Brain White Matter Volume Research Articles

Quantifying brain health in acute ischemic stroke through effective reserve.

To quantify brain health using a measure of reserve that incorporates pre-existing pathology. We analyzed two retrospective ischemic stroke cohorts (GASROS and SALVO) with neuroimaging and 90-day modified Rankin Scores (mRS) available. White matter hyperintensity (WMHv), brain, and intracranial volumes were automatically extracted, and brain parenchymal fraction (BPF) calculated. The latent variable effective reserve (eR) was modeled using age, WMHv, and BPF or brain volume in GASROS. Models were compared using Bayes Information Criterion (BIC). The best model's eR estimates were categorized into quartiles and evaluated in SALVO. GASROS included 476 (median age: 65.8; 65.3% male) and SALVO included 43 (median age: 69.2; 62.8% male) patients. Inverse associations between eR and mRS was seen in both models, with brain volume outperforming BPF (path coefficients: -0.67, -0.48, respectively; p < 0.001; |ΔBIC| = 362). Quartile-based eR stratification in SALVO showed a similar inverse trend, with worse outcomes in the low reserve group (mRS≤2 - highest vs lowest quartile: 85/90% vs 59/45% for GASROS/SALVO). Expanding the concept of eR, highlights its clinical translational potential. The strong link between higher eR and better outcomes underscores its value as a protective brain health metric.

Associations between Parenting and Cognitive and Language Abilities at 2 Years of Age Depend on Prenatal Exposure to Disadvantage

To investigate whether parenting or neonatal brain volumes mediate associations between prenatal social disadvantage (SD) and cognitive/language abilities and whether these mechanisms vary by level of disadvantage. Pregnant women were prospectively recruited from obstetric clinics in St Louis, Missouri. Prenatal SD encompassed access to social (eg, education) and material (eg, income-to-needs, health insurance, area deprivation, and nutrition) resources during pregnancy. Neonates underwent brain magnetic resonance imaging. Mother-child dyads (N=202) returned at age 1-year for parenting observations and at age 2-years for cognition/language assessments (Bayley-III). Generalized additive and mediation models tested hypotheses. Greater prenatal SD associated nonlinearly with poorer cognitive/language scores. Associations between parenting and cognition/language were moderated by disadvantage, such that supportive and non-supportive parenting behaviors related only to cognition/language in children with lesser prenatal SD. Parenting mediation effects differed by level of disadvantage: both supportive and non-supportive parenting mediated prenatal SD-cognition/language associations in children with lesser disadvantage, but not in children with greater disadvantage. Prenatal SD-associated reductions in neonatal subcortical grey matter (β=.19, q=.03), white matter (β=.23, q=.02), and total brain volume (β=.18, q=.03) were associated with lower cognition, but did not mediate associations between prenatal SD and cognition. Parenting moderates and mediates associations between prenatal SD and early cognition and language, but only in families with less social disadvantage. These findings, although correlational, suggest that there may be a critical threshold of disadvantage, below which mediating or moderating factors become less effective, highlighting the importance of reducing disadvantage as primary prevention.

Menstrual cycle-driven hormone concentrations co-fluctuate with white and gray matter architecture changes across the whole brain.

Cyclic fluctuations in hypothalamic-pituitary-gonadal axis (HPG-axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T1-weighted imaging during three estimated menstrual cycle phases (menses, ovulation, and mid-luteal) to investigate whether HPG-axis hormone concentrations co-fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17β-estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (μFA; 17β-estradiol: β1 = 0.145, highest density interval (HDI) = [0.211, 0.4]; LH: β1 = 0.111, HDI = [0.157, 0.364]), while follicle-stimulating hormone (FSH) was directly proportional to CT (β1 = 0 .162, HDI = [0.115, 0.678]). Within several individual regions, FSH and progesterone demonstrated opposing relationships with mean diffusivity (Diso) and CT. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Finally, progesterone was associated with increased tissue (β1 = 0.66, HDI = [0.607, 15.845]) and decreased cerebrospinal fluid (CSF; β1 = -0.749, HDI = [-11.604, -0.903]) volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain-wide changes in human WM microstructure and CT coinciding with menstrual cycle-driven hormone rhythms. Effects were observed in both classically known HPG-axis receptor-dense regions (medial temporal lobe, prefrontal cortex) and in other regions located across frontal, occipital, temporal, and parietal lobes. Our results suggest that HPG-axis hormone fluctuations may have significant structural impacts across the entire brain.

Risk of type 2 diabetes, MASLD and cardiovascular disease in people living with polycystic ovary syndrome.

Abstract Background Polycystic ovary syndrome (PCOS) is associated with adverse clinical outcomes that may differ according to PCOS phenotype. Methods Using UK Biobank data, we compared the incidence of type 2 diabetes (T2D), metabolic dysfunction associated steatotic liver disease, cardiovascular disease (CVD), hormone-dependent cancers, and dementia between PCOS participants and age- and body mass index-matched controls. We also compared multiorgan (liver, cardiac, and brain) magnetic resonance imaging (MRI) data and examined the impact of PCOS phenotype (hyperandrogenic and normoandrogenic) on these outcomes. Results We included 1008 women with PCOS (defined by diagnostic codes, self-reported diagnoses, or clinical/biochemical features of hyperandrogenism and a/oligoCmenorrhoea) and 5017 matched controls (5:1 ratio); median age, 61 years, body mass index, 28.4 kg/m². Adjusted Cox proportional hazard modeling demonstrated PCOS participants had greater incident T2D [hazard ratio (HR) 1.47; 95% confidence interval (CI), 1.11-1.95] and all-cause CVD (1.76; 1.35-2.30). No between-group differences existed for cancers or dementia. Liver MRI confirmed more PCOS participants had hepatic steatosis (proton density fat fraction &amp;gt;5.5%: 35.9 vs 23.9%; P = .02) and higher fibroinflammation (corrected T1 721.4 vs 701.5 ms; P = &amp;lt;.01) vs controls. No between-group difference existed for cardiac (biventricular/atrial structure and function) or brain (grey and white matter volumes) imaging. Normoandrogenic (but not hyperandrogenic) PCOS participants had greater incident all-cause CVD (1.82; 1.29-2.56) while hyperandrogenic (but not normoandrogenic) PCOS participants were more likely to have hepatic steatosis (8.96 vs 6.04 vs 5.23%; P = .03) with greater fibroinflammation (776.3 vs 707.7 vs 701.9 ms; P=&amp;lt;.01). Conclusion Cardiometabolic disease may be increased in PCOS patients with a disease phenotype-specific pattern.

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis: insights from structural connectome graph theoretical network analysis

BackgroundAnti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis.MethodsStructural networks from 61 NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and 61 age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically constrained tractography and volumetry of a selection of subcortical and white matter brain volumes was performed. We calculated global, modular, and nodal graph measures with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were investigated regarding their potential association with clinical course, disease severity, and cognitive outcome.ResultsPatients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left: p = 0.049; right: p = 0.013) and increased node strength of right precuneus (p = 0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex (p = 0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment (p = 0.021). We found decreased left (p = 0.013) and right (p = 0.001) hippocampal volumes that were associated with hippocampal node strength (left p = 0.009; right p < 0.001).ConclusionsFocal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study

BackgroundThe relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function.MethodsThis study recruited 1111 participants aged 25–83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function.ResultsCompared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = − 0.25, 95% confidence interval [CI] − 0.39 to − 0.11 and beta = − 0.15, 95% CI − 0.29 to − 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = − 0.24, 95% CI − 0.38 to − 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = − 0.18, 95% CI − 0.32 to − 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline.ConclusionsIt is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

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.

Basic Environmental Supports for Positive Brain and Cognitive Development in the First Year of Life

Defining basic psychosocial resources to facilitate thriving in the first year of life could tangibly inform policy and enhance child development worldwide. To determine if key environmental supports measured as a thrive factor (T-factor) in the first year of life positively impact brain, cognitive, and socioemotional outcomes through age 3. This prospective longitudinal cohort study took place at a Midwestern academic medical center from 2017 through 2022. Participants included singleton offspring oversampled for those facing poverty, without birth complications, congenital anomalies, or in utero substance exposures (except cigarettes and marijuana) ascertained prenatally and followed up prospectively for the first 3 years of life. Data were analyzed from March 9, 2023, through January 3, 2024. Varying levels of prenatal social disadvantage advantage and a T-factor composed of environmental stimulation, nutrition, neighborhood safety, positive caregiving, and child sleep. Gray and white matter brain volumes and cortical folding at ages 2 and 3 years, cognitive and language abilities at age 3 years measured by the Bayley-III, and internalizing and externalizing symptoms at age 2 years measured by the Infant-Toddler Social and Emotional Assessment. The T-factor was positively associated with child cognitive abilities (β = 0.33; 95% CI, 0.14-0.52), controlling key variables including prenatal social disadvantage (PSD) and maternal cognitive abilities. The T-factor was associated with child language (β = 0.36; 95% CI, 0.24-0.49), but not after covarying for PSD. The association of the T-factor with child cognitive and language abilities was moderated by PSD (β = -0.32; 95% CI, -0.48 to -0.15 and β = -0.36; 95% CI, -0.52 to -0.20, respectively). Increases in the T-factor were positively associated with these outcomes, but only for children at the mean and 1 SD below the mean of PSD. The T-factor was negatively associated with child externalizing and internalizing symptoms over and above PSD and other covariates (β = -0.30; 95% CI, -0.52 to -0.08 and β = -0.32; 95% CI, -0.55 to -0.09, respectively). Increasing T-factor scores were associated with decreases in internalizing symptoms, but only for children with PSD 1 SD above the mean. The T-factor was positively associated with child cortical gray matter above PSD and other covariates (β = 0.29; 95% CI, 0.04-0.54), with no interaction between PSD and T-factor. Findings from this study suggest that key aspects of the psychosocial environment in the first year impact critical developmental outcomes including cognitive, brain, and socioemotional development at age 3 years. This suggests that environmental resources and enhancement in the first year of life may facilitate every infant's ability to thrive, setting the stage for a more positive developmental trajectory.

Bridging the gap: improving correspondence between low-field and high-field magnetic resonance images in young people.

Portable low-field-strength magnetic resonance imaging (MRI) systems represent a promising alternative to traditional high-field-strength systems with the potential to make MR technology available at scale in low-resource settings. However, lower image quality and resolution may limit the research and clinical potential of these devices. We tested two super-resolution methods to enhance image quality in a low-field MR system and compared their correspondence with images acquired from a high-field system in a sample of young people. T1- and T2-weighted structural MR images were obtained from a low-field (64mT) Hyperfine and high-field (3T) Siemens system in N = 70 individuals (mean age = 20.39 years, range 9-26 years). We tested two super-resolution approaches to improve image correspondence between images acquired at high- and low-field: (1) processing via a convolutional neural network ('SynthSR'), and (2) multi-orientation image averaging. We extracted brain region volumes, cortical thickness, and cortical surface area estimates. We used Pearson correlations to test the correspondence between these measures, and Steiger Z tests to compare the difference in correspondence between standard imaging and super-resolution approaches. Single pairs of T1- and T2-weighted images acquired at low field showed high correspondence to high-field-strength images for estimates of total intracranial volume, surface area cortical volume, subcortical volume, and total brain volume (r range = 0.60-0.88). Correspondence was lower for cerebral white matter volume (r = 0.32, p = 0.007, q = 0.009) and non-significant for mean cortical thickness (r = -0.05, p = 0.664, q = 0.664). Processing images with SynthSR yielded significant improvements in correspondence for total brain volume, white matter volume, total surface area, subcortical volume, cortical volume, and total intracranial volume (r range = 0.85-0.97), with the exception of global mean cortical thickness (r = 0.14). An alternative multi-orientation image averaging approach improved correspondence for cerebral white matter and total brain volume. Processing with SynthSR also significantly improved correspondence across widespread regions for estimates of cortical volume, surface area and subcortical volume, as well as within isolated prefrontal and temporal regions for estimates of cortical thickness. Applying super-resolution approaches to low-field imaging improves regional brain volume and surface area accuracy in young people. Finer-scale brain measurements, such as cortical thickness, remain challenging with the limited resolution of low-field systems.

Long-Term Brain Structure and Cognition Following Bariatric Surgery

Weight loss induced by bariatric surgery (BS) is associated with improved cognition and changed brain structure; however, previous studies on the association have used small cohorts and short follow-up periods, making it difficult to determine long-term neurological outcomes associated with BS. To investigate long-term associations of weight loss after BS with cognition and brain structure and perfusion. This cohort study included participants from the Bariatric Surgery Rijnstate and Radboudumc Neuroimaging and Cognition in Obesity study. Data from participants with severe obesity (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] >40, or BMI >35 with comorbidities) eligible for Roux-en-Y gastric bypass and aged 35 to 55 years were enrolled from a hospital specialized in BS (Rijnstate Hospital, Arnhem, the Netherlands). Participants were recruited between September 2018 and December 2020 with follow-up till March 2023. Data were collected before BS and at 6 and 24 months after BS. Data were analyzed from March to November 2023. Roux-en-Y gastric bypass. Primary outcomes included body weight, BMI, waist circumference, blood pressure, medication use, cognitive performance (20% change index of compound z-score), brain volumes, cortical thickness, cerebral blood flow (CBF), and spatial coefficient of variation (sCOV). Secondary outcomes include cytokines, adipokines, depressive symptoms (assessed using the Beck Depression Inventory), and physical activity (assessed using the Baecke Questionnaire). A total of 133 participants (mean [SD] age, 46.8 [5.7] years; 112 [84.2%] female) were included. Global cognition was at least 20% higher in 52 participants (42.9%) at 24 months after BS. Compared with baseline, at 24 months, inflammatory markers were lower (mean [SD] high-sensitivity C-reactive protein: 4.77 [5.80] μg/mL vs 0.80 [1.09] μg/mL; P < .001), fewer patients used antihypertensives (48 patients [36.1%] vs 22 patients [16.7%]), and patients had lower depressive symptoms (median [IQR] BDI score: 9.0 [5.0-13.0] vs 3.0 [1.0-6.0]; P < .001) and greater physical activity (mean [SD] Baecke score: 7.64 [1.29] vs 8.19 [1.35]; P < .001). After BS, brain structure and perfusion were lower in most brain regions, while hippocampal and white matter volume remained stable. CBF and sCOV did not change in nucleus accumbens and parietal cortex. The temporal cortex showed a greater thickness (mean [SD] thickness: 2.724 [0.101] mm vs 2.761 [0.007] mm; P = .007) and lower sCOV (median [IQR] sCOV: 4.41% [3.83%-5.18%] vs 3.97% [3.71%-4.59%]; P = .02) after BS. These findings suggest that BS was associated with health benefits 2 years after surgery. BS was associated with improved cognition and general health and changed blood vessel efficiency and cortical thickness of the temporal cortex. These results may improve treatment options for patients with obesity and dementia.

Sex Differences in the Association of Age at Hypertension Diagnosis With Brain Structure.

Sex differences exist in the likelihood of cognitive decline. The age at hypertension diagnosis is a unique contributor to brain structural changes associated with cerebral small vessel disease. However, whether this relationship differs between sexes remains unclear. Therefore, our objective was to evaluate sex differences in the association between the age at hypertension diagnosis and cerebral small vessel disease-related brain structural changes. We used data from the UK Biobank to select participants with a known age at hypertension diagnosis and brain magnetic resonance imaging (n=9430) and stratified them by sex and age at hypertension diagnosis. Control participants with magnetic resonance imaging scans but no hypertension were chosen at random matched by using propensity score matching. For morphological brain structural changes, generalized linear models were used while adjusting for other vascular risk factors. For the assessment of white matter microstructure, principal component analysis led to a reduction in the number of fractional anisotropy variables, followed by regression analysis with major principal components as outcomes. Males but not females with a younger age at hypertension diagnosis exhibited lower brain gray and white matter volume compared with normotensive controls. The volume of white matter hyperintensities was greater in both males and females with hypertension than normotensive controls, significantly higher in older females with hypertension. Compared with normotensive controls, white matter microstructural integrity was lower in individuals with hypertension, which became more prominent with increasing age. Our study demonstrates that the effect of hypertension on cerebral small vessel disease-related brain structure differs by sex and by age at hypertension diagnosis.

Brains of endurance athletes differ in the association areas but not in the primary areas.

Regular participation in sports results in a series of physiological adaptations. However, little is known about the brain adaptations to physical activity. Here we aimed to investigate whether young endurance athletes and non-athletes differ in the gray and white matter of the brain and whether cardiorespiratory fitness (CRF) is associated with these differences. We assessed the CRF, volumes of the gray and white matter of the brain using structural magnetic resonance imaging (sMRI), and brain white matter connections using diffusion magnetic resonance imaging (dMRI) in 20 young male endurance athletes and 21 healthy non-athletes. While total brain volume was similar in both groups, the white matter volume was larger and the gray matter volume was smaller in the athletes compared to non-athletes. The reduction of gray matter was located in the association areas of the brain that are specialized in processing of sensory stimuli. In the microstructure analysis, significant group differences were found only in the association tracts, for example, the inferior occipito-frontal fascicle (IOFF) showing higher fractional anisotropy and lower radial diffusivity, indicating stronger myelination in this tract. Additionally, gray and white matter brain volumes, as well as association tracts correlated with CRF. No changes were observed in other brain areas or tracts. In summary, the brain signature of the endurance athlete is characterized by changes in the integration of sensory and motor information in the association areas.

Cigarette smoking and structural brain deficits in patients with atrial fibrillation

Abstract Background Brain lesions are common in patients with atrial fibrillation (AF). Whether cigarette smoking is associated with an increased risk of brain lesions and reduced brain volume in patients with AF is currently unknown. Purpose In this analysis, we aimed to investigate the association of cigarette smoking habits with cerebral small vessel disease and overall brain volume. Methods For this cross-sectional analysis, we included AF patients from a multicentre cohort study. Smoking habits were defined by smoking status categories (never, former, current), duration (tertiles of years), cigarettes per day (CPD as obtained at baseline), packyears (PKY, tertiles) and time since smoking cessation (≤5 years, 6-10 years, 11-15 and ≥16 years). A standardized brain magnetic resonance imaging was done to assess the prevalence of small vessel disease white matter lesions (WML, graded according to the Fazekas scale) and small non-cortical infarcts (SNCI). Additionally, MRI was used to quantify the volumes of WML and SNCI; as well as to measure grey matter (GM) and white matter (WM) brain volumes. Multivariable adjusted logistic and linear regression analyses were applied. Results 1746 patients were enrolled (mean age 72.6 years, 27.5% females). 131 (7.5%) were current smokers, 846 (48.5%) former and 769 (44%) never smokers. Patients with a longer smoking duration, higher amount of CPD and PKY had reduced GM brain volume (p for linear trend 0.05, 0.005 and 0.02, respectively). Patient with higher CPD also had a reduced WM brain volume (p for linear trend 0.04). Compared to patients with a smoking duration in the lowest tertile (≤18 years), patients who had smoked for 19-34 years (second tertile) and more than 35 years (third tertile) had a higher risk for WML Fazekas ≥2 with an OR (95% CI) of 1.85 (1.29; 2.66, p=0.001) and 1.46 (1.01; 2.09, p=0.04) (Figure 1). Additionally, increasing smoking duration tertiles exhibited larger WML volumes, with a significant linear trend (p=0.05). AF patients who quit smoking ≥16 years ago had a lower odds for SNCI (OR 0.47 (0.24; 0.94, p= 0.03), less WML volume (β: -0.451 (-0.8; -0.11, p=0.01), and a higher WM brain volume (β: 16.9 (0.3; 33.6, p= 0.05) compared to patients who quit 5 years prior to the study enrolment (Figure 2). We found no significant difference in any structural brain deficit between current and former smokers compared to never smokers. Conclusion In a large AF population, we found that smoking duration and amount were associated with the loss of brain volumes. Smoking duration and time since smoking cessation were associated with small vessel disease.

A hydrolyzed lipid blend diet promotes myelination in neonatal piglets in a region and concentration-dependent manner.

The impact of early life nutrition on myelin development is of interest given that cognitive and behavioral function depends on proper myelination. Evidence shows that myelination can be altered by dietary lipid, but most of these studies have been performed in the context of disease or impairment. Here, we assessed the effects of lipid blends containing various levels of a hydrolyzed fat (HF) system on myelination in healthy piglets. Piglets were sow-reared, fed a control diet, or a diet containing 12%, 25%, or 53% HF consisting of cholesterol, fatty acids, monoglycerides, and phospholipid from lecithin. At postnatal day 28/29, magnetic resonance imaging (MRI) was performed to assess changes to brain development, followed by brain collection for microscopic analyses of myelin in targeted regions using CLARITY tissue clearing, immunohistochemistry, and electron microscopy techniques. Sow-reared piglets exhibited the highest overall brain white matter volume by MRI. However, a 25% HF diet resulted in the greatest total myelin density in the prefrontal cortex based on 3D modeling analysis of myelinated filaments. Nodal gap length and g-ratio were inversely correlated with percentage of HF in the corpus callosum, as well as in the PFC and internal capsule for g-ratio, indicating that a 53% HF diet resulted in the thickest myelin per axon and a 0% HF control diet the thinnest in specific brain regions. These findings indicate that HF promoted myelination in the neonatal piglet in a region- and concentration-dependent manner.

U-fiber diffusion kurtosis and susceptibility characteristics in relapsing-remitting multiple sclerosis may be related to cognitive deficits and neurodegeneration.

To evaluate the diffusion kurtosis and susceptibility change in the U-fiber region of patients with relapsing-remitting multiple sclerosis (pwRRMS) and their correlations with cognitive status and degeneration. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), kurtosis fractional anisotropy (KFA), and the mean relative quantitative susceptibility mapping (mrQSM) values in the U-fiber region were compared between 49 pwRRMS and 48 healthy controls (HCs). The U-fiber were divided into upper and deeper groups based on the location. The whole brain volume, gray and white matter volume, and cortical thickness were obtained. The correlations between the mrQSM values, DKI-derived metrics in the U-fiber region and clinical scale scores, brain morphologic parameters were further investigated. The decreased MK, AK, RK, KFA, and increased mrQSM values in U-fiber lesions (p < 0.001, FDR corrected), decreased RK, KFA, and increased mrQSM values in U-fiber non-lesions (p = 0.034, p < 0.001, p < 0.001, FDR corrected) were found in pwRRMS. There were differences in DKI-derived metrics and susceptibility values between the upper U-fiber region and the deeper one for U-fiber non-lesion areas of pwRRMS and HCs (p < 0.05), but not for U-fiber lesions in DKI-derived metrics. The DKI-derived metrics and susceptibility values were widely related with cognitive tests and brain atrophy. RRMS patients show abnormal diffusion kurtosis and susceptibility characteristics in the U-fiber region, and these underlying tissue abnormalities are correlated with cognitive deficits and degeneration. The macroscopic and microscopic tissue damages of U-fiber help to identify cognitive impairment and brain atrophy in multiple sclerosis and provide underlying pathophysiological mechanism. • Diffusion kurtosis and susceptibility changes are present in the U-fiber region of multiple sclerosis. • There are gradients in diffusion kurtosis and susceptibility characteristics in the U-fiber region. • Tissue damages in the U-fiber region are correlated with cognitive impairment and brain atrophy.

Association of smoking with brain gray and white matter volume: a Mendelian randomization study.

Observational studies have found a significant association between smoking and smaller gray matter volume, but this finding was limited by the reverse causality bias and possible confounding factors. Therefore, we conducted a Mendelian randomization (MR) study to explore the causal association of smoking with brain gray and white matter volume from a genetic perspective, and to investigate the possible mediators influencing the association. Smoking initiation (ever being a regular smoker) was used as the primary exposure from the GWAS & Sequencing Consortium of Alcohol and Nicotine use in up to 1,232,091 individuals of European descent. Their associations with brain volume were acquired from a recent genome-wide association study of brain imaging phenotypes conducted among 34,298 individuals of the UK Biobank. The random-effects inverse-variance weighted method was applied as the main analysis. Multivariable MR analysis was performed to assess the potential interference of confounding factors on causal effect. Genetic liability to smoking initiation was significantly associated with lower gray matter volume (beta, -0.100; 95% CI, -0.156 to -0.043; P=5.23×10-4) but not with white matter volume. Multivariable MR results suggested that the association with lower gray matter volume might be mediated by alcohol drinking. Regarding localized gray matter volume, genetic liability to smoking initiation was associated with lower gray matter volume in left superior temporal gyrus, anterior division and right superior temporal gyrus, posterior division. This MR study supports the association between smoking and lower gray matter volume, and highlights the importance of never smoking.

Renal function affects circulating levels of neurofilament light chain: MarkVCID‐CHARGE

AbstractBackgroundPlasma NfL is a promising fluid biomarker for risk stratification and quantifying the extent of neuronal injury in conditions such as vascular cognitive impairment and dementia (VCID) and Alzheimer’s dementia. However, systemic factors such as kidney function can affect circulating levels and this requires further investigation to ensure appropriate use as a biomarker.MethodWe examined the cross‐sectional association between plasma NfL levels and renal function among adult participants from four community‐based studies in the MarkVCID‐Cohorts for Heart and Aging Research in Genomic Epidemiology consortium who were free from stroke, multiple sclerosis, dementia, and renal failure. Estimated glomerular filtration rate (eGFR, mL/min/1.73m2) was calculated using the CKD‐EPI equation and categorized using Kidney Disease: Improving Global Outcomes (KDIGO) classification. Plasma NfL was measured using single molecule array technology. Multivariable linear regression models were used to investigate the linear relationship between eGFR and NfL, overall and stratified by KDIGO category. Study level estimates were combined in meta‐analysis. Models were adjusted for age, sex, sub‐cohort, hypertension, diabetes, body mass index, smoking, and race. Factors affecting eGFR can also cause MRI brain injury, hence we examined whether any apparent increase in NfL levels in persons with a lower eGFR merely reflected greater brain injury by performing a sensitivity analysis in a subsample with brain MRI, additionally adjusting in a single model for brain volume, white matter hyperintensities, and free water.ResultIn meta‐analysis (n = 5,954), lower eGFR was associated with higher plasma NfL (β = ‐0.0073, standard error[SE] = 0.0021, P = 0.0006). This relationship persisted within categories of reduced renal function, eGFR 60‐74 (mild), 45‐59 (moderate), and 15‐44 (severe) (P‐values&lt;0.0001), but was not evident with normal eGFR ≥90 (P = 0.3) or mildly decreased eGFR 75‐89 (P = 0.2). Further adjustment for white matter hyperintensities, brain volume, and free water among a subgroup with brain MRI (n = 2192) did not change the associations of eGFR and NfL (β = ‐0.0065,SE = 0.0025, P = 0.0091).ConclusionReduced renal function is associated with higher circulating NfL, even at an eGFR range (60‐74) considered normal in clinical practice. Adjusting for renal function may improve the accuracy of plasma NfL as a biomarker for risk stratification or for assessment of neuronal injury in conditions such as VCID.

Integration of epigenetic and genetic profiles identifies multiple sclerosis disease-critical cell types and genes

Genome-wide association studies (GWAS) successfully identified multiple sclerosis (MS) susceptibility variants. Despite this notable progress, understanding the biological context of these associations remains challenging, due in part to the complexity of linking GWAS results to causative genes and cell types. Here, we aimed to address this gap by integrating GWAS data with single-cell and bulk chromatin accessibility data and histone modification profiles from immune and nervous systems. MS-GWAS associations are significantly enriched in regulatory regions of microglia and peripheral immune cell subtypes, especially B cells and monocytes. Cell-specific polygenic risk scores were developed to examine the cumulative impact of the susceptibility genes on MS risk and clinical phenotypes, showing significant associations with risk and brain white matter volume. The findings reveal enrichment of GWAS signals in B cell and monocyte/microglial cell-types, consistent with the known pathology and presumed targets of effective MS therapeutics.

Brain dysfunction in gait disorders of Caribbean atypical Parkinsonism and progressive supranuclear palsy patients: A comparative study

IntroductionGait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorders in Caribbean AP and PSP-RS patients. MethodsWe assessed gait and balance using clinical scales and gait recordings in 16 Caribbean AP and 15 PSP-RS patients and 17 age-matched controls. We measured the grey and white matter brain volumes on 3 T brain MRI images. We performed a principal component analysis (PCA) including all the data to determine differences and similarities between groups, and explore the relationship between gait disorders and brain volumes. ResultsBoth Caribbean AP patients and PSP-RS have marked gait and balance disorders with similar severity. In both groups, gait and balance disorders were found to be most strongly related to structural changes in the lateral cerebellum, caudate nucleus, and fronto-parietal areas. In Caribbean AP patients, gait disorders were also related to additional changes in the cortex, including frontal, insular, temporal and cuneus lobes, whereas in PSP-RS patients, additional white matter changes involved the mesencephalon and parahippocampal gyrus. ConclusionGait and balance disorders in Caribbean AP patients are mainly related to dysfunction of cortical brain areas involved in visuo-sensorimotor processing and self-awareness, whereas these signs mainly result from premotor-brainstem-cerebellar network dysfunction in PSP-RS patients, brain areas involved in initiation and maintenance of locomotor pattern and postural adaptation.

Arterial stiffness and its influence on cerebral morphology and cognitive function.

Recently, arterial stiffness has been associated with cerebral small vessel disease (SVD), brain atrophy and vascular dementia. Arterial stiffness is assessed via pulse wave velocity (PWV) measurement and is strongly dependent on arterial blood pressure. While circadian blood pressure fluctuations are important determinants of end-organ damage, the role of 24-h PWV variability is yet unclear. We here investigated the association between PWV and its circadian changes on brain morphology and cognitive function in community-dwelling individuals. Single-centre, prospective, community-based follow-up study. The study cohort comprised elderly community-based participants of the Austrian Stroke Prevention Family Study which was started in 2006. Patients with any history of cerebrovascular disease or dementia were excluded. The study consists of 84 participants who underwent ambulatory 24-h PWV measurement. White matter hyperintensity volume and brain volume were evaluated by 3-Tesla magnetic resonance imaging (MRI). A subgroup of patients was evaluated for cognitive function using an extensive neuropsychological test battery. PWV was significantly related to reduced total brain volume (p = 0.013), which was independent of blood pressure and blood pressure variability. We found no association between PWV with markers of cerebral SVD or impaired cognitive functioning. Only night-time PWV values were associated with global brain atrophy (p = 0.005). This study shows a relationship of arterial stiffness and reduced total brain volume. Elevations in PWV during night-time are of greater importance than day-time measures.