The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: IAC is associated with the total CSVD burden score and single imaging signs.

BACKGROUND: 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.
CONCLUSIONS: Quantitative assessment of WMHs provides a valuable neuro-imaging tool for enhancing the prediction of ischemic stroke recurrence risk.

BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
CONCLUSIONS: 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.

White matter hyperintensity (WMH) shape is associated with long-term dementia risk in community-dwelling older adults, however, the underlying structural correlates of this association are unknown. We therefore aimed to investigate the association between baseline WMH shape and cerebrovascular disease progression over time in community-dwelling older adults. The association of WMH shape and cerebrovascular disease markers was investigated using linear and logistic regression models in the Age, Gene/Environment Susceptibility-Reykjavik (AGES) study (n = 2297; average time to follow-up: 5.2 years). A more irregular shape of periventricular/confluent WMH at baseline was associated with a larger increase in WMH volume, and with occurrence of new subcortical infarcts, new microbleeds, new enlarged perivascular spaces, and new cerebellar infarcts at the 5.2-year follow-up (all p < 0.05). Furthermore, less elongated and more irregularly shaped deep WMHs were associated with a larger increase in WMH volume, and new cortical infarcts at follow-up (p < 0.05). A less elongated shape of deep WMH was associated with new microbleeds at follow-up (p < 0.05). Our findings show that WMH shape may be indicative of the type of cerebrovascular disease marker progression. This underlines the significance of WMH shape to aid in the assessment of cerebrovascular disease progression.

OBJECTIVE: White matter hyperintensities (WMH) are common among the elderly. Although WMH play a key role in lowering the threshold for the clinical expression of dementia in Alzheimer\'s disease (AD)-related pathology, the clinical significance of their location is not fully understood. This study aimed to investigate the association between WMH and cognitive function according to the location of WMH in AD.
METHODS: Subjects underwent clinical evaluations including volumetric brain magnetic resonance imaging study and neuropsychological tests using the Korean version of the Consortium to Establish a Registry for Alzheimer\'s Disease Assessment Packet. WMH were calculated using automated quantification method. According to the distance from the lateral ventricular surface, WMH within 3 mm, WMH within 3-13 mm, and WMH over 13 mm were classified as juxtaventricular WMH (JVWMH), periventricular WMH (PVWMH), and deep WMH (DWMH), respectively.
RESULTS: Total WMH volume was associated with poor performance in categorical verbal fluency test (β=-0.197, p=0.035). JVWMH volume was associated with poor performances on categorical verbal fluency test (β=-0.201, p=0.032) and forward digit span test (β= -0.250, p=0.012). PVWMH volume was associated with poor performances on categorical verbal fluency test (β=-0.185, p=0.042) and word list memory test (β=-0.165, p=0.042), whereas DWMH volume showed no association with cognitive tests. PVWMH volume were also related to Clinical Dementia Rating Scale Sum of Boxes score (β=0.180, p=0.026).
CONCLUSIONS: WMH appear to exhibit different associations with the severity of dementia and cognitive impairment according to the distance from ventricle surface in AD.

BACKGROUND: Segmentation of white matter hyperintensities (WMH) in CADASIL, one of the most severe cerebral small vessel disease of genetic origin, is challenging.
METHODS: We adapted and validated an automatic method based on a convolutional neural network (CNN) algorithm and using a large dataset of 2D and/or 3D FLAIR and T1-weighted images acquired in 132 patients, to measure the progression of WMH in this condition.
RESULTS: The volume of WMH measured using this method correlated strongly with reference data validated by experts. WMH segmentation was also clearly improved compared to the BIANCA segmentation method. Combining two successive learning models was found to be of particular interest, reducing the number of false-positive voxels and the extent of under-segmentation detected after a single-stage process. With the two-stage approach, WMH progression correlated with measures derived from the reference masks for lesions increasing with age, and with the variable WMH progression trajectories at individual level. We also confirmed the expected effect of the initial load of WMH and the influence of the type of MRI acquisition on measures of this progression.
CONCLUSIONS: Altogether, our findings suggest that WMH progression in CADASIL can be measured automatically with adequate confidence by a CNN segmentation algorithm.

BACKGROUND: Information on trajectories of diffuse subcortical brain damage of vascular origin associated with binge drinking in older adults is limited. We sought to evaluate the impact of this drinking pattern on the progression of white matter hyperintensities (WMH) of presumed vascular origin in individuals aged ≥60 years taken from the community.
METHODS: Following a longitudinal prospective design, participants of the Atahualpa Project Cohort received interviews to assess patterns of alcohol intake as well as baseline and follow-up brain MRIs. Only men were included because alcohol consumption in women is negligible and tend not to engage in binge drinking in our studied population. Poisson regression models were fitted to assess the incidence rate ratio of WMH progression by patterns of alcohol use (binge drinking or not), after adjusting for demographics, level of education and cardiovascular risk factors.
RESULTS: The study included 114 men aged ≥60 years (mean age: 65.1±5.4 years). Thirty-seven participants (32%) reported binge drinking for more than 30 years. Follow-up MRIs revealed WMH progression in 45 participants (39%) after a median of 7.2 years. In unadjusted analysis, the risk of WMH progression among individuals with binge drinking was 2.08 (95% C.I.: 1.16-3.73). After adjustment for age, education level and vascular risk factors, participants with this drinking pattern were 2.75 times (95% C.I.: 1.42-5.30) more likely to have WMH progression than those who did not.
CONCLUSIONS: Study results show an independent association between binge drinking and WMH progression in community-dwelling older men.

BACKGROUND: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer\'s disease (AD) biomarkers remain largely unexplored.
METHODS: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume.
RESULTS: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes.
CONCLUSIONS: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks.
CONCLUSIONS: White matter hyperintensities (WMHs) increased 10 years before Alzheimer\'s disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas.