Parietal Gray Matter Research Articles

BCL3, GBP1, IFI16, and CCR1 as potential brain-derived biomarkers for parietal grey matter lesions in multiple sclerosis

BCL3, GBP1, IFI16, and CCR1 as potential brain-derived biomarkers for parietal grey matter lesions in multiple sclerosis

Data-independent acquisition proteomic analysis of the brain microvasculature in Alzheimer’s disease identifies major pathways of dysfunction and upregulation of cytoprotective responses

Brain microvascular dysfunction is an important feature of Alzheimer’s disease (AD). To better understand the brain microvascular molecular signatures of AD, we processed and analyzed isolated human brain microvessels by data-independent acquisition liquid chromatography with tandem mass spectrometry (DIA LC–MS/MS) to generate a quantitative dataset at the peptide and protein level. Brain microvessels were isolated from parietal cortex grey matter using protocols that preserve viability for downstream functional studies. Our cohort included 23 subjects with clinical and neuropathologic concordance for Alzheimer’s disease, and 21 age-matched controls. In our analysis, we identified 168 proteins whose abundance was significantly increased, and no proteins that were significantly decreased in AD. The most highly increased proteins included amyloid beta, tau, midkine, SPARC related modular calcium binding 1 (SMOC1), and fatty acid binding protein 7 (FABP7). Additionally, Gene Ontology (GO) enrichment analysis identified the enrichment of increased proteins involved in cellular detoxification and antioxidative responses. A systematic evaluation of protein functions using the UniProt database identified groupings into common functional themes including the regulation of cellular proliferation, cellular differentiation and survival, inflammation, extracellular matrix, cell stress responses, metabolism, coagulation and heme breakdown, protein degradation, cytoskeleton, subcellular trafficking, cell motility, and cell signaling. This suggests that AD brain microvessels exist in a stressed state of increased energy demand, and mount a compensatory response to ongoing oxidative and cellular damage that is associated with AD. We also used public RNAseq databases to identify cell-type enriched genes that were detected at the protein level and found no changes in abundance of these proteins between control and AD groups, indicating that changes in cellular composition of the isolated microvessels were minimal between AD and no-AD groups. Using public data, we additionally found that under half of the proteins that were significantly increased in AD microvessels had concordant changes in brain microvascular mRNA, implying substantial discordance between gene and protein levels. Together, our results offer novel insights into the molecular underpinnings of brain microvascular dysfunction in AD.

Neural correlates of harm avoidance: a multimodal meta-analysis of brain structural and resting-state functional neuroimaging studies

Harm avoidance (HA) is a Cloninger personality trait that describes behavioural inhibition to avoid aversive stimuli. It serves as a predisposing factor that contributes to the development of mental disorders such as anxiety and major depressive disorder. Neuroimaging research has identified some brain anatomical and functional correlates of HA, but reported findings are inconsistent. We therefore conducted a multimodal meta-analysis of whole-brain structural and resting-state functional neuroimaging studies to identify the most stable neural substrate of HA. Included were a total of 10 structural voxel-based morphometry studies (11 datasets) and 13 functional positron emission tomography or single photon emission computed tomography studies (16 datasets) involving 3053 healthy participants without any psychiatric or neurological disorders evaluated for HA using the Three-Dimensional Personality Questionnaire (TPQ) or the Temperament and Character Inventory (TCI). The meta-analysis revealed brain volumetric correlates of HA in parietal and temporal cortices, and resting-state functional correlates in prefrontal, temporal and parietal gray matter. Volumetric and functional correlates co-occurred in the left superior frontal gyrus and left middle frontal gyrus, and were dissociated in the left rectus gyrus. Our meta-analysis is the first study to give a comprehensive picture of the structural and functional correlates of HA, a contribution that may help bridge the grievous gap between the neurobiology of HA and the pathogenesis, prevention and treatment of HA-related mental disorders.

Cortical lobar volume reductions associated with homocysteine-related subcortical brain atrophy and poorer cognition in healthy aging.

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

Pro-atherogenic medical conditions are associated with widespread regional brain metabolite abnormalities in those with alcohol use disorder.

Widespread brain metabolite abnormalities in those with alcohol use disorder (AUD) were reported in numerous studies, but the effects of the pro-atherogenic conditions of hypertension, type 2 diabetes mellitus, hepatitis C seropositivity, and hyperlipidemia on metabolite levels were not considered. These conditions were associated with brain metabolite abnormalities in those without AUD. We predicted treatment-seeking individuals with AUD and pro-atherogenic conditions (Atherogenic+) demonstrate lower regional metabolite markers of neuronal viability [N-acetylaspartate (NAA)] and cell membrane turnover/synthesis [choline-containing compounds (Cho)], compared with those with AUD without pro-atherogenic conditions (Atherogenic-) and healthy controls (CON). Atherogenic+ (n = 59) and Atherogenic- (n = 51) and CON (n = 49) completed a 1.5T proton magnetic resonance spectroscopic imaging study. Groups were compared on NAA, Cho, total creatine, and myoinositol in cortical gray matter (GM), white matter (WM), and select subcortical regions. Atherogenic+ had lower frontal GM and temporal WM NAA than CON. Atherogenic+ showed lower parietal GM, frontal, parietal and occipital WM and lenticular nuclei NAA level than Atherogenic- and CON. Atherogenic- showed lower frontal GM and WM NAA than CON. Atherogenic+ had lower Cho level than CON in the frontal GM, parietal WM, and thalamus. Atherogenic+ showed lower frontal WM and cerebellar vermis Cho than Atherogenic- and CON. Findings suggest proatherogenic conditions in those with AUD were associated with increased compromise of neuronal integrity and cell membrane turnover/synthesis. The greater metabolite abnormalities observed in Atherogenic+ may relate to increased oxidative stress-related compromise of neuronal and glial cell structure and/or impaired arterial vasoreactivity/lumen viability.

Gray matter volume mediates the association of long-term blood pressure variability with cognitive function in an adult population.

We delineated the associations among long-term blood pressure variability (BPV), brain structure, and cognitive function. We included 1254 adult participants from the Kailuan study. BPV was calculated from 2006 to 2020. Brain magnetic resonance imaging (MRI) and Montreal Cognitive Assessment (MoCA) were conducted in 2020. Higher systolic BPV (SBPV) and diastolic BPV (DBPV) were associated with lower total and frontal gray matter (GM) volume, and higher SBPV was associated with lower temporal GM volume. Elevated DBPV was associated with lower volume of total brain and parietal GM, and higher white matter hyperintensity (WMH) volume. Higher SBPV and DBPV were associated with lower MoCA scores. Decreased total and regional GM volume and increased WMH volume were associated with lower MoCA scores. The association between SBPV and cognitive function was mediated by total, frontal, and temporal GM volume. GM volume may play key roles in the association between SBPV and cognitive function. SBPV and DBPV were negatively associated with total and regional brain volume. SBPV and DBPV were negatively associated with cognitive function. Decreased brain volume was associated with cognitive decline. GM volume mediated the negative association between SBPV and cognitive function.

SHARED AND DISTINCT ASSOCIATIONS OF MANUAL DEXTERITY AND GROSS MOTOR FUNCTION WITH BRAIN ATROPHY

Abstract Poor motor function is associated with brain volume and cognitive impairment. Less is known about the associations among motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6±10.1 years, 56%women, 27%Black), 525 of whom had repeat MRI scans over 5.0±2.1 years. Two motor domains were operationalized as latent variables. Manual dexterity using the Purdue Pegboard and gross motor function using grip strength and comprehensive physical performance testing. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p<.05). Higher manual dexterity was also cross-sectionally associated with greater parietal gray matter ( =0.14;95%CI:0.05,0.23), hippocampal ( =0.10;95%CI:0.01,0.20), postcentral gyrus ( =0.11;95%CI:0.01,0.20), and occipital white matter ( =0.10;95%CI:0.01,0.21) volumes, and better gross motor function with greater temporal gray matter volume ( =0.16;95%CI:0.05,0.26). Longitudinally, higher manual dexterity and gross motor function were associated with lower temporal white matter and occipital gray matter atrophy (all p<0.05). Greater manual dexterity was also associated with a slower rate of ventricular enlargement ( =-0.17;95%CI:-0.29,-0.05) and less atrophy of occipital white matter ( =0.39;95%CI:0.04,0.71). Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time.

Creatine supplementation combined with breathing exercises reduces respiratory discomfort and improves creatine status in patients with long-COVID.

Eight long-COVID patients with moderate fatigue that had lasted for ≥3 months were recruited. All patients were allocated in a double-blind parallel-group design to receive either 4 g of creatine per day plus breathing exercises (study group) or breathing exercises only (control group) for 3 months. Creatine induced a significant increase in tissue total creatine levels for all 14 locations evaluated in the present study ( P < 0.05), while its levels significantly dropped in the right frontal gray matter and left parietal mesial gray matter at follow-up in the control group ( P < 0.05). No change in time to exhaustion was demonstrated in the control group (P > 0.05), while the mean time to exhaustion was significantly improved for 54 s in the study group post-administration (P = 0.05). These preliminary findings suggest that creatine is as an effective adjuvant therapeutic to breathing exercises for tackling the clinical features in long-COVID.

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values&gt;0.31) nor p‐tau (p‐values&gt;0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values&gt;0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values&lt;0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

The aftermath of boxing: Longitudinal changes of cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers

AbstractBackgroundChronic traumatic encephalopathy (CTE), formerly known as “boxer’s encephalopathy” is a neurodegenerative disease associated with mild‐repetitive TBI. CTE is characterized by the deposition of hyperphosphorylated tau as neurofibrillary tangles around small blood vessels of the cortex, typically at the sulcal depths. Although tau PET studies on American football players reported findings consistent with neuropathological changes identified by postmortem brains, there are no reports of tau PET studies in boxers, and longitudinal changes of tau depositions following boxing remains unknown. The present study was aimed to characterize cerebral retention patterns of 18F‐florzolotau (18F‐APN‐1607) in the former professional boxers.MethodTwenty‐nine former boxers (43.4 ± 10.3 years) and 27 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐florzolotau and 11C‐PiB. Eleven former boxers underwent a second tau PET scan (average interval: 874days). Standard uptake value ratio (SUVR) with the optimized reference tissue was calculated. Regions of interest were defined on brain regions of the gray matter (GM), white matter (WM) and the gray‐white matter boundary (GWB). Association of regional SUVR values with neurocognitive symptoms and various indexes related boxing was investigated.ResultOne boxer was [11C]PiB positive. Former boxers showed higher 18F‐florzolotau retentions than HC subjects in the bilateral frontal GM, right parietal GM, bilateral frontal WM, right parietal WM (P &lt; 0.001). There was a significant correlation between SUVR values in the whole GM and the total number of bouts (p = 0.07,r = 0.40). Subtyping using z‐score heatmap with predetermined criteria revealed heterogeneity in 18F‐florzolotau retention patterns in boxers. Of the 29 boxers, (1) 10 showed increased retention of 18F‐florzolotau in GM (GM dominant), (2) 4 showed increased accumulation mainly in WM (WM dominant), (3) 5 showed increased accumulation in GWB (GWB dominant), and (4) 10 showed no significant increased accumulation in the brain (No tau). These types vary in longitudinal changes of 18F‐florzolotau retention patterns, as well as in clinical features.ConclusionThe present study not only supports pathological heterogeneity of late‐sequalae of professional boxing, but also suggests utility of 18F‐florzolotau PET in detection of late‐life neurodegenerative diseases following mild‐repetitive TBI.

Shared and Distinct Associations of Manual Dexterity and Gross Motor Function With Brain Atrophy.

Poor motor function is associated with brain atrophy and cognitive impairment. Less is known about the relationship between motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6 ± 10.1 years, 56% women, 27% Black), 525 of whom had repeat MRI scans over an average of 5.0 ± 2.1 years. Two motor domains, manual dexterity and gross motor, were operationalized as latent variables. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p < .05). Manual dexterity was also cross-sectionally associated with parietal gray matter (B = 0.14; 95% CI: 0.05, 0.23), hippocampus (B = 0.10; 95% CI: 0.01, 0.20), postcentral gyrus (B = 0.11; 95% CI: 0.01, 0.20), and occipital white matter (B = 0.10; 95% CI: 0.01, 0.21) volumes, and gross motor function with temporal gray matter volume (B = 0.16; 95% CI: 0.05, 0.26). Longitudinally, both higher manual dexterity and gross motor function were associated with less temporal white matter and occipital gray matter atrophy (all p < .05). Manual dexterity was also associated with a slower rate of ventricular enlargement (B = -0.17; 95% CI: -0.29, -0.05) and less atrophy of occipital white matter (B = 0.39; 95% CI: 0.04, 0.71). Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time.

1H-MRS neurometabolite profiles and motor development in school-aged children who are HIV-exposed uninfected: a birth cohort study.

Alterations in regional neurometabolite levels as well as impaired neurodevelopmental outcomes have previously been observed in children who are HIV-exposed uninfected (CHEU). However, little is known about how neurometabolite profiles may relate to their developmental impairment. This study aimed to compare neurometabolite concentrations in school-aged CHEU and children who are HIV-unexposed (CHU) and to explore associations of neurometabolite profiles with functional neurodevelopment in the context of perinatal HIV exposure. We used 3 T single voxel proton magnetic resonance spectroscopy (1H-MRS) to quantify absolute and relative neurometabolites in the parietal gray and parietal white matter in school-aged CHEU and aged- and community-matched CHU. Functional neurodevelopmental outcomes were assessed using the early learning outcome measure (ELOM) tool at 6 years of age. Our study included 152 school-aged children (50% males), 110 CHEU and 42 CHU, with an average age of 74 months at the neuroimaging visit. In an adjusted multiple linear regression analysis, significantly lower glutamate (Glu) concentrations were found in CHEU as compared to CHU in the parietal gray matter (absolute Glu, p = 0.046; Glu/total creatine (Cr+PCr) ratios, p = 0.035) and lower total choline to creatine ratios (GPC+PCh/Cr+PCr) in the parietal white matter (p = 0.039). Using factor analysis and adjusted logistic regression analysis, a parietal gray matter Glu and myo-inositol (Ins) dominated factor was associated with HIV exposure status in both unadjusted (OR 0.55, 95% CI 0.17-0.45, p = 0.013) and adjusted analyses (OR 0.59, 95% CI 0.35-0.94, p = 0.031). With Ins as one of the dominating metabolites, this neurometabolic factor was similar to that found at the age of two years. Furthermore, this factor was also found to be correlated with ELOM scores of gross motor development in CHEU (Pearson's r = -0.48, p = 0.044). In addition, in CHEU, there was a significant association between Ins/Cr+PCr ratios in the parietal white matter and ELOM scores of fine motor coordination and visual motor integration in CHEU (Pearson's r = 0.51, p = 0.032). Reduced Glu concentrations in the parietal gray matter may suggest regional alterations in excitatory glutamatergic transmission pathways in the context of perinatal HIV and/or antiretroviral therapy (ART) exposure, while reduced Cho ratios in the parietal white matter suggest regional myelin loss. Identified associations between neurometabolite profiles and gross and fine motor developmental outcomes in CHEU are suggestive of a neurometabolic mechanism that may underlie impaired motor neurodevelopmental outcomes observed in CHEU.

Quantification of regional CMRO2 in human brain using dynamic 17O-MRI at 3T

ObjectiveTo investigate the feasibility of cerebral metabolic rate of oxygen consumption (CMRO2) measurements with MRI at 3 Tesla in different brain regions. MethodsCMRO2 represents a key indicator of the physiological state of brain tissue. Dynamic 17O-MRI with inhalation of isotopically enriched 17O gas has been used to quantify global CMRO2 in brain white (WM) and gray matter (GM). However, global CMRO2 can only reflect the overall oxygen metabolism of the brain and cannot provide enough information on local tissue oxygen metabolism. To investigate the feasibility of determination of regional CMRO2 at a clinical 3 T MRI system, CMRO2 values in frontal, parietal and occipital WM and GM were determined in 5 healthy volunteers and compared to evaluate the regional differences of oxygen metabolism in WM and GM. Additionally, regional CMRO2 values were determined in deep brain structures including thalamus, dorsal striatum, caudate nucleus and insula cortex and in the cerebella, and compared with literature values from 15O-PET studies. ResultsIn cortical GM the determined CMRO2 values were in good agreement with the literature, whereas values in WM were about 32–48% higher than literature values. Regional analysis revealed a significantly higher CMRO2 in the occipital GM compared to the frontal and parietal GM. By contrast, no significant difference of CMRO2 was observed across the WM. In addition, CMRO2 in deep brain structures was lower compared to literature values and in the cerebella a good hemispheric symmetry of the tissue oxygen metabolism was found. ConclusionDynamic 17O-MRI enables direct, non-invasive determination of regional CMRO2 in brain structures in healthy volunteers at 3T.

Brain proton MR spectroscopy measurements in CLN3 disease.

CLN3 is an autosomal recessive lysosomal disorder with intracellular accumulation of ceroid-lipofuscins. CLN3 classically has onset around 4-6years of age involving vision loss, followed by developmental regression and seizures. Symptoms are progressive and result in premature death. Because treatments are under development, here we explore magnetic resonance spectroscopy (MRS) measurements of metabolite levels in the brain as a potential objective outcome measures. Individuals with genetically confirmed CLN3 were enrolled from October 2017-November 2021 in a prospective natural history study (NCT033007304). Baseline concentrations of brain metabolites measured by MRS were compared to concurrently collected dimensional assessment measures: Vineland-3 Adaptive Behavior Composite (ABC) score, verbal intelligence quotient (VIQ), and the Physical, Capability with actual vision, and Clinical global impression of change sub-domains of the Unified Batten Disease Rating Scale (UBDRS). 27 participants with typical CLN3 presentation (15F:12M; ages 6.0-20.7years) completed MRS, ABC, and UBDRS; 20 (12F:8M; ages 6.5-20.7years) also completed the VIQ assessment. N-acetyl aspartate [B(95% CI)=-0.61(-0.78;-0.45)] and glutamine/glutamate/GABA [B(95% CI)=-0.82(-1.04;-0.6)] in the parietal gray matter (PGM) decreased across the ages. The strongest correlations between MRS metabolite measurements and the clinical severity assessments were found with N-acetyl aspartate [VIQ (ρ=0.58), Vineland-3 ABC (ρ=0.59), UBDRS |ρ| range=(0.57;0.7)] and glutamine/glutamate/GABA [VIQ (ρ=0.57), Vineland-3 ABC (ρ=0.60), UBDRS |ρ| range=(0.59;0.77)] measured in the midline PGM. These correlations were accounted for when age was considered. Based on their correlations to established assessments, NAA and glutamine/glutamate/GABA measured in the midline parietal gray matter may be useful indicators of CLN3 disease state. In a clinical trial, divergence of the MRS measurements and clinical severity markers from age may be useful as surrogate measures for treatment responses.

Abstract 123: In Vivo Permeability Of The Aging Brain With Cerebral Microbleeds

Introduction: Age-related cerebral microbleeds (CMBs) are vascular changes associated with an increased risk of intracerebral hemorrhage (ICH) and neurocognitive decline. CMBs share a strikingly similar appearance on MRI to cerebral cavernous malformations (CCMs), which are leaky capillary lesions predisposing patients to brain bleeding. Our team had previously shown increased vascular permeability in CCM and in the brain of older subjects, with common circulating biomarkers of angiogenesis and inflammation. We examine here whether vascular permeability is greater in the aging brain harboring CBMs. Methods: Dynamic Contrast-Enhanced Quantitative Perfusion (DCEQP) MRI, which assesses vascular permeability, was acquired for 7 patients with CMBs (&gt;50 years old), 10 old (&gt;50 years old), and 9 young (18-30 years old) healthy subjects without CMBs. Cases with active brain disease, stroke or seizure in the prior year were excluded. DCEQP scans were co-registered onto their respective T1-weighted images, normalized using the Desikan-Killiany atlas, and finally segmented into white and gray matter within frontal, temporal, parietal, and occipital lobes. The mean permeability was calculated within each segmented area, and values were compared between the 3 groups of interest. Results: Increased permeability was observed within the frontal white and gray matter as well as the parietal gray matter of patients with CMBs compared to age matched old healthy controls (both: p&lt;0.05). In addition, greater background brain permeability was also observed in old healthy controls compared to young healthy controls, in the occipital white matter, as well as the white and gray matter in the temporal and parietal lobes (all: p&lt;0.05). Conclusion: We confirm that the human brain exhibits increased vascular permeability with aging, and this is more pronounced in brains harboring CMBs. This may provide insight into the pathogenesis of CMBs, potentially reflecting end stage age-related failure of the blood brain barrier, associated with frank bleeding. These results offer a starting point for the development of diagnostic and prognostic imaging biomarkers of CMBs, which can help stratify patients at higher risk of future ICH and cognitive decline.

Longitudinal evolution of neuropathological substrates of Alzheimer’s disease in obese patients

AbstractBackgroundObesity is a metabolic condition with increasing prevalence all over the world. Patients with a body mass index (BMI) higher than 30 are considered obese. Obesity is also a risk factor for chronic morbidities such as type 2 diabetes and may increase the risk of developing Alzheimer's disease (AD). Not much is known about longitudinal changes in Alzheimer’s pathology in these patients. We hypothesised that BMI would predict longitudinal pathological alterations derived from imaging parameters.Method252 participants (n=107 obese non‐diabetic patients with BMI&gt;30) cognitively normal (n=80) and with mild cognitive impairment (n=172) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (Mean age = 73.6 years, SD = 8.0). All participants had two T1‐weighted MPRAGE MRI scans within two‐years (Mean gap=718 days, SD=107). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. Individual gray matter density maps were computed using voxel‐based morphometry (VBM) and regional values were sampled in various cortical regions. Regional cortical thickness and gray matter density are expressed as delta values between baseline and followup (Value followup ‐ Value Baseline). Spearman’s correlation coefficients were calculated to assess the relationship between BMI and imaging biomarkers.ResultIn the whole cohort, we found that BMI is significantly negatively correlated with longitudinal changes in cortical thickness in anterior cingulate (ACC, p=0.0073, r=‐0.17) and posterior cingulate (PCC, p=0.0147, r=‐0.15) cortical thickness. We also found that BMI is significantly negatively correlated with longitudinal changes in frontal (p=0.0184, r=‐0.15), parietal (p=0.0057, r=‐0.18) and temporal (p=0.0141, r=‐0.16) gray matter density. When looking only at MCI participants, we found similar results with even stronger correlations. BMI is significantly negatively correlated with delta anterior cingulate (ACC, p=0.0008, r=‐0.25) and posterior cingulate (PCC, p=0.004, r=‐0.22) cortical thickness.ConclusionIn this cohort of obese and non‐obese participants cognitively normal and with MCI, we found that obesity was associated with a longitudinal 2‐years worsening of macrostructural changes. Higher BMI was associated with a higher reduction of cortical thickness and with a decreased gray matter density in several brain regions.

Blood-brain barrier leakage years after pre-eclampsia: dynamic contrast-enhanced 7-Tesla MRI study.

Pre-eclampsia is a hypertensive complication of pregnancy that is associated with an increased risk of long-term cardiovascular and cerebrovascular disorders. Although the underlying mechanism of persistent susceptibility to cerebral complications after pre-eclampsia remains largely unclear, impaired blood-brain barrier (BBB) integrity has been suggested to precede several cerebrovascular diseases. In this study, we aimed to investigate the integrity of the BBB years after pre-eclampsia. This was an observational study of premenopausal formerly pre-eclamptic women and controls with a history of normotensive pregnancy who underwent cerebral magnetic resonance imaging (MRI) at ultra-high field (7Tesla) to assess the integrity of the BBB. Permeability of the BBB was determined by assessing leakage rate and fractional leakage volume of the contrast agent gadobutrol using dynamic contrast-enhanced MRI. BBB leakage measures were determined for the whole brain and lobar white and gray matter. Multivariable analyses were performed, and odds ratios were calculated to compare women with and those without a history of pre-eclampsia, adjusting for potential confounding effects of age, hypertension status at MRI and Fazekas score. Twenty-two formerly pre-eclamptic women (mean age, 37.8 ± 5.4 years) and 13 control women with a history of normotensive pregnancy (mean age, 40.8 ± 5.5 years) were included in the study. The time since the index pregnancy was 6.6 ± 3.2 years in the pre-eclamptic group and 9.0 ± 3.7 years in controls. The leakage rate and fractional leakage volume were significantly higher in formerly pre-eclamptic women than in controls in the global white (P = 0.001) and gray (P = 0.02) matter. Regionally, the frontal (P = 0.04) and parietal (P = 0.009) cortical gray matter, and the frontal (P = 0.001), temporal (P &lt; 0.05) and occipital (P = 0.007) white matter showed higher leakage rates in formerly pre-eclamptic women. The odds of a high leakage rate after pre-eclampsia were generally higher in white-matter regions than in gray-matter regions. This observational study demonstrates global impairment of the BBB years after a pre-eclamptic pregnancy, which could be an early marker of long-term cerebrovascular disorders. © 2022 The Authors. Ultrasound in Obstetrics &amp; Gynecology published by John Wiley &amp; Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Pattern of Altered Magnetization Transfer Rate in Alzheimer's Disease.

Biomarkers for Alzheimer's disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.

Gray matter volume alteration is associated with insistence on sameness and cognitive flexibility in autistic youth.

Restricted and repetitive behaviors (RRBs) are hallmark characteristics of autism spectrum disorder (ASD). Previous studies suggest that insistence on sameness (IS) characterized as higher-order RRBs may be a promising subgrouping variable for ASD. Cognitive inflexibility may underpin IS behaviors. However, the neuroanatomical correlates of IS and associated cognitive functions remain unclear. We analyzed data from 140 autistic youth and 124 typically developing (TD) youth (mean age=15.8 years). Autistic youth were stratified by median-split based on three current IS items in the autism diagnostic interview-revised into two groups (high, HIS, n=70, and low, LIS, n=70). Differences in cognitive flexibility were assessed by the Cambridge neuropsychological test automated battery (CANTAB). T1-weighted brain structural images were analyzed using voxel-based morphometry (VBM) to identify differences in gray matter (GM) volume among the three groups. GM volume of regions showing group differences was then correlated with cognitive flexibility. The HIS group showed decreased GM volumes in the left supramarginal gyrus compared to the LIS group and increased GM volumes in the vermis VIII and left cerebellar lobule VIII compared to TD individuals. We did not find significant correlations between regional GM volumes and extra-dimensional shift errors. IS may be a unique RRB component and a potentially valuable stratifier of ASD. However, the neurocognitive underpinnings require further clarification. LAY SUMMARY: The present study found parietal, temporal and cerebellar gray matter volume alterations in autistic youth with greater insistence on sameness. The findings suggest that insistence on sameness may be a useful feature to parse the heterogeneity of the autism spectrum yet further research investigating the underlying neurocognitive mechanism is warranted.

A Neurometabolic Pattern of Elevated Myo-Inositol in Children Who Are HIV-Exposed and Uninfected: A South African Birth Cohort Study.

IntroductionExposure to maternal HIV in pregnancy may be a risk factor for impaired child neurodevelopment during the first years of life. Altered neurometabolites have been associated with HIV exposure in older children and may help explain the mechanisms underlying this risk. For the first time, we explored neurometabolic profiles of children who are HIV-exposed and uninfected (CHEU) compared to children who are HIV-unexposed (CHU) at 2-3 years of age.MethodsThe South African Drakenstein Child Health Study enrolled women during pregnancy and is following mother-child pairs through childhood. MRI scans were acquired on a sub-group of children at 2-3 years. We used single voxel magnetic resonance spectroscopy to measure brain metabolite ratios to total creatine in the parietal grey matter, and left and right parietal white matter of 83 children (36 CHEU; 47 CHU). Using factor analysis, we explored brain metabolite patterns in predefined parietal voxels in these groups using logistic regression models. Differences in relative concentrations of individual metabolites (n-acetyl-aspartate, myo-inositol, total choline, and glutamate) to total creatine between CHEU and CHU groups were also examined.ResultsFactor analysis revealed four different metabolite patterns, each one characterized by covarying ratios of a single metabolite in parietal grey and white matter. The cross-regional pattern dominated by myo-inositol, a marker for glial reactivity and inflammation, was associated with HIV exposure status (OR 1.63; 95% CI 1.11–2.50) which held after adjusting for child age, sex, and maternal alcohol use during pregnancy (OR 1.59; 95% CI 1.07 –2.47). Additionally, higher relative concentrations of myo-inositol to total creatine were found in left and right parietal white matter of CHEU compared to CHU (p=0.025 and p=0.001 respectively).DiscussionIncreased ratios of myo-inositol to total creatine in parietal brain regions at age 2-3 years in CHEU are suggestive of early and ongoing neuroinflammatory processes. Altered relative concentrations of neurometabolites were found predominantly in the white matter, which is sensitive to neuroinflammation, and may contribute to developmental risk in this population. Future work on the trajectory of myo-inositol over time in CHEU, alongside markers of neurocognitive development, and the potential for specific neurodevelopmental interventions will be useful.