Plasma Neurofilament Light and Markers of Sensorimotor Function in a Predominantly Hispanic Population of Older Adults in San Antonio, Texas

Background: Sensorimotor and blood-based biomarkers are promising dementia biomarkers with high accessibility and limited invasiveness. Although sensorimotor changes appear with aging, more severe changes may precede cognitive decline, dementia, and other neurological diseases. Additionally, blood-based neurofilament light (NfL), a broad marker of neuroaxonal injury, is commonly elevated in many types of neurological disease. Prior studies have suggested that increased blood levels of NfL in conjunction with sensorimotor decline may allow for earlier neurological disease diagnosis and/or prediction of disease severity, but little is known about the correlation of these markers in the general population. We examined the association between NfL and sensorimotor markers in a predominantly Hispanic population in San Antonio, Texas. Method: Our sample included older adults from our San Antonio MarkVCID and South Texas Alzheimer’s Disease Research Center (ADRC) cohorts (n=152, mean age 71.2±7.63, 60.4% women, 79.5% Hispanic) with available plasma NfL, olfaction (B-SIT age-adjusted percentile), grip strength, and touch (monofilament) data (Table 1). NfL concentrations were log-transformed to achieve a normal distribution. We used linear or logistic regression models, as appropriate, to assess the association between NfL and sensorimotor outcomes, adjusting for age, sex, race, ethnicity, and cognitive diagnosis. Result: Higher plasma NfL was significantly associated with decreased olfaction score percentiles (Beta [95% Confidence Interval], β=-8.79; [95% CI -16.89; -0.12], p=0.05), grip strength in either hand (left: β=-3.62; [95% CI -5.51; -1.74], p=0.0002; right: β=-2.99; [95% CI -5.01; -1.03], p=0.003), and impaired touch perception (Odds Ratio [95% CI], OR=2.56; [95% CI 1.01; 6.48]; p=0.05), independent of the potential confounders listed above. Conclusion: These results highlight the association of plasma NfL with several markers of sensorimotor function, which may reflect central and peripheral neuroaxonal injury. Additional studies are needed in larger community samples to confirm these findings and explore the potential of NfL as a marker of functional decline in longitudinal studies. We plan to continue collecting these markers, as well as gait and balance, longitudinally to gain a better understanding of the link between neurodegeneration, sensorimotor markers, and neurological disease trajectory in our unique South Texas population

Cognitive performance and normative data between Hispanic and non-Hispanic cohorts: Results from the South Texas Alzheimer’s Disease Research Center (ADRC)

Background: The prevalence of Alzheimer\u27s disease and related dementias (ADRD) in the United States was estimated as 6.5 million people in 2022, with a five-fold increase for the Hispanic/Latinx population expected by 2060. The South Texas Alzheimer\u27s Disease Center (STAC) was designated as a new ADRC in 2021 by the National Institute on Aging (NIA) with a specific aim to serve the growing needs of the local underrepresented Hispanic population. As cultural and linguistic factors can impact performance on cognitive tests, the goal of the study was to compare UDS-3 cognitive test raw scores and normative data in Hispanic and non-Hispanic adults without cognitive impairment residing in South Texas. Method: Participants from the STAC cohort completed the Uniform Data Set (UDS), V.3.0, which includes demographics and neuropsychological battery. All batteries were administered in the participants’ preferred language, English. Normative data was calculated using Weintraub et al. (2018)’s age, sex, and education adjusted regression models for UDSNB 3.0. Mean differences between baseline visit raw scores and normative data were compared using independent sample t-tests among Hispanic and non-Hispanic participants. Result: Thirty-four Hispanic (mean age=70.4, 67.6% female) and thirty-eight non-Hispanic (mean age=71.9, 57.9% female) participants were included. Hispanic participants had fewer years of education relative to non-Hispanic participants [M(SD)] = [14.7(2.5)] to [16.5(2.5)], respectively; (t(70.1)=3.0, p =0.004); although, the groups did not differ in age or sex distribution (p\u3e0.05). Hispanic and non-Hispanic participants generally performed equivalently on the neuropsychological battery. However, Hispanics had lower mean raw scores on the Montreal Cognitive Assessment (MoCA) (t(70.8)= 3.6, p Conclusion: Overall, Hispanic and non-Hispanic participants performed similarly on the UDS-3 neuropsychological battery. However, Hispanics had lower mean raw and normative scores on the MINT, as well as the MoCA which also includes language measures. Our findings highlight the importance of future research validating the sensitivity and specificity of normative data used in underrepresented populations, especially those at higher risk for ADRD

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice

© 2019, The Author(s). Alzheimer’s disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD