White Matter Hyperintensity Volume Research Articles

Migraine or any headaches and white matter hyperintensities and their progression in women and men

BackgroundCross-sectional and longitudinal studies have been conducted to investigate the association between migraine and any headache and white matter hyperintensities (WMH). However, studies are inconsistent regarding the strength of the association and its clinical significance. The aim of our study was to investigate the association between headache and its subtypes (migraine with aura (MigA+), migraine without aura (MigA-), non-migraine headache (nonMigHA)) and WMH and its course in the population-based 1000BRAINS study using state-of-the-art imaging techniques and migraine classification according to modified international classification of headache disorders.MethodsData from 1062 participants (45% women, 60.9 ± 13.0 years) with ever or never headache (neverHA) and complete quantitative (WMH volume) and qualitative (Fazekas classification) WMH data at first imaging and after 3.7 ± 0.7 years (393 participants) were analyzed. The sex-specific association between headache and its subtypes and WMH volume and its change was evaluated by linear regression, between headache and its subtypes and Fazekas score high vs. low (2–3 vs. 0–1) by log-binomial regression, adjusted for confounders.ResultsThe lifetime prevalence of headache was 77.5% (10.5% MigA+, 26.9% MigA-, 40.1% nonMigHA). The median WMH volume was 4005 (IQR: 2454–6880) mm3 in women and 4812 (2842–8445) mm3 in men. Women with any headaches (all headache types combined) had a 1.23 [1.04; 1.45]-fold higher WMH volume than women who reported never having had a headache. There was no indication of higher Fazekas grading or more WMH progression in women with migraine or any headaches. Men with migraine or any headaches did not have more WMH or WMH progression compared to men without migraine or men who never had headache.ConclusionsOur study demonstrated no increased occurrence or progression of WMH in participants with mgiraine. But, our results provide some evidence of greater WMH volume in women with headache of any type including migraine. The underlying pathomechanisms and the reasons why this was not shown in men are unclear and require further research.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N=299), mild cognitive impairment (MCI; N=192), or dementia (DEM; N=65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Plasma biomarkers differed across diagnostic groups (DEM>MCI>CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Plasma biomarkers differ across diagnostic groups (DEM>MCI>CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

A pathway linking pulse pressure to dementia in adults with Down syndrome

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

Cardiovascular disease risk exacerbates brain aging among Hispanic/Latino adults in the SOL-INCA-MRI Study

BackgroundCardiovascular disease (CVD) risk factors are highly prevalent among Hispanic/Latino adults, while the prevalence of MRI infarcts is not well-documented. We, therefore, sought to examine the relationships between CVD risk factors and infarcts with brain structure among Hispanic/Latino individuals.MethodsParticipants included 1,886 Hispanic/Latino adults (50–85 years) who underwent magnetic resonance imaging (MRI) as part of the Study of Latinos—Investigation of Neurocognitive Aging-MRI (SOL-INCA-MRI) study. CVD risk was measured approximately 10.5 years before MRI using the Framingham cardiovascular risk score, a measure of 10-year CVD risk (low (<10%), medium (10- < 20%), and high (≥20%)). MR infarcts were determined as present or absent. Outcomes included total brain, cerebral and lobar cortical gray matter, hippocampal, lateral ventricle, and total white matter hyperintensity (WMH) volumes. Linear regression models tested associations between CVD risk and infarct with MRI outcomes and for modifications by age and sex.ResultsSixty percent of participants were at medium or high CVD risk. Medium and high CVD risk were associated with lower total brain and frontal gray matter and higher WMH volumes compared to those with low CVD risk. High CVD risk was additionally associated with lower total cortical gray matter and parietal volumes and larger lateral ventricle volumes. Men tended to have greater CVDRF-related differences in total brain volumes than women. The association of CVD risk factors on total brain volumes increased with age, equal to an approximate 7-year increase in total brain aging among the high-CVD-risk group compared to the low-risk group. The presence of infarct(s) was associated with lower total brain volumes, which was equal to an approximate 5-year increase in brain aging compared to individuals without infarcts. Infarcts were also associated with smaller total cortical gray matter, frontal and parietal volumes, and larger lateral ventricle and WMH volumes.ConclusionThe high prevalence of CVD risk among Hispanic/Latino adults may be associated with accelerated brain aging.

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study

BackgroundSodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD.MethodsGenetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.ResultsA lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.ConclusionsSGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

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.

Orthostatic hypotension, cognition and structural brain imaging in hemodynamically impaired patients

BackgroundOrthostatic hypotension (OH) is associated with an increased risk of dementia, potentially attributable to cerebral hypoperfusion. We investigated which patterns and characteristics of OH are related to cognition or to potentially underlying structural brain injury in hemodynamically impaired patients and healthy reference participants. MethodsParticipants with carotid occlusive disease or heart failure, and reference participants from the Heart-Brain Connection Study underwent OH measurements, neuropsychological assessment and brain MRI. We analyzed the association between OH, global cognitive functioning, white matter hyperintensity (WMH) volume and brain parenchymal fraction with linear regression. We stratified by participant group, severity and duration of OH, chronotropic incompetence and presence of orthostatic symptoms. ResultsOf 337 participants (mean age 67.3 ± 8.8 years, 118 (35.0%) women), 113 (33.5%) had OH. Overall, presence of OH was not associated with cognitive functioning (β: −0.12 [−0.24–0.00]), but we did observe worse cognitive functioning in those with severe OH (≥ 30/15 mmHg; β: −0.18 [−0.34 to −0.02]) and clinically manifest OH (β: −0.30 [−0.52 to −0.08]). These associations did not differ significantly by OH duration or chronotropic incompetence, and were similar between patient groups and reference participants. Similarly, both severe OH and clinically manifest OH were associated with a lower brain parenchymal fraction, and severe OH also with a somewhat higher WMH volume. ConclusionsSevere OH and clinically manifest OH are associated with worse cognitive functioning. This supports the notion that specific patterns and characteristics of OH determine its impact on brain health.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized β [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

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.

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 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 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.

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.

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.

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.

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.

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.

Nonalcoholic Fatty Liver Disease and Longitudinal Change in Imaging and Plasma Biomarkers of Alzheimer Disease and Vascular Pathology.

Prospective measures of plasma and cerebral MRI biomarkers of Alzheimer disease (AD) and vascular neuropathology provide an opportunity to investigate possible mechanisms linking liver disease and dementia. We aimed to quantify the association of midlife nonalcoholic fatty liver disease (NAFLD) with change in plasma and brain MRI biomarkers of AD and vascular neuropathology. We included participants from the Atherosclerosis Risk in Communities Study with brain MRI measurements of white matter hyperintensity (WMH) volume and temporal-parietal lobe cortical thickness meta region of interest (ROI) at up to 2 different visits, in 2011-13 and 2016-19, and plasma biomarkers of β-amyloid (Aβ)42:40, phosphorylated tau at threonine 181, and neurofilament light (NfL) were measured up to 3 times in 1993-95, 2011-13, and 2016-19. NAFLD was categorized using the fatty liver index in 1990-92. Multivariate linear regression was performed for associations between midlife NAFLD and change in plasma and brain MRI biomarkers of AD and vascular neuropathology. The primary models adjusted for demographics, Apolipoprotein E, alcohol use, and kidney function. Among 1,706 participants (mean age 56 years, 62% female, 28% Black), midlife NAFLD vs no NAFLD was associated with greater late-life WMH volume (difference per SD 0.19, 95% CI 0.06-0.31) and faster late-life WMH increase over 6 years (difference in annual change, SD 0.28, 95% CI 0.05-0.51), suggesting accumulating vascular pathology. Midlife NAFLD vs no NAFLD was also associated with AD biomarkers in midlife (lower Aβ42:40 [SD -0.21, 95% CI -0.39 to -0.04] measured in 1993-95) and late life (lower Aβ42:40 [SD -0.13, 95% CI -0.23 to -0.03] and lower temporal-parietal lobe cortical thickness meta ROI [SD -0.16, 95% CI -0.28 to -0.05] measured in 2011-13). Although midlife NfL was lower in individuals with vs without midlife NAFLD, those with NAFLD exhibited a faster rate of NfL increase that accelerated over time. Midlife NAFLD shows associations with AD and accumulating vascular pathology, revealing potential pathways linking liver function to dementia. Plasma biomarkers of neuropathology and neuronal injury may serve as easily measurable and dynamic indicators for monitoring the impacts of impaired liver function on brain health.

Social Determinants of Health, Risk and Resilience against Alzheimer's Disease and Related Dementias: The Healthy Brain Initiative.

Few studies have investigated associations between perceived social determinants of health (SDOH) and Alzheimer's disease and related dementia (ADRD) biomarkers or between SDOH and resilience against ADRD. To examine associations between perceived and objective SDOH and ADRD-related outcomes. We used cross-sectional data on≥50-year-olds without dementia in the Healthy Brain Initiative (n = 162). Questionnaires captured trust in neighbors and indices of perceived neighborhood greenspace access, time spent in neighborhood greenspaces, and interpersonal discrimination. Residential addresses were linked to 2021 Area Deprivation Index scores. The Vulnerability Index (VI) is based on 12 dementia risk factors (e.g., age, race/ethnicity, diabetes) and Resilience Index (RI) is based on 6 protective factors (e.g., diet, mindfulness, physical activity). Cognitive measured included number symbol coding task and Montreal Cognitive Assessment. Biomarkers included Aβ42/40 and pTau-217/npTau-217, hippocampal and white matter hyperintensity volume, lipoprotein A, and high-sensitivity c-reactive protein. Perceived greater access to greenspaces (estimate = 2.83, 95% CI = 1.40-4.26) and greater time in neighborhood greenspaces were associated with greater RI scores (estimate = 2.30, 95% CI = 1.24-3.35). Reporting greater discrimination (estimate = 0.10, 95% CI = 0.04-0.16) and living in higher deprivation neighborhoods were associated with greater VI scores (estimate = 0.017, 95% CI = 0.003-0.032). Greater discrimination was associated with greater white matter hyperintensity volume (estimate = 0.27, 95% CI = 0.04-0.51). Perceived greenspace access and time spent in greenspaces were associated with resilience against ADRD, and interpersonal discrimination was associated with vulnerability to ADRD. Future work needs to validate perceived SDOH measures, examine associations in racially/ethnic diverse populations, and investigate longitudinal associations between SDOH and ADRD-related biomarkers.