Smaller Brain Volumes Research Articles

Children had smaller brain volumes and cortical surface areas after prenatal opioid maintenance therapy exposure.

The studies have shown that infants with prenatal OMT exposure had smaller brain volumes than non-exposed controls, but long-term outcome data are lacking. We examined 5-13-year-old OMT-exposed children with brain MRI and tested motor and visual-motor functions and possible associations between brain morphology and outcome. To this retrospective cohort study, we recruited 55 children with prenatal OMT exposure and 59 age- and gender-matched controls. They were examined with brain MRI, Movement-ABC and Beery-VMI. MRI images were processed with the Free Surfer® software to obtain volumetrics and estimates of cortical surface area and thickness. We used a general linear regression model (GLM) to calculate group differences. The children in the OMT group had smaller mean total intracranial volume (ICV), 1407 cm3 (CI 95% 1379-1434) versus 1450 cm3 (CI 95% 1423-1476) in the control group (p = 0.026). After adjusting for ICV, significant group differences persisted for volumes of amygdala, basal ganglia and mid-posterior part of corpus callosum. Cortical surface area was smaller in the left caudal middle frontal gyrus and the right inferior parietal lobule in the OMT-group. Visual-motor function was significantly correlated with ICV. Prenatal OMT exposure may alter early brain development with possible negative long-term functional consequences.

Examining associations between brain morphology in late childhood and early alcohol or tobacco use initiation in adolescence: findings from a large prospective cohort

A prominent challenge in understanding neural consequences of substance use involves disentangling predispositional risk factors from resulting consequences of substance use. Existing literature has identified pre-existing brain variations as vulnerability markers for substance use throughout adolescence. As early initiation of use is an important predictor for later substance use problems, we examined whether pre-existing brain variations are associated with early initiation of use.In the Generation R Study, a prospective population-based cohort, brain morphology (gray matter volume, cortical thickness and surface area) was assessed at ages 10 and 14 using neuroimaging. In the second wave, participants reported on alcohol and tobacco use initiation. From a base study population (N = 3019), we examined the longitudinal (N = 2218) and cross-sectional (N = 1817) association between brain morphology of frontolimbic regions of interest known to be associated with substance use risk, and very early (age < 13) alcohol/tobacco use initiation. Additionally, longitudinal and cross-sectional associations were examined with a brain surface-based approach. Models were adjusted for age at neuroimaging, sex and relevant sociodemographic factors.No associations were found between brain morphology (ages 10 and 14) and early alcohol/tobacco use initiation (<13 years). Sex-specific analyses suggested a cross-sectional association between smaller brain volume and early initiated tobacco use in girls. Our findings are important for interpreting studies examining neural consequences of substance use in the general population. Future longitudinal studies are needed to specify whether these findings can be extended to initiation and continuation of alcohol/tobacco use in later stages of adolescence.

Abstract 22: Evaluation of the effects of CD8 knock-out on cognitive decline in the TAC-induced hypertension mouse model

Hypertension is one of the main risk factors for cognitive impairment and dementia. We and others demonstrated the role of immunoinflammatory challenges in the establishment of cerebral injury following hypertension, highlighting a major role of inflammatory cytokines as interferon-gamma (IFN-γ) and finding increased parenchymal infiltration of CD8+ T cells. To establish the mechanistic role of these cells in cognitive impairment we subjected mice lacking CD8 cells (CD8 KO) and matched controls to aortic coarctation (TAC) and performed advanced neuroimaging analyses with a dedicated 7T small animal MRI, evaluating perfusion, brain volumes, and white matter microstructural integrity. Cognitive performance was evaluated at 4 weeks using the Morris Water Maze (MWM) test. Brain perfusion analyses shown protection from cerebral hypoperfusion in TAC CD8 KO mice compared to TAC WT mice (TAC WT vs TAC KO: 108 vs 148 ml/100g/min, p=0.0298) (Figure A). CD8 KO show preserved microstructural structure at DTI MRI, a typical trait of cerebral injury in clinical and experimental hypertension (Fimbria Fractional Anisotropy, TAC WT vs TAC KO: 0.45 vs 0.54, p=0.0210) , and show no a preserved cognition at MWM (Figure B), with a preserved learning curve at acquisition trial and a preserved memory retention capability evidenced at the probe trial (TAC WT vs TAC KO: 16,4 vs 32.2 seconds spent in platform quadrant, p=0.0014). The rescue from cerebral injury evidenced at MRI and the absence of cognitive impairment in CD8 KO mice demonstrate the pivotal role of CD8+ lymphocytes in the pathogenesis of hypertension-induced cognitive impairment.

Association of chronotype with language and episodic memory processing in children: implications for brain structure.

Chronotype refers to individual preference in circadian cycles and is associated with psychiatric problems. It is mainly classified into early (those who prefer to be active in the morning and sleep and wake up early) and late (those who prefer to be active in the evening and sleep and wake up late) chronotypes. Although previous research has demonstrated associations between chronotype and cognitive function and brain structure in adults, little is known regarding these associations in children. Here, we aimed to investigate the relationship between chronotype and cognitive function in children. Moreover, based on the significant association between chronotype and specific cognitive functions, we extracted regions-of-interest (ROI) and examined the association between chronotype and ROI volumes. Data from 4,493 children (mean age of 143.06 months) from the Adolescent Brain Cognitive Development Study were obtained, wherein chronotype (mid-sleep time on free days corrected for sleep debt on school days) was assessed by the Munich Chronotype Questionnaire. Subsequently, the associations between chronotype, cognitive function, and ROI volumes were evaluated using linear mixed-effects models. Behaviorally, chronotype was negatively associated with vocabulary knowledge, reading skills, and episodic memory performance. Based on these associations, the ROI analysis focused on language-related and episodic memory-related areas revealed a negative association between chronotype and left precentral gyrus and right posterior cingulate cortex volumes. Furthermore, the precentral gyrus volume was positively associated with vocabulary knowledge and reading skills, while the posterior cingulate cortex volume was positively associated with episodic memory performance. These results suggest that children with late chronotype have lower language comprehension and episodic memory and smaller brain volumes in the left precentral gyrus and right posterior cingulate cortex associated with these cognitive functions.

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Childhood adiposity underlies numerous adult brain traits commonly attributed to midlife obesity.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study aimed to investigate whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We utilised a two-sample lifecourse Mendelian randomization study in 37,501 adults recruited to UK Biobank (UKB) imaging centers from 2014, with secondary analyses in 6,996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a GWAS of 407,741 UKB participants. Primary outcomes were adult total brain volume; grey matter volume, thickness, and surface area; white matter volume and hyperintensities; and hippocampus, amygdala, and thalamus volumes at mean age 55 in UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In UKB, individuals who were genetically-predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume (e.g. z-score difference in normalised brain volume per category increase in adiposity [95%CI] = -0.20 [-0.28, -0.12]; p = 4 × 10-6). These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null (e.g. adult z-score [95%CI] for total volume = 0.06 [-0.05,0.17]; p = 0.3). Observational analyses in ABCD showed a similar pattern of changes already present in those with a high BMI by age 10 (z-score [95%CI] = -0.10 [-0.13, -0.07]; p = 8 × 10-13), with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood (childhood z-score [95%CI] for intracranial volume = 0.14 [0.05,0.23]; p = 0.002), rather than smaller brain sizes per se. Our data suggest that persistence of early-life developmental differences across the lifecourse may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life.

Linking Dementia Pathology and Alteration in Brain Activation to Complex Daily Functional Decline During the Preclinical Dementia Stages: Protocol for a Prospective Observational Cohort Study.

Progressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer disease (AD) and other dementias. However, to justify early intervention, those at risk need to be detected earlier and more accurately. The decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (eg, eating and dressing). Our goal is to establish the neural signature of decline in CdF during the preclinical dementia period. Gait is central to many CdF and community-based activities. Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic approach to measuring gait-related brain activation while participants perform complex gait-based functional tasks. We hypothesize that dementia-related pathology during the preclinical period activates a unique gait-related electroencephalographic (grEEG) pattern that predicts a subsequent decline in CdF. We provide preliminary findings showing that older adults reporting CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and white matter hyperintensities in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical AD (plasma amyloid-β) and vascular (white matter hyperintensities) pathologies. We aim to (1) establish the unique grEEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; (2) determine associations between dementia-related pathologies and incidence of the neural signature of CdF; and (3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. By establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of ADs and other dementias. Our approach has important research and translational implications because grEEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real-world benefits. DERR1-10.2196/56726.

Association of past and current sleep duration with structural brain differences: A large population-based study from the UK Biobank

ObjectiveThis study aimed to examine the association between past/current sleep duration and macro-/micro-structural brain outcomes and explore whether hypertension or social activity plays a role in such association. MethodsWithin the UK Biobank, 40 436 dementia-free participants (age 40–70 years) underwent a baseline assessment followed by a brain magnetic resonance imaging (MRI) scan 9 years later. Past (baseline) and current (MRI scans) sleep duration (hours/day) were recorded and classified as short (≤5), intermediate (6–8), and long (≥9). Brain structural volumes and diffusion markers were assessed by MRI scans. ResultsCompared with past intermediate sleep, past short sleep was related to smaller cortex volumes (standardized β [95 % CI]: −0.04 [-0.07, −0.02]) and lower regional fractional anisotropy (FA) (−0.08 [-0.13, −0.03]), while past long sleep was related to smaller regional subcortical volumes (standardized β: −0.04 to −0.07 for thalamus, accumbens, and hippocampus). Compared to current intermediate sleep, current short sleep was associated with smaller cortex volumes (−0.03 [-0.05, −0.01]), greater white matter hyperintensities (WMH) volumes (0.04 [0.01, 0.08]), and lower regional FA (−0.07 [-0.11, −0.02]). However, current long sleep was related to smaller total brain (−0.03 [-0.05, −0.02]), grey matter (−0.05 [-0.07, −0.03]), cortex (−0.05 [-0.07, −0.03]), regional subcortical volumes [standardized β: −0.05 to −0.09 for putamen, thalamus, hippocampus, and accumbens]), greater WMH volumes (0.06 [0.03, 0.09]), as well as lower regional FA (−0.05 [-0.09, −0.02]). The association between current long sleep duration and poor brain health was stronger among people with hypertension or low frequency of social activity (all Pinteraction <0.05). ConclusionsBoth past and current short/long sleep are associated with smaller brain volume and poorer white matter health in the brain, especially in individuals with hypertension and low frequency of social activity. Our findings highlight the need to maintain 6–8 h’ sleep duration for healthy brain aging.

Postnatal Cerebral Hemodynamics and Placental Vascular Malperfusion Lesions in Neonates With Congenital Heart Disease

BackgroundNeonates with congenital heart disease (CHD) have smaller brain volume at birth. High rates of placental vascular malperfusion lesions may play a role in disrupted brain development. MethodsThis is a single-center retrospective cohort study of infants born between 2010 and 2019 who were diagnosed with a major cardiac defect requiring surgery in the first year of life. Doppler ultrasound RI of the middle cerebral artery (MCA) and anterior cerebral artery were calculated within the first 72 hours of life. Placentas were evaluated using a standardized approach. ResultsOver the study period, there were 52 patients with hypoplastic left heart syndrome (HLHS), 22 with single-ventricle right ventricular outflow tract obstruction (SV-RVOTO), 75 with a two-ventricle cardiac defect (2V), and 25 with transposition of the great arteries (TGA). MCA Doppler RI were significantly higher for all subgroups of CHD compared with control subjects (0.68 ± 0.11 in control subjects compared with 0.78 ± 0.13 in HLHS, P = 0.03; 0.77 ± 0.10 in SV-RVOTO, P = 0.002; 0.78 ± 0.13 in 2V, P = 0.03; and 0.80 ± 0.14 in TGA; P = 0.001) with the highest average MCA RI in the TGA group. In subgroup analyses, placental fetal vascular malperfusion in the 2V group was associated with higher MCA RI, but this relationship was not present in other subgroups, nor in regards to maternal vascular malperfusion. ConclusionsMajor forms of CHD are associated with significantly higher cerebral artery RI postnatally, but placental vascular malperfusion lesions may not contribute to this hemodynamic adaptation.

Abstract 01: Childhood Socioeconomic Position is Associated With Accelerated Brain Aging in U.S Hispanic/Latino Population. Findings From the Hispanic Community Health Study/Study of Latinos

Introduction: Low childhood socioeconomic position (SEP) may have a long-lasting influence on functional and structural brain development. However, little is known about whether early-life SEP is associated with a steeper age-related reduction in measures of brain structure, previously linked to Alzheimer’s Disease and Related Dementias (ADRD) vulnerability. Hypothesis: Low childhood SEP measured by parental education modifies the association between age and magnetic resonance imaging (MRI)-derived brain volumes, with worse age-related brain volumes among adults with low early-life SEP. Methods: We used data from adults (age range 50-85) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL-INCA-MRI), a population-based cohort study conducted in four major U.S cities. Measures of brain structure (e.g., total brain volume-TBV, total gray matter volume-TGMV, total cortical gray volume-TCGV, hippocampus volume-HV, and white matter hyperintensity volume-WMHV were quantified using MRI in 2400 adults with normal and impaired cognitive function. We used participants' self-reports of the highest education attained by either their father or mother as a proxy for childhood SEP (&lt; high school and ≥ high school). We conducted survey linear regression models of age on brain volumes adjusting for participant’s sex, Hispanic/Latino background, field center, nativity, and age at immigration. We then included interaction terms between age and childhood SEP. Results: In multivariable regression models, older age was associated with smaller brain volumes (β, and 95% confidence interval-CI for TBV for each year increment in age: -3.22, 95% CI: -3.73, -2.71), while older age was associated with larger log-transformed WMHV (β: 0.90, 95% CI: 0.08, 0.10). Childhood SEP modifies the association between age and brain volumes, with significant smaller age-related brain volumes among adults whose parents have less than high school (β for TBV:-3.65, 95% CI: -4.25, -3.04; and TGMV: -1.29, 95% CI: -1.62, -0.95) as compared with those with high school or more (β for TBV: -2.32, 95% CI: -3.17, -1.45; p-value for interaction: 0.024; and TGMV: -0.54, 95% CI: -0.98, -0.10; p-value for interaction: 0.017). These smaller age-related volumes persisted after accounting for participant’s education and income. In contrast, higher childhood SEP was associated with a slightly larger age-related WMHV (β for interaction term: 0.03, 95% CI: 0.01, 0.05, p-value: 0.016). Conclusions: This study highlights the unique contributions of childhood SEP to accelerated brain aging. The age by childhood SEP interaction suggests that childhood socioeconomic disadvantage has a long-lasting influence in accelerated disparities in brain aging as indexed by bran MRI.

Prenatal Exposure to the 1944-45 Dutch Famine and Risk for Dementia up to Age 75: An Analysis of Primary Care Data.

A poor prenatal environment adversely affects brain development. Studies investigating long-term consequences of prenatal exposure to the 1944-45 Dutch famine have shown that those exposed to famine in early gestation had poorer selective attention, smaller brain volumes, poorer brain perfusion, older appearing brains, and increased reporting of cognitive problems, all indicative of increased dementia risk. In the current population-based study, we investigated whether dementia incidence up to age 75 was higher among individuals who had been prenatally exposed to famine. We included men (n=6,714) and women (n=7,051) from the Nivel Primary Care Database who had been born in seven cities affected by the Dutch famine. We used Cox regression to compare dementia incidence among individuals exposed to famine during late (1,231), mid (1,083), or early gestation (601) with those unexposed (born before or conceived after the famine). We did not observe differences in dementia incidence for those exposed to famine in mid or early gestation compared to those unexposed. Men and women exposed to famine in late gestation had significantly lower dementia rates compared to unexposed individuals (HR 0.52 (95%CI 0.30-0.89)). Sex-specific analyses showed a lower dementia rate in women exposed to famine in late gestation (HR 0.39 (95%CI 0.17-0.86)) but not in men (HR 0.68 (95%CI 0.33-1.41)). Although prenatal exposure to the Dutch famine has previously been associated with measures of accelerated brain aging, the present population-based study did not show increased dementia incidence up to age 75 in those exposed to famine during gestation.

Association of Win-Loss Record With Neuropsychiatric Symptoms and Brain Health Among Professional Fighters.

Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes. The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data. Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume. These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health.

Common infections and neuroimaging markers of dementia in three UK cohort studies.

We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain =2632; NAPOE-interaction =1810). Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β=-3.89mL [-5.81, -1.97], Padjusted <0.05); these were largely attenuated in fully adjusted models (β=-1.59mL [-3.55, 0.36], P=0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Association between Body Mass Index and Brain Health in Adults: A 16-Year Population-Based Cohort and Mendelian Randomization Study.

Background: The cumulative effect of body mass index (BMI) on brain health remains ill-defined. The effects of overweight on brain health across different age groups need clarification. We analyzed the effect of cumulative BMI on neuroimaging features of brain health in adults of different ages. Methods: This study was based on a multicenter, community-based cohort study. We modeled the trajectories of BMI over 16 years to evaluate cumulative exposure. Multimodality neuroimaging data were collected once for volumetric measurements of the brain macrostructure, white matter hyperintensity (WMH), and brain microstructure. We used a generalized linear model to evaluate the association between cumulative BMI and neuroimaging features. Two-sample Mendelian randomization analysis was performed using summary level of BMI genetic data from 681,275 individuals and neuroimaging genetic data from 33,224 individuals to analyze the causal relationships. Results: Clinical and neuroimaging data were obtained from 1,074 adults (25 to 83 years). For adults aged under 45 years, brain volume differences in participants with a cumulative BMI of >26.2 kg/m2 corresponded to 12.0 years [95% confidence interval (CI), 3.0 to 20.0] of brain aging. Differences in WMH were statistically substantial for participants aged over 60 years, with a 6.0-ml (95% CI, 1.5 to 10.5) larger volume. Genetic analysis indicated causal relationships between high BMI and smaller gray matter and higher fractional anisotropy in projection fibers. Conclusion: High cumulative BMI is associated with smaller brain volume, larger volume of white matter lesions, and abnormal microstructural integrity. Adults younger than 45 years are suggested to maintain their BMI below 26.2 kg/m2 for better brain health. Trial Registration: This study was registered on clinicaltrials.gov (Clinical Indicators and Brain Image Data: A Cohort Study Based on Kailuan Cohort; No. NCT05453877; https://clinicaltrials.gov/ct2/show/NCT05453877).

Cerebral Small Vessel Disease Is Associated With Smaller Brain Volumes in Adults With Type 1 Diabetes.

Introduction: Type 1 diabetes has been linked to brain volume reductions as well as to cerebral small vessel disease (cSVD). This study concerns the relationship between normalized brain volumes (volume fractions) and cSVD, which has not been examined previously. Methods: We subjected brain magnetic resonance imaging studies of 187 adults of both sexes with Type 1 diabetes and 30 matched controls to volumetry and neuroradiological interpretation. Results: Participants with Type 1 diabetes had smaller thalami compared to controls without diabetes (p = 0.034). In subgroup analysis of the Type 1 diabetes group, having any sign of cSVD was associated with smaller cortical (p = 0.031) and deep gray matter volume fractions (p = 0.029), but a larger white matter volume fraction (p = 0.048). After correcting for age, the smaller putamen volume remained significant. Conclusions: We found smaller thalamus volume fractions in individuals with Type 1 diabetes as compared to those without diabetes, as well as reductions in brain volume fractions related to signs of cSVD in individuals with Type 1 diabetes.

Association between G‐Protein Coupled Receptor 55 (GPR55) Single Nucleotide Polymorphisms and Alzheimer’s Disease

AbstractBackgroundG‐protein‐coupled receptor 55 (GPR55) is a lysophosphatidylinositol and novel cannabinoid receptor. GPR55 signalling and single nucleotide polymorphisms (SNPs) have been implicated as a potential therapeutic target for neurodegenerative diseases such as Alzheimer’s Disease (AD); however, foundational knowledge on the role of GPR55 in AD progression remains lacking. We hypothesised GPR55 SNP minor allele carriers would have greater brain atrophy, cognitive decline, and AD‐related biomarker changes.MethodThis retrospective, longitudinal, observational study used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We selected participants with clinically normal cognition, mild cognitive impairment (MCI) or mild AD from ADNI2 and ADNIGO phases as a discovery sample. Exploratory screening of GPR55 SNPs identified rs2969126G/C associated with brain volume. Cerebrospinal fluid amyloid beta‐42 (CSF‐Aβ42), total and phosphorylated‐tau (t/p‐tau) were considered. Mini‐Mental State Exam and the Logical Memory Delayed Recall Test were also selected to evaluate overall cognitive status, executive function, and memory. ANCOVA models evaluated baseline differences between SNP carriers and major allele homozygotes (dominant model), controlling for sex, age, baseline cognitive status and APOE e4 across AD biomarkers, brain volumetrics and cognitive measures. Longitudinal associations were assessed as interactions between SNP and visit (baseline, 12 and 24 months) in mixed models.ResultIn ADNI2/GO (n = 755), minor allele carriers represented 15% of the sample. Significantly greater decline in CSF‐Aβ42 levels was observed in Aβ42‐positive clinically normal minor allele carriers (F(1,45.2) = 6.35, p = 0.015). Carriers with MCI had significantly higher t‐tau (F(1,126) = 4.303, p = 0.04) and p‐tau concentrations (F(1,129) = 6.98, p = 0.009) longitudinally. Significantly smaller hippocampal volumes over time were seen in minor allele carriers in the whole group (F(1,444) = 5.74, p = 0.017), with a trend in the AD/MCI subgroup (F(1,325) = 3.364, p = 0.06). Clinically normal minor allele carriers had significantly poorer baseline logical memory scores (F(1,285) = 6.92, p = 0.009). These results did not replicate in the ADNI3 cohort.ConclusionCarriers of the GPR55 SNP rs2969126G/C minor allele had greater Aβ42 and tau biomarker abnormalities, smaller brain volumes and poorer memory scores over time in different stages of AD. This preliminary study prompts replication studies in different stages of AD progression to implicate GPR55 as a potential therapeutic target for AD.

Longitudinal relationships between lifestyle risk factors and neurodevelopment in early adolescence.

The goal of this study is to investigate the cross-sectional and longitudinal relationships between clustered lifestyle risk factors (sleep, physical activity, body mass index [BMI], and screen time) and neurodevelopment over the early adolescent period. Data from the ABCD Study Data Release 3.0 consisted of 11,878 participants (aged 9-10 years) at baseline and 6,571 participants (aged 11-12 years) at 2-year follow-up. The interrelationships between lifestyle risk factors and brain structure were analyzed using bivariate multiple indicator latent change score models. Using confirmatory factor analysis, a single lifestyle risk factor domain (measured by sleep, physical activity, BMI, and screen time) was shown to fit the data well. Using exploratory and confirmatory factor analysis, seven brain structure domains were extracted and labeled as temporal-parietal, frontotemporal, occipital, orbitofrontal, temporal, cingulate, parietal, and cuneus domains. All bivariate latent change score models accounted for age, sex at birth, race/ethnicity, parental education, and marital status. Higher lifestyle risk was associated with smaller brain volume at baseline. Higher baseline lifestyle risk was also associated with a greater rate of change (i.e., greater decreases) in brain volume for the temporal-parietal, frontotemporal, orbitofrontal, parietal, and cuneus domains. Effects were not reciprocal; baseline brain volume did not predict changes in lifestyle behaviors over time. These findings are important for understanding the biological mechanisms underpinning health risk factors and can be used to target interventions and improve brain health during this critical developmental phase. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Investigating associations of multiple common infections with brain structure and white matter lesions: findings from prospective neuroimaging studies

AbstractBackgroundEvidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common pathogens – selected based on their relevance to public health – and brain volume, hippocampal volume, and white matter lesions in two population‐based cohorts in the UK.MethodSerology and imaging data were available for 1371 participants across two studies: the UK Biobank (N = 935, mean age(SD)[years] = 55.3(7.7) at serology; 63.8(7.7) at imaging) and the Medical Research Council National Survey of Health and Development [N = 436, mean age(SD) [years] = 63.3(1.1) years at serology; 70.7(0.7) years at imaging). Serology measures included a) serostatuses of 17 pathogens, b) total proportion of 17 pathogens exposed to, and c) total proportion of 11 neurotropic pathogens exposed to (Table 1). Associations between serology measures and outcomes (brain volume, hippocampal volume, and white matter lesion volume) were tested using linear regression. Regression models included adjustments for total intracranial volume and clinic information (basic models), and age, sex, ethnicity, education, socioeconomic position and lifestyle factors (Figure 1). Findings across cohorts were meta‐analysed using random‐effects models. The present study will be expanded to include an additional cohort (Southall and Brent Revisited,N≤1200) to add more precision for identifying associations.ResultSeropositivity to seven pathogens associated with an outcome in basic models, and four in fully‐adjusted models: seropositivity to JC virus was associated with smaller brain volumes, Epstein‐Barr virus with larger brain volumes, Merkel cell virus with larger hippocampal volumes and fewer white matter lesions, and C.trachomatis with fewer white matter lesions (Figure 2). Neurotropic pathogen burden scores associated with smaller hippocampal volumes in basic models, but no associations were seen for either pathogen burden score in fully‐adjusted models.ConclusionWe found some evidence of both positive and negative associations between common infections and imaging markers of subclinical cerebrovascular disease and neurodegeneration, with no evidence of relationships with pathogen burden. This work highlights key relationships for further investigation, which may reveal novel pathways associated with brain structure and cerebrovascular pathology.

Visually guided and context-dependent spatial navigation in the translucent fish Danionella cerebrum

Danionella cerebrum (DC) is a promising vertebrate animal model for systems neuroscience due to its small adult brain volume and inherent optical transparency, but the scope of their cognitive abilities remains an area of active research. In this work, we established a behavioral paradigm to study visual spatial navigation in DC and investigate their navigational capabilities and strategies. We initially observed that adult DC exhibit strong negative phototaxis in groups but less so as individuals. Using their dark preference as a motivator, we designed a spatial navigation task inspired by the Morris water maze. Through a series of environmental cue manipulations, we found that DC utilize visual cues to anticipate a reward location and found evidence for landmark-based navigational strategies wherein DC could use both proximal and distal visual cues. When subsets of proximal visual cues were occluded, DC were capable of using distant contextual visual information to solve the task, providing evidence for allocentric spatial navigation. Without proximal visual cues, DC tended to seek out a direct line of sight with at least one distal visual cue while maintaining a positional bias toward the reward location. In total, our behavioral results suggest that DC can be used to study the neural mechanisms underlying spatial navigation with cellular resolution imaging across an adult vertebrate brain.

Abstract 13374: The Intersection of Prenatal Clinical and Demographic Factors in Predicting Fetal Brain Volume and Neurodevelopmental Outcome in Single Ventricle CHD

Background: Fetuses with single ventricle (SV) CHD have small total brain volumes (TBV) which has been linked to neurodevelopmental impairment (NDI). Evidence suggests a prenatal origin of NDI for CHD. Our primary aim was to use machine learning methods to identify prenatal variables that predict fetal brain growth and in turn early NDI. Methods: This is a multi-center prospective cohort study of maternal-infant dyads with a fetal diagnosis of SV who underwent fetal brain MRI and in-depth prenatal clinical and sociodemographic data collection (self reported race/ethnicity, income, education, area deprivation index, maternal health, genetics, placental health). Infants had ND testing at 12-30 months with Bayley Scales of Infant and Toddler Development. Machine learning models used recursive partitioning to predict 1) gestational-age (GA) and sex-adjusted fetal TBV and 2) ND outcome while including fetal TBV in the models. Results: A total of 67 maternal-infant dyads were enrolled with a mean GA of 33.4 weeks (SD=3.4) at fetal MRI and male predominance (57%); 48 infants had follow-up at median age of 23.5 months (SD=6.3). Key predictors of fetal brain volume were race/ethnicity, maternal age, and cardiac anatomy (Figure 1A). For NDI, fetal brain volume was the strongest predictor of motor outcomes but was not associated with other domains (Figure 1D). Cardiac anatomy was the strongest predictor of cognitive outcome (Figure 1B), while race/ethnicity was the strongest predictor of language (Figure 1C). Cardiac anatomy, maternal age, and cerebral and placental hemodynamics (e.g., middle cerebral or umbilical artery pulsatility) each predicted multiple domains of neurodevelopment. Conclusions: In regression tree modeling, sociodemographic variables are the strongest predictors of fetal TBV, which in turn predicts motor outcome. Prenatal factors predicting NDI across all domains span sociodemographic, cardiac, and placental characteristics.