Abstract
Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological ...traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.
Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) have been inconsistent. Recent meta-analyses have, however, reported reduced hippocampal grey matter ...volume in MDD and reduced white matter integrity in several brain regions. The use of different diagnostic criteria, scanners and imaging sequences may, however, obscure further anatomical differences. In this study, we tested for differences in subcortical grey matter volume (n = 1157) and white matter integrity (n = 1089) between depressed individuals and controls in the subset of 8590 UK Biobank Imaging study participants who had undergone depression assessments. Whilst we found no significant differences in subcortical volumes, significant reductions were found in depressed individuals versus controls in global white matter integrity, as measured by fractional anisotropy (FA) (β = -0.182, p = 0.005). We also found reductions in FA in association/commissural fibres (β = -0.184, p
= 0.010) and thalamic radiations (β = -0.159, p
= 0.020). Tract-specific FA reductions were also found in the left superior longitudinal fasciculus (β = -0.194, p
= 0.025), superior thalamic radiation (β = -0.224, p
= 0.009) and forceps major (β = -0.193, p
= 0.025) in depression (all betas standardised). Our findings provide further evidence for disrupted white matter integrity in MDD.
Social functioning is often impaired in schizophrenia (SZ) and Alzheimer's disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive.
Using ...data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis.
As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen's d's 0.81-1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen's d's 0.65-1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen's d's 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p's <0.001), even more so than severity of disease.
AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.
Introduction
Angiotensin‐converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and ...other common dementias is largely unknown.
Methods
We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two‐sample Mendelian randomization (MR) approach.
Results
Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE 95% confidence interval; 1.07 1.04–1.10, P = 5 × 10−07) and frontotemporal dementia (1.16 1.04–1.29, P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses.
Discussion
This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition.
HIGHLIGHTS
This study evaluated genetically proxied angiotensin‐converting enzyme (ACE) inhibition association with dementias.
The results suggest an association between ACE inhibition and Alzheimer's disease.
The results suggest an association between ACE inhibition and frontotemporal dementia.
Those associations can be interpreted as potentially causal.
Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we ...examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin.
The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine P value cutoffs for PRS generation explaining most variance.
The PRS for DD was significantly associated with a positive family history for DD, age at onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI.
Although GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in the future.
Risk, III.
•Polygenic risk score-based screen for identifying shared genetic etiology.•There is genetic sharing between Alzheimer’s disease and lipid levels in the blood.•Genetic concordance implies higher ...levels of specific lipids in Alzheimer’s disease.•These results may be leveraged to develop novel therapeutic interventions.
Late-onset Alzheimer's disease (AD) has a significant genetic component, but the molecular mechanisms through which genetic risk factors contribute to AD pathogenesis are unclear. We screened for genetic sharing between AD and the blood levels of 615 metabolites to elucidate how the polygenic architecture of AD affects metabolomic profiles. We retrieved summary statistics from genome-wide association studies of AD and the metabolite blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 31 metabolites, all of which were lipids, we identified and replicated genetic sharing with AD. We also found a positive genetic concordance - implying that genetic risk factors for AD are associated with higher blood levels - for 16 of the 31 replicated metabolites. In the brain, lipids and their intermediate metabolites have essential structural and functional roles, such as forming and dynamically regulating synaptic membranes. Our results imply that genetic risk factors for AD affect lipid levels, which may be leveraged to develop novel treatment strategies for AD.
What combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between ...APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-β pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals.
We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-β status was assessed by visual read of
Fflutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-β status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-β status, and their interaction on changes in cognitive functioning over time.
Fifty-two participants (19%) had abnormal amyloid-β, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-β status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-β status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-β×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE β(SE)=-0.05(0.02); AD-PRS β(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-β status and AD-PRS predicted a steeper decline in memory functioning (amyloid-β β(SE)=-0.07(0.04); AD-PRS β(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-β status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-β abnormal individuals only (β(SE)=-0.13(0.06); β(SE)=-0.22(0.07), respectively).
Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-β only. Furthermore, independent of amyloid-β status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.
Genetic factors play a major role in Alzheimer's disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) ...proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition, mild cognitive impairment, and AD-type dementia from the Alzheimer's Disease Neuroimaging Initiative. Out of 412 proteins, 201 were associated with PGRS. Hierarchical clustering analysis on proteins associated with PGRS at different single-nucleotide polymorphism p-value inclusion thresholds identified 3 clusters: (1) a protein cluster correlated with highly significant single-nucleotide polymorphisms, associated with amyloid-beta pathology and complement cascades; (2) a protein cluster associated with PGRS additionally including variants contributing to modest risk, involved in neural injury; (3) a protein cluster that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. These findings suggest that CSF protein levels reflect varying degrees of genetic liability for AD and may serve as a tool to investigate biological mechanisms in AD.
Background
In Alzheimer’s Disease (AD), loss of social interactions has a major impact on well‐being. Therefore, AD patients would benefit from early detection of symptoms of social withdrawal. ...Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone applications, which measure social behavior passively and objectively. Here, we examine social interactions through passive remote monitoring with the smartphone application BEHAPP in cognitively impaired participants. This study aims to investigate (1) the association between demographic characteristics and BEHAPP outcome variables in cognitively normal (CN) older adults, (2) if social behavior as measured using the passive smartphone app BEHAPP is impaired in cognitively impaired (CI) participants compared to subjects with subjective cognitive decline (SCD), and CN older adults. In addition, we explored in a subset of individuals the association between BEHAPP outcomes and neuropsychiatric symptoms.
Method
CN (n=209), SCD (n=55) and CI (n=22) participants, older than 45 years, installed the BEHAPP app on their own Android smartphone for 7‐42 days. CI participants had a clinical diagnosis of mild cognitive impairment or AD‐type dementia. The app continuously measured communication events, application usage and location. Neuropsychiatric Inventory (NPI) total scores were available from 20 SCD and 22 CI participants.
Result
We found that older cognitively healthy participants called less frequently and made less use of apps. No sex effects were found. Linear models corrected for age, sex and education showed that compared to the CN and SCD groups, CI participants called less unique contacts and contacted the same contacts relatively more often (Figure 1). They also made less use of apps, visited less unique places and traveled less far from home. Higher total NPI scores were associated with more unique stay points and further travelling. Similar behavior patterns were found when correcting for multiple comparisons.
Conclusion
Cognitively impaired individuals show reduced social activity, as measured by the smartphone application BEHAPP. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with BEHAPP. This research shows that a passive and remote smartphone application is able to objectively and passively measure altered social behavior in a cognitively impaired population.
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