Association of Sleep, Neuropsychological Performance, and Gray Matter Volume With Glymphatic Function in Community-Dwelling Older Adults

Background and Objectives:The glymphatic system, which is robustly enabled during some stages of sleep, is a fluid-transport pathway that clears cerebral waste products. Most contemporary knowledge regarding glymphatic system is inferred from rodent experiments and human research is limited. The objective of the research is to explore the associations between human glymphatic function, sleep, neuropsychological performances, and cerebral gray matter volumes.Methods:This cross-sectional study included individuals 60 years or older who had participated in the Integrating Systemic Data of Geriatric Medicine to Explore the Solution for Health Aging study between September 2019 and October 2020. Community-dwelling older adults were enrolled at 2 different sites. Participants with dementia, major depressive disorders, and other major organ system abnormalities were excluded. Sleep profile was accessed using questionnaires and polysomnography. Administered neuropsychological test batteries included Everyday Cognition (ECog) and the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB). Gray matter volumes were estimated based on magnetic resonance imaging (MRI). Diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) index was used as the MRI marker of glymphatic function.Results:A total of 84 participants (mean [SD] age, 73.3 [7.1] years, 47 [56.0%] women) were analyzed. Multivariate linear regression model determined that age (unstandardized β, -0.0025 [SE, 0.0001]; P = 0.02), N2 sleep duration (unstandardized β, 0.0002 [SE, 0.0001]; P = 0.04), and the apnea-hypopnea index (unstandardized β, -0.0011 [SE, 0.0005]; P = 0.03) were independently associated with DTI-ALPS. Higher DTI-ALPS was associated with better ECog language scores (unstandardized β, -0.59 [SE, 0.28]; P = 0.04) and better CERAD-NB word-list-learning delayed recall subtest scores (unstandardized β, 6.17 [SE, 2.31]; P = 0.009) after co-varying for age and education. Higher DTI-ALPS was also associated with higher gray matter volume (unstandardized β, 107.00 [SE, 43.65]; P = 0.02) after controlling for age, gender, and total intracranial volume.Discussion:Significant associations were identified between glymphatic function and sleep stressing the importance of sleep for brain health. This study also revealed associations between DTI-ALPS, neuropsychological performances, and cerebral gray matter volumes suggesting the potential of DTI-ALPS as a biomarker for cognitive disorders.

Linking gene expression patterns and brain morphometry to trauma and symptom severity in patients with functional seizures

ObjectiveAdverse life experiences (ALEs) increase the susceptibility to functional (somatoform/dissociative) symptoms, likely through neurodevelopmental effects. This analysis aimed to illuminate potential genetic influences in neuroanatomical variation related to functional symptoms and ALEs in patients with functional seizures.MethodsQuestionnaires, structural brain MRIs and Allen Human Brain Atlas gene expression information were used to probe the intersection of functional symptom severity (Somatoform Dissociation Questionnaire, SDQ-20), ALE burden, and gray matter volumes in 20 patients with functional seizures.ResultsFunctional symptom severity positively correlated with the extent of sexual trauma, emotional neglect, and threat to life experiences. In voxel-based morphometry analyses, increased SDQ-20 scores related to decreased bilateral insula, left orbitofrontal, right amygdala, and perigenual and posterior cingulate gray matter volumes. Left insula findings held adjusted for psychiatric comorbidities. Increased sexual trauma burden correlated with decreased right posterior insula and putamen volumes; increased emotional neglect related to decreased bilateral insula and right amygdala volumes. The sexual trauma–right insula/putamen and emotional neglect– right amygdala relationships held adjusting for individual differences in psychiatric comorbidities. When probing the intersection of symptom severity and sexual trauma volumetric findings, genes overrepresented in adrenergic, serotonergic, oxytocin, opioid, and GABA receptor signaling pathways were spatially correlated. This set of genes was over-expressed in cortical and amygdala development.ConclusionALEs and functional symptom severity were associated with gray matter alterations in cingulo-insular and amygdala areas. Transcriptomic analysis of this anatomical variation revealed a potential involvement of several receptor signaling pathways.

Leisure Activity Variety and Brain Volume Among Community-Dwelling Older Adults: Analysis of the Neuron to Environmental Impact Across Generations Study Data

Background: Recent findings indicate that leisure activity (LA) delays cognitive decline and reduces the risk of dementia. However, the association between LA and brain volume remains unclear. This study aimed to examine the association between LA variety and brain volume with a focus on the hippocampus and gray matter.Methods: Data were obtained from the baseline survey of the Neuron to Environmental Impact across Generations study, which had targeted community-dwelling older adults living in Niigata, Japan. We divided LAs into 10 categories, and counted the number of categories of activities in which the participants engaged. We classified them as follows: 0 (i.e., no activity), 1, 2, or ≥ 3 types. Brain volume was assessed through magnetic resonance imaging, and hippocampal and gray matter volumes were ascertained.Results: The sample size was 482. Multiple linear regression analysis showed that hippocampal and gray matter volumes were significantly greater among participants with ≥ 3 types of LAs than among their no-activity counterparts. Hippocampal volume was significantly greater among those who engaged in one type of LA than among those who engaged in no such activity. Sex-stratified analysis revealed that hippocampal volumes were significantly greater among males who engaged in ≥ 3 types of LAs and one type of LA. However, no such association was found among females.Conclusion: The present findings suggest that engaging in a wide range of LAs is related to hippocampal and gray matter volumes. Furthermore, there was a sex difference in the association between LA variety and brain volume.

Mbnl1 and Mbnl2 regulate brain structural integrity in mice

Myotonic Dystrophy Type I (DM1) patients demonstrate widespread and variable brain structural alterations whose etiology is unclear. We demonstrate that inactivation of the Muscleblind-like proteins, Mbnl1 and Mbnl2, initiates brain structural defects. 2D FSE T2w MRIs on 4-month-old Mbnl1+/−/Mbnl2−/− mice demonstrate whole-brain volume reductions, ventriculomegaly and regional gray and white matter volume reductions. Comparative MRIs on 2-month-old Mbnl1−/−, Mbnl2−/− and Mbnl1−/−/Mbnl2+/− brains show genotype-specific reductions in white and gray matter volumes. In both cohorts, white matter volume reductions predominate, with Mbnl2 loss leading to more widespread alterations than Mbnl1 loss. Hippocampal volumes are susceptible to changes in either Mbnl1 or Mbnl2 levels, where both single gene and dual depletions result in comparable volume losses. In contrast, the cortex, inter/midbrain, cerebellum and hindbrain regions show both gene and dose-specific volume decreases. Our results provide a molecular explanation for phenotype intensification in congenital DM1 and the variability in the brain structural alterations reported in DM1.

Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes

Objective: To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T 1 -weighted imaging for quantifying gray matter volumes and T 2 -weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory & Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (β=−3.6 [mm 3 /y]/[m/s]; [95% CI, −7.2 to −0.02] P =0.049) and occipital lobe (β=−34.2 [mm 3 /y]/[m/s]; [95% CI, −67.8 to −0.55] P =0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (β=17.0 [mm 3 /y]/[m/s]; [95% CI, 7.2–26.9] P <0.001). All associations may be driven by outliers. Conclusions: In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.

Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population-representative longitudinal birth cohort

Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7–26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.

Trends in regional morphological changes in the brain after the resolution of hypercortisolism in Cushing’s disease: a complex phenomenon, not mere partial reversibility

The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing’s disease (CD). However, the relative alterations in regional hypercortisolism in the brain remain unclear. Thus, we investigated regional volumetric alterations in CD patients. We also analyzed the associations between these volumetric changes and clinical characteristics. The study participants comprised of active CD (n = 60), short-term-remitted CD (n = 28), and long-term-remitted CD (n = 32) patients as well as healthy control subjects (n = 66). Gray matter volumes (GMVs) were measured via voxel-based morphometry. The GMVs of substructures were defined using the automated anatomical labeling (AAL) atlas. Trends for partial reversibility of GMVs were found in 87 brain substructures of CD patients. However, significantly different trends, including enlarged, irreversible, and unburden trends, were observed in the rest of the brain substructures. Trends toward normalization in GMV were found in most brain substructures of CD patients. Different trends, including enlarged, irreversible, and unburden GMVs, were observed in the other subregions, such as the amygdala, thalamus, and caudate. Morphological changes in GMVs after the resolution of hypercortisolism are a complex phenomenon; the characteristics of these changes significantly differ within the brain substructures.