An Autopsy Case of Dextromethorphan Poisoning.

A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of unconsciousness and respiratory arrest at home. She was pronounced dead 12 hours after she was discovered. Her autopsy revealed symmetrical hemorrhagic necrosis in the putamen on both sides of her cerebrum. Although many drugs were detected in her blood, all of those other than dextromethorphan (DXM) were within or below the therapeutic range. Her blood DXM was 1.73 µg/ml at admission and 1.61 µg/ml at autopsy, which were within the toxic range or coma-to-death range. The cause of death was diagnosed as DXM poisoning. DXM can cause hallucinations and euphoria if taken in excess, but since it is available as an over-the-counter drug at general pharmacies, an increasing number of young people are overdosing on it, mistakenly believing it to be a safe drug with few side effects. We believe that further social measures against DXM are necessary in Japan, such as disseminating correct knowledge in society and regulating over-the-counter sales.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Lack of Immune Resilience Negatively Affects Physical Resilience: Results From the InCHIANTI Follow-Up Study.

There is consistent evidence that immune response declines with aging, with wide interindividual variability and a still unclear relationship with the development of frailty. To address this question, we assessed the role of immune resilience (capacity to restore immune functions), operationalized as the neutrophil-to-lymphocytes ratio (NL-ratio) and monocytes-to-lymphocytes ratio (ML-ratio), in the pathway that from robust status shifts to pre-frailty and frailty, and finally to death. The InCHIANTI study enrolled representative samples from the registry lists of 2 towns in Tuscany, Italy. Baseline data were collected in 1998, with follow-up visits every 3 years. The 1 453 participants enrolled were assessed and followed for lifestyle, clinical condition, physical performance, clinical, and physiological measures. For the purpose of this analysis, we used only 1 022 subjects aged 65 or older at baseline. Participants in the 3 highest deciles of distribution for NL-ratio (>2.44) were more likely to experience a transition from robust to pre-frail, and to overt frailty status. Moreover, NL-ratio (tenth decile > 3.53) and ML-ratio (tenth decile > 2.02) were both predictors of mortality. These results were independent of chronological age, sex, comorbidities, and chronic low-grade inflammation assessed by high sensitivity C-reactive protein measurement. The 2 leucocytes-derived ratios, NL-ratio and ML-ratio, represent markers of immune resilience and predict changes in physical resilience and mortality. These biomarkers are inexpensive because they are based on data routinely collected in clinical practice and can be used to assess the risk of frailty progression and mortality. Clinical Trials Registration Number: NCT01331512.

Associations between dietary indices and hearing status among middle-older aged adults - results from the Baltimore Longitudinal Study of Aging.

BACKGROUND: Hearing loss, a public health issue in older populations, is closely related to functional decline. OBJECTIVE: To investigate the longitudinal associations between 4 dietary indices and hearing status. METHODS: Data from the Baltimore Longitudinal Study of Aging were used and included 882 participants ≥45 y of age. Dietary intake was assessed using a validated food frequency questionnaire, and 4 dietary scores (Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet [MIND], Mediterranean style diet score [MDS], Alternative Healthy Eating Index [AHEI], and Healthy Eating Index [HEI]) were calculated as averages over time. Hearing status was examined using pure-tone audiometry, and pure-tone average (PTA) of hearing thresholds were calculated at speech-level (PTA(500, 1000, 2000, 4000 Hz)), low (PTA(500, 1000 Hz)), and high (PTA(4000, 8000 Hz)) frequencies, with lower thresholds indicating better hearing. Multivariable linear mixed-effect models were used to examine associations between dietary indices and hearing threshold change over time adjusted for confounders. RESULTS: At baseline, the mean age of participants was 67 y and 55% were female. Over a median of 8 y of follow-up, MDS ≥7 was associated with 3.5 (95% CI: -6.5, -0.4) and 5.0 (95% CI: -9.1, -1.0) dB lower PTA(500, 1000, 2000, 4000 Hz) and PTA(4000, 8000 Hz), respectively, compared with MDS ≤3; the highest tertile of the AHEI was associated with 2.3 (95% CI: -4.6, -0.1) and 5.0 (95% CI: -8.0, -2.0) dB lower PTA(500, 1000, 2000, 4000 Hz) and PTA(4000, 8000 Hz); and each standard deviation increment in HEI was associated with 1.6 dB (95% CI: -2.7, -0.6), 1.1 dB (95% CI: -2.1, -0.1), and 2.1 dB (95% CI: -3.5, -0.6) lower PTA(500, 1000, 2000, 4000 Hz), PTA(500, 1000 Hz), and PTA(4000, 8000 Hz), respectively. CONCLUSIONS: Adherence to healthy dietary patterns was associated with better hearing status, with stronger associations at high frequencies. Am J Clin Nutr 20xx;x:xx.

Neutrophil, lymphocyte count, and neutrophil to lymphocyte ratio predict multimorbidity and mortality-results from the Baltimore Longitudinal Study on Aging follow-up study.

Immunosenescence is the age-related changes in the immune system, namely, progressively higher levels of circulating inflammatory markers, characteristics changes of circulating immune subset cells and altered immune function. The neutrophil to lymphocyte ratio (NL ratio) has been identified as a prognostic indicator for neoplastic disease progression, in predicting chronic degenerative diseases, and as a potential indirect marker of healthy aging. This study aims to examine the longitudinal association of neutrophil, lymphocyte absolute count, and their ratio with longitudinal risk for multimorbidity and mortality. The Baltimore Longitudinal Study of Aging (BLSA) is an open observational cohort study of community-dwelling volunteers that are followed every 1-4 years depending on their age. The sample considered in the study consists of 1769 participants (5090 follow-ups) with completed data for physical examination, health history assessment, and donated a blood sample. The NL ratio increased with age and was associated with a higher risk of mortality, while a lower NL ratio was inversely correlated with multimorbidity. Neutrophils increased with aging and an increase in their absolute number predicted mortality risk. However, the absolute number of lymphocytes was associated with age only in a cross-sectional analysis. In conclusion, this study supports the importance of the NL ratio and absolute neutrophil count as markers of aging health status, and as significant predictors of all-cause mortality and multimorbidity in aging individuals. It remains to be demonstrated whether interventions contrasting these trends in circulating cells may result in improved health outcomes.

Plant-based diets and the gut microbiome: findings from the Baltimore Longitudinal Study of Aging.

BACKGROUND: Mounting evidence indicates that although some plant-based diets are healthful, others are not. Changes in the gut microbiome and microbiome-dependent metabolites, such as trimethylamine N-oxide (TMAO), may explain differential health effects of plant-based diets. However, human data are sparse on whether qualitatively distinct types of plant-based diets differentially affect gut microbiome diversity, composition, particularly at the species level, and/or metabolites. OBJECTIVES: We aimed to examine cross-sectional associations of different plant-based indices with adult gut microbiome diversity, composition, and the metabolite TMAO. METHODS: We studied 705 adults in the Baltimore Longitudinal Study of Aging with data for diet, fecal microbiome (shotgun metagenomic sequencing), and key covariates. We derived healthful plant-based diet index (hPDI) and unhealthful plant-based diet index (uPDI) using data from food frequency questionnaires. We examined plant-based diet indices with microbiome α-diversity (richness and evenness measures), ß-diversity (Bray-Curtis and UniFrac measures), composition (species level), and plasma TMAO. We used regression models to determine associations before and after adjustment for age, sex, education, physical activity, smoking status, body mass index, and total energy intake. RESULTS: The analytic sample (mean age, 71.0 years, SD = 12.8 years) comprised 55.6% female and 67.5% non-Hispanic White participants. hPDI was positively and uPDI negatively associated with microbiome α-diversity, driven by microbial evenness (Pielou P < 0.05). hPDI was also positively associated with relative abundance of 3 polysaccharide-degrading bacterial species (Faecalibacterium prausnitzii, Eubacterium eligens, and Bacteroides thetaiotaomicron) and inversely associated with 6 species (Blautia hydrogenotrophica, Doreasp CAG 317, Eisenbergiella massiliensis, Sellimonas intestinalis, Blautia wexlerae, and Alistipes shahii). Furthermore, hPDI was inversely associated with TMAO. Associations did not differ by age, sex, or race. CONCLUSIONS: Greater adherence to a healthful plant-based diet is associated with microbiome features that have been linked to positive health; adherence to an unhealthful plant-based diet has opposing or null associations with these features.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Serum Proteomic Signatures of Common Health Outcomes among Older Adults.

INTRODUCTION: In aging populations, the coexistence of multiple health comorbidities represents a significant challenge for clinicians and researchers. Leveraging advances in omics techniques to characterize these health conditions may provide insight into disease pathogenesis as well as reveal biomarkers for monitoring, prognostication, and diagnosis. Researchers have previously established the utility of big data approaches with respect to comprehensive health outcome measurements in younger populations, identifying protein markers that may provide significant health information with a single blood sample. METHODS: Here, we employed a similar approach in two cohorts of older adults, the Baltimore Longitudinal Study of Aging (mean age = 76.12 years) and InCHIANTI Study (mean age = 66.05 years), examining the relationship between levels of serum proteins and 5 key health outcomes: kidney function, fasting glucose, physical activity, lean body mass, and percent body fat. RESULTS: Correlations between proteins and health outcomes were primarily shared across both older adult cohorts. We further identified that most proteins associated with health outcomes in the older adult cohorts were not associated with the same outcomes in a prior study of a younger population. A subset of proteins, adiponectin, MIC-1, and NCAM-120, were associated with at least three health outcomes in both older adult cohorts but not in the previously published younger cohort, suggesting that they may represent plausible markers of general health in older adult populations. CONCLUSION: Taken together, these findings suggest that comprehensive protein health markers have utility in aging populations and are distinct from those identified in younger adults, indicating unique mechanisms of disease with aging.

Cross-sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments.

The study of age-related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age-related changes within and between compartments as these changes are likely highly interconnected. Understanding age-related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22-92 years, and identified 92, 34, and 35 age-associated metabolites, respectively. The metabolic pathways that were identified across compartments included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Beyond Inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, Results From the InCHIANTI Study.

Aging is characterized by chronic low-level inflammation and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocyte ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow-up visits every 3 years. Out of the 1 453 participants enrolled at baseline, this study includes 1 179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and body mass index (BMI). Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocyte-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, interleukine-6 (IL-6), male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult.

Proteomic Analysis of the Senescence-Associated Secretory Phenotype: GDF-15, IGFBP-2, and Cystatin-C Are Associated With Multiple Aging Traits.

Cellular senescence, a hallmark of aging, results in a senescence-associated secretory phenotype (SASP) with an increased production of proinflammatory cytokines, growth factors, and proteases. Evidence from nonhuman models demonstrates that SASP contributes to tissue dysfunction and pathological effects of aging. However, there are relatively few human studies on the relationship between SASP and aging-related health outcomes. Proteins from the SASP Atlas were measured in plasma using aptamer-based proteomics (SomaLogic). Regression models were used to identify SASP protein associations with aging-related traits representing multiple aspects of physiology in 1 201 participants from 2 human cohort studies (BLSA/GESTALT and InCHIANTI). Traits examined were fasting glucose, C-reactive protein, interleukin-6, alkaline phosphatase, blood urea nitrogen, albumin, red blood cell distribution width, waist circumference, systolic and diastolic blood pressure, gait speed, and grip strength. Study results were combined with a fixed-effect inverse-variance weighted meta-analysis. In the meta-analysis, 28 of 77 SASP proteins were significantly associated with age. Of the 28 age-associated SASP proteins, 18 were significantly associated with 1 or more clinical traits, and 7 SASP proteins were significantly associated with 3 or more traits. Growth/differentiation factor 15, Insulin-like growth factor-binding protein 2, and Cystatin-C showed significant associations with inflammatory markers and measures of physical function (grip strength or gait speed). These results support the relevance of SASP proteins to human aging, identify specific traits that are potentially affected by SASP, and prioritize specific SASP proteins for their utility as biomarkers of human aging.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Plant Protein but Not Animal Protein Consumption Is Associated with Frailty through Plasma Metabolites.

There is evidence that the association of protein intake and frailty may depend on the source of dietary protein. The mechanism underlying this association is not clear. In this study, we explore circulating metabolites as mediators of the relationship between dietary protein and of frailty in participants of the Baltimore Longitudinal Study of Aging (BLSA). Cross-sectional analyses in 735 BLSA participants of associations between plant and animal protein intake and frailty. Usual protein intake from plant and animal sources were estimated with a Food Frequency Questionnaire (FFQ) and frailty was assessed with a 44-item Frailty Index (FI). Compared with the lowest quartile, higher quartiles of plant, but not animal, protein were associated with lower FI. Twenty-five plasma metabolites were associated with plant protein intake; of these, fifteen, including phosphatidylcholines, cholesterol esters, sphingomyelins, and indole metabolites, mediated the association between plant protein intake and FI. The protective association between plant protein consumption and FI is mediated by lower abundance of lipid metabolites and higher abundance of tryptophan-related metabolites.

Genetic insights into resting heart rate and its role in cardiovascular disease.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Epigenetic signature of human immune aging in the GESTALT study.

Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4+ and CD8+ T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1ß) and REST transcription factor (TF) motifs, respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to TF motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.

Unbiased proteomics and multivariable regularized regression techniques identify SMOC1, NOG, APCS, and NTN1 in an Alzheimer's disease brain proteomic signature.

Advancements in omics methodologies have generated a wealth of high-dimensional Alzheimer's disease (AD) datasets, creating significant opportunities and challenges for data interpretation. In this study, we utilized multivariable regularized regression techniques to identify a reduced set of proteins that could discriminate between AD and cognitively normal (CN) brain samples. Utilizing eNetXplorer, an R package that tests the accuracy and significance of a family of elastic net generalized linear models, we identified 4 proteins (SMOC1, NOG, APCS, NTN1) that accurately discriminated between AD (n = 31) and CN (n = 22) middle frontal gyrus (MFG) tissue samples from Religious Orders Study participants with 83 percent accuracy. We then validated this signature in MFG samples from Baltimore Longitudinal Study of Aging participants using leave-one-out logistic regression cross-validation, finding that the signature again accurately discriminated AD (n = 31) and CN (n = 19) participants with a receiver operating characteristic curve area under the curve of 0.863. These proteins were strongly correlated with the burden of neurofibrillary tangle and amyloid pathology in both study cohorts. We additionally tested whether these proteins differed between AD and CN inferior temporal gyrus (ITG) samples and blood serum samples at the time of AD diagnosis in ROS and BLSA, finding that the proteins differed between AD and CN ITG samples but not in blood serum samples. The identified proteins may provide mechanistic insights into the pathophysiology of AD, and the methods utilized in this study may serve as the basis for further work with additional high-dimensional datasets in AD.

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias.

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Large-scale rare variant burden testing in Parkinson's disease.

Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.