White Matter Hyperintensities Research Articles

Retinal Ischemic Perivascular Lesion Reflects Cerebral Small Vessel Disease Burden in Single Subcortical Infarction.

Retinal ischemic perivascular lesions (RIPLs) are an indicator of ischemia in the middle retina. We aimed to determine the relationship between RIPLs and single subcortical infarction (SSI). We also investigated the differences in cerebral small vessel disease imaging burden between groups with and without RIPLs in SSI. In this case-control study, we enrolled 82 patients with SSI and 72 nonstroke controls. All participants underwent magnetic resonance imaging and swept-source optical coherence tomography/optical coherence tomography angiography. Small vessel disease markers such as lacunes, cerebral microbleeds, white matter hyperintensity, and perivascular spaces were rated on brain imaging. RIPLs were assessed via swept-source optical coherence tomography. Optical coherence tomography angiography was used to measure the superficial vascular complex and deep vascular complex of the retina. After adjusting for risk factors, the presence of RIPLs was significantly associated with SSI (odds ratio [OR], 1.506 [95% CI, 1.365-1.662], P<0.001). Eyes with RIPLs showed lower deep vascular complex density (P=0.035) compared with eyes without RIPLs in patients with SSI. After adjusting for vascular risk factors, the presence of RIPLs in patients with SSI was associated with an increased periventricular white matter hyperintensity burden (β=0.414 [95% CI, 0.181-0.647], P<0.001) and perivascular spaces-basal ganglia (β=0.296 [95% CI, 0.079-0.512], P=0.008). RIPLs are associated with SSI independent of underlying risk factors. The relationship between the presence of RIPLs and small vessel disease markers provides evidence that RIPLs might be an additional indicator of cerebral ischemic changes.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

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.

The impact of sunlight exposure on brain structural markers in the UK Biobank

Sunlight is closely intertwined with daily life. It remains unclear whether there are associations between sunlight exposure and brain structural markers. General linear regression analysis was used to compare the differences in brain structural markers among different sunlight exposure time groups. Stratification analyses were performed based on sex, age, and diseases (hypertension, stroke, diabetes). Restricted cubic spline was performed to examine the dose–response relationship between natural sunlight exposure and brain structural markers, with further stratification by season. A negative association of sunlight exposure time with brain structural markers was found in the upper tertile compared to the lower tertile. Prolonged natural sunlight exposure was associated with the volumes of total brain (β: − 0.051, P < 0.001), white matter (β: − 0.031, P = 0.023), gray matter (β: − 0.067, P < 0.001), and white matter hyperintensities (β: 0.059, P < 0.001). These associations were more pronounced in males and individuals under the age of 60. The results of the restricted cubic spline analysis showed a nonlinear relationship between sunlight exposure and brain structural markers, with the direction changing around 2 h of sunlight exposure. This study demonstrates that prolonged exposure to natural sunlight is associated with brain structural markers change.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study

BackgroundSphingolipids 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.MethodsBrain 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.ResultsIn 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 = &amp;lt; 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 = &amp;lt;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.ConclusionOverall, 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.

Artificial intelligence for volumetric measurement of cerebral white matter hyperintensities on thick-slice fluid-attenuated inversion recovery (FLAIR) magnetic resonance images from multiple centers

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.

Predicting amyloid-PET and clinical conversion in apolipoprotein E ε3/ε3 non-demented individuals with multidimensional factors.

The apolipoprotein E (APOE) ε4 is a well-established risk factor of amyloid-β (Aβ) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non-demented and have Aβ pathology. There are limited studies on assessing Aβ status and clinical conversion in the APOE ε3/ε3 non-demented population. Two hundred and ninety-three non-demented individuals with APOE ε3/ε3 from ADNI database were divided into Aβ-positron emission tomography (Aβ-PET) positivity (+) and Aβ-PET negativity (-) groups using cut-off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aβ-PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aβ-PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p-tau 181 and WMH can accurately predict Aβ-PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non-invasive and effective tool to improve the efficiency of screening Aβ-PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials.

The possible causal relationship between COVID-19 and imaging markers of cerebral small vessel disease: a Mendelian randomization study

ABSTRACT Objectives Observational studies have suggested that SARS-CoV-2 infection may increase the burden of cerebral small vessel disease (CSVD). This study aims to explore the causal correlation between COVID-19 and the imaging markers of CSVD using Mendelian randomization (MR) methods. Methods Summary-level genome-wide association study (GWAS) statistics for COVID-19 susceptibility, hospitalization, and severity were utilized as proxies for exposure. Large-scale meta-analysis GWAS data on three neuroimaging markers of white matter hyperintensity, lacunar stroke, and brain microbleeds, were employed as outcomes. Our primary MR analysis employed the inverse variance weighted (IVW) approach, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. We also conducted multivariable MR analysis to address confounding bias and validate the robustness of the established causal estimates. Comprehensive sensitivity analyses included Cochran’s Q test, Egger-intercept analysis, MR-PRESSO, and leave-one-out analysis. Results The MR analysis revealed a significant causal correlation between the severity of COVID-19 and an increased risk of lacunar stroke, as demonstrated by the IVW method (ORivw = 1.08, 95% CI: 1.03–1.16, pivw = 0.005, FDR = 0.047). Nevertheless, no causal correlations were observed between COVID-19 susceptibility or hospitalization and any CSVD imaging markers. The robustness and stability of these findings were further confirmed by multivariable MR analysis and comprehensive sensitivity analyses. Discussion This study provides compelling evidence of a potential causal effect of severe COVID-19 on the incidence of lacunar stroke, which may bring fresh insights into the understanding of the comorbidity between COVID-19 and CSVD.

Association of vulnerable plaques with white matter hyperintensities on high-resolution magnetic resonance imaging

Association of vulnerable plaques with white matter hyperintensities on high-resolution magnetic resonance imaging

Perivascular Spaces, Diffusivity Along Perivascular Spaces, and Free Water in Cerebral Small Vessel Disease.

Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline. This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances. In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (β = -0.09, p = 0.030), but not vice versa (β = -0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (β = 0.33, p-corrected < 0.001) and lacune numbers (β = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (β = 0.30, p-corrected < 0.001), lacune numbers (β = 0.28, p-corrected < 0.001), and brain volumes (β = -0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (β = -0.20, p-corrected = 0.002) and brain volumes (β = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (β = -0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: β = -0.25, p-corrected < 0.001; DTI-ALPS: β = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: β = -0.29, p-corrected < 0.001; DTI-ALPS: β = 0.21, p-corrected < 0.001). Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

THE POTENTIAL ROLE OF EXERCISE IN DELAYING GENETIC DESTINY: EXAMINING THE RELATIONSHIP BETWEEN EXERCISE AND KEY BIOMARKERS IN DOMINANTLY INHERITED ALZHEIMER’S DISEASE

INTRODUCTION Greater physical activity is associated with reduced risk for Alzheimer’s disease (AD), and lower levels of AD-related biomarkers, such as beta-amyloid (Aβ) and tau, measured in the cerebrospinal fluid (CSF) and brain. A small proportion of Alzheimer’s disease (&amp;lt;1%) cases are caused by a rare dominant genetic mutation. The aim of the current study was to examine associations between self-reported exercise participation and AD-related biomarkers (from CSF and brain imaging) over time, in individuals we know will develop Alzheimer’s disease at an early age (i.e., dominant AD mutation carriers). METHODS The sample included n = 308 mutation carriers from the Dominantly Inherited Alzheimer’s Network (DIAN) study with data available for self-reported exercise participation, brain imaging (hippocampal volume, total brain volume, gray matter volume, white matter hyperintensities, brain Aβ levels), and biomarkers quantified from CSF (several Aβ and tau species and ratios). Participants were assessed regularly (time interval depending on mutation type) from baseline to 10+ years post-baseline. Associations between exercise and AD biomarkers (i.e., from brain imaging and CSF) were examined using linear mixed models, corrected for various confounding variables. RESULTS The sample had a mean age of 39.7 ± 10.8 years and were 56% female. Greater baseline exercise was associated with a slower decrease in right (B=0.06, p &amp;lt; 0.001) and left (B=0.06, p&amp;lt;0.05) hippocampal volume; and slower accumulation of brain Aβ (B=0.04, p&amp;lt;0.001). CONCLUSION These findings demonstrate that exercise is associated with more favourable profiles of AD-related biomarkers in those with ADAD mutations. This work may have implications for our understanding of how exercise influences disease development in late-onset sporadic AD. Nevertheless, the causal direction of our findings is difficult to ascertain, and future study designs investigating the therapeutic potential of exercise in both ADAD and late-onset AD should be considered.

Impaired Glymphatic Flow on Diffusion Tensor MRI as a Marker of Neurodegeneration in Alzheimer's Disease: Correlation with Gray Matter Volume Loss and Cognitive Decline Independent of Cerebral Amyloid Deposition.

Impaired glymphatic flow on the Alzheimer's disease (AD) spectrum may be evaluated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). We aimed to validate impaired glymphatic flow and explore its association with gray matter volume, cognitive status, and cerebral amyloid deposition on the AD spectrum. 80 participants (mean age, 76.9±8.5 years; 57 women) with AD (n = 65) and cognitively normal (CN) (n = 15) who underwent 3T brain MRI including DTI and/or amyloid PET were included. After adjusting for age, sex, apolipoprotein E status, and burden of white matter hyperintensities, the ALPS-index was compared according to the AD spectrum. The association between the ALPS-index and gray matter volume, cognitive status, and quantitative amyloid from PET was assessed. The ALPS-index in the AD was significantly lower (mean, 1.476; 95% CI, 1.395-1.556) than in the CN (1.784;1.615-1.952; p = 0.026). Volumes of the entorhinal cortex, hippocampus, temporal pole, and primary motor cortex showed significant associations with the ALPS-index (all, p < 0.05). There was a positive correlation between the ALPS-index and MMSE score (partial r = 0.435; p < 0.001), but there was no significant correlation between the ALPS-index and amyloid SUVRs (all, p > 0.05). Decreased glymphatic flow measured by DTI-ALPS in AD may serve as a marker of neurodegeneration correlating with structural atrophy and cognitive decline.

Association between loneliness and cognitive function, and brain volume in community-dwelling elderly

IntroductionWe investigated the relationship between loneliness, cognitive impairment, and regional brain volume among elderly individuals residing in the Korean community.MethodsData from the ARIRANG aging-cognition sub-cohort, collected between 2020 and 2022, were utilized for the present study. Loneliness was assessed using the UCLA-Loneliness Scale (UCLA-LS) questionnaire and the relevant item from Center for Epidemiologic Studies Depression Scale Korean version (CES-D-K). Cognitive impairment was measured through Mini-Mental State Examination (K-MMSE-2) and Seoul Neuropsychological Screening Battery (SNSB-C), with five sub-categories: attention, memory, visuospatial function, language, and executive function. Logistic regression was employed for prevalence ratios related to cognitive impairment, while linear regression was used for regional brain volume including white matter hyperintensity (WMH) and cortical thickness.ResultsOur analysis involved 785 participants (292 men and 493 women). We observed increased cognitive impairment assessed by K-MMSE-2 [UCLA-LS: odds ratio (OR) 3.133, 95% confidence interval (CI) 1.536–6.393; loneliness from CES-D: OR 2.823, 95% CI 1.426–5.590] and SNSB-C total score (UCLA-LS: OR 2.145, 95% CI 1.304–3.529) in the lonely group compared to the non-lonely group. Specifically, the lonely group identified by UCLA-LS showed an association with declined visuospatial (OR 1.591, 95% CI 1.029–2.460) and executive function (OR 1.971, 95% CI 1.036–3.750). The lonely group identified by CES-D-K was associated with impaired memory (OR 1.577, 95% CI 1.009–2.466) and executive function (OR 1.863, 95% CI 1.036–3.350). In the regional brain volume analysis, loneliness was linked to reduced brain volume in frontal white matter (left: −1.24, 95% CI −2.37 ∼−0.12; right: −1.16, 95% CI −2.31 ∼ −0.00), putamen (left: −0.07, 95% CI −0.12 ∼−0.02; right: −0.06, 95% CI −0.11 ∼−0.01), and globus pallidus (−15.53, 95% CI −30.13 ∼−0.93). There was no observed association in WMH and cortical thickness.ConclusionLoneliness is associated with cognitive decline and volumetric reduction in the frontal white matter, putamen, and globus pallidus.

The Associations Between Serum Insulin-like Growth Factor-I, Brain White Matter Volumes, and Cognition in Mild Cognitive Impairment and Alzheimer's Disease.

Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer's disease (AD). To explore whether serum IGF-I is associated with magnetic resonance imaging - estimated brain white matter volumes or cognitive functions. In a prospective study of SCI/MCI (n = 106) and AD (n = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and Stroop tests I-III at baseline, and after 2 years. IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain.

Association of objective sleep duration with cognition and brain aging biomarkers in older adults

Abstract The neuropathological mechanisms underlying the association between sleep duration and mild cognitive impairment (MCI) remain poorly understood. This population-based study included 2032 dementia-free people (age ≥ 60 years; 55.1% women) derived from participants in the Multimodal Interventions to Delay Dementia and Disability in Rural China; of these, data were available in 841 participants for Alzheimer’s plasma biomarkers (e.g., amyloid-β[Aβ], total tau, and neurofilament light chain), 1044 for serum microvascular biomarkers (e.g., soluble adhesion molecules), and 834 for brain MRI biomarkers (e.g., whiter matter, grey matter, hippocampus, lacunes, enlarged perivascular spaces [EPVS], and white matter hyperintensity [WMH]). We used electrocardiogram-based cardiopulmonary coupling analysis to measure sleep duration, a neuropsychological test battery to assess cognitive function, and the Petersen’s criteria to define MCI. Data were analysed with multivariable logistic and general linear models. In the total sample (n = 2032), 510 participants were defined with MCI, including 438 with amnestic MCI and 72 with non-amnestic MCI. Long sleep duration (&amp;gt;8 vs. 6-8 hours) was significantly associated with increased likelihoods of MCI and non-amnestic MCI, and lower scores in global cognition, verbal fluency, attention, and executive function (Bonferroni-corrected P &amp;lt; .05). In the subsamples, long sleep duration was associated with higher plasma Aβ40 and total tau, a lower Aβ42/Aβ40 ratio, and smaller grey matter volume (Bonferroni-corrected P &amp;lt; .05). Sleep duration was not significantly associated with serum soluble adhesion molecules, WMH volume, global EPVS, and lacunes (P &amp;gt; .05). Alzheimer’s and neurodegenerative pathologies may represent common pathways linking long sleep duration with MCI and low cognition in older adults.

Association of past and current sleep duration with structural brain differences: A large population-based study from the UK Biobank

ObjectiveThis study aimed to examine the association between past/current sleep duration and macro-/micro-structural brain outcomes and explore whether hypertension or social activity plays a role in such association. MethodsWithin the UK Biobank, 40 436 dementia-free participants (age 40–70 years) underwent a baseline assessment followed by a brain magnetic resonance imaging (MRI) scan 9 years later. Past (baseline) and current (MRI scans) sleep duration (hours/day) were recorded and classified as short (≤5), intermediate (6–8), and long (≥9). Brain structural volumes and diffusion markers were assessed by MRI scans. ResultsCompared with past intermediate sleep, past short sleep was related to smaller cortex volumes (standardized β [95 % CI]: −0.04 [-0.07, −0.02]) and lower regional fractional anisotropy (FA) (−0.08 [-0.13, −0.03]), while past long sleep was related to smaller regional subcortical volumes (standardized β: −0.04 to −0.07 for thalamus, accumbens, and hippocampus). Compared to current intermediate sleep, current short sleep was associated with smaller cortex volumes (−0.03 [-0.05, −0.01]), greater white matter hyperintensities (WMH) volumes (0.04 [0.01, 0.08]), and lower regional FA (−0.07 [-0.11, −0.02]). However, current long sleep was related to smaller total brain (−0.03 [-0.05, −0.02]), grey matter (−0.05 [-0.07, −0.03]), cortex (−0.05 [-0.07, −0.03]), regional subcortical volumes [standardized β: −0.05 to −0.09 for putamen, thalamus, hippocampus, and accumbens]), greater WMH volumes (0.06 [0.03, 0.09]), as well as lower regional FA (−0.05 [-0.09, −0.02]). The association between current long sleep duration and poor brain health was stronger among people with hypertension or low frequency of social activity (all Pinteraction <0.05). ConclusionsBoth past and current short/long sleep are associated with smaller brain volume and poorer white matter health in the brain, especially in individuals with hypertension and low frequency of social activity. Our findings highlight the need to maintain 6–8 h’ sleep duration for healthy brain aging.

Sex differences in the correlation between white matter hyperintensity and 3-month outcome in acute stroke patients

BackgroundThe severity of white matter hyperintensities (WMH) has been shown to be an independent predictor of poor stroke outcome, but the effect of sex on this correlation has not been investigated further. Therefore, the purpose of our study was to assess whether there was a sex difference between the severity of WMH and poor stroke outcome. MethodsThis retrospective study included 449 patients with acute ischemic stroke (AIS) who received intravenous thrombolysis. WMH severity was graded based on the Fazekas scale. The association between WMH severity and stroke outcome was explored through multivariable regression analyses in men and women. ResultsAmong women, when dividing WMH severity into tertiles, T3 (Fazekas scale >3) had a 5.334 times higher risk for unfavorable outcomes than T1 (Fazekas scale <2) (p-trend = 0.026) in the adjusted model. In addition, moderate-severe WMH (Fazekas scale 3–6) had a 3.391 (1.151–9.991) times higher risk than none-mild WMH (Fazekas scale 0–2) (p = 0.027). ConclusionsThe risk of unfavorable outcomes increased proportionally with the enlargement of the WMH severity in females, suggesting the sex-specific value of the WMH severity in optimizing the risk stratification of stroke.

Functional MRI brain state occupancy in the presence of cerebral small vessel disease—a pre-registered replication analysis of the Hamburg City Health Study

Abstract We aimed to replicate recent findings on the association between the extent of cerebral small vessel disease (cSVD), functional brain network dedifferentiation, and cognitive impairment. We analyzed demographic, imaging, and behavioral data from the prospective population-based Hamburg City Health Study. Using a fully prespecified analysis pipeline, we estimated discrete brain states from structural and resting-state functional magnetic resonance imaging (MRI). In a multiverse analysis, we varied brain parcellations and functional MRI confound regression strategies. The severity of cSVD was operationalized as the volume of white matter hyperintensities of presumed vascular origin. Processing speed and executive dysfunction were quantified using the Trail Making Test (TMT). We hypothesized a) that a greater volume of supratentorial white matter hyperintensities would be associated with less time spent in functional MRI-derived brain states of high fractional occupancy; and b) that less time spent in these high-occupancy brain states associated with a longer time to completion in part B of the TMT. High-occupancy brain states were characterized by activation or suppression of the default mode network. Every 5.1-fold increase in WMH volume was associated with a 0.94-fold reduction in the odds of occupying DMN-related brain states (P = 5.01×10−8). Every 5% increase in time spent in high-occupancy brain states was associated with a 0.98-fold reduction in the TMT-B completion time (P = 0.0116). Findings were robust across most brain parcellations and confound regression strategies. In conclusion, we successfully replicated previous findings on the association between cSVD, functional brain occupancy, and cognition in an independent sample. The data provide further evidence for a functional network dedifferentiation hypothesis of cSVD-related cognitive impairment. Further research is required to elucidate the mechanisms underlying these associations.

Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men

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.

White Matter Hyperintensities and Microstructural Alterations in Contact Sport Athletes from Adolescence to Early Midlife.

Studies have demonstrated associations between cumulative concussion and repetitive head impact exposure (RHI) via contact sports with white matter (WM) alterations later in life. The course of WM changes associated with exposure earlier in the lifespan are unclear. This study investigated alterations in white matter (WM hyperintensity [WMH] volume and microstructural changes) associated with concussion and RHI exposure from adolescence to early midlife, as well as the interaction between exposure and age-cohort (i.e., adolescent/young adult compared to early midlife athlete cohorts) on WM outcomes. Participating football players included an adolescent/young adulthood cohort (n=82; Mage=18.41.7) and an early midlife cohort (37 former collegiate players approximately 15-years removed from sport; Mage=37.71.4). Years of football participation and number of prior concussions were exposures of interest. White matter outcomes included log-transformed manually segmented total WMH volume and neurite orientation dispersion and density imaging metrics of microstructure/organization (isotropic volume fraction[Viso], intra-cellular volume fraction[Vic], and orientation dispersion[OD]). Regression models were fit to test effects of concussion history, years of football participation, and age-cohort by years of football participation with WM outcomes. Spearman's correlations assessed associations between significant WM metrics and measures of cognitive and psychological function. A significant age-cohort by years of participation effect was observed for whole brain white matter OD, B=-0.002, SE=0.001, p=0.001. The interaction was driven by a negative association between years of participation and OD within the younger cohort, B=-0.001, SE=0.0004, p=0.008, whereas a positive association between participation and OD in the early midlife cohort, B=0.001, SE=0.0003, p=0.039, was observed. Follow-up ROI analyses showed significant interaction effects for OD in the body of the corpus callosum, genu of the corpus callosum, cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, posterior thalamic radiation (ps<0.05). Greater concussion history was significantly associated with greater Viso in the early midlife cohort, B=0.001, SE= 0.0002, p=0.010. Years of participation and concussion history were not associated with WMH volume, ps>0.05. Performance on a measure of executive function was significantly associated with years of participation, =.34, p=.04, and a trend was observed for OD, =.28, p=.09 in the early midlife cohort only. The global characterization of white matter changes associated with years of football participation were broadly similar and stable from adolescence through early midlife (i.e., microstructural alterations, but not macroscopic lesions). An inverse association between years of participation and orientation dispersion across age-cohorts may represent a process of initial recovery/reorganization proximal to sport, followed by later reduction of white matter coherence.

Strategic white matter hyperintensity locations associated with post-stroke cognitive impairment: a multicenter study in 1568 stroke patients.

Post-stroke cognitive impairment (PSCI) occurs in up to 50% of stroke survivors. Presence of pre-existing vascular brain injury, in particular the extent of white matter hyperintensities (WMH), is associated with worse cognitive outcome after stroke, but the role of WMH location in this association is unclear. We determined if WMH in strategic white matter tracts explain cognitive performance after stroke. Individual patient data from 9 ischemic stroke cohorts with MRI were harmonized through the Meta VCI Map consortium. The association between WMH volumes in strategic tracts and domain-specific cognitive functioning (attention and executive functioning, information processing speed, language and verbal memory) was assessed using linear mixed models and lasso regression. We used a hypothesis-driven design, primarily addressing four white matter tracts known to be strategic in memory clinic patients: the left and right anterior thalamic radiation, forceps major and left inferior fronto-occipital fasciculus. The total study sample consisted of 1568 patients (39.9% female, mean age: 67.3 years). Total WMH volume was strongly related to cognitive performance on all four cognitive domains. WMH volume in the left anterior thalamic radiation was significantly associated with cognitive performance on attention and executive functioning and information processing speed, and WMH volume in the forceps major with information processing speed. The multivariable lasso regression showed that these associations were independent of age, sex, education, and total infarct volume and had larger coefficients than total WMH volume. These results show tract-specific relations between WMH volume and cognitive performance after ischemic stroke, independent of total WMH volume. This implies that the concept of strategic lesions in PSCI extends beyond acute infarcts and also involves pre-existing WMH. The Meta VCI Map consortium is dedicated to data sharing, following our guidelines.