Characterization of white matter hyperintensities in Down syndrome.

INTRODUCTION: 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. DISCUSSION: 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. HIGHLIGHTS: 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.

Development and validation of a two-stage convolutional neural network algorithm for segmentation of MRI white matter hyperintensities for longitudinal studies in CADASIL.

BACKGROUND: Segmentation of white matter hyperintensities (WMH) in CADASIL, one of the most severe cerebral small vessel disease of genetic origin, is challenging. METHOD: 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. CONCLUSION: Altogether, our findings suggest that WMH progression in CADASIL can be measured automatically with adequate confidence by a CNN segmentation algorithm.

Binge drinking and progression of white matter hyperintensities of presumed vascular origin in older men.

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.

Prolonged ventricular repolarization associated with mild cognitive impairment and white matter hyperintensities: a cross-sectional study.

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.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

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.

Brain structure, amyloid, and behavioral features for predicting clinical progression in subjective cognitive decline.

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.

Cerebrovascular lesion loads and accelerated brain aging: insights into the cognitive spectrum.

Introduction: White matter hyperintensities (WMHs) and cerebral microbleeds are widespread among aging population and linked with cognitive deficits in mild cognitive impairment (MCI), vascular MCI (V-MCI), and Alzheimer's disease without (AD) or with a vascular component (V-AD). In this study, we aimed to investigate the association between brain age, which reflects global brain health, and cerebrovascular lesion load in the context of pathological aging in diverse forms of clinically-defined neurodegenerative conditions. Methods: We computed brain-predicted age difference (brain-PAD: predicted brain age minus chronological age) in the Comprehensive Assessment of Neurodegeneration and Dementia cohort of the Canadian Consortium on Neurodegeneration in Aging including 70 cognitively intact elderly (CIE), 173 MCI, 88 V-MCI, 50 AD, and 47 V-AD using T1-weighted magnetic resonance imaging (MRI) scans. We used a well-established automated methodology that leveraged fluid attenuated inversion recovery MRIs for precise quantification of WMH burden. Additionally, cerebral microbleeds were detected utilizing a validated segmentation tool based on the ResNet50 network, utilizing routine T1-weighted, T2-weighted, and T2* MRI scans. Results: The mean brain-PAD in the CIE cohort was around zero, whereas the four categories showed a significantly higher mean brain-PAD compared to CIE, except MCI group. A notable association trend between brain-PAD and WMH loads was observed in aging and across the spectrum of cognitive impairment due to AD, but not between brain-PAD and microbleed loads. Discussion: WMHs were associated with faster brain aging and should be considered as a risk factor which imperils brain health in aging and exacerbate brain abnormalities in the context of neurodegeneration of presumed AD origin. Our findings underscore the significance of novel research endeavors aimed at elucidating the etiology, prevention, and treatment of WMH in the area of brain aging.

Reproductive hormones in relation to white matter hyperintensity volumes among midlife women.

INTRODUCTION: Although reproductive hormones are implicated in cerebral small vessel disease in women, few studies consider measured hormones in relation to white matter hyperintensity volume (WMHV), a key indicator of cerebral small vessel disease. Even fewer studies consider estrone (E1), the primary postmenopausal estrogen, or follicle-stimulating hormone (FSH), an indicator of ovarian age. We tested associations of estradiol (E2), E1, and FSH to WMHV among women. METHODS: Two hundred twenty-two women (mean age = 59) underwent hormone assays (E1, E2, FSH) and 3T brain magnetic resonance imaging. Associations of hormones to WMHV were tested with linear regression. RESULTS: Higher E2 (B[standard error (SE)] = -0.17[0.06], P = 0.008) and E1 (B[SE] = -0.26[0.10], P = 0.007) were associated with lower whole-brain WMHV, and higher FSH (B[SE] = 0.26[0.07], P = 0.0005) with greater WMHV (covariates age, race, education). When additionally controlling for cardiovascular disease risk factors, associations of E1 and FSH to WMHV remained. DISCUSSION: Reproductive hormones, particularly E1 and FSH, are important to women's cerebrovascular health. HIGHLIGHTS: Despite widespread belief that sex hormones are important to women's brain health, little work has considered how these hormones in women relate to white matter hyperintensities (WMH), a major indicator of cerebral small vessel disease. We considered relations of estradiol (E2), estrone (E1), and follicle-stimulating hormone (FSH) to WMH in midlife women. Higher E2 and E1 were associated with lower whole-brain WMH volume (WMHV), and higher FSH with higher whole-brain WMHV. Associations of E1 and FSH, but not E2, to WMHV persisted with adjustment for cardiovascular disease risk factors. Findings underscore the importance of E2 and FSH to women's cerebrovascular health.

Correlation between matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 and white matter hyperintensities in patients with cerebral small vessel disease based on cranial magnetic resonance 3D imaging.

OBJECTIVE: The objective of this study was to investigate the correlation between serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels and their ratios with the severity of white matter hyperintensities (WMHs) in patients with cerebral small vessel disease (CSVD). METHODS: This cross-sectional study was done on a prospective cohort of patients with CSVD. Qualitative and quantitative analyses of WMHs were performed using Fazekas grading and lesion prediction algorithm (LPA) methods. Biomarkers MMP-2, MMP-9, and TIMP-1 were measured to explore their correlation with the severity of WMHs. RESULTS: The sample consisted of 144 patients with CSVD. There were 63 male and 81 female patients, with an average age of 67.604 ± 8.727 years. Among these, 58.33% presented with white matter hyperintensities at Fazekas grading level 1, with an average total template volume of WMHs of 4.305 mL. MMP-2 (P = 0.025), MMP-9 (P = 0.008), TIMP-1 (P = 0.026), and age (P = 0.007) were identified as independent correlates of WMHs based on Fazekas grading. Independent correlates of the total template volume of WMHs included MMP-2 (P = 0.023), TIMP-1 (P = 0.046), age (P = 0.047), systolic blood pressure (P = 0.047), and homocysteine (Hcy) (P = 0.014). In addition, age (P = 0.003; P < 0.001), interleukin-6 (IL-6) (P < 0.001; P = 0.044), Hcy (P < 0.001; P < 0.001), glycated hemoglobin (HbA1c) (P = 0.016; P = 0.043), and chronic kidney disease (P < 0.001; P < 0.001) were associated with both WMHs Fazekas grading and the total template volume of WMHs. CONCLUSION: Serum levels of MMP-9, MMP-2, and TIMP-1 were independently associated with the Fazekas grading, while serum TIMP-1 and MMP-2 levels were independently related to the total template volume of WMHs. The association of TIMP-1 and MMP-2 with the severity of CSVD-related WMHs suggests their potential role as disease-related biomarkers. However, further research is required to uncover the specific mechanisms underlying these interactions.

Can white matter hyperintensities based Fazekas visual assessment scales inform about Alzheimer's disease pathology in the population?

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.

Beyond Hypertension: Examining Variable Blood Pressure's Role in Cognition and Brain Structure.

OBJECTIVES: Hypertension or high blood pressure (BP) is one of the twelve 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 post-mortem 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 Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. Participants were divided into one of three 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 was also observed in variable compared to high and normal BP. In post-mortem neuropathology, both variable and high BP had increased rates compared to normal BP. All the 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 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.

Long-standing neuromyelitis optica with leukodystrophy-like asymptomatic MRI changes.

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.

Decoding the best automated segmentation tools for vascular white matter hyperintensities in the aging brain: a clinician's guide to precision and purpose.

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.

Ring finger protein 216 loss-of-function induces white matter hyperintensities by inhibiting oligodendroglia proliferation.

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.

Molecular profiling of frontal and occipital subcortical white matter hyperintensities in Alzheimer's disease.

White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer's disease. Despite their frequent appearance and their association with cognitive decline, the molecular factors contributing to WMHs remain unclear. In this study, we investigated the transcriptomic profiles of two commonly affected brain regions with coincident AD pathology-frontal subcortical white matter (frontal-WM) and occipital subcortical white matter (occipital-WM)-and compared with age-matched healthy controls. Through RNA-sequencing in frontal- and occipital-WM bulk tissues, we identified an upregulation of genes associated with brain vasculature function in AD white matter. To further elucidate vasculature-specific transcriptomic features, we performed RNA-seq analysis on blood vessels isolated from these white matter regions, which revealed an upregulation of genes related to protein folding pathways. Finally, comparing gene expression profiles between AD individuals with high- versus low-WMH burden showed an increased expression of pathways associated with immune function. Taken together, our study characterizes the diverse molecular profiles of white matter changes in AD compared to normal aging and provides new mechanistic insights processes underlying AD-related WMHs.

The Spectrum of Cerebral Small Vessel Disease: Emerging Pathophysiologic Constructs and Management Strategies.

Cerebral small vessel disease (CSVD) is a spectrum of disorders that affect small arterioles, venules, cortical and leptomeningeal vessels, perivascular spaces, and the integrity of neurovascular unit, blood brain barrier, and surrounding glia and neurons. CSVD is an important cause of lacunar ischemic stroke and sporadic hemorrhagic stroke, as well as dementia-which will constitute some of the most substantive population and public health challenges over the next century. This article provides an overview of updated pathophysiologic frameworks of CSVD; discusses common and underappreciated clinical and neuroimaging manifestations of CSVD; and reviews emerging genetic risk factors linked to sporadic CSVD.

Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients.

BACKGROUND: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by NOTCH3 mutation. Nailfold capillaroscopy is a non-invasive technique typically used for rheumatic diseases. It has potential in other conditions linked to vascular pathology. However, capillaroscopy in CADASIL has not been explored. This study aims to investigate whether capillaroscopy measurements can correlate with brain vascular changes in preclinical CADASIL patients, specifically those with NOTCH3 mutation. METHODS: This study included 69 participants from the Taiwan Precision Medicine Initiative (TPMI) dataset who visited Taichung Veterans General Hospital from January to December 2022. All individuals underwent genetic studies, brain imaging and nailfold capillaroscopy. The Mann-Whitney U test was used to compare results of brain imaging between carriers and controls. It was also used to compare measurements in nailfold capillaroscopy within each group. Spearman Rank Correlation Analysis was used to explore the relationship between capillary measurements and brain MRI results. RESULTS: White matter hyperintensities (WMH) expression was positively correlated with capillary dimension and negatively correlated with density. Our results presented that R544C carriers exhibited a diffuse increase in WMH (p < 0.001) and a global reduction in gray matter volume but preserved in specific areas. The white matter lesion scores in all brain regions were higher in the mutation carriers than the controls. (p < 0.001). CONCLUSION: This research highlights the association of nailfold capillaroscopy findings with white matter lesions in preclinical CADASIL patients. Capillaroscopy guides an effective screening strategy in individuals with NOTCH3 mutations.

Estimated bone mineral density and white matter hyperintensities: A bidirectional Mendelian randomization study.

PURPOSE: Greater white matter hyperintensities (WMH) in older adults have been associated with reduced bone mineral density (BMD) and increased fractures and falls. However, it is unclear whether there is a causal relationship between BMD reduction and WMH. In this study, Mendelian randomization (MR) was used to find the causality between WMH and estimated BMD (eBMD). METHODS: We performed a two-sample bidirectional MR analysis using statistical data obtained from publicly available genome-wide association studies (GWAS). The main method of MR analysis is the inverse-variance weighted (IVW) method. To identify and account for the impact of horizontal pleiotropy, we also employed MR-Egger regression, MR pleiotropy residual sum, and outlier (MR-PRESSO). RESULTS: MR analysis found a causal relationship between eBMD and WMH (IVW OR = 0.938, 95 % CI: 0.889-0.990, p = 0.020). Our causal estimates are unlikely to be distorted by horizontal pleiotropy according to heterogeneity test (both p > 0.05) and MR-Egger regression (p > 0.05). However, in the reverse MR analysis, there was no evidence that WMH was causally correlated with eBMD (IVW OR = 0.979, 95 % CI: 0.954-1.005, p = 0.109). CONCLUSION: Our results suggest that low eBMD increased the risk of WMH; conversely, no evidence that WMH causally affects eBMD was found.

The relationship between cortical thickness and white matter hyperintensities in mid to late life.

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.

Divergent functional connectivity changes associated with white matter hyperintensities.

Age-related white matter hyperintensities are a common feature and are known to be negatively associated with structural integrity, functional connectivity, and cognitive performance. However, this has yet to be fully understood mechanistically. We analyzed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment. White matter hyperintensities were automatically quantified using fluid-attenuated inversion recovery MRI and parameters from diffusion tensor imaging were estimated in major white matter fibre tracts. We calculated fMRI resting state-derived functional connectivity within and between predefined cortical regions structurally linked by the white matter tracts. How change in functional connectivity is affected by white matter lesions and related to cognition (in the form of executive function and processing speed) was explored. We examined the functional changes using a measure of sample entropy. As expected hyperintensities were associated with disrupted structural white matter integrity and were linked to reduced functional interregional lobar connectivity, which was related to decreased processing speed and executive function. Simultaneously, hyperintensities were also associated with increased intraregional functional connectivity, but only within the frontal lobe. This phenomenon was also associated with reduced cognitive performance. The increased connectivity was linked to increased entropy (reduced predictability and increased complexity) of the involved voxels' blood oxygenation level-dependent signal. Our findings expand our previous understanding of the impact of white matter hyperintensities on cognition by indicating novel mechanisms that may be important beyond this particular type of brain lesions.