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BackgroundPlasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.MethodsWe examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.ResultsAfter adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.ConclusionsThese results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

ObjectiveTo compare white matter hyperintensities (WMHs) on T2-weighted magnetic resonance imaging (MRI) of patients with sudden sensorineural hearing loss (SSNHL) and analyze subpopulations with age-matched controls.MethodsT2-weighted MRI scans of 150 patients with SSNHL were assessed for WMHs and compared with the data of 148 healthy age-matched adults. Assessments of WMHs included independent grading of deep white matter hyperintensities (DWMHs) and periventricular hyperintensities (PVHs). WMH severity was visually rated using the Fazekas and Mirsen scales by two independent observers.ResultsFazekas grades for PVHs (p < 0.001) and DWMHs (p < 0.001) of SSNHL patients were found to be significantly greater than those of healthy participants. The average Mirsen grades for DWMHs of healthy and SSNHL patients were evaluated to be 0.373 ± 0.550 and 2.140 ± 0.859, respectively. Mirsen grades for DWMHs of SSNHL patients were found to be significantly greater (p < 0.001) than those of healthy participants. The Mirsen scale was found to have higher sensitivity (p < 0.001) than the Fazekas scale in grading PVHs and DWMHs. No significant difference (p = 0.24) was found in specificities between the two scales.ConclusionsPatients with sudden hearing loss have a much higher likelihood of having periventricular and deep white matter hyperintensities compared to age-matched controls. These findings indicate that sudden hearing loss patients are more likely to have microvascular changes in the brain, which may indicate a vascular and/or migraine origin to sudden sensorineural hearing loss.

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Patients with Alzheimer's disease (AD) often exhibit characteristic clinical manifestations, particularly neuropsychiatric symptoms. Previous studies have shown that white matter hyperintensity (WMH) is strongly associated with AD progression, as well as neuropsychiatric symptoms. The purpose of this study was to investigate the clinical and neuropsychological characteristics of AD patients with WMH. Methods: This retrospective study involved 104 18-fluorodeoxyglucose-positron emission computed tomography (18FDG-PET-CT)-defined AD patients treated at Tianjin Huanhu Hospital from January 2010 to December 2022. Cranial magnetic resonance imaging (MRI) provided semi-quantitative data on brain structure and WMH. Collect and analyze patient clinical data. Neuropsychological assessments were used to evaluate cognitive function and psychobehavioral traits. Results: Among the 104 patients, 66 were in the WMH group (63.5%) and 38 in the non-white matter hyperintensity (non-WMH) group (36.5%). There were no significant differences in gender, age, age of onset, education, BMI, smoking, drinking, diabetes, coronary heart disease, dementia family history, fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) between the two groups. The WMH group showed higher rates of hypertension, homocysteine (Hcy) levels, NPI, and CDR scores as compared to the non-WMH group (p < 0.05). MMSE and MoCA scores were significantly lower in the WMH group (p < 0.05). In the MMSE subitem analysis, patients in the WMH group showed a decrease in attention, recall, and language scores. In the MOCA subitem analysis, WMH patients had lower scores in executive function, naming, attention, language, abstraction, and orientation (p < 0.05). Furthermore, subgroup analysis of NPI showed a higher incidence of delusions, depression, and apathy in the WMH group (p < 0.05). According to the hierarchical analysis of mild, moderate and severe dementia groups, the hypertension, leukoencephalopathy, Hcy level, Fazekas total score, PWMH and DWMH scores in the severe dementia group were significantly higher than those in the mild and moderate dementia groups (p < 0.05). As the disease progresses, more and more patients show increased white matter hyperintensity. Conclusion: White matter lesions are closely correlated with cognitive decline and psychobehavioral symptoms in AD patients, and may be used as an indicator of disease progression. Priority should be given to early screening and prevention of WMH-related risk factors. [ABSTRACT FROM AUTHOR]

Background: Our intent was to explore the mediating role of interstitial free water (FW) linking deep medullary vein (DMV) score to white matter hyperintensity (WMH) volume. Methods: Our research team conducted a forward-looking analysis of initial clinical and imaging information gathered from 125 patients with cerebral small vessel disease. We identified six anatomic DMV regions on susceptibility weighted imaging (SWI) studies. Each region earned a score of 0–3, determined by the visual conditions of vessels, summing all six to generate a DMV score. We utilized fluid-attenuated inversion recovery (FLAIR) sequences to measure the volume of WMH. Additionally, we employed diffusion tensor imaging (DTI) to assess FW value. Results: DMV score significantly positively correlated with FW value and with WMH volume (p < 0.05), and value of FW positively correlated with WMH volume (p < 0.05). The indirect effect of DMV score on WMH volume was mediated by FW (β = 0.281, 95% confidence interval [CI]: 0.178–0.388), whether adjusted for age and gender (β = 0.142, 95% CI: 0.058–0.240) or for age, gender and vascular risk factors (β = 0.141, 95% CI: 0.054–0.249). Conclusion: DMV score correlate with WMH volume by virtue of FW increases in white matter. [ABSTRACT FROM AUTHOR]

White matter hyperintensity (WMH) is strongly correlated with age‐related dementia and hypertension, but its pathogenesis remains obscure. Genome‐wide association studies identified TRIM47 at the 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss‐of‐function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found highly expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially induced autophagy while downregulated in hypertension‐like conditions. Using in silico simulation, immunocytochemistry and super‐resolution microscopy, we predicted a highly conserved binding site between TRIM47 and the LIR (LC3‐interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription, and vacuole formation. Together, we demonstrate that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47‐mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Patients with Alzheimer's disease (AD) often exhibit characteristic clinical manifestations, particularly neuropsychiatric symptoms. Previous studies have shown that white matter hyperintensity (WMH) is strongly associated with AD progression, as well as neuropsychiatric symptoms. The purpose of this study was to investigate the clinical and neuropsychological characteristics of AD patients with WMH. Methods: This retrospective study involved 104 18-fluorodeoxyglucosepositron emission computed tomography (18FDG-PET-CT)-defined AD patients treated at Tianjin Huanhu Hospital from January 2010 to December 2022. Cranial magnetic resonance imaging (MRI) provided semi-quantitative data on brain structure and WMH. Collect and analyze patient clinical data. Neuropsychological assessments were used to evaluate cognitive function and psychobehavioral traits. Results: Among the 104 patients, 66 were in the WMH group (63.5%) and 38 in the non-white matter hyperintensity (non-WMH) group (36.5%). There were no significant differences in gender, age, age of onset, education, BMI, smoking, drinking, diabetes, coronary heart disease, dementia family history, fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) between the two groups. The WMH group showed higher rates of hypertension, homocysteine (Hcy) levels, NPI, and CDR scores as compared to the non-WMH group (p < 0.05). MMSE and MoCA scores were significantly lower in the WMH group (p < 0.05). In the MMSE subitem analysis, patients in the WMH group showed a decrease in attention, recall, and language scores. In the MOCA subitem analysis, WMH patients had lower scores in executive function, naming, attention, language, abstraction, and orientation (p < 0.05). Furthermore, subgroup analysis of NPI showed a higher incidence of delusions, depression, and apathy in the WMH group (p < 0.05). According to the hierarchical analysis of mild, moderate and severe dementia groups, the hypertension, leukoencephalopathy, Hcy level, Fazekas total score, PWMH and DWMH scores in the severe dementia group were significantly higher than those in the mild and moderate dementia groups (p < 0.05). As the disease progresses, more and more patients show increased white matter hyperintensity. Conclusion: White matter lesions are closely correlated with cognitive decline and psychobehavioral symptoms in AD patients, and may be used as an indicator of disease progression. Priority should be given to early screening and prevention of WMH-related risk factors. [ABSTRACT FROM AUTHOR]

Objective: White matter hyperintensities (WMH) are the most common neuroimaging manifestation of cerebral small vessel disease, and is frequently observed in Alzheimer's disease (AD). This study aimed to investigate the relationship between WMH and cognition and to verify the mediation of grey matter atrophy in this relationship. Methods: The diffusion tensor imaging (DTI) technique analyses white matter fiber tract to assess white matter integrity. Voxel-based morphometry was applied to measure the grey matter volume (GMV). A linear regression model was applied to examine the associations between WMH and GMV, and mediation analyses was performed to determine the mediating role of regional GMV in the effect of WMH on cognitive function. Results: Compared to the HC group, AD group have 8 fiber tract fractional anisotropy (FA) decreased and 16 fiber tract mean diffusivity (MD) increased. Compared to AD without WMH, AD with high WMH had 9 fiber tracts FA decreased and 13 fiber tracts MD increased. High WMH volume was negatively correlated with GMV in the frontal--parietal region. Low WMH volume was also negatively correlated with GMV except for the three regions (right angular gyrus, right superior frontal gyrus and right middle/inferior parietal gyrus), where GMV was positively correlated. Mediation analysis showed that the association between WMH and executive function or episodic memory were mediated by GMV in the frontal--parietal region. Conclusion: Damage to white matter integrity was more severe in AD with WMH. Differential changes in DTI metrics may be caused by progressive myelin and axonal damage. There was a negative correlation between WMH and grey matter atrophy in frontal--parietal regions in a volume-dependent manner. This study indicates the correspondence between WMH volume and GMV in cognition, and GMV being a key modulator between WMH and cognition in AD. This result will contribute to understanding the progression of the disease process and applying targeted therapeutic intervention in the earlier stage to delay neurodegenerative changes in frontal--parietal regions to achieve better treatment outcomes and affordability. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to analyze the brain white matter hyperintensities (WMHs) of patients with vascular dementia (VaD) and Alzheimer's disease (AD) using magnetic resonance imaging to determine whether white matter lesions in the brain could be detected by a computer using image processing methods. Patients and methods: In this retrospective observational study, a unimodal, unsupervised, and automatic method was developed, and magnetic resonance imaging of 35 patients were examined. Of the 35 patients, 19 (14 males, 5 females; mean age: 73.2±6.7 years; range, 56 to 83 years) were picked from patients with AD or VaD who were admitted to a neurology clinic between January 2016 and December 2022 (Group 1). The remaining 16 patients (10 females, 5 males; mean age: 80.4±5.4 years; range, 69 to 92 years) were included from the ABVIB (Aging Brain: Vasculature, Ischemia, and Behavior) study from the ADNI (Alzheimer's Disease Neuroimaging Initiative) database (Group 2). To calculate the volume of WMHs, a detailed analysis was conducted. Initially, skull stripping was performed, and then the brain was segmented. Afterward, two types of masks (Mask- 1 and Mask-2) were obtained by applying painting, decreasing, and blurring processes to the segmented white matter. These masks limited the region that was searched for WMHs. With this limitation, false positives that could arise from gray matter intensities were tried to be prevented. To evaluate the accuracy of WMH detection, a user interface was developed, and manual marking was conducted by an expert neurologist. After WMH detection, WMH volumes were calculated. Results: For Group 1, the similarity index was found to be 0.76 for Mask-1 and 0.80 for Mask-2, while for Group 2, the similarity index was 0.71 for Mask-1 and 0.87 for Mask-2. In patients with AD, the mean WMH lesion load (LL) was 15.16±16.59 mL. In patients with VaD, who were expected to suffer more from WMHs, the mean WMH LL was 29.22±11.40 mL. In Group 2, the mean WMH LL was 17.77±12.26 mL. Conclusion: This study may contribute to the literature since it is an automatic, unimodal, and unsupervised method that was applied to both a completely unique data set with many different scanning parameters and an open database data set. [ABSTRACT FROM AUTHOR]

Objective: To explore the correlation between the fat attenuation index (FAI) and plaque quantification parameters with brain white matter hyperintensities (WMH). Methods: A retrospective collection of clinical, coronary computed tomography angiography (CCTA) and brain magnetic resonance imaging (MRI) data of 407 patients from January 2021 and December 2022 was conducted. The severity of WMH was assessed using the Fazekas score, dividing patients into mild WMH group (Fazekas score 0-2) and moderate to severe WMH group (Fazekas score 3-6). Clinical data, FAI, and plaque quantification parameters of the two groups were compared to identify independent risk factors for moderate to severe WMH. Results: There were statistically significant differences in FAI and plaque quantification parameters between the two groups (P < 0.05). The results of multivariable logistic regression showed that age (OR=1.116, 95% CI: 1.074-1.160, P < 0.001), coronary artery disease (OR=2.737, 95%CI: 1.270-6.017, P= 0.010), plaque burden (OR=4.142, 95% CI: 1.228-13.977, P=0.022), and FAI >-70.1 HU (OR=5.089, 95%CI: 1.899-13.640, P= 0.001) were independent influencing factors for moderate to severe WMH. Conclusion: Older age, presence of coronary artery disease, higher plaque burden, and FAI>-70.1 HU are associated with a higher likelihood of developing moderate to severe WMH, providing a theoretical basis for the joint management of coronary atherosclerosis and WMH. [ABSTRACT FROM AUTHOR]

Abstract Background Our intent was to explore the mediating role of interstitial free water (FW) linking deep medullary vein (DMV) score to white matter hyperintensity (WMH) volume. Methods Our research team conducted a forward-looking analysis of initial clinical and imaging information gathered from 125 patients with cerebral small vessel disease. We identified six anatomic DMV regions on susceptibility weighted imaging (SWI) studies. Each region earned a score of 0–3, determined by the visual conditions of vessels, summing all six to generate a DMV score. We utilized fluid-attenuated inversion recovery (FLAIR) sequences to measure the volume of WMH. Additionally, we employed diffusion tensor imaging (DTI) to assess FW value. Results DMV score significantly positively correlated with FW value and with WMH volume (p

目的 探讨不同亚型脑白质高信号（white matter hyperintensity，WMH）及脑白质高信号半暗带（white matter hyperintensity penumbra，WMH-P）内血流灌注、微结构损伤与认知障碍的关系。 方法 前瞻性连续纳入2021年5月—2023年3月就诊于唐山市工人医院，WMH为改良Fazekas分级Ⅰ～Ⅱ级的脑小血管病（cerebral small vessel disease，CSVD）患者，进行包括三维动脉自旋标记（three-dimensional arterial spin labeling，3D-ASL）、弥散峰度成像（diffusion kurtosis imaging，DKI）序列在内的3.0 T MRI扫描。分析患者深部脑白质高信号（deep white matter hyperintensity，DWMH）感兴趣区（region of interest，ROI）（界定为ROI1）及其WMH-P感兴趣区（内层为ROI1-1，外层为ROI1-2），脑室旁脑白质高信号（periventricular white matter hyperintensity，PVWMH）感兴趣区（界定为ROI2）及其WMH-P感兴趣区（内层为ROI2-1，外层为ROI2-2）内血流灌注指标——脑血流量（cerebral blood flow，CBF），以及反映微结构改变的指标——轴向扩散系数（axial diffusivity，AD）、平均扩散系数（mean diffusivity，MD）、径向扩散系数（radial diffusivity，RD）、轴向峰度（axial kurtosis，AK）、平均峰度（mean kurtosis，MK）、径向峰度（radial kurtosis，RK）、各向异性分数（fraction anisotropy，FA）。评估患者的认知功能，用Spearman相关分析计算不同亚型WMH（DWMH和PVWMH）及其WMH-P内上述反映血流灌注和微结构改变的指标与认知障碍严重程度的相关性。 结果 共纳入61例CSVD患者，平均年龄（61±1）岁。DWMH（ROI1）内RD值（r=0.296）与认知障碍严重程度呈正相关，MK值（r=－0.287）、RK值（r=－0.315）与认知障碍严重程度呈负相关；其WMH-P内AD值（ROI1-1：r=0.274；ROI1-2：r=0.261）、MD值（ROI1-1：r=0.370；ROI1-2：r=0.387）、RD值（ROI1-1： r=0.411；ROI1-2：r=0.430）与认知障碍严重程度呈正相关，AK值（ROI1-1：r=－0.270；ROI1-2： r=－0.297）、MK值（ROI1-1：r=－0.367；ROI1-2：r=－0.325）、RK值（ROI1-1：r=－0.379；ROI1-2： r=－0.309）、FA值（ROI1-1：r=－0.286；ROI1-2：r=－0.256）与认知障碍严重程度呈负相关。PVWMH（ROI2）内MK值（r=0.354）、RK值（r=0.293）与认知障碍严重程度呈正相关；其WMH-P内各微结构改变的指标与认知障碍严重程度的相关性均无统计学意义。WMH及WMH-P内CBF值与认知障碍严重程度的相关性均无统计学意义。 结论 CSVD患者DWMH及其WMH-P、PVWMH内微结构损伤与认知障碍存在弱相关性，但PVWMH周围WMH-P内的微结构与认知障碍无相关性；WMH及WMH-P内血流灌注与认知障碍无相关性。 Abstract: Objective To investigate the relationship between blood perfusion, microstructural damage that in different subtypes of white matter hyperintensity (WMH) and white matter hyperintensity penumbra (WMH-P), and cognitive impairment. Methods The patients with cerebral small vessel disease (CSVD) patients with the WMH rating of modified Fazekas grade Ⅰ-Ⅱ at Tangshan Gongren Hospital from May 2021 to March 2023 were included. The 3.0 T MRI scan [three-dimensional arterial spin labeling (3D-ASL), diffusion kurtosis imaging (DKI) sequences] were conducted on these patients. The blood perfusion index [cerebral blood flow (CBF)] and the indexes [axial diffusivity (AD), mean diffusivity (MD), radial diffusivity (RD), axial kurtosis (AK), mean kurtosis (MK), radial kurtosis (RK), and fraction anisotropy (FA)] reflecting the microstructural changes within the deep white matter hyperintensity (DWMH) region of interest (ROI1) and its WMH-P (ROI1-1 in the inner layer and ROI1-2 in the outer layer), as well as periventricular white matter hyperintensity (PVWMH) (ROI2) and its WMH-P (ROI2-1 in the inner layer and ROI2-2 in the outer layer) of patients were analyzed. The cognitive function of patients was analyzed. The Spearman correlation was used to analyze the relationship between the above indexes reflecting blood perfusion changes and microstructural changes in different subtypes of WMH (DWMH and PVWMH) and its corresponding WMH-P and the severity of cognitive impairment. Results A total of 61 patients with CSVD were included, with an average age of (61±1) years. The RD value (r=0.296) in DWMH (ROI1) was positively correlated with the severity of cognitive impairment, while the MK value (r=－0.287) and the RK value (r=－0.315) were negatively correlated with the severity of cognitive impairment. The values of AD (ROI1-1: r=0.274; ROI1-2: r=0.261), MD (ROI1-1: r=0.370; ROI1-2: r=0.387), and RD (ROI1-1: r=0.411; ROI1-2: r=0.430) in WMH-P were positively correlated with the severity of cognitive impairment, while the values of AK (ROI1-1: r=－0.270; ROI1-2: r=－0.297), MK (ROI1-1: r=－0.367; ROI1-2: r=－0.325), RK (ROI1-1: r=－0.379; ROI1-2: r=－0.309), and FA (ROI1-1: r=－0.286; ROI1-2: r=－0.256) were negatively correlated with the severity of cognitive impairment. The MK value (r=0.354) and RK value (r=0.293) in PVWMH were positively correlated with the severity of cognitive impairment. There was no significant correlation between the indexes that reflecting the changes of microstructures in WMH-P and cognitive impairment. The CBF values in WMH and WMH-P were not significantly correlated with the severity of cognitive impairment. Conclusions In CSVD patients, the microstructural damages of DWMH, WMH-P of DWMH, and PVWMH were weakly correlated with cognitive impairment, but the microstructure in WMH-P of PVWMH was not correlated with cognitive impairment. In addition, blood perfusion in WMH and WMH-P was not correlated with cognitive impairment.

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

Age-dependent cerebral small vessel disease (CSVD) is a common disease with a high social burden characterized by heterogeneity of forms and frequent comorbidity with Alzheimer's disease (AD). Previously, we identified two MRI types of CSVD with specific clinical presentation and, probably, different mechanisms. The present study included 34 patients with CSVD and white matter hyperintensity (WMH) of stage Fazekas (F) 3 (mean age 61.7 ± 8.9) and 11 volunteers (mean age 57.3 ± 9.7). Total RNA was isolated from peripheral blood leukocytes. The expression of 58 protein-coding genes associated with CSVD and/or AD and 4 reference genes were assessed as part of the original panel for the NanoString nCounter analyzer. Testing results were validated by real-time PCR. There was a significant decrease in the expression levels of the ACOX1, CD33, CD2AP, TNFR1, and VEGFC genes in MRI type 2 relative to the control group as well as a decrease in the expression level of the CD33 gene in MRI type 2 compared to MRI type 1. Processes associated with inflammatory pathways with decreased expression of the identified genes are important in the development of MRI type 2 of CSVD. Given the direct connection of the established genes with AD, the importance of this form of CSVD in comorbidity with AD has been assumed. [ABSTRACT FROM AUTHOR]

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Background: Stroke patients with coexisting intracranial artery stenosis (ICAS) and white matter lesions (WML) usually have a poor outcome. However, how WML affects stroke prognosis has not been determined. Objective: To investigate the quantitative forward flow at the middle cerebral artery in ICAS patients with different degrees of WML using 4D flow. Design: Single-center cross-sectional cohort study. Methods: Ischemic stroke patients with symptomatic middle cerebral artery (MCA) atherosclerosis were included, and they were divided into 2 groups based on Fazekas scale on Flair image (mild group = Fazekas 0-2, and severe group = Fazekas >2), TOF-MRA and 4D flow were performed to quantify the stenosis degree and forward flow at the proximal of stenosis. The flow parameters were compared between different white matter hyperintensity (WMH) groups, as well as in different MCA stenosis groups, logistic regression was used to validate the association between forward flow and WMH. Results: A total of 66 patients were included in this study (mean age 56 years old, 68.2% male). 77.3% of them presented with WMH (Fazekas 1-5). Comparison of flow index between mild and severe WMH groups found a significantly lower forward flow (2.34 ± 1.09 vs 3.04 ± 1.35), higher PI (0.75 ± 0.43 vs 0.66 ± 0.32), and RI (0.49 ± 0.19 vs 0.46 ± 0.15) at ipsilateral infarction MCA in the severe WMH group, all P -values <0.05. After adjusting for other covariates, forward mean flow at ipsilateral infarction MCA is still associated with severe WMH independently, OR = 0.537, 95% CI (0.294, 0.981), P = 0.043. Conclusion: Intracranial artery stenosis patients with coexisting severe WMH suffer from significantly decreased flow, which could explain the poor clinical outcome in this population, and also provide some insight into recanalization therapy in the future. Plain language summary: Why was the study done? stroke patients with intracranial artery stenosis (ICAS) have a high prevalence of white matter hyperintensities (WMH), a surrogate biomarker of small vessel disease (SVD), and patients with coexisting ICAS and WMH are more likely to have unfavorable clinical outcomes and higher stroke recurrence risk. However, how WMH affects stroke outcomes has been unknown. What did the researchers do? In this study, we compared the flow and perfusion index between different WMH groups, as well as in different ICAS groups using 4D flow combined with ASL, to obtain the quantitative flow relationship in this population. What did the researchers find? As a result, we found that both the degree of intracranial artery stenosis and WMH burden is associated with decreased flow, and the flow decrease is more significant at the ipsilateral of infarct. What do the findings mean? This is the first study investigating the complicated hemodynamic status using 4D flow combined with ASL in stroke patients with coexisting ICAS and WMH. The results in this study could not only provide some evidence for unfavorable clinical outcomes in ICAS patients with severe WMH burden but also give us some insight into recanalization therapy in this population. [ABSTRACT FROM AUTHOR]

Background: As key regulators of gene expression, microRNAs affect many cardiovascular mechanisms and have been associated with several cardiovascular diseases. In this study, we aimed to investigate the relation of whole blood microRNAs with several quantitative measurements of vascular function, and explore their biological role through an integrative microRNA-gene expression analysis. Methods: Peripheral whole blood microRNA expression was assessed through RNA-Seq in 2606 participants (45.8% men, mean age: 53.93, age range: 30 to 95 years) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Weighted gene co-expression network analysis was used to cluster microRNAs with highly correlated expression levels into 14 modules. Through linear regression models, we investigated the association between each module's expression and quantitative markers of vascular health, including pulse wave velocity, total arterial compliance index, cardiac index, stroke index, systemic vascular resistance index, reactive skin hyperemia and white matter hyperintensity burden. For each module associated with at least one trait, one or more hub-microRNAs driving the association were defined. Hub-microRNAs were further characterized through mapping to putative target genes followed by gene ontology pathway analysis. Results: Four modules, represented by hub-microRNAs miR-320 family, miR-378 family, miR-3605-3p, miR-6747-3p, miR-6786-3p, and miR-330-5p, were associated with total arterial compliance index. Importantly, the miR-320 family module was also associated with white matter hyperintensity burden, an effect partially mediated through arterial compliance. Furthermore, hub-microRNA miR-192-5p was related to cardiac index. Functional analysis corroborated the relevance of the identified microRNAs for vascular function by revealing, among others, enrichment for pathways involved in blood vessel morphogenesis and development, angiogenesis, telomere organization and maintenance, and insulin secretion. Conclusions: We identified several microRNAs robustly associated with cardiovascular function, especially arterial compliance and cardiac output. Moreover, our results highlight miR-320 as a regulator of cerebrovascular damage, partly through modulation of vascular function. As many of these microRNAs were involved in biological processes related to vasculature development and aging, our results contribute to the understanding of vascular physiology and provide putative targets for cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno‐associated virus delivery of vascular endothelial growth factor‐C (VEGF‐C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF‐C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: Although white matter hyperintensity (WMH) is closely associated with cognitive decline, the precise neurobiological mechanisms underlying this relationship are not fully elucidated. Connectome studies have identified a primary‐to‐transmodal gradient in functional brain networks that support the spectrum from sensation to cognition. However, whether connectome gradient structure is altered as WMH progresses and how this alteration is associated with WMH‐related cognitive decline remain unknown. Methods: A total of 758 WMH individuals completed cognitive assessment and resting‐state functional MRI (rs‐fMRI). The functional connectome gradient was reconstructed based on rs‐fMRI by using a gradient decomposition framework. Interrelations among the spatial distribution of WMH, functional gradient measures, and specific cognitive domains were explored. Results: As the WMH volume increased, the executive function (r = −0.135, p = 0.001) and information‐processing speed (r = −0.224, p = 0.001) became poorer, the gradient range (r = −0.099, p = 0.006), and variance (r = −0.121, p < 0.001) of the primary‐to‐transmodal gradient reduced. A narrower gradient range (r = 0.131, p = 0.001) and a smaller gradient variance (r = 0.136, p = 0.001) corresponded to a poorer executive function. In particular, the relationship between the frontal/occipital WMH and executive function was partly mediated by gradient range/variance of the primary‐to‐transmodal gradient. Conclusions: These findings indicated that WMH volume, the primary‐to‐transmodal gradient, and cognition were interrelated. The detrimental effect of the frontal/occipital WMH on executive function was partly mediated by the decreased differentiation of the connectivity pattern between the primary and transmodal areas. [ABSTRACT FROM AUTHOR]

Although hyperintensity in the anterior portion of the callosal splenium on FLAIR (aCS-hyperintensity) is a common finding in elderly adults, no previous studies have examined the clinical significance. In this large elderly population study, we aimed to investigate the associations of aCS-hyperintensity with vascular risk factors, cognitive decline, and other MRI measurements. This cross-sectional study included 2110 participants (median age, 69 years; 61.1% females) who underwent 3 T MRI. The participants were grouped as 215 with mild cognitive impairment (MCI) and 1895 cognitively normal older adults (NOAs). Two neuroradiologists evaluated aCS-hyperintensity by using a four-point scale (none, mild, moderate, and severe). Periventricular hyperintensities (PVHs) were also rated on a four-point scale according to the Fazekas scale. The total intracranial volume (ICV), total brain volume, choroid plexus volume (CPV), and lateral ventricle volume (LVV) were calculated. Logistic regression analysis showed diabetes was the main predictor of aCS-hyperintensity after adjusting for potential confounders (age, sex, hypertension, and hyperlipidemia) (p < 0.01), whereas PVH was associated with hypertension (p < 0.01). aCS-hyperintensity rated as "severe" was associated with a presence of MCI (p < 0.01). For the imaging factors, LVV was an independent predictor of aCS-hyperintensity when brain volume and PVH grade were added to the analysis (p < 0.01). Cerebral small vessel disease due to diabetes is a major contributor to the development of aCS-hyperintensity. Cerebrospinal fluid clearance failure may also relate to aCS-hyperintensity, which may offer new insights into the pathologic processes underlying MCI. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Despite prior research on the association between sarcopenia and cognitive impairment in the elderly, a comprehensive model that integrates various brain pathologies is still lacking. METHODS: We used data from 528 non‐demented older adults with or without sarcopenia in the Catholic Aging Brain Imaging (CABI) database, containing magnetic resonance imaging scans, positron emission tomography scans, and clinical data. We also measured three key components of sarcopenia: skeletal muscle index (SMI), hand grip strength (HGS), and the five times sit‐to‐stand test (5STS). RESULTS: All components of sarcopenia were significantly correlated with global cognitive function, but cortical thickness and amyloid‐beta (Aβ) retention had distinctive relationships with each measure. In the path model, brain atrophy resulting in cognitive impairment was mediated by Aβ retention for SMI and periventricular white matter hyperintensity for HGS, but directly affected by the 5STS. DISCUSSION: Treatments targeting each sub‐domain of sarcopenia should be considered to prevent cognitive decline. Highlights: We identified distinct impacts of three sarcopenia measures on brain structure and Aβ.Muscle mass is mainly associated with Aβ and has an influence on the brain atrophy.Muscle strength linked with periventricular WMH and brain atrophy.Muscle function associated with cortical thinning in specific brain regions.Interventions on sarcopenia may be important to ease cognitive decline in the elderly. [ABSTRACT FROM AUTHOR]

Introduction: Literature suggests a common pathophysiological ground between carotid atherosclerosis (CAS) and white matter alterations in the brain. However, the association between carotid intima-media thickness (CIMT) and white matter hyperintensities (WMH) has not been conclusively reported. The current systematic review explores and reports the relationship between CIMT and WMH among asymptomatic/non-stroke adults. Methods: A recent literature search on PubMed, SCOPUS, and Web of Science databases was conducted in compliance with the PRISMA protocol. The pre-defined Population-Intervention-Comparison-Outcome-Study (PICOS) criteria included observational studies investigating the CIMT-WMH association among non-stroke adults undergoing magnetic resonance imaging and carotid ultrasound. Results: Out of 255 potential results, 32 studies were critically assessed for selection, and finally, 10 articles were included, comprising 5,116 patients (females = 60.2%; males = 39.8%) aged between 36-71 years. The included studies earned high quality ratings (6-9) based on the Newcastle-Ottawa-Scale criteria. Qualitative synthesis showed a significantly parallel relationship between increased CIMT and greater WMH burden in 50% of the studies. In addition, significant risk factors related to the CIMT-WMH association included older age, hypertension, depression, migraine, Hispanic ethnicity, and apolipoprotein E (ɛ4) in postmenopausal women. Conclusion: Overall, the cumulative evidence showed a consistent CIMT-WMH association in asymptomatic middle-aged and older non-stroke adults, indicating that CAS may contribute to the progression of pathologically hyperintense white matter in the brain. However, further research is warranted to infer the plausible relationship between CIMT and WMH in the absence of stroke. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to identify predictors of severe white matter hyperintensity (WMH) with obesity (SWO), and to build a prediction model for screening obese people with severe WMH without Nuclear Magnetic Resonance Imaging (MRI) examination. Patients subjects and methods: From September 2020 to October 2021, 650 patients with WMH were recruited consecutively. The subjects were divided into two groups, SWO group and non-SWO group. Univariate and Logistic regression analysis were was applied to explore the potential predictors of SWO. The Youden index method was adopted to determine the best cut-off value in the establishment of the prediction model of SWO. Each parameter had two options, low and high. The score table of the prediction model and nomogram based on the logistic regression were constructed. Of the 650 subjects, 487 subjects (75%) were randomly assigned to the training group and 163 subjects (25%) to the validation group. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. Results: Logistic regression demonstrated that hypertension, uric acid (UA), complement 3 (C3) and Interleukin 8 (IL-8) were independent risk factors for SWO. Hypertension, UA, C3, IL-8, folic acid (FA), fasting C-peptide (FCP) and eosinophil could be used to predict the occurrence of SWO in the prediction models, with a good diagnostic performance, Areas Under Curves (AUC) of Total score was 0.823 (95% CI: 0.760--0.885, p < 0.001), sensitivity of 60.0%, specificity of 91.4%. In the development group, the nomogram's AUC (C statistic) was 0.829 (95% CI: 0.760--0.899), while in the validation group, it was 0.835 (95% CI: 0.696, 0.975). In both the development and validation groups, the calibration curves following 1,000 bootstraps showed a satisfactory fit between the observed and predicted probabilities. DCA showed that the nomogram had great clinical utility. Conclusion: Hypertension, UA, C3, IL-8, FA, FCP and eosinophil models had the potential to predict the incidence of SWO. When the total score of the model exceeded 9 points, the risk of SWO would increase significantly, and the nomogram enabled visualization of the patient's WMH risk. The application prospect of our models mainly lied in the convenient screening of SWO without MRI examination in order to detect SWO and control the WMH hazards early. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMHs) are associated with higher anxiety or depression (A/D) incidence. We investigated associations of WMHs with A/D, cerebrovascular reactivity (CVR), and functional connectivity (FC) to identify potential pathomechanisms. Participants with WMH (n = 239) and normal controls (NCs, n = 327) were assessed for A/D using the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD). The CVR and FC maps were constructed from resting-state functional MRI. Two-way analysis of covariance with fixed factors A/D and WMH was performed to identify regional CVR abnormalities. Seed-based FC analyses were then conducted on regions with WMH × A/D interaction effects on CVR. Logistic regression models were constructed to examine the utility of these measurements for identifying WMH-related A/D. Participants with WMH related A/D exhibited significantly greater CVR in left insula and lower CVR in right superior frontal gyrus (SFG.R), and HAMA scores were negatively correlated with CVR in SFG.R (r = −0.156, P = 0.016). Insula–SFG.R negative FC was significantly weaker in WMH patients with suspected or definite A/D. A model including CVR plus FC changes identified WMH-associated A/D with highest sensitivity and specificity. In contrast, NCs with A/D exhibited greater CVR in prefrontal cortex and stronger FC within the default mode network (DMN) and between the DMN and executive control network. This cross-sectional study requires validation by longitudinal and laboratory studies. Impaired CVR in SFG.R and weaker negative FC between prefrontal cortex and insula may contribute to WMH-related A/D, providing potential diagnostic imaging markers and therapeutic targets. • Impaired CVR in right superior frontal gyrus can aggravate WMH related anxiety or depression. • Negative hyper-connectivity of prefrontal-insula existed in WMH with anxiety or depression. • Altered CVR and FC were both potential imaging markers of WMH-related anxiety or depression. • The CVR and FC were increased as compensation in control subjects with anxiety or depression. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Age‐related magnetic resonance imaging (MRI) T2 white matter hyperintensities (WMHs) are common and associated with neurological decline. We investigated the histopathological underpinnings of MRI WMH and surrounding normal appearing white matter (NAWM), with a focus on astroglial phenotypes. METHODS: Brain samples from 51 oldest old Oregon Alzheimer's Disease Research Center participants who came to autopsy underwent post mortem (PM) 7 tesla MRI with targeted histopathological sampling of WMHs and NAWM. Stained slides were digitized and quantified. Mixed‐effects models determined differences in molecular characteristics between WMHs and the NAWM and across NAWM. RESULTS: PM MRI‐targeted WMHs are characterized by demyelination, microglial activation, and prominent astrocytic alterations, including disrupted aquaporin (AQP) expression. Similar changes occur within the surrounding NAWM in a pattern of decreasing severity with increased distance from WMHs. DISCUSSION: Decreased AQP expression within WMH and proximal NAWM suggest an overwhelmed system wherein water homeostasis is no longer maintained, contributing to WM damage in older individuals. Highlights: Post mortem magnetic resonance imaging (MRI) was used to characterize the pathology of white matter hyperintensities (WMHs) and surrounding normal appearing white matter (NAWM).Stained immunohistochemical (IHC) slides from targeted WMH and NAWM samples were digitized and quantified.WMHs and NAWM were associated with inflammation, demyelination, and gliosis.WMHs and NAWM astrocytic changes included decreased AQP1 and AQP4 expression.Abnormal NAWM pathology diminished in severity with increasing distance from WMH. [ABSTRACT FROM AUTHOR]

Background White matter hyperintensities (WMH) and their progression are associated with risk of dementia and stroke, so are an important target for clinical trials. The cost of broad magnetic resonance imaging (MRI) screening to identify eligible individuals, however, limits the feasibility of designing clinical trials targeting WMH. A low‐cost retinal or clinical screening measure before MRI could reduce recruitment costs versus an MRI‐only screening design in a hypothetical clinical trial. Methods and Results Data from the Atherosclerosis Risk in Communities study with valid retinal and WMH measurements (N=1311) were used. To identify a population at greater likelihood of significant WMH on MRI and thus reduce the number of screening MRIs required, we evaluated 3 theoretical prescreening measures: (1) retinal, (2) clinical, (3) combined clinical‐retinal. Given a target sample for clinical trials (N=646), we calculated screening sample sizes based on the proportion within the population having an elevated score for each prescreening measure (separately) multiplied by the proportion of significant WMH among those with that prescreening feature. Recruitment costs were calculated using estimated retinal and MRI cost estimates. Compared with the estimated cost of MRI‐only screening (>$4.24 million, requiring MRI on 6526 participants), prescreening for a high clinical score resulted in total cost of $2.47 million, with an initial screening group of 52 778 participants, with MRI in 3801. A high clinical‐retinal score cutoff resulted in costs of $2.9 million while requiring 13 572 participants, with 3801 completing MRI. Conclusions A 2‐stage design with low‐cost prescreening measures is a promising approach, resulting in reduced theoretical recruitment costs compared with an MRI‐only design.

Abstract We aimed to develop a new artificial intelligence software that can automatically extract and measure the volume of white matter hyperintensities (WMHs) in head magnetic resonance imaging (MRI) using only thick-slice fluid-attenuated inversion recovery (FLAIR) sequences from multiple centers. We enrolled 1092 participants in Japan, comprising the thick-slice Private Dataset. Based on 207 randomly selected participants, neuroradiologists annotated WMHs using predefined guidelines. The annotated images of participants were divided into training (n = 138) and test (n = 69) datasets. The WMH segmentation model comprised a U-Net ensemble and was trained using the Private Dataset. Two other models were trained for validation using either both thin- and thick-slice MRI datasets or the thin-slice dataset alone. The voxel-wise Dice similarity coefficient (DSC) was used as the evaluation metric. The model trained using only thick-slice MRI showed a DSC of 0.820 for the test dataset, which is comparable to the accuracy of human readers. The model trained with the additional thin-slice dataset showed only a slightly improved DSC of 0.822. This automatic WMH segmentation model comprising a U-Net ensemble trained on a thick-slice FLAIR MRI dataset is a promising new method. Despite some limitations, this model may be applicable in clinical practice.

Abstract Background Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations. Methods We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61–73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter. Results After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals. Conclusions These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

Abstract Background Growing evidence suggests that not only cerebrovascular disease but also Alzheimer’s disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aβ) and tau deposition, and WMHs through longitudinal approach. Methods Total 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aβ or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aβ or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies. Results Baseline Aβ deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aβ or tau deposition for 2 years. We also found a significant interaction effect between baseline Aβ deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female, but not in male. Conclusions Our findings suggest that Aβ deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aβ increase. The results also did not support any direction of influence between tau deposition and WMHs.

Abstract Background The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for VCI in patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. The primary objective of this research was to investigate the relationship between peripheral serological markers, white matter damage, and cognitive function in individuals with NICE. Methods We collected clinical data, demographic information, and medical history from 257 patients with NICE. Using the MoCA upon admission, patients were categorized into either normal cognitive function (NCF) or VCI groups. Furthermore, they were classified as having mild white matter hyperintensity (mWMH) or severe WMH based on Fazekas scores. We then compared the levels of serological markers between the cognitive function groups and the WMH groups. Results Among 257 patients with NICE, 165 were male and 92 were female. Lymphocyte count (OR = 0.448, P

Background: Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear. Aim: We investigated associations between carotid atherosclerosis and cognitive function and neuroimaging markers of brain health in a UK multi-ethnic community-based sample including older people of European, South Asian, and African-Caribbean ethnicity. Methods: Carotid plaques and intima-media thickness (cIMT) were assessed using ultrasound in 985 people (mean age 73.2y, 56 % male). Associations of carotid atherosclerosis with cognitive function (memory, executive function, language and CSI-D, a global measure of cognitive state) and neuroimaging measures (total brain volume, hippocampal volume, white matter (WM) lesion volume and coalescence score) were analysed using regression analyses, with and without adjustment for potential confounders using two models: 1) adjustment for age, sex, and ethnicity; 2) model 1 plus education, physical activity category, body mass index, hypertension, diabetes, total and high density lipoprotein cholesterol, atrial fibrillation, smoking, previous CVD, alcohol consumption, and presence of chronic kidney disease. Results: People with carotid plaque or higher cIMT had lower CSI-D score, poorer memory poorer executive function and higher WM lesion volume and coalescence. Language was poorer in people with plaque but was not correlated with cIMT. Associations with plaque were preserved after full adjustment (model 2) but relationships for cIMT were attenuated. Associations with other plaque characteristics were generally unconvincing after adjustment. Conclusions: This multi-ethnic cohort study provides evidence that presence of carotid plaque, is associated with poorer cognitive function and brain health.

AbstractPurpose: There is evidence that blood pressure variability (BPV) is associated with cerebral small vessel disease (SVD) and may therefore increase the risk of stroke and dementia. It remains unclear if BPV is associated with SVD progression over years. We examined whether visit-to-visit BPV is associated with white matter hyperintensity (WMH) progression over 14 years and MRI markers after 14 years.Materials and methods: We included participants with SVD from the Radboud University Nijmegen Diffusion tensor Magnetic resonance-imaging Cohort (RUNDMC) who underwent baseline assessment in 2006 and follow-up in 2011, 2015 and 2020. BPV was calculated as coefficient of variation (CV) of BP at all visits. Association between WMH progression rates over 14 years and BPV was examined using linear-mixed effects (LME) model. Regression models were used to examine association between BPV and MRI markers at final visit in participants.Results: A total of 199 participants (60.5 SD 6.6 years) who underwent four MRI scans and BP measurements were included, with mean follow-up of 13.7 (SD 0.5) years. Systolic BPV was associated with higher progression of WMH (β = 0.013, 95% CI 0.005 − 0.022) and higher risk of incident lacunes (OR: 1.10, 95% CI 1.01–1.21). There was no association between systolic BPV and grey and white matter volumes, Peak Skeleton of Mean Diffusivity (PSMD) or microbleed count after 13.7 years.Conclusions: Visit-to-visit systolic BPV is associated with increased progression of WMH volumes and higher risk of incident lacunes over 14 years in participants with SVD. Future studies are needed to examine causality of this association.

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P

BackgroundWhite matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease.ObjectiveConducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol.MethodsThe NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity.ResultsICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression.ConclusionsThe present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Background: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Methods: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. Results: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Conclusion: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone. [ABSTRACT FROM AUTHOR]

We aimed to develop a new artificial intelligence software that can automatically extract and measure the volume of white matter hyperintensities (WMHs) in head magnetic resonance imaging (MRI) using only thick-slice fluid-attenuated inversion recovery (FLAIR) sequences from multiple centers. We enrolled 1092 participants in Japan, comprising the thick-slice Private Dataset. Based on 207 randomly selected participants, neuroradiologists annotated WMHs using predefined guidelines. The annotated images of participants were divided into training (n = 138) and test (n = 69) datasets. The WMH segmentation model comprised a U-Net ensemble and was trained using the Private Dataset. Two other models were trained for validation using either both thin- and thick-slice MRI datasets or the thin-slice dataset alone. The voxel-wise Dice similarity coefficient (DSC) was used as the evaluation metric. The model trained using only thick-slice MRI showed a DSC of 0.820 for the test dataset, which is comparable to the accuracy of human readers. The model trained with the additional thin-slice dataset showed only a slightly improved DSC of 0.822. This automatic WMH segmentation model comprising a U-Net ensemble trained on a thick-slice FLAIR MRI dataset is a promising new method. Despite some limitations, this model may be applicable in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: White matter hyperintensity (WMH) is suggested to cause stroke and dementia in older adults. Retinal structural thicknesses revealed by optical coherence tomography (OCT) are associated with structural changes in the brain. We aimed to explore the association between the peripapillary retinal nerve fiber layer (RNFL) and cerebral microstructural changes in participants with white matter hyperintensities (WMH). Methods: Seventy-four participants (37 controls, healthy control (HC), and 37 older adults with WMH) underwent retinal and brain imaging using OCT and magnetic resonance imaging (MRI) respectively. Peripapillary RNFL thickness was assessed by the OCT. Gray matter volume (GMV) was assessed from a T1-weighted MRI. White matter integrity was assessed with diffusion tensor imaging (DTI) while WMH severity was assessed with the Fazekas scale. All participants underwent a neuropsychological examination (Mini-Mental State Examination, MMSE). Results: Older adults with WMH showed thinner peripapillary RNFL (p = 0.004) thickness when compared with the control group after adjusting for age, hypertension and gender. In our older adults with WMH, RNFL thickness correlated with fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) (Rho = -0.331, p < 0.001). In older adults with WMH, RNFL was significantly associated with MMSE scores (Rho = 0.422, p < 0.001) and Fazekas scores (Rho = -0.381, p = 0.022) respectively. Conclusions: We suggest neurodegeneration of peripapillary RNFL in older adults with WMH was associated with cerebral microstructural volume, impaired cerebral axonal damage, and cognitive performances. OCT metrics may provide evidence of neurodegeneration that may underpin WMH and cerebral microstructural changes in the brain. Clinical Trial Registration: This study was registered online at the China Clinical Trial Registration Center (registration number: ChiCTR-ROC-17011819). [ABSTRACT FROM AUTHOR]

Background: Despite previous research suggesting a potential association between cerebral small vessel disease (CSVD) and epilepsy, the precise causality and directionality between cerebral small vessel disease (CSVD) and epilepsy remain incompletely understood. We aimed to investigate the causal link between CSVD and epilepsy. Method: A bidirectional two-sample Mendelian randomization (MR) analysis was performed to evaluate the causal relationship between CSVD and epilepsy. The analysis included five dimensions of CSVD, namely small vessel ischemic stroke (SVS), intracerebral hemorrhage (ICH), white matter damage (including white matter hyperintensity [WMH], fractional anisotropy, and mean diffusivity), lacunar stroke, and cerebral microbleeds. We also incorporated epilepsy encompassing both focal epilepsy and generalized epilepsy. Inverse variance weighted (IVW) was used as the primary estimate while other four MR techniques were used to validate the results. Pleiotropic effects were controlled by adjusting vascular risk factors through multivariable MR. Result: The study found a significant association between SVS (odds ratio [OR] 1.117, PFDR = 0.022), fractional anisotropy (OR 0.961, PFDR = 0.005), mean diffusivity (OR 1.036, PFDR = 0.004), and lacunar stroke (OR 1.127, PFDR = 0.007) with an increased risk of epilepsy. The aforementioned correlations primarily occurred in focal epilepsy rather than generalized epilepsy on subgroup analysis and retained their significance in the multivariable MR analysis. Conclusion: Our study demonstrated that genetic susceptibility to CSVD independently elevates the risk of epilepsy, especially focal epilepsy. Diffusion tensor imaging may help screen patients at high risk for epilepsy in CSVD. Improved management of CSVD may be a significant approach in reducing the overall prevalence of epilepsy. [ABSTRACT FROM AUTHOR]

Background: The evidence for the association between white matter hyperintensity (WMH) severity and neurological deterioration (ND) in patients with single subcortical infarction (SSI) remains unclear and whether the association between them is modified by anterior circulation parent artery steno‐occlusion (PAS) is unknown. Herein, we aimed to prospectively investigate the internal relevance. Methods: In this prospective study, the severity of WMH and PAS were assessed in 288 consecutive patients with anterior circulation SSI arriving at our hospital, a tertiary teaching hospital affiliated with Fudan University, 24 h after onset from January 2017 to December 2018. The multivariable logistic regression model was used to estimate the association between WMH severity and the risk of ND within 7 days after stroke onset as well as the interactive effect between WMH severity and PAS on ND among patients with SSI. Results: PAS modified the association between WMH severity and ND among patients with SSI (pinteraction =.029). After multivariate adjustment, the odds ratios of moderate‐severe WMH associated with ND were 1.61 (95% CI, 0.50–5.19; ptrend =.428) for patients with PAS, and 0.37 (95% CI, 0.14–0.97; ptrend =.043) for those without PAS. Adding WMH severity to conventional risk factors improved risk prediction for ND in patients without PAS (net reclassification improvement: 48.2%, p =.005; integrated discrimination index: 2.5%, p =.004) but not in those with PAS. Conclusion: There was a modified effect of PAS on the association between WMH severity and ND within 7 days after stroke onset among patients with anterior circulation SSI, which deserves more research attention. WMH was negatively associated with ND in anterior circulation SSI patients without PAS. [ABSTRACT FROM AUTHOR]

Discontinuation of the deep medullary veins (DMVs) may be an early imaging marker for identifying cognitive impairment caused by cerebral small vessel disease (CSVD). However, this method lacks mechanistic exploration. We aimed to investigate whether the DMV score is related to CSVD imaging markers and cognitive impairment in patients with CSVD. This retrospective study included patients with CSVD who completed DMV score and cognition (e.g., MMSE, MoCA) assessments, and underwent MRI scanning (T2-FLAIR for white matter hyperintensities (WMH) volume, T1-weighted MRI for brain parenchymal fractions (BPF) analysis, and SWI for assessment of DMV score). The CSVD imaging markers were quantitatively assessed using the AccuBrain® system. We assessed the diagnostic value of neuroimaging biomarkers for detecting CSVD-related cognitive impairment. In addition, we explored the relationship between the DMV score, CSVD imaging markers, and cognition using mediation analysis. Ninety-four patients with CSVD were divided into a cognitive impairment group (n = 39) and a non-cognitive impairment group (n = 55). Higher DMV scores, larger WMH volumes, and smaller BPF were observed in the cognitive impairment group than those in the non-cognitive impairment group. Receiver operating characteristics (ROC) analysis revealed that the discovery value of the integration of patient age, BPF, whole WMH volume, and DMV score for cognitive impairment was 0.742, with a sensitivity and specificity of 79.5 % and 61.5 %, respectively. Mediation analysis showed mediation by WMH and BPF in the relationship between DMV score and cognitive impairment (all P < 0.05). This study did not evaluate the DMV score in subregions according to DMV anatomy. The DMV score is significantly associated with cognitive impairment in patients with CSVD, and this association is mediated through WMH and BPF. • We aimed to investigate DMV score and WMH in CSVD. • We included 94 CSVD patients. • DMV scores were associated with cognitive impairment in CSVD patients. • This association is mediated through WMH and brain parenchymal fraction. [ABSTRACT FROM AUTHOR]

Background: High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in ischemic stroke. However, the role of NLR in cerebral small vessel disease (CSVD) is controversial. Herein, we evaluated the value of NLR in identifying CSVD and its relationship with the common imaging markers of CSVD. Methods: A total of 667 patients were enrolled in this study, including 368 in the CSVD group and 299 in the non‐CSVD group. Clinical, laboratory, and imaging data were collected. The relationship of NLR with CSVD and common imaging markers of CSVD were analyzed with univariate and multivariate logistic regression analysis. The predictive value of NLR was assessed with the receiver operating characteristic curve. Results: NLR (odds ratio [OR] = 1.929, 95% confidence interval [CI] = 1.599–2.327, p <.001) was an independent risk factor for CSVD. NLR was also independently associated with moderate to severe white matter hyperintensity (WMH) (OR = 2.136, 95% CI = 1.768–2.580, p <.001), moderate to severe periventricular WMH (OR = 2.138, 95% CI = 1.771–2.579, p <.001), and moderate to severe deep WMH (OR = 1.654, 95% CI = 1.438–1.902, p <.001), moderately to severely enlarged perivascular spaces (EPVS) (OR = 1.248, 95% CI = 1.110–1.402, p <.001), moderately to severely EPVS in the basal ganglia (OR = 1.136, 95% CI = 1.012–1.275, p =.030), and moderately to severely EPVS in the centrum semiovale (OR = 1.140, 95% CI = 1.027–1.266, p =.014). However, NLR was not statistically significantly associated with lacune. The optimal cutoff point of NLR in predicting CSVD was 2.47, with sensitivity and specificity of 84.2% and 66.9%, respectively (p <.01). The diagnostic effect was maximized when NLR was combined with other risk factors. Conclusions: NLR is an independent risk factor for CSVD and is independently associated with common imaging markers of CSVD. NLR may serve as a valid and convenient biomarker for assessing CSVD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: While elevated blood glial fibrillary acidic protein (GFAP) has been associated with brain amyloid pathology, whether this association occurs in populations with high cerebral small vessel disease (CSVD) concomitance remains unclear. METHODS: Using a Singapore‐based cohort of cognitively impaired subjects, we assessed associations between plasma GFAP and neuroimaging measures of brain amyloid and CSVD, including white matter hyperintensities (WMH). We also examined the diagnostic performance of plasma GFAP in detecting brain amyloid beta positivity (Aβ+). RESULTS: When stratified by WMH status, elevated brain amyloid was associated with higher plasma GFAP only in the WMH– group (β = 0.383; P < 0.001). The diagnostic performance of plasma GFAP in identifying Aβ+ was significantly higher in the WMH– group (area under the curve [AUC] = 0.896) than in the WMH+ group (AUC = 0.712, P = 0.008). DISCUSSION: The biomarker utility of plasma GFAP in detecting brain amyloid pathology is dependent on the severity of concomitant WMH. Highlight: Glial fibrillary acidic protein (GFAP)'s association with brain amyloid is unclear in populations with high cerebral small vessel disease (CSVD).Plasma GFAP was measured in a cohort with CSVD and brain amyloid.Plasma GFAP was better in detecting amyloid in patients with low CSVD versus high CSVD.Biomarker utility of GFAP in detecting brain amyloid depends on the severity of CSVD. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests that not only cerebrovascular disease but also Alzheimer’s disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aβ) and tau deposition, and WMHs through longitudinal approach. Methods: Total 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aβ or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aβ or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies. Results: Baseline Aβ deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aβ or tau deposition for 2 years. We also found a significant interaction effect between baseline Aβ deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female, but not in male. Conclusions: Our findings suggest that Aβ deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aβ increase. The results also did not support any direction of influence between tau deposition and WMHs. [ABSTRACT FROM AUTHOR]