Hippocampal Volume Is Smaller In Female Double Carriers Of Two Strongest AD Genetic Risk Factors
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ABSTRACT:
SUBMITTER: Ukraintseva S
PROVIDER: S-EPMC8681179 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In animals, exposure to severe stress can damage the hippocampus. Recent human studies show smaller hippocampal volume in individuals with the stress-related psychiatric condition posttraumatic stress disorder (PTSD). Does this represent the neurotoxic effect of trauma, or is smaller hippocampal volume a pre-existing condition that renders the brain more vulnerable to the development of pathological stress responses? In monozygotic twins discordant for trauma exposure, we found evidence that smaller hippocampi indeed constitute a risk factor for the development of stress-related psychopathology. Disorder severity in PTSD patients who were exposed to trauma was negatively correlated with the hippocampal volume of both the patients and the patients' trauma-unexposed identical co-twin. Furthermore, severe PTSD twin pairs-both the trauma-exposed and unexposed members-had significantly smaller hippocampi than non-PTSD pairs.
| S-EPMC2819093 | biostudies-literature
Project description:BackgroundSmaller hippocampal volume in patients with posttraumatic stress disorder (PTSD) represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD-associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features.MethodsCase-control cross-sectional studies of U.S. military veterans (n = 282) from the Iraq and Afghanistan era were grouped into PTSD (n = 142) and trauma-exposed controls (n = 140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3 T. Segmentation with FreeSurfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus-amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model.ResultsSignificantly lower subfield volumes were associated with PTSD in left CA1 (P = 0.01; d = 0.21; uncorrected), CA3 (P = 0.04; d = 0.08; uncorrected), and right CA3 (P = 0.02; d = 0.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L-CA1 with PTSD (F4, 221 = 3.32, P = 0.07) is present and the other subfield findings are nonsignificant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD-associated differences in global hippocampal shape were nonsignificant.ConclusionsThe present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety-like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.
| S-EPMC6261348 | biostudies-literature
Project description:ObjectiveTo determine whether structural and individual forms of stigma are associated with neurodevelopment in children.MethodStigma related to gender, race, and Latinx ethnicity was measured at the structural level using objective state-level indicators of social policies and prejudicial attitudes and at the individual level using self-reports of perceived discrimination. Respective associations of stigma with hippocampal volume and amygdala reactivity to threat were examined using data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 11,534, mean age 9.9 years), the first multisite neuroimaging study that provided substantial variability in sociopolitical contexts and that included individual-level measures of stigma among youth.ResultsIn a preregistered analysis, Black (B = -58.26, p = .023) and Latinx (B = -40.10, p = .044) youths in higher (vs lower) structural stigma contexts were found to have smaller hippocampal volume, controlling for total intracranial volume, demographics, and family socioeconomic status. This association was also observed at a trend-level among girls (p = .082). The magnitude of the difference in hippocampal volume between high and low structural stigma states was equivalent to the predicted impact of a $20,000 difference in annual family income in this sample. As hypothesized, structural stigma was not associated with hippocampal volume in nonstigmatized youths, providing evidence of specificity. Perceived discrimination was unrelated to hippocampal volume in stigmatized groups. No associations between perceived discrimination or structural stigma and amygdala reactivity to threat were observed.ConclusionThis study provides novel evidence that an objective measure of structural stigma may be more strongly related to hippocampal volume than subjective perceptions of stigma, suggesting that contextual approaches to stigma could yield new insights into neurodevelopment among marginalized youth.
| S-EPMC8888779 | biostudies-literature
Project description:Much research has focused on neurodegeneration in aging and Alzheimer's disease (AD). We developed Scoring by Nonlocal Image Patch Estimator (SNIPE), a non-local patch-based measure of anatomical similarity and hippocampal segmentation to measure hippocampal change. While SNIPE shows enhanced predictive power over hippocampal volume, it is unknown whether SNIPE is more strongly associated with group differences between normal controls (NC), early MCI (eMCI), late (lMCI), and AD than hippocampal volume. Alzheimer's Disease Neuroimaging Initiative older adults were included in the first analyses (N = 1666, 513 NCs, 269 eMCI, 556 lMCI, and 328 AD). Sub-analyses investigated amyloid positive individuals (N = 834; 179 NC, 148 eMCI, 298 lMCI, and 209 AD) to determine accuracy in those on the AD trajectory. We compared SNIPE grading, SNIPE volume, and Freesurfer volume as features in seven different machine learning techniques classifying participants into their correct cohort using 10-fold cross-validation. The best model was then validated in the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). SNIPE grading provided the highest classification accuracy for all classifications in both the full and amyloid positive sample. When classifying NC:AD, SNIPE grading provided an 89% accuracy (full sample) and 87% (amyloid positive sample). Freesurfer volume provided much lower accuracies of 65% (full sample) and 46% (amyloid positive sample). In the AIBL validation cohort, SNIPE grading provided a 90% classification accuracy for NC:AD. These findings suggest SNIPE grading provides increased classification accuracy over both SNIPE and Freesurfer volume. SNIPE grading offers promise to accurately identify people with and without AD.
| S-EPMC10365231 | biostudies-literature
Project description:The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimer's disease (AD). The E4 allele is also associated with functional and structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess volumes of deep grey matter structures of 22 healthy younger ApoE4 carriers and 22 non-carriers (20-38 years). Volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, thalamus and brain stem were calculated by FMRIB's Integrated Registration and Segmentation Tool (FIRST) algorithm. A significant drop in volume was found in the right hippocampus of ApoE4 carriers (ApoE4+) relative to non-carriers (ApoE4-), while there was a borderline significant decrease in the volume of the left hippocampus of ApoE4 carriers. The volumes of no other structures were found to be significantly affected by genotype. Atrophy has been found to be a sensitive marker of neurodegenerative changes, and our results show that within a healthy young population, the presence of the ApoE4+ carrier gene leads to volume reduction in a structure that is vitally important for memory formation. Our results suggest that the hippocampus may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age. Although volume reductions were noted bilaterally in the hippocampus, atrophy was more pronounced in the right hippocampus. This finding relates to previous work which has noted a compensatory increase in right hemisphere activity in ApoE4 carriers in response to preclinical declines in memory function. Possession of the ApoE4 allele may lead to greater predilection for right hemisphere atrophy even in healthy young subjects in their twenties.
| S-EPMC3494711 | biostudies-literature
Project description:Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.
| S-EPMC11342757 | biostudies-literature
Project description:Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol·l-1·min-1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol·l-1·min-1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.
| S-EPMC4277348 | biostudies-literature
Project description:Sporadic solar energetic particle (SEP) events affect the Earth's atmosphere and environment, in particular leading to depletion of the protective ozone layer in the Earth's atmosphere, and pose potential technological and even life hazards. The greatest SEP storm known for the last 11 millennia (the Holocene) occurred in 774-775 AD, serving as a likely worst-case scenario being 40-50 times stronger than any directly observed one. Here we present a systematic analysis of the impact such an extreme event can have on the Earth's atmosphere. Using state-of-the-art cosmic ray cascade and chemistry-climate models, we successfully reproduce the observed variability of cosmogenic isotope 10Be, around 775 AD, in four ice cores from Greenland and Antarctica, thereby validating the models in the assessment of this event. We add to prior conclusions that any nitrate deposition signal from SEP events remains too weak to be detected in ice cores by showing that, even for such an extreme solar storm and sub-annual data resolution, the nitrate deposition signal is indistinguishable from the seasonal cycle. We show that such a severe event is able to perturb the polar stratosphere for at least one year, leading to regional changes in the surface temperature during northern hemisphere winters.
| S-EPMC5368659 | biostudies-literature
Project description:BACKGROUND:Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this cross-sectional case-control study was to investigate potential causes and consequences of reduced BDNF expression in these patients by examining the association between BDNF levels and measures of stress, inflammation, and hippocampal volume in first-episode psychosis. METHOD:Brain-derived neurotrophic factor, interleukin (IL)-6, and tumor necrosis factor (TNF)-? messenger RNA levels were measured in the leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, all aged 18 to 65 years, recruited between January 2006 and December 2008. Patients were recruited from inpatient and outpatient units of the South London and Maudsley National Health Service Foundation Trust in London, United Kingdom, and the healthy controls were recruited from the same catchment area via advertisement and volunteer databases. In these same subjects, we measured salivary cortisol levels and collected information about psychosocial stressors (number of childhood traumas, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured using brain magnetic resonance imaging in a subsample of 19 patients. RESULTS:Patients had reduced BDNF (effect size, d = 1.3; P < .001) and increased IL-6 (effect size, d = 1.1; P < .001) and TNF-? (effect size, d = 1.7; P < .001) gene expression levels when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R(2) = 0.23, P = .009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels all significantly and independently predicted a smaller left hippocampal volume (adjusted R(2) = 0.71, P < .001). CONCLUSIONS:Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis through an effect on BDNF.
| S-EPMC4082665 | biostudies-literature
Project description:Genetic mapping of hippocampal shape, an under-explored area, has strong potential as a neurodegeneration biomarker for AD and MCI. This study investigates the genetic effects of top candidate single nucleotide polymorphisms (SNPs) on hippocampal shape features as quantitative traits (QTs) in a large cohort. FS+LDDMM was used to segment hippocampal surfaces from MRI scans and shape features were extracted after surface registration. Elastic net (EN) and sparse canonical correlation analysis (SCCA) were proposed to examine SNP-QT associations, and compared with multiple regression (MR). Although similar in power, EN yielded substantially fewer predictors than MR. Detailed surface mapping of global and localized genetic effects were identified by MR and EN to reveal multi-SNP-single-QT relationships, and by SCCA to discover multi-SNP-multi-QT associations. Shape analysis identified stronger SNP-QT correlations than volume analysis. Sparse multivariate models have greater power to reveal complex SNP-QT relationships. Genetic analysis of quantitative shape features has considerable potential for enhancing mechanistic understanding of complex disorders like AD.
| S-EPMC3196668 | biostudies-literature