Lower Gray Matter Volume Research Articles

Genetic evidence suggests a genetic association between major depressive disorder and reduced cortical gray matter volume: A Mendelian randomization study and mediation analysis

BackgroundSeveral studies have suggested an association between major depressive disorder (MDD) and abnormal brain structure. However, it is unclear whether MDD affects cortical gray matter volume, a common indicator of cognitive function. We aimed to determine whether MDD was associated with decreased cortical gray matter volume (GMV) through a Mendelian randomization (MR) study. MethodsWe obtained summary genetic data from a study conducted by the Psychiatric Genomics Consortium, which recruited a total of 480,359 participants (135,458 cases and 344,901 controls). Genetic tools—single nucleotide polymorphisms (SNPs)—of MDD were extracted from the study and their effects on gray matter volumes of the cortex and total brain were evaluated in a large cohort from the UK Biobank (n = 8427). The effects of the SNPs were pooled using inverse variance weighted (IVW) analysis and further tested in several sensitivity analyses. We tested whether C-reactive protein (CRP) levels and interleukin-6 signaling were the mediators of the effects using a multivariate MR model. ResultsThirty-three SNPs were identified and adopted as genetic tools for predicting MDD. IVW analysis showed that MDD was associated with lower overall GMV (beta value −0.106, 95%CI -0.188 to −0.023, p = 0.011) in the frontal pole (left frontal pole, −0.152, 95%CI -0.177 to −0.127, p = 0.013; right frontal pole, −0.133, 95%CI -0.253 to −0.013, p = 0.028). Multivariate and mediation analysis showed that interleukin-6 was an important mediator of GMV reduction. Reverse causality analysis found no evidence that total GMV affected the risk of MDD, but showed that increased left precuneus cortex volume and left posterior cingulate cortex volume were associated with increased risk of MDD. LimitationsPotential pleiotropic effects and overestimation of real-world effects. Key assumptions for MR analysis may not be satisfactorily met. ConclusionMDD was associated with a reduced GMV, and interleukin-6 might be a mediator of GMV reduction.

Exploring structural brain changes in children with neonatal brachial plexus palsy: a voxel-based morphometry analysis

BACKGROUND: Obstetric brachial plexus palsy (OBPP) is paralysis of the upper limb resulting from nerve injury during vaginal delivery. Although current treatment approaches frequently lead to complete reinnervation of the limb, some patients show long-term motor deficits. These impairments may result from upper limb disuse that causes structural brain changes. AIM: This study aimed to compare deep gray matter volumes between children with OBPP and healthy controls. METHODS: We analyzed the structural magnetic resonance imaging results of 46 children with OBPP (n=24, mean age — 10.20, of whom 12 were girls) and healthy age-matched controls (n=22, mean age — 9.63, of whom 10 were girls) using a voxel-based morphometry technique in SPM12 package (Statistical Parametric Mapping) in MATLAB R2019b. To minimize false discoveries, we used a stringent procedure to control the family-wise error rate. RESULTS: We found volumetric brain differences between children with OBPP and healthy controls (all FWE-corrected p 0.005). Children with OBPP had significantly lower gray matter volumes in the left amygdala, bilateral hippocampus, and right entorhinal cortex. CONCLUSION: Integrating our findings with previous work, we speculate that the amygdala–hippocampus–entorhinal cortex complex might play a significant role in motor disorders.

Clinical Manifestations.

Mild behavioral impairment (MBI) identifies a high-risk group for Alzheimer's disease and related dementias (ADRD), leveraging the risk associated with later-life emergent and persistent neuropsychiatric symptoms (NPS). MBI may act as a complementary behavioral analog to later-life emergent cognitive symptoms (mild cognitive impairment, MCI). These constructs are not mutually exclusive and can co-occur. We characterized the relationship between MBI, grey matter volume in the hippocampus and entorhinal cortex, and incident cognitive decline in older adults with normal cognition (NC) and MCI. Seven-hundred-forty-two participants were included from the National Alzheimer's Coordinating Center Uniform Dataset. The Normative Morphometry Image Statistics tool was used to generate estimates of grey matter volume for the bilateral hippocampi and entorhinal cortices, normalized by age, sex, total intracranial volume, and image quality. NPS were evaluated using the informant-rated Neuropsychiatric Inventory Questionnaire, from which MBI scores were derived based on a published algorithm. Associations between MBI status and the regions-of-interest were modelled separately in NC and MCI using multivariable linear regressions, adjusting for education and clinical-MRI visit interval time. Associations between MBI status and incident cognitive decline were modelled using Cox proportional hazards regressions. Participant characteristics are summarized in Table 1. As per Figures 1 and 2, NC participants with MBI had lower grey matter volume in the bilateral hippocampi (B = -0.40, 95%CI:[-0.66, -0.15], p = .004), and a greater hazard of incident MCI or dementia, than those without MBI (HR = 3.34, 95%CI:[2.04, 5.48), p<.001). NC MBI+ participants also had lower grey matter volume in the bilateral entorhinal cortices compared to NC MBI- participants, although not statistically significant (B = -0.13, 95%CI:[-0.35, -0.08], p = .22). In MCI, participants with MBI had lower grey matter volume bilaterally in both the hippocampus (B = -0.46, 95%CI:[-0.80, -0.12], p = .01) and entorhinal cortex (B = -0.42, 95%CI:[-0.76, -0.12], p = .009), and had greater progression-rates to dementia (HR = 4.13, 95%CI:[2.45, 6.94), p<.001), than those without MBI. Our findings suggest that evaluating dementia-free older adults for MBI status in conjunction with cognitive status identifies a group further along the ADRD continuum than those without MBI, who have greater baseline atrophy in key ADRD regions and greater progression rates to later cognitive stages.

Exploring gray matter volume atrophy associations with hearing in the UK Biobank

AbstractBackgroundHearing impairment was recently recognized as a modifiable risk factor for dementia. Theories to explain this relationship propose that hearing impairment results in reduced sensory input across the brain, which negatively affects brain structure. Therefore, large exploratory studies are needed to examine potential relationships between hearing and brain volume.Method2,000 participants (age = 63±7 years, 50% female) from the UK Biobank were include in this study. Voxelwise multiple regression models examined the association between hearing and baseline MRI gray matter volume. Hearing was assessed using a speech‐in‐noise task, with positive scores reflecting poorer hearing. Interactions between hearing and sex on brain volume were also explored. Covariates included age, sex (except in model with sex interaction), socioeconomic status, and total intracranial volume. Given the exploratory aim of the analysis, a threshold of p&lt;0.001 was used.ResultThe multiple regression model results showed that poorer hearing is associated with lower gray matter volume in bilateral temporal auditory regions (Heschl’s gyrus, superior temporal gyrus) and left amygdala. While hearing scores did not significantly differ by sex, there were significant hearing‐by‐sex interactions. In women, poorer hearing was associated with lower volume in bilateral auditory regions. In men, poorer hearing was associated with lower volume in right hippocampus and higher volume in posterior cingulate cortex.ConclusionThis study sought to address a major gap in the current literature and explored voxelwise associations between hearing and brain volume in a large sample. The results show that poorer hearing is associated with lower brain volume in lateral and medial temporal regions, which differed by sex. Poorer hearing in women was associated with lower volume in auditory regions, while in men, poorer hearing was associated with lower volume in regions similarly affected by Alzheimer’s disease and dementia. Together, these data provide support for a potential mechanistic explanation for the association between hearing loss and dementia through increased brain atrophy.

Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms

AbstractBackgroundSubclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.MethodCognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p&lt;0.05.ResultHigher blood epinephrine level (p&lt;0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p&lt;0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p&lt;0.007) and Subiculum (p&lt;0.013) subfields (Fig.2). Lower GM volume in the CA1 (p&lt;0.008) and DG/CA2‐3‐4 (p&lt;0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.ConclusionSubclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.

Sex modifies the associations of regional fat with cognitive functioning and AD‐related brain volumes, in Israeli middle‐aged adults at high AD risk

AbstractBackgroundHigh body mass index (BMI) has been consistently linked to poorer cognition and higher dementia risk, with different associations in males and females. However, BMI does not represent well specific fat depots. We examined in middle‐aged adults at high Alzheimer’s dementia (AD) risk, whether regional abdominal adiposity is associated with cognitive functioning and brain indices and whether sex modifies these associations.Methods204 healthy Israeli middle‐aged AD offspring (59.44 [SD = 7.60] years old, 60% females) underwent abdominal Magnetic Resonance Imaging (MRI) to quantify hepatic, pancreatic, and peripheral fat %‐visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A broad cognitive battery defined global cognition and specific cognitive domains (episodic memory, working memory, executive functions, and language). A subsample of 142 participants had brain MRI to assess regional brain volumes (total gray matter [GM], hippocampus, and inferior, middle, and superior frontal gyrus [IFG, MFG, and SFG, respectively]). Partial correlations examined associations of regional abdominal adiposity with cognitive functioning, and brain indices, adjusting for age, sex, education, BMI, and time interval between abdominal MRI and the dependent variable. Fisher‐z transformation compared partial correlations between males and females.ResultsIn the whole sample, the only significant association was of higher hepatic fat % with lower GM volume (r = ‐264, p = 0.003), with similar associations in males and females. Only in males, higher pancreatic fat % was associated with lower global cognitive functioning (Males: r = ‐.276, p = .028; Females: r = 0.009, p = 0.93), executive functioning (Males: r = ‐0.267, p = 0.034; Females: r = 0.015, p = 0.87) and episodic memory (Males: r = ‐0.278, p = 0.027; Females: r = 0.068, p = 0.484) as well as with lower IFG volume (Males: r = ‐0.343, p = .017; Females: r = 0.117; p = 0.326). Also only in males, higher VAT% was associated with SFG volume (Males: r = .261, p = .045; Females: r = ‐0.198; p = 0.091).ConclusionIn middle‐aged males, but not in females, at high AD risk, regional abdominal adiposity, primarily pancreatic fat, was associated with lower cognitive functioning and lower AD‐related brain volumes. Results suggest sex differences in the contributions of fat to brain and cognitive aging. Since fat % is modifiable, these results may suggest that interventions to decrease distinct fats for the advancement of brain health must be sex‐specific.

Childhood community advantage and late‐life brain health among a racially/ethnically diverse cohort

AbstractBackgroundMany studies associate late‐life community disadvantage with worse late‐life brain health. It is unknown if childhood community disadvantage is associated with late‐life brain health in racially/ethnically diverse populations.MethodKHANDLE and STAR are racially/ethnically diverse harmonized cohorts of older members of Kaiser Permanente Northern California. A random subset of participants (N = 411) underwent 3T MRI; regional brain volumes and white matter integrity were measured. Stabilized inverse probability weights were estimated to account for imaging selection based on study, race/ethnicity, baseline age, and sex/gender. Residence at birth was geocoded and linked to historical Area Deprivation Indices (ADI) from the Neighborhood Atlas. ADI is a nationally ranked percentile, where higher scores represent greater relative community disadvantage. Weighted general linear models investigated associations between continuous ADI (rescaled so 1 unit = a change of 10 percentile points of national ADI rankings) and imaging measures among participants age 65+. Separate weighted models examined associations between national ADI quintiles grouped for analysis as &lt;20th percentile (the most advantaged quintile), 20th‐79th percentiles (middle 3 quintiles) and &gt; = 80 (most disadvantaged quintile) and imaging measures.ResultCompared with the complete KHANDLE/STAR cohorts, the imaging sample was younger with larger proportions of Latino adults and STAR participants (Table 1). Among the imaging sample, those with ADI&gt; = 80 were older, had lower educational attainment, were more likely to be Black and less likely to be White or Asian when compared with those with ADI&lt;20. Increases in continuous ADI were associated with worse brain health, including lower gray matter volume (β = ‐0.05, 95% CI = ‐0.08, ‐0.02), larger lateral ventricle (β = 0.06, 95% CI = 0.02, 0.10), and larger white matter hyperintensities (β = 0.06, 95% CI = 0.03, 0.08; Table 2, Model Set 1). In models examining categorical ADI, those with ADI&gt; = 80 (least advantaged communities) had significantly worse brain health across all measures and those with ADI = 20‐79 had larger white matter hyperintensities when compared with those with ADI&lt;20 (ref = most advantaged quintile; Table 2, Model Set 2).ConclusionCommunity disadvantage in childhood is associated with worse brain health in late life. Future work will explore the potential pathways (e.g., individual education attainment; midlife cardiovascular risks) that may explain these associations.

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women.

In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women. We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-β (Aβ) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses. FSH levels were positively associated with Aβ load in frontal cortex (multivariable adjusted P≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aβ load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores. Increasing serum gonadotropin levels, especially FSH, are associated with higher Aβ load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.

Low bone mineral density is associated with gray matter volume decrease in UK Biobank.

Previous research has found an association of low bone mineral density (BMD) and regional gray matter (GM) volume loss in Alzheimer's disease (AD). We were interested whether BMD is associated with GM volume decrease in brains of a healthy elderly population from the UK Biobank. T1-weighted images from 5,518 women (MAge = 70.20, SD = 3.54; age range: 65-82 years) and 7,595 men (MAge = 70.84, SD = 3.68; age range: 65-82 years) without neurological or psychiatric impairments were included in voxel-based morphometry (VBM) analysis in CAT12 with threshold-free-cluster-enhancement (TFCE) across the whole brain. We found a significant decrease of GM volume in women in the superior frontal gyri, middle temporal gyri, fusiform gyri, temporal poles, cingulate gyri, precunei, right parahippocampal gyrus and right hippocampus, right ventral diencephalon, and right pre- and postcentral gyrus. Only small effects were found in men in subcallosal area, left basal forebrain and entorhinal area. BMD is associated with low GM volume in women but less in men in regions afflicted in the early-stages of AD even in a sample without neurodegenerative diseases.

Gray matter and episodic memory associations with olfaction in middle-aged to older adults.

Age-related declines in olfaction contribute to low quality of life and appear to occur with declines in cognitive function, including diminished episodic memory. We tested the hypothesis that low gray matter volume within cortical regions that support olfaction and episodic memory can explain age-related differences in olfactory and episodic memory functions. T1-weighted images, Sniffin' Sticks olfactory measures, and the NIH Toolbox-Cognition Battery were administered to 131 middle-aged to older adults (50-86 years; 66% female). Correlation was used to examine the associations between these measures. A network-based image processing approach was then used to examine the degree to which spatial patterns of gray matter variance were related to the olfactory and cognitive measures. Structural equation modeling was used to characterize the relative specificity of olfactory, cognitive, gray matter, and aging associations. Olfactory threshold, discrimination, and identification exhibited small to medium effect size associations with episodic memory performance (rs=0.27-0.42, ps<0.002). Gray matter volume within medial temporal and orbitofrontal cortex was also related to olfactory (discrimination and identification) and episodic memory function (rs=0.21-0.36, ps<0.019). Age and episodic memory explained the same variance in olfaction that was explained by the medial temporal and orbitofrontal pattern of gray matter volume. The results of this cross-sectional study suggest that identifying mechanisms contributing to differences in medial temporal and orbitofrontal cortex will advance our understanding of co-morbid olfactory and cognitive declines.

Associations among prenatal exposure to gestational diabetes mellitus, brain structure, and child adiposity markers.

The aim of this study was to investigate the mediating role of child brain structure in the relationship between prenatal gestational diabetes mellitus (GDM) exposure and child adiposity. This was a cross-sectional study of 9- to 10-year-old participants and siblings across the US. Data were obtained from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study®. Brain structure was evaluated by magnetic resonance imaging. GDM exposure was self-reported, and discordance for GDM exposure within biological siblings was identified. Mixed effects and mediation models were used to examine associations among prenatal GDM exposure, brain structure, and adiposity markers with sociodemographic covariates. The sample included 8521 children (7% GDM-exposed), among whom there were 28 sibling pairs discordant for GDM exposure. Across the entire study sample, prenatal exposure to GDM was associated with lower global and regional cortical gray matter volume (GMV) in the bilateral rostral middle frontal gyrus and superior temporal gyrus. GDM-exposed siblings also demonstrated lower global cortical GMV than unexposed siblings. Global cortical GMV partially mediated the associations between prenatal GDM exposure and child adiposity markers. The results identify brain markers of prenatal GDM exposure and suggest that low cortical GMV may explain increased obesity risk for offspring prenatally exposed to GDM.

Volumetric gray matter findings in autonomic network regions of people with focal epilepsy.

Voxel-based morphometry (VBM) studies of people with focal epilepsies revealed gray matter (GM) alterations in brain regions involved in cardiorespiratory regulation, which have been linked to the risk of sudden unexpected death in epilepsy (SUDEP). It remains unclear whether the type and localization of epileptogenic lesions influence the occurrence of such alterations. To test the hypothesis that VBM alterations of autonomic network regions are independent of epileptogenic lesions and that they reveal structural underpinnings of SUDEP risk, VBM was performed in 100 people with focal epilepsies without an epileptogenic lesion identifiable on MRI (mean age ± standard deviation = 35 ± 11 years, 56 female). The group was further stratified in high (sample size n = 29) and low risk of SUDEP (n = 71). GM volumes were compared between these two subgroups and to 100 matched controls. People with epilepsy displayed higher GM volume in both amygdalae and parahippocampal gyri and lower GM volume in the cerebellum and occipital (p<.05, familywise error corrected). There were no significant volumetric differences between high and low SUDEP risk subgroups. Our findings confirm that autonomic networks are structurally altered in people with focal epilepsy and they question VBM as a suitable method to show structural correlates of the SUDEP risk score.

A - 58 Verbal Fluency Word Generation Slope among Older Adults with MS.

The decreasing rate of within-person word generation in verbal fluency (VF) tasks, here referred to as slope, is associated with mild cognitive impairment and with lower grey matter volume in select regions. While VF is sensitive to cognitive decline in Multiple Sclerosis (MS), VF slopes have yet to be assessed in older adults with MS. We, therefore, examined VF slopes in letter and category VF among dementia-free older adults with and without MS. 84 community-dwelling adults with MS (Mage = 64.7) and 86 without MS (Mage = 70.8) completed standard 60-sec letter (F, A, S) and category (fruits, vegetables, animals) VF tasks; responses were recorded in 20-sec intervals for each iteration of the task. Linear regressions showed that MS was associated with lower total word generation on category, but not letter, VF after accounting for age, sex, race, education, and health status (95% CI, [-2.27, -0.98], p < 0.001). Linear mixed effects models showed that word generation declined during the course of both tasks (all p's < 0.001) in both groups; MS status did not moderate category or letter VF slopes. Extant literature on total letter and category VF word generation in MS is mixed. The current study indicates that in community-dwelling older adults MS was associated with lower total word scores in category but not letter VF. Negative word generation slopes were documented in category and letter VF irrespective of group status. These results suggest that time effects on word generation in VF tasks were generalizable to normal aging and MS.

Misfolded α-Synuclein in Cerebrospinal Fluid of Contact Sport Athletes.

Misfolded α-synuclein in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can be detected using the real-time quaking-induced conversion (RT-QuIC) technique in cerebrospinal fluid (CSF). The objectives are (1) to examine misfolded CSF α-synuclein incidence, and (2) to compare clinical presentation, sports history, brain volumes, and RT-QuIC α-synuclein positivity in former athletes. Thirty former athletes with magnetic resonance imaging, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-β 42 (Aβ42), and neurofilament light chain (NfL). CSF α-synuclein was detected using RT-QuIC. Six (20%) former athletes were α-synuclein positive. α-Synuclein positive athletes were similar to α-synuclein negative athletes on demographics, sports history, clinical features, CSF p-tau, t-tau, Aβ42, and NfL; however, had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula and right olfactory cortices. α-Synuclein RT-QuIC analysis of CSF may be useful as a prodromal biofluid marker of PD and DLB. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Altered morphological characteristics and structural covariance connectivity associated with verbal working memory performance in ADHD children.

Deficits in verbal working memory (VWM) observed in attention deficit hyperactivity disorder (ADHD)children can persist into adulthood. Although previous studies have identified brain regions that are activated during VWM tasks, the neural mechanisms underlying the relationship between VWM deficits remain unclear. The objective of this study was to investigate the structural covariance network connectivity and brain morphology changes that are associated with VWM performance in ADHD children. For this study, we selected 26 ADHD children and 26 healthy control (HC) participants. Participants were instructed to perform a n-back VWM task and their accuracy and response times were subsequently recorded. This research utilized voxel-based morphometry to measure the grey matter (GM) volume, and conducted structural covariance connectivity network analysis to explore the changes of brain in ADHD. Voxel-based morphometry analysis showed that lower GM volume in the right cerebellum lobule VI and the left parahippocampal gryus in ADHD children. Moreover, a positive correlation was found between the GM volume in the right cerebellum lobule VI and the accuracy of 2-back VWM task with verbal, small reward, and delayed feedback (VSD). Structural covariance network analysis found decreased structural connectivity between right cerebellum lobule VI and right precentral gyrus, right postcentral gyrus, left paracentral lobule, right superior parietal gyrus, left hippocampus in ADHD children. The low GM volume and altered structural covariance connectivity in the right cerebellum lobule VI might potentially affect VWM performance in ADHD children. The innovation of this study lies in its more focused discussion on the morphological characteristics and structural covariance connectivity of verbal working memory deficits in ADHD children, and the innovative finding of a positive correlation between gray matter volume in the right cerebellum lobule VI and accuracy in completing the 2-back VWM task with verbal instructions, small reward, and delayed feedback(VSD). This expands upon previous research by elucidating the specific brain structures involved in verbal working memory deficits in ADHD children and highlights the potential importance of the cerebellum in this cognitive process. Overall, these innovative findings advance our understanding of the neural basis of ADHD and may have important implications for the development of targeted interventions for verbal working memory deficits.

Abnormal grey matter structural changes in patients with end-stage kidney disease and mild cognitive impairment: correlations with clinical features

End-stage kidney disease and mild cognitive impairment (ESKD-MCI) affect the quality of life and long-term treatment outcomes of patients affected by these diseases. Clarifying the morphological changes from brain injuries in ESKD-MCI and their relationship with clinical features is helpful for the early identification and intervention of MCI before it progresses to irreversible dementia. This study gathered data from 23 patients with ESKD-MCI, 24 patients with ESKD and non-cognitive impairment (NCI), and 27 health controls (HCs). Structural magnetic resonance studies, cognitive assessments, and general clinical data were collected from all participants. Voxel-based morphometry analysis was performed to compare grey matter (GM) volume differences between the groups. The patients’ GM maps and clinical features were subjected to univariate regression to check for possible correlations. Patients with ESKD-MCI displayed significantly more impairments in multiple cognitive domains, including global cognition, visuospatial and executive function, and memory, compared to patients with ESKD-NCI. Using a more liberal threshold (P < 0.001, uncorrected), we found that compared to patients with ESKD-NCI, patients with ESKD-MCI exhibited clusters of regions with lower GM volumes, including the right hippocampus (HIP), parahippocampal gyrus (PHG), Rolandic operculum, and supramarginal gyrus. The volumes of the right HIP and PHG were negatively correlated with serum calcium levels. ESKD-MCI was associated with a subtle volume reduction of GM in several brain areas known to be involved in memory, language, and auditory information processing. We speculate that these slight morphometric impairments may be associated with disturbed calcium metabolism.

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration.

Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types.

Association of Kidney Function With Dementia and Structural Brain Differences: A Large Population-Based Cohort Study.

The association between kidney function and dementia risk and the mechanisms underlying this relationship remain unclear. Within the UK Biobank, 191 970 dementia-free participants aged ≥60 (mean age: 64.1 ± 2.9 years) were followed for 16 years to detect incident dementia. Serum creatinine and Cystatin C were measured at baseline to calculate estimated glomerular filtration rate (eGFR, mL/min/1.73 m2). Kidney function was categorized as normal (eGFR ≥ 90), mildly impaired (60 ≤ eGFR < 90), or moderately to severely impaired (eGFR < 60). Dementia was assessed based on self-reported medical history and medical records. During the follow-up, a subsample of 12 637 participants underwent brain MRI scans. Volumes of total brain, gray matter, white matter, hippocampus, and white matter hyperintensities were assessed. Over the follow-up, 5 327 (2.8%) participants developed dementia. Compared to normal kidney function, there was an increased risk of dementia with moderate to severely impaired kidney function (hazard ratio = 1.53, 95% confidence interval [CI]: 1.32-1.76) but not mildly impaired kidney function. In Laplace regression, dementia onset among people with moderate to severely impaired kidney function occurred 1.53 (95% CI: 0.98-2.08) years earlier than those with normal kidney function. Moderate to severely impaired kidney function was related to significantly lower gray matter volume (β = -0.11, 95% CI: -0.19 to -0.03), but not to other brain magnetic resonance imaging measures. Impaired kidney function is associated with about 50% increased risk of dementia and anticipates dementia onset by more than 1.5 years. Brain neurodegeneration may underlie the kidney function-dementia association.

Brain Volumes and Cognition in Patients with Sickle Cell Anaemia: A Systematic Review and Meta-Analysis.

Cognitive decline is a major problem in paediatric and adult patients with sickle cell anaemia (SCA) and affects the quality of life. Multiple studies investigating the association between quantitative and qualitative neuroimaging findings and cognition have had mixed results. Hence, the aetiology of cognitive decline in this population is not clearly understood. Several studies have established cerebral atrophy in SCA children as well as adults, but the relationship between cognition and brain volumes remains unclear. The purpose of this systematic review was therefore to evaluate the literature on regional brain volumes and their association with cognitive outcomes. We also meta-analysed studies which compared regional brain volumes between patients and controls. Studies report that patients with SCA tend to have lower grey matter volumes, including total subcortical volumes in childhood as compared to controls, which stabilise in young adulthood and may be subjected to decline with age in older adulthood. White matter volumes remain stable in children but are subjected to reduced volumes in young adulthood. Age and haemoglobin are better predictors of cognitive outcomes as compared to regional brain volumes.

Alterations in cortical morphometry of the contralesional hemisphere in children, adolescents, and young adults with perinatal stroke

Perinatal stroke causes most hemiparetic cerebral palsy and cognitive dysfunction may co-occur. Compensatory developmental changes in the intact contralesional hemisphere may mediate residual function and represent targets for neuromodulation. We used morphometry to explore cortical thickness, grey matter volume, gyrification, and sulcal depth of the contralesional hemisphere in children, adolescents, and young adults after perinatal stroke and explored associations with motor, attention, and executive function. Participants aged 6–20 years (N = 109, 63% male) with unilateral perinatal stroke underwent T1-weighted imaging. Participants had arterial ischemic stroke (AIS; n = 36), periventricular venous infarction (PVI; n = 37) or were controls (n = 36). Morphometry was performed using the Computational Anatomy Toolbox (CAT12). Group differences and associations with motor and executive function (in a smaller subsample) were assessed. Group comparisons revealed areas of lower cortical thickness in contralesional hemispheres in both AIS and PVI and greater gyrification in AIS compared to controls. Areas of greater grey matter volume and sulcal depth were also seen for AIS. The PVI group showed lower grey matter volume in cingulate cortex and less volume in precuneus relative to controls. No associations were found between morphometry metrics, motor, attention, and executive function. Cortical structure of the intact contralesional hemisphere is altered after perinatal stroke. Alterations in contralesional cortical morphometry shown in perinatal stroke may be associated with different mechanisms of damage or timing of early injury. Further investigations with larger samples are required to more thoroughly explore associations with motor and cognitive function.