend was observed for OD, ρ = 0.28, p = 0.09 in the early midlife cohort only. The global characterization of white matter changes associated with years of football participation were broadly similar and stable from adolescence through early midlife (i.e., microstructural alterations, but not macroscopic lesions). An inverse association between years of participation and orientation dispersion across age cohorts may represent a process of initial recovery/reorganization proximal to sport, followed by later reduction of white matter coherence. [ABSTRACT FROM AUTHOR]

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

Introduction: This study evaluates the role of quantitative characteristics of white matter hyperintensities (WMHs) in predicting the 1-year recurrence risk of ischemic stroke. Methods: We conducted a retrospective analysis of 1061 patients with ischemic stroke from January 2018 to April 2021. WMHs were automatically segmented using a cluster-based method to quantify their volume and number of clusters (NoC). Additionally, two radiologists independently rated periventricular and deep WMHs using the Fazekas scale. The cohort was divided into a training set (70%) and a testing set (30%). We employed Cox proportional hazards models to develop predictors based on quantitative WMH characteristics, Fazekas scores, and clinical factors, and compared their performance using the concordance index (C-index). Results: A total of 180 quantitative variables related to WMHs were extracted. A higher NoC in deep white matter and brainstem, advanced age (> 90 years old), specific stroke subtypes, and absence of discharge antiplatelets showed stronger associations with the risk of ischemic stroke recurrence within 1 year. The nomogram incorporating quantitative WMHs data showed superior discrimination compared to those based on the Fazekas scale or clinical factors alone, with C-index values of 0.709 versus 0.647 and 0.648, respectively, in the testing set. Notably, a combined model including both WMHs and clinical factors achieved the highest predictive accuracy, with a C-index of 0.735 in the testing set. Conclusion: Quantitative assessment of WMHs provides a valuable neuro-imaging tool for enhancing the prediction of ischemic stroke recurrence risk. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) and cognitive profiles in patients with mild traumatic brain injury (mTBI) are often discordant. Conventional MRI seldom captures the full extent of pathological changes in the normal‐appearing white matter (NAWM). The divided subtracted inversion recovery (dSIR) technique may enhance T1 differences in NAWM, making them easily visible. We aimed to implement dSIR on a clinical scanner and tested results in mTBI patients. To produce dSIR images, Inversion Recovery‐Turbo Spin Echo sequences were modified using six different inversion times (TI) on a 3‐T scanner in healthy participants and patients with mTBI. The multiple TIs determined normal white (TIshort) and gray matter (TIlong) nulling points in healthy subjects, which were used to create dSIR images. In one patient, the protocol was repeated at 3 months to identify changes after rehabilitation. Diffusion tensor imaging (DTI)‐derived mean diffusivity (MD) and fractional anisotropy (FA) maps were aligned to dSIR images to ensure that signal was not artefactual. Ten healthy participants (five females; age 24 ± 3 [95% CI: 21, 26] years) were included. TIshort and TIlong were set at 450 and 750 ms, respectively. In both patients (one male, age 17 years; one female, age 14 years), dSIR images revealed areas with increased T1 in the NAWM not visible on conventional MRI. dSIR‐based hyperintensities corresponded to elevated MD and reduced FA. Substantial changes were found at follow‐up with improvement in DTI‐based parameters. dSIR images enhance subtle changes in the NAWM of patients with mTBI by amplifying their intrinsic T1 signal. [ABSTRACT FROM AUTHOR]

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health. [ABSTRACT FROM AUTHOR]

Background: While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted. Methods: We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer's Disease (AD) Assessment Scale's (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS. Results: Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94–5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19–0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05–1.39) and 0.63 units (95% CI 0.19–1.08) more severe NPS. NPS number (MMSE mean difference − 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26–2.56) and severity (MMSE − 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57–1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect − 0.08, 95% CI -0.22 to -0.002). Discussion: This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA. [ABSTRACT FROM AUTHOR]

Introduction: White matter hyperintensities (WMH) are commonly associated with balance and gait disturbances. Little is known whether WMH may affect post-stroke balance and gait recovery. We aim to investigate the association of post-stroke balance and gait recovery with imaging marker of WMH on magnetic resonance imaging (MRI). Methods: This prospective cohort study will enroll consecutive patients with first-ever ischemic hemisphere stroke, between September 2023 and December 2024. Clinical data will be collected on day 30 ± 3 and at 3 months after stroke onset. WMH on FLAIR are graded according to the modified Fazekas scale. Resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) will be acquired to evaluate functional and structural connectivity. The primary endpoint is balance recovery, defined as a Postural Assessment Scale for Stroke score of 32 or higher at 3 months. The secondary endpoint is gait recovery, assessed using the modified Fugl-Meyer Gait Assessment at 3 months. We will investigate the association of post-stroke balance and gait recovery with WMH severity as well as WMH-related functional and structural connectivity. Conclusion: The study may contribute to clarify the effect of WMH on post-stroke balance and gait disorder recovery. [ABSTRACT FROM AUTHOR]

Objectives Hypertension or high blood pressure (BP) is one of the 12 modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although hypertension is associated with cognitive decline and structural brain changes, less is known about the long-term association between variable BP and cognitive/brain changes. This study examined the relationship between variable BP and longitudinal cognitive, white matter hyperintensity (WMH), gray matter (GM), and white matter (WM) volume change over time and postmortem neuropathology. Methods A total of 4,606 participants (32,776 follow-ups) from RADC Research Resource Sharing Hub (RUSH) and 2,114 participants (9,827 follow-ups) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. Participants were divided into 1 of 3 groups: normal, high, or variable BP. Linear-mixed models investigated the relationship between BP and cognition, brain structure, and neuropathology. Results Older adults with variable BP exhibited the highest rate of cognitive decline followed by high and then normal BP. Increased GM volume loss and WMH burden were also observed in variable compared to high and normal BP. In postmortem neuropathology, both variable and high BP had increased rates compared to normal BP. Results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings. Discussion Damages potentially associated with variable BP may reduce resilience to future dementia-related pathology and increased the risk of dementia more than that caused by high BP. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMH) are associated with cortical thinning. Although they are primarily detected in older participants, these lesions can appear in younger and midlife individuals. Here, we tested whether WMH are associated with cortical thinning in relatively younger (26–50 years) and relatively older (58–84) participants who were free of dementia, and how these associations are moderated by WMH localization. WMH were automatically quantified and categorized according to the localization of three classes of white matter tracts: association, commissural and projection fibers. Mediation analyses were used to infer whether differences in cortical thickness between younger and older participants were explained by WMH. Our results revealed that total WMH explained between 20.6 % and 65.5 % of the effect of age on cortical thickness in AD-signature regions including the lateral temporal lobes and supramarginal gyrus, among others. This mediation was slightly stronger for projection WMH, although it was still significant for association and commissural WMH. These results suggest that there is an interplay between vascular and AD causes of cognitive impairment that starts at younger ages. • White matter hyperintensities (WMH) are apparent in middle-age. • WMH correlate with cortical thickness, especially in younger adults. • WMH explain up to 65.6 % of age-related cortical thickness differences. • The effect of WMH on atrophy starts during the mid-life. [ABSTRACT FROM AUTHOR]

Abstract Background For 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. Methods We 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. Results Our findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P

Lihao Zhang,1 Yan Su,2 Qian Wang,1 Yan Wang,1 Yikun Guo1 1Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 2Department of Radiology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of ChinaCorrespondence: Yikun Guo, Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, 68&num; Middle Gehu Road, Changzhou, Jiangsu Province, 213000, People’s Republic of China, Tel +86-519-81087079, Fax +86-519-81087711, Email guoyikun000@163.comObjective: To explore the role of white matter hyperintensities (WMH) in predicting early neurological deterioration (END) in patients with embolic stroke of undetermined source (ESUS) without reperfusion therapy.Methods: In a retrospective analysis, 111 acute ESUS patients not treated with reperfusion therapy were enrolled. WMH severity was evaluated using the Fazekas scale, with patients categorized into mild (Fazekas score ≤ 2) or moderate-to-severe (Fazekas score ≥ 3) WMH groups. Clinical data were compared between the groups, and END was monitored within 72 hours of hospital admission. The association between WMH and END was assessed using binary logistic regression.Results: Patients with moderate-to-severe WMH were significantly older (p = 0.001) and more likely to have a history of stroke (28.6% vs 10.5%, p = 0.017) compared to the mild WMH group. The END group (n=16) presented with higher baseline NIHSS scores and a greater prevalence of moderate-to-severe WMH (p < 0.05). Binary logistic regression identified moderate-to-severe WMH (OR = 4.012, 95% CI: 1.080– 14.906, p = 0.038), smoking (OR = 4.368, 95% CI: 1.171– 16.293, p = 0.028), and diabetes mellitus (OR = 3.986, 95% CI: 1.007– 15.789, p = 0.049) as independent predictors of END in ESUS patients.Conclusion: Moderate-to-severe WMH is an independent risk factor for END in ESUS patients not receiving reperfusion therapy, highlighting the importance of considering WMH in the clinical evaluation and management of stroke patients.Keywords: white matter hyperintensities, early neurological deterioration, embolic stroke of undetermined source, risk factors

Abstract Background While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted. Methods We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer’s Disease (AD) Assessment Scale’s (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS. Results Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94–5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19–0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05–1.39) and 0.63 units (95% CI 0.19–1.08) more severe NPS. NPS number (MMSE mean difference − 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26–2.56) and severity (MMSE − 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57–1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect − 0.08, 95% CI -0.22 to -0.002). Discussion This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA.

Patients with neuromyelitis optica (NMO) are unlikely to develop clinically silent lesions on brain magnetic resonance imaging (MRI), unlike patients with multiple sclerosis (MS). We encountered a patient with NMO who showed radiological progression and leukodystrophy-like changes on MRI during a long-standing, clinically asymptomatic period.

ObjectivesPhysical activity (PA) may help maintain brain structure and function in aging. Since the intensity of PA needed to effect cognition and cerebrovascular health remains unknown, we examined associations between PA and cognition, regional white matter hyperintensities (WMH), and regional cerebral blood flow (CBF) in older adults.MethodForty-three older adults without cognitive impairment underwent magnetic resonance imaging (MRI) and comprehensive neuropsychological assessment. Waist-worn accelerometers objectively measured PA for approximately one week.ResultsHigher time spent in moderate to vigorous PA (MVPA) was uniquely associated with better memory and executive functioning after adjusting for all light PA. Higher MVPA was also uniquely associated with lower frontal WMH volume although the finding was no longer significant after additionally adjusting for age and accelerometer wear time. MVPA was not associated with CBF. Higher time spent in all light PA was uniquely associated with higher CBF but not with cognitive performance or WMH volume.ConclusionsEngaging in PA may be beneficial for cerebrovascular health, and MVPA in particular may help preserve memory and executive function in otherwise cognitively healthy older adults. There may be differential effects of engaging in lighter PA and MVPA on MRI markers of cerebrovascular health although this needs to be confirmed in future studies with larger samples. Future randomized controlled trials that increase PA are needed to elucidate cause-effect associations between PA and cerebrovascular health.

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, M age 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. • White matter hyperintensities are significant predictors of sustained attention. • Cerebral grey matter volumes are significant predictors of sustained attention. • Cerebral white matter volumes are significant predictors of sustained attention. • Structural brain volumes completely mediate age effects on sustained attention. • These sMRI findings explain the attentional variability prevailing in older adults. [ABSTRACT FROM AUTHOR]

White matter hyperintensities of vascular origin (WMH) are commonly found in individuals over 60 and increase in prevalence with age. The significance of WMH is well-documented, with strong associations with cognitive impairment, risk of stroke, mental health, and brain structure deterioration. Consequently, careful monitoring is crucial for the early identification and management of individuals at risk. Luckily, WMH are detectable and quantifiable on standard MRI through visual assessment scales, but it is time-consuming and has high rater variability. Addressing this issue, the main aim of our study is to decipher the utility of quantitative measures of WMH, assessed with automatic tools, in establishing risk profiles for cerebrovascular deterioration. For this purpose, first, we work to determine the most precise WMH segmentation open access tool compared to clinician manual segmentations (LST-LPA, LST-LGA, SAMSEG, and BIANCA), offering insights into methodology and usability to balance clinical precision with practical application. The results indicated that supervised algorithms (LST-LPA and BIANCA) were superior, particularly in detecting small WMH, and can improve their consistency when used in parallel with unsupervised tools (LST-LGA and SAMSEG). Additionally, to investigate the behavior and real clinical utility of these tools, we tested them in a real-world scenario (N = 300; age > 50 y.o. and MMSE > 26), proposing an imaging biomarker for moderate vascular damage. The results confirmed its capacity to effectively identify individuals at risk comparing the cognitive and brain structural profiles of cognitively healthy adults above and below the resulted threshold. [ABSTRACT FROM AUTHOR]

Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood–brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID. [ABSTRACT FROM AUTHOR]

Abstract Introduction This study evaluates the role of quantitative characteristics of white matter hyperintensities (WMHs) in predicting the 1-year recurrence risk of ischemic stroke. Methods We conducted a retrospective analysis of 1061 patients with ischemic stroke from January 2018 to April 2021. WMHs were automatically segmented using a cluster-based method to quantify their volume and number of clusters (NoC). Additionally, two radiologists independently rated periventricular and deep WMHs using the Fazekas scale. The cohort was divided into a training set (70%) and a testing set (30%). We employed Cox proportional hazards models to develop predictors based on quantitative WMH characteristics, Fazekas scores, and clinical factors, and compared their performance using the concordance index (C-index). Results A total of 180 quantitative variables related to WMHs were extracted. A higher NoC in deep white matter and brainstem, advanced age (> 90 years old), specific stroke subtypes, and absence of discharge antiplatelets showed stronger associations with the risk of ischemic stroke recurrence within 1 year. The nomogram incorporating quantitative WMHs data showed superior discrimination compared to those based on the Fazekas scale or clinical factors alone, with C-index values of 0.709 versus 0.647 and 0.648, respectively, in the testing set. Notably, a combined model including both WMHs and clinical factors achieved the highest predictive accuracy, with a C-index of 0.735 in the testing set. Conclusion Quantitative assessment of WMHs provides a valuable neuro-imaging tool for enhancing the prediction of ischemic stroke recurrence risk.

Abstract Background The 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. Methods We 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. Results A 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 [β std] = -0.25, P = 0.01), female (β std = 0.20, P = 0.04), and diabetes mellitus (β std = -0.22, P

Commonly plaguing in the frigid zone of the world, vitamin D deficiency, as indicated by low levels of 25-hydroxyvitamin D, exacerbated inflammatory responses and impaired endothelial function. Leukoaraiosis (LA) is a prevalent cause of cognitive dysfunction in the elderly and is potentially associated with inflammatory responses. This study aimed to investigate the impact of vitamin D on the severity of LA.

Abstract Background White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer’s disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging. Methods We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC). Results Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p

Abstract Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen’s criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p

Abstract Background This study aimed to investigate the alterations in structural integrity of superior longitudinal fasciculus subcomponents with increasing white matter hyperintensity severity as well as the relationship to cognitive performance in cerebral small vessel disease. Methods 110 cerebral small vessel disease study participants with white matter hyperintensities were recruited. According to Fazekas grade scale, white matter hyperintensities of each subject were graded. All subjects were divided into two groups. The probabilistic fiber tracking method was used for analyzing microstructure characteristics of superior longitudinal fasciculus subcomponents. Results Probabilistic fiber tracking results showed that mean diffusion, radial diffusion, and axial diffusion values of the left arcuate fasciculus as well as the mean diffusion value of the right arcuate fasciculus and left superior longitudinal fasciculus III in high white matter hyperintensities rating group were significantly higher than those in low white matter hyperintensities rating group (p

The major vascular cause of dementia is cerebral small vessel disease (SVD). Its diagnosis relies on imaging hallmarks, such as white matter hyperintensities (WMH). WMH present a heterogenous pathology, including myelin and axonal loss. Yet, these might be only the “tip of the iceberg.” Imaging modalities imply that microstructural alterations underlie still normal‐appearing white matter (NAWM), preceding the conversion to WMH. Unfortunately, direct pathological characterization of these microstructural alterations affecting myelinated axonal fibers in WMH, and especially NAWM, is still missing. Given that there are no treatments to significantly reduce WMH progression, it is important to extend our knowledge on pathological processes that might already be occurring within NAWM. Staining of myelin with Luxol Fast Blue, while valuable, fails to assess subtle alterations in white matter microstructure. Therefore, we aimed to quantify myelin surrounding axonal fibers and axonal‐ and microstructural damage in detail by combining (immuno)histochemistry with polarized light imaging (PLI). To study the extent (of early) microstructural damage from periventricular NAWM to the center of WMH, we refined current analysis techniques by using deep learning to define smaller segments of white matter, capturing increasing fluid‐attenuated inversion recovery signal. Integration of (immuno)histochemistry and PLI with post‐mortem imaging of the brains of individuals with hypertension and normotensive controls enables voxel‐wise assessment of the pathology throughout periventricular WMH and NAWM. Myelin loss, axonal integrity, and white matter microstructural damage are not limited to WMH but already occur within NAWM. Notably, we found that axonal damage is higher in individuals with hypertension, particularly in NAWM. These findings highlight the added value of advanced segmentation techniques to visualize subtle changes occurring already in NAWM preceding WMH. By using quantitative MRI and advanced diffusion MRI, future studies may elucidate these very early mechanisms leading to neurodegeneration, which ultimately contribute to the conversion of NAWM to WMH. [ABSTRACT FROM AUTHOR]

Background: The 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. Methods: We 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. Results: A 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. Conclusions: We 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. [ABSTRACT FROM AUTHOR]

Background and purpose: Arteriosclerotic cerebral small vessel disease (aCSVD) is a cause of cognitive impairment, dementia, and stroke. Developing a better understanding of the risk factor of aCSVD is key to reducing the incidence of these conditions. This study investigated the association between intracranial arterial calcification (IAC) and total cerebral small vessel disease (CSVD) burden score. Materials and methods: This is a retrospective study, the subjects were transient ischemic attack (TIA) or acute ischemic stroke (AIS) patients. The data of 303 inpatients admitted to our study hospital between December 2018 and July 2020 were analyzed. Four imaging markers of CSVD (lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces) were evaluated by magnetic resonance imaging, and a total CSVD burden score was calculated. The experimental group was divided into four subgroups according to total CSVD burden score (1-4 points). Patients without CSVD (0 points) served as the control group. Head computerized tomography (CT) scans were used to assess ICA, using Babiarz's method. The correlations between IAC and single imaging markers of CSVD were determined using Spearman's rank correlation. Binary logic regression analysis and multivariate ordered logic regression analysis were used to determine the associations between IAC and aCSVD. Results: IAC was positively correlated with total CSVD burden score (r = 0.681), deep white matter hyperintensities (r = 0.539), periventricular white matter hyperintensities (r = 0.570), cerebral microbleeds (r = 0.479), lacunes (r = 0.541), and enlarged perivascular spaces (r = 0.554) (all p<0.001). After adjusting for the confounding factors of age, diabetes, and hypertension, aCSVD was independently associated with IAC grade 1-2 [odds ratio (OR) = 23.747, 95% confidence interval (CI) = 8.376-67.327] and IAC grade 3-4 (OR = 30.166, 95% CI = 8.295-109.701). aCSVD severity was independently associated with IAC grade 3-4 (OR = 4.697, 95% CI = 1.349-16.346). Conclusion: IAC is associated with the total CSVD burden score and single imaging signs. [ABSTRACT FROM AUTHOR]

\nIntroduction: The association between earlobe crease (ELC) and cerebral small vessel disease, including white matter hyperintensities (WMHs) and brain atrophy, is unclear, especially in the setting of acute ischemic stroke (AIS). Here, we aimed to investigate the association between ELC and WMHs as well as brain atrophy among AIS patients. Methods: A total of 730 AIS patients from China were enrolled. Patients were divided into groups without and with ELC, unilateral and bilateral ELC according to pictures of bilateral ears. Logistic regression models were employed to assess the impact of ELC, bilateral ELC on WMHs, periventricular hyperintensities (PVHs), deep white matter hyperintensities (DWMHs), and brain atrophy, as measured by the Fazekas scale and global cortical atrophy scale, in brain magnetic resonance imaging. Results: There were 520 (71.2%) AIS patients with WMHs, 445 (61.0%) with PVH, 462 (63.3%) with DWMH, and 586 (80.3%) with brain atrophy. Compared to those without ELC, patients with ELC were significantly associated with an increased risk of PVH (odds ratio [OR] 1.79; 95% confidence interval [CI], 1.15–2.77) and brain atrophy (OR: 6.18; 95% CI: 3.60–10.63) but not WMHs and DWMH. The presence of bilateral ELC significantly increased the odds of WMHs (OR: 1.60; 95% CI: 1.00–2.56), PVH (OR: 1.87; 95% CI: 1.18–2.96), and brain atrophy (OR: 8.50; 95% CI: 4.62–15.66) when compared to individuals without ELC. Furthermore, we discovered that the association between bilateral ELC and WMHs, PVH, and DWMH was significant only among individuals aged ≤68 (median age) years (all p trend ≤0.041). However, this association was not observed in patients older than 68 years. Conclusions: In Chinese AIS patients, the presence of the visible aging sign, ELC, especially bilateral ELC, showed independent associations with both WMHs and brain atrophy, particularly among those younger than 68 years old. Early detection of subtle white matter hyperintensities (WMHs) or brain atrophy might be important in terms of diagnosis and treatment. We hypothesize that earlobe crease (ELC), a visible sign of aging, may correlate with and aid in the early identification of WMHs and brain atrophy. We reported the association between the ELC and WMHs and brain atrophy among 730 patients with acute ischemic stroke (AIS). We observed that in AIS patients the presence of ELC, especially bilateral ELC, showed independent associations with both WMHs and brain atrophy, particularly among those younger than 68 years old. Our findings suggest that ELC, especially bilateral ELC, might be an easy-to-observe and widely used indicator for predicting the presence of WMHs or brain atrophy. [ABSTRACT FROM AUTHOR]

Leukoaraiosis (LA) appears as white matter hyperintensities on T2-weighted brain magnetic resonance imaging scans. Age and hypertension are considered the primary risk factors for LA, but its pathogenesis remains uncertain. This study aims to investigate the correlation between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and LA. A total of 140 patients with LA and 136 neuroimaging alteration-free controls were recruited in a case–control study. ACE I/D polymorphism was determined using the polymerase chain reaction method. The allele and genotype distributions of the ACE I/D polymorphism were significantly different between subjects with and without LA. Significant difference was observed in the genotypic distribution between LA patients and controls for recessive and additive models. A statistically significant association remained apparent after adjusting for potential risk factors (D/D vs. I/D + I/I: adjusted OR 3.251, 95% CI 1.185–8.918; D/D vs. I/I: adjusted OR 3.277, 95% CI 1.187–9.047). Our results indicate that the D/D genotype and D allele are important risk factors for LA. Future studies with larger populations are needed to validate our results. [ABSTRACT FROM AUTHOR]

Hypoxic-ischemic brain damage presents a significant neurological challenge, often manifesting during the perinatal period. Specifically, periventricular leukomalacia (PVL) is emerging as a notable contributor to cerebral palsy and intellectual disabilities. It compromises cerebral microcirculation, resulting in insufficient oxygen or blood flow to the periventricular region of the brain. As widely documented, these pathological conditions can be caused by several factors encompassing preterm birth (4–5% of the total cases), as well single cotwin abortion and genetic variants such as those associated with GTPase pathways. Whole exome sequencing (WES) analysis identified a de novo causative variant within the pleckstrin homology domain-containing family G member 1 (PLEKHG1) gene in a patient presenting with PVL. The PLEKHG1 gene is ubiquitously expressed, showing high expression patterns in brain tissues. PLEKHG1 is part of a family of Rho guanine nucleotide exchange factors, and the protein is essential for cell division control protein 42 (CDC42) activation in the GTPase pathway. CDC42 is a key small GTPase of the Rho-subfamily, regulating various cellular functions such as cell morphology, migration, endocytosis, and cell cycle progression. The molecular mechanism involving PLEKHG1 and CDC42 has an intriguing role in the reorientation of cells in the vascular endothelium, thus suggesting that disruption responses to mechanical stress in endothelial cells may be involved in the formation of white matter lesions. Significantly, CDC42 association with white matter abnormalities is underscored by its MIM phenotype number. In contrast, although PLEKHG1 has been recently associated with patients showing white matter hyperintensities, it currently lacks a MIM phenotype number. Additionally, in silico analyses classified the identified variant as pathogenic. Although the patient was born prematurely and subsequently to dichorionic gestation, during which its cotwin died, we suggest that the variant described can strongly contribute to PVL. The aim of the current study is to establish a plausible association between the PLEKHG1 gene and PVL. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV's stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = ‐0.125 ± 0.054, 95% bootstrap confidence interval [CI] [‐0.2309, ‐0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. Highlights: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease.Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury.PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration.PVS's effect on executive function was mediated by GFAP and white matter disease. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (CSVD) is closely related to gait disorders. Previous studies have found a negative correlation between the severity of MRI white matter hyperintensities (WMH) and gait speed. However, not every individual with WMH experiences a gait disorder. Purpose: To investigate the mechanisms underlying the mismatch between the severity of MRI WMH and gait impairment, in particular in subjects with severe WMH (Fazekas 3, scale 0–3) resulting from vascular disease. Study Type: Cohort. Population: 54 subjects with severe WMH and gait disorder (WMH‐GD; 29 males) and 114 subjects with severe WMH with no gait disorder (WMH‐nGD; 60 males). Field Strength/Sequence: 3T/diffusion tensor imaging (DTI), and T1‐weighted, T2‐weighted, FLAIR, DWI, SWI. Assessment: Trace‐based spatial statistics analysis (TBSS) approach (fractional anisotropy, FA; mean diffusivity; radial diffusivity; axial diffusivity); Cognitive assessment; Conventional MRI markers of CSVD (WMH, enlarged perivascular spaces, lacunae, and cerebral microbleeds); Gait parameters (gait speed; cadence; stride length; gait cycle duration; step duration; time‐up‐and‐go test, TUG). Gait disorder was defined as a TUG time exceeding 12 sec. Statistical Tests: The t‐tests, Mann–Whitney U tests, Chi‐square tests, and partial correlation analysis (Pearson or Spearman) were used. P < 0.05 with threshold‐free cluster enhancement corrected was considered statistically significant for TBSS. Results: After adjusting for age, sex, height, and other conventional MRI markers of CSVD, the WMH‐nGD group showed significantly decreased FA values in the corpus callosum, bilateral superior longitudinal fasciculus, left corona radiata, and left posterior thalamic radiation. There was a significant association between FA values and TUG time, gait speed, and stride length in multiple WM tracts, independent of other conventional CSVD markers. Data Conclusion: This study provides evidence for microstructural damage of specific fibers in WMH‐GD subjects compared to WMH‐nGD subjects. This may explain the mismatch between WMH and gait impairment in subjects with severe WMH. Level of Evidence: 1 Technical Efficacy: Stage 3 [ABSTRACT FROM AUTHOR]

Background: Monogenic Alzheimer's disease (AD) has severe health and socioeconomic repercussions. Its rarest cause is presenilin 2 (PSEN2) gene mutations. We present two new cases with presumed PSEN2-AD with unusual clinical and neuroimaging findings in order to provide more information on the pathophysiology and semiology of these patients. Methods: Women aged 69 and 62 years at clinical onset, marked by prominent behavioral and language dysfunction, progressing to severe dementia within three years were included. The complete study is depicted. In addition, a systematic review of the PSEN2-AD was performed. Results: Neuroimaging revealed pronounced frontal white matter hyperintensities (WMH) and frontotemporal atrophy/hypometabolism. The genetic study unveiled PSEN2 variants: c.772G>A (p.Ala258Thr) and c.1073-2_1073-1del. Both cerebrospinal fluid (CSF) and experimental blood biomarkers shouldered AD etiology. Conclusions: Prominent behavioral and language dysfunction suggesting frontotemporal dementia (FTD) may be underestimated in the literature as a clinical picture in PSEN2 mutations. Thus, it may be reasonable to include PSEN2 in genetic panels when suspecting FTDL. PSEN2 mutations may cause striking WMH, arguably related to myelin disruption induced by amyloid accumulation. [ABSTRACT FROM AUTHOR]

As a potential preclinical stage of Alzheimer's dementia, subjective cognitive decline (SCD) reveals a higher risk of future cognitive decline and conversion to dementia. However, it has not been clear whether SCD status increases the clinical progression of older adults in the context of amyloid deposition, cerebrovascular disease (CeVD), and psychiatric symptoms. We identified 99 normal controls (NC), 15 SCD individuals who developed mild cognitive impairment in the next 2 years (P‐SCD), and 54 SCD individuals who did not (S‐SCD) from ADNI database with both baseline and 2‐year follow‐up data. Total white matter hyperintensity (WMH), WMH in deep (DWMH) and periventricular (PWMH) regions, and voxel‐wise grey matter volumes were compared among groups. Furthermore, using structural equation modelling method, we constructed path models to explore SCD‐related brain changes longitudinally and to determine whether baseline SCD status, age, and depressive symptoms affect participants' clinical outcomes. Both SCD groups showed higher baseline amyloid PET SUVR, baseline PWMH volumes, and larger increase of PWMH volumes over time than NC. In contrast, only P‐SCD had higher baseline DWMH volumes and larger increase of DWMH volumes over time than NC. No longitudinal differences in grey matter volume and amyloid was observed among NC, S‐SCD, and P‐SCD. Our path models demonstrated that SCD status contributed to future WMH progression. Further, baseline SCD status increases the risk of future cognitive decline, mediated by PWMH; baseline depressive symptoms directly contribute to clinical outcomes. In conclusion, both S‐SCD and P‐SCD exhibited more severe CeVD than NC. The CeVD burden increase was more pronounced in P‐SCD. In contrast with the direct association of depressive symptoms with dementia severity progression, the effects of SCD status on future cognitive decline may manifest via CeVD pathologies. Our work highlights the importance of multi‐modal longitudinal designs in understanding the SCD trajectory heterogeneity, paving the way for stratification and early intervention in the preclinical stage. Practitioner Points: Both S‐SCD and P‐SCD exhibited more severe CeVD at baseline and a larger increase of CeVD burden compared to NC, while the burden was more pronounced in P‐SCD.Baseline SCD status increases the risk of future PWMH and DWMH volume accumulation, mediated by baseline PWMH and DWMH volumes, respectively.Baseline SCD status increases the risk of future cognitive decline, mediated by baseline PWMH, while baseline depression status directly contributes to clinical outcome. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer's disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging. Methods: We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC). Results: Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.82 and 0.74). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97) and showed poor correlation with amyloid and tau PET markers similar to the visual grading. Conclusion: Our study investigated risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research. [ABSTRACT FROM AUTHOR]

Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen's criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval. [ABSTRACT FROM AUTHOR]

Background: Osteopontin (OPN) is a proinflammatory cytokine that has been recently implicated in neuroinflammation and neurodegeneration. We hypothesized that an increase in plasma OPN is a deleterious neuroinflammatory marker in people with dementia and cerebral small vessel disease (CSVD). Methods: A pilot study was conducted on participants in the Northern Manhattan Study (NOMAS). Three groups were selected based on their dementia status and evidence of subclinical CSVD and chosen to be similar in age, sex, and education attainment: No dementia/No CSVD (n = 19), Dementia/No CSVD (n = 22), and Dementia + CSVD (n = 21). Dementia (any type) was diagnosed by consensus adjudication following a series of comprehensive neuropsychological assessments and a review of the medical history. CSVD was indicated by silent brain infarcts, enlarged perivascular spaces, cerebral microbleeds, and white matter hyperintensity volumes (WMHV) on MRI. Multinomial logistic regression was used to examine the difference in OPN levels across groups, adjusting for key determinants of CSVD and neurodegeneration. Results: Plasma OPN levels were elevated in the Dementia+CSVD group (mean = 70.69 ± 39.00 ng/mL) but not in the Dementia/No CSVD group (mean = 45.46 ± 19.11 ng/mL) compared to the No Dementia/No CSVD group (mean = 36.43 ± 15.72 ng/mL). OPN was associated with Dementia+CSVD (Odds Ratio [OR] per ng/mL = 1.06, 95% CI 1.02–1.11) after adjusting for covariates, including brain volume. OPN was strongly correlated with WMHV (Spearman's rank correlation ρ = 0.46, p = 0.0001) but not with other components of CSVD. Conclusion: In this pilot, greater levels of plasma OPN were associated with dementia with evidence of CSVD. This link was predominately driven by the contribution of OPN to dementia through the burden of white matter lesions. [ABSTRACT FROM AUTHOR]

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = −.02, 95% CI (-.04, −.008), p =.003] and in APOE4 carriers [B = −.03, 95% CI (-.06, −.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH. • Cerebrovascular reactivity (CVR) is a dynamic marker of cerebrovascular function. • Impaired cerebral vasodilation is associated with higher WMH burden. • APOE4 carriers may be vulnerable to small vessel damage due to CVR changes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) incorporated non‐hemorrhagic imaging markers. Their prevalence and significance in patients with cognitive impairment remain uncertain. METHODS: We studied 622 memory clinic patients with available magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers. Two raters assessed non‐hemorrhagic markers, and we explored their association with clinical characteristics through multivariate analyses. RESULTS: Most patients had mild cognitive impairment; median age was 71 years and 50% were female. Using the v2.0 criteria, possible or probable CAA increased from 75 to 383 patients. Sixty‐eight percent of the sample had non‐hemorrhagic CAA markers, which were independently associated with age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01–1.07), female sex (OR = 1.68, 95% CI = 1.11–2.54), and hemorrhagic CAA markers (OR = 2.11, 95% CI = 1.02–4.35). DISCUSSION: Two‐thirds of patients from a memory clinic cohort had non‐hemorrhagic CAA markers, increasing the number of patients meeting the v2.0 CAA criteria. Longitudinal approaches should explore the implications of these markers, particularly the hemorrhagic risk in this population. Highlights: The updated Boston criteria for cerebral amyloid angiopathy (CAA) now include non‐hemorrhagic markers.The prevalence of non‐hemorrhagic CAA markers in memory clinic patients is unknown.Two‐thirds of patients in our memory clinic presented non‐hemorrhagic CAA markers.The presence of these markers was associated with age, female sex, and hemorrhagic CAA markers.The hemorrhagic risk of patients presenting these type of markers remains unclear. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMHs) refer to a group of diseases with numerous etiologies while oligodendrocytes remain the centerpiece in the pathogenesis of WMHs. Ring Finger Protein 216 (RNF216) encodes a ubiquitin ligase, and its mutation begets WMHs, ataxia, and cognitive decline in patients. Yet no study has revealed the function of RNF216 in oligodendroglia and WHIs before. In this study, we summarized the phenotypes of RNF216‐mutation cases and explored the normal distribution of RNF216 in distinct brain regions and neuronal cells by bioinformatic analysis. Furthermore, MO3.13, a human oligodendrocyte cell line, was applied to study the function alteration after RNF216 knockdown. As a result, WMHs were the most common symptom in RNF216‐mutated diseases, and RNF216 was indeed relatively enriched in corpus callosum and oligodendroglia in humans. The downregulation of RNF216 in oligodendroglia remarkably hampered cell proliferation by inhibiting the Akt pathway while having no significant effect on cell injury and oligodendrocyte maturation. Combining clinical, bioinformatical, and experimental evidence, our study implied the pivotal role of RNF216 in WMHs which might serve as a potent target in the therapy of WMHs. Significance statement: White matter hyperintensities lay at the center of Ring Finger Protein 216(RNF216)‐mutated disorders.RNF216 was relatively enriched in corpus callosum and oligodendroglia in human samples.RNF216 knockdown in human oligodendrocyte cell line suppressed cell proliferation.Combining in silico and in vitro evidence, this study revealed the significant role of RNF216 in white matter hyperintensities which might serve as a potential treatment target in the future. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective of this study was to evaluate the prevalence of white matter hyperintensities (WMHs) in patients who experience migraine and compare findings between adult male and female patients. Specific symptoms and comorbidities also were analyzed to determine whether they were associated with WMH prevalence or the sex of patients with migraine. We hypothesized that females would have a higher prevalence of WMHs, experience more frequent and more severe migraine headaches, and be more likely to have certain comorbidities associated with migraine than males. Background: An increased prevalence of WMHs in patients with migraine has been proposed, although this relation is not well‐supported by data from population‐based MRI studies. The difference in brain morphology between males and females is of research interest, and females in the general population appear to have a higher prevalence of WMHs. Sex differences and various comorbidities in patients with migraine relative to the number of WMHs on brain imaging have not been fully investigated. Methods: This was a cross‐sectional study of 177 patients aged 18 years and older with a diagnosis of migraine who were seen in the Lehigh Valley Fleming Neuroscience Institute's Headache Center between January 1, 2000, and January 1, 2017. Patients' baseline characteristics were extracted from electronic medical records, including demographics, review of systems documentation, and brain imaging from MRI. Variables including headache severity, frequency of head pain, insomnia, and comorbidities (anxiety, depression, diabetes, hyperlipidemia, hypertension, and neck pain) also were analyzed for associations with the presence of WMHs. Results: Females were found to have a significantly higher number of WMHs than males (median 3 [IQR: 0–7] vs. 0 [IQR: 0–3], p = 0.023). Patients with WMHs were significantly more likely than those without WMHs to have hypertension (39.8% of patients with WMHs vs. 20.3% without WMHs, p = 0.011), constipation (20.9% vs. 8.3%, p = 0.034), and sleep disorder (55.7% vs. 37.3%, p = 0.022). Females with migraine were significantly more likely to experience constipation than males (20.0% vs. 2.9%, p = 0.015). None of the migraine characteristics studied (frequency, severity, presence of aura) were different between sexes, nor were they significantly associated with the presence of WMHs. Conclusion: This study suggests that females with migraine may be more likely to have WMHs and experience constipation than males with migraine. Migraine frequency and severity were not different between sexes, nor were they significantly associated with the presence of WMHs. The findings of this study do not support a specific etiology of WMH development in individuals with migraine that differs from findings in the general population. Further studies are warranted. Plain Language Summary: We evaluated brain scans of adults with migraine to assess for problems in their white matter, which is a type of brain tissue. We also explored whether patient sex, migraine features like severity or frequency, or co‐existing health conditions were related to white matter problems. While more females than males with migraine had abnormal white matter, our findings did not support any specific cause for this, so more studies are needed on this topic. [ABSTRACT FROM AUTHOR]

To examine the relation between baseline white matter hyperintensities (WMH) and change in naming, content production, and efficiency after treatment in subacute aphasia. We hypothesized that more severe baseline WMH would result in less improvement with treatment. Retrospective analysis of a cohort from a double-blind randomized controlled trial (RCT). Outpatient clinical setting or participant home. We retrospectively reviewed imaging and behavioral data for 52 participants with subacute aphasia due to left-hemisphere ischemic stroke enrolled in the RCT. RCT inclusion criteria: English proficiency, normal/corrected-to-normal hearing/vision, and no history of neurologic conditions other than the stroke resulting aphasia. One participant with a chronic right-hemisphere lesion was retained as she presented with no residual deficits on neurologic examination. Individuals with scalp sensitivities or on medications that lower seizure threshold or any N-methyl-D-aspartate (NMDA) antagonists were excluded. Of the 52 participants, for this analysis, 2 were excluded for not having a magnetic resonance imaging, and 7 were excluded for not participating in treatment or pre/post assessment for at least 1 outcome, resulting in final sample of 43 participants (20 women sex, M [ SD ] age=64.4 [11.9] and M [SD] education=14.9 [3.1] years). Participants received 15 sessions (2-3 times/week) of computerized lexical-semantic (ie, verification) treatment with [sham/active] transcranial direct current stimulation (tDCS). Sessions were approximately 45 minutes each (tDCS for first 20 minutes). Naming accuracy, content units (CUs, a measure of semantically accurate production), and efficiency (ie, syllables/CU) on a picture description task. Periventricular WMH severity was independently associated with recovery in picture naming for the active tDCS group. Deep WMH severity was associated with recovery for CU production for the sham tDCS group. Baseline periventricular and deep WMH, among other factors, may be an important consideration for prognosis and treatment planning, especially when considered in conjunction with tDCS treatment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH‐connected cortex using multimodal images. METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aβ) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography. RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aβ and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18F‐SynVesT‐1 PET. In addition, higher ratios of Aβ in the deep WMH‐connected versus WMH‐unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH‐connected cortex reduced more than WMH‐unconnected cortex over 12 months. DISCUSSION: Our results suggest that WMH may be associated with AD‐intrinsic processes of degeneration, in addition to vascular mechanisms. Highlights: We studied white matter hyperintensities (WMHs) and WMH‐connected cortical changes.WMHs are associated with more severe regional cortical degeneration.Findings suggest WMHs may be associated with Alzheimer's disease–intrinsic processes of degeneration. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recent studies have suggested an association between dysfunction of the choroid plexus and the glymphatic system. However, information is inconclusive. Following a population-based study design, we aimed to assess the association between choroid plexus calcifications (CPCs)—as a surrogate of choroid plexus dysfunction—and severity and progression of putative markers of glymphatic dysfunction, including white matter hyperintensities (WMH) of presumed vascular origin and abnormally enlarged basal ganglia perivascular spaces (BG-PVS). Methods: This study recruited community-dwellers aged ≥40 years living in neighboring Ecuadorian villages. Participants who had baseline head CTs and brain MRIs were included in cross-sectional analyses and those who additional had follow-up MRIs (after a mean of 6.4 ± 1.5 years) were included in longitudinal analyses. Logistic and Poisson regression models, adjusted for demographics and cardiovascular risk factors, were fitted to assess associations between CPCs and WMH and enlarged BG-PVS severity and progression. Results: A total of 590 individuals were included in the cross-sectional component of the study, and 215 in the longitudinal component. At baseline, 25% of participants had moderate-to-severe WMH and 27% had abnormally enlarged BG-PVS. At follow-up, 36% and 20% of participants had WMH and enlarged BG-PVS progression, respectively. Logistic regression models showed no significant differences between CPCs volumes stratified in quartiles and severity of WMH and enlarged BG-PVS. Poisson regression models showed no association between the exposure and WMH and enlarged BG-PVS progression. Baseline age remained significant in these models. Conclusions: Choroid plexus calcifications are not associated with putative markers of glymphatic system dysfunction. [ABSTRACT FROM AUTHOR]