Biomedical subjects

Steven E Arnold

Publications and source records attributed to Steven E Arnold.

At least 19 recordsLinked to original sources

PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗

PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗

PubMed2007

Hemodynamic responses in neural circuitries for detection of visual target and novelty: An event-related fMRI study.

The oddball paradigm examines attentional processes by establishing neural substrates for target detection and novelty. Event-related functional imaging enables characterization of hemodynamic changes associated with these processes. We studied 36 healthy participants (17 men) applying a visual oddball event-related design at 4 Tesla, and performed an unbiased determination of the hemodynamic response function (HRF). Targets were associated with bilateral, albeit leftward predominant changes in frontal-parietal temporal and occipital cortices, and limbic and basal ganglia regions. Activation to novelty was more posteriorly distributed, and frontal activation occurred only on the right, while robust activation was seen in occipital regions bilaterally. Overlapping regions were left thalamus, caudate and cuneus and right parietal precuneus. While robust HRFs characterized most regions, target detection was associated with a negative HRF in the right parietal precuneus and a biphasic HRF in thalamus, basal ganglia, and all occipital regions. Both height of the HRF and longer time to peak in the right cingulate were associated with slower response time. Sex differences were observed, with higher HRF peaks for novelty in men in right occipital regions, and longer time to peak in the left hemisphere. Age was associated with reduced peak HRF in left frontal region. Thus, indices of the HRF can be used to better understand the relationship between hemodynamic changes and performance and can be sensitive to individual differences.

Adolescent↗

PubMed2006

Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin.

Variations in the gene encoding the novel protein dysbindin-1 (DTNBP1) are among the most commonly reported genetic variations associated with schizophrenia. Recent studies show that those variations are also associated with cognitive functioning in carriers with and without psychiatric diagnoses, suggesting a general role for dysbindin-1 in cognition. Such a role could stem from the protein's known ability to affect neuronal glutamate release. How dysbindin-1 might affect glutamate release nevertheless remains unknown without the discovery of the protein's neuronal binding partners and its subcellular locus of action. We demonstrate here that snapin is a binding partner of dysbindin-1 in vitro and in the brain. Tissue fractionation of whole mouse brains and human hippocampal formations revealed that both dysbindin-1 and snapin are concentrated in tissue enriched in synaptic vesicle membranes and less commonly in postsynaptic densities. It is not detected in presynaptic tissue fractions lacking synaptic vesicles. Consistent with that finding, immunoelectron microscopy showed that dysbindin-1 is located in (i) synaptic vesicles of axospinous terminals in the dentate gyrus inner molecular layer and CA1 stratum radiatum and in (ii) postsynaptic densities and microtubules of dentate hilus neurons and CA1 pyramidal cells. The labeled synapses are often asymmetric with thick postsynaptic densities suggestive of glutamatergic synapses, which are likely to be derived from dentate mossy cells and CA3 pyramidal cells. The function of dysbindin-1 in presynaptic, postsynaptic and microtubule locations may all be related to known functions of snapin.

Aged↗

PubMed2006

Chronic psychological distress and risk of Alzheimer's disease in old age.

Clinical and pathological data from the Rush Memory and Aging Project were used to test the hypothesis that distress proneness is associated with increased risk of Alzheimer's disease (AD). More than 600 older persons without dementia completed a 6-item measure of neuroticism, a stable indicator of proneness to psychological distress. At annual intervals thereafter, they underwent uniform evaluations that included clinical classification of AD and administration of 18 cognitive tests. Those who died underwent brain autopsy from which composite measures of AD pathology were derived. During a mean of about 3 years of follow-up, 55 people were clinically diagnosed with AD. In analyses that controlled for age, sex, and education, persons with a high level of distress proneness (score = 24, 90th percentile) were 2.7 times more likely to develop AD than those not prone to distress (score = 6, 10th percentile). Adjustment for depressive symptomatology or frequency of cognitive, social, and physical activity did not substantially change this effect. Distress proneness was also associated with more rapid cognitive decline. Among 45 participants who died and underwent brain autopsy, distress proneness was unrelated to diverse measures of AD pathology and was inversely related to cognition after controlling for AD pathology. The results support the hypothesis that distress proneness is associated with increased risk of dementia and suggest that neurobiologic mechanisms other than AD pathology may underlie the association.

Aged↗

PubMed2006

Variations in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) are associated with bipolar i disorder.

The vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) maps to the shared bipolar disorder (BPD)/schizophrenia (SZ) susceptibility locus on chromosome 8p21. Vesicular monoamine transporters are involved in transport of monoamine neurotransmitters which have been postulated to play a relevant role in the etiology of BPD and/or SZ. Variations in the VMAT1 gene might affect transporter function and/or expression and might be involved in the etiology of BPD and/or SZ. Genotypes of 585 patients with BPD type I and 563 control subjects were obtained for three missense single nucleotide polymorphisms (SNPs) (Thr4Pro, Thr98Ser, Thr136Ile) and four non-coding SNPs (rs988713, rs2279709, rs3735835, rs1497020). All cases and controls were of European descent. Allele frequencies differed significantly for the potential functional polymorphism Thr136Ser between BPD patients and controls (p=0.003; df=1; OR=1.34; 95% CI: 1.11-1.62). Polymorphisms in the promoter region (rs988713: p=0.005, df=1; OR=1.31; 95% CI: 1.09-1.59) and intron 8 (rs2279709: p=0.039, df=1; OR=0.84; 95% CI: 0.71-0.99) were also associated with disease. Expression analysis confirmed that VMAT1 is expressed in human brain at the mRNA and protein level. Results suggest that variations in the VMAT1 gene may confer susceptibility to BPD in patients of European descent. Additional studies are necessary to confirm this effect and to elucidate the role of VMAT1 in central nervous system physiology.

Adult↗

PubMed2006

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4-PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

Animals↗

PubMed2006

Frontotemporal dementia: clinicopathological correlations.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology. METHODS: A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia. RESULTS: Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function. INTERPRETATION: Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.

Adult↗

PubMed2006

The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study.

BACKGROUND: Few data are available about how social networks reduce the risk of cognitive impairment in old age. We aimed to measure this effect using data from a large, longitudinal, epidemiological clinicopathological study. METHODS: 89 elderly people without known dementia participating in the Rush Memory and Aging Project underwent annual clinical evaluation. Brain autopsy was done at the time of death. Social network data were obtained by structured interview. Cognitive function tests were Z scored and averaged to yield a global and specific measure of cognitive function. Alzheimer's disease pathology was quantified as a global measure based on modified Bielschowsky silver stain. Amyloid load and the density of paired helical filament tau tangles were also quantified with antibody-specific immunostains. We used linear regression to examine the relation of disease pathology scores and social networks to level of cognitive function. FINDINGS: Cognitive function was inversely related to all measures of disease pathology, indicating lower function at more severe levels of pathology. Social network size modified the association between pathology and cognitive function (parameter estimate 0.097, SE 0.039, p=0.016, R(2)=0.295). Even at more severe levels of global disease pathology, cognitive function remained higher for participants with larger network sizes. A similar modifying association was observed with tangles (parameter estimate 0.011, SE 0.003, p=0.001, R(2)=0.454). These modifying effects were most pronounced for semantic memory and working memory. Amyloid load did not modify the relation between pathology and network size. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases. INTERPRETATION: These findings suggest that social networks modify the relation of some measures of Alzheimer's disease pathology to level of cognitive function.

Aged↗

PubMed2006

Olfactory functioning in schizophrenia: relationship to clinical, neuropsychological, and volumetric MRI measures.

Deficits in odor identification and detection threshold sensitivity have been observed in schizophrenia but their relationship to clinical, cognitive, and biologic measures have not been clearly established. Our objectives were to examine the relationship between measures of odor identification and detection threshold sensitivity and clinical, neuropsychological, and anatomic brain measures. Twenty-one patients with schizophrenia and 20 healthy controls were administered psychophysical tests of odor identification and detection threshold sensitivity to phenyl ethyl alcohol. In addition, clinical symptom ratings, neuropsychological measures of frontal and temporal lobe function and whole brain MRIs were concurrently obtained. Patients exhibited significant deficits in odor identification but normal detection threshold sensitivity. Poorer odor identification scores were associated with longer duration of illness, increased negative and disorganized symptoms, and the deficit syndrome, as well as impairments in verbal and nonverbal memory. Better odor detection thresholds were specifically associated with first-rank or productive symptoms. Larger left temporal lobe volumes with MRI were associated with better odor identification in controls but not in patients. Given the relevance of the neural substrate, and the evidence of performance deficits, psychophysical probes of the integrity of the olfactory system hold special promise for illuminating aspects of the neurobiology underlying schizophrenia.

Adult↗

PubMed2006

Childhood adversity and psychosocial adjustment in old age.

OBJECTIVE: The objective of this study was to test the hypothesis that higher level of childhood adversity is associated with lower level of psychosocial adjustment in old age. METHOD: Participants are 253 older persons (mean age: 79.8, standard deviation: 2.1; 73.9% women) from the Rush Memory and Aging Project, a clinicopathologic study of common chronic conditions of old age. Childhood adversity was assessed with a 16-item measure based on portions of the Childhood Trauma Questionnaire and other inventories. Psychosocial adjustment was assessed with multiple measures of neuroticism (i.e., proneness to negative emotions) and social engagement. RESULTS: Based in part on a factor analysis, composite measures of total adversity, emotional neglect, parental intimidation, parental violence, family turmoil, and financial need were developed. In a series of linear regression models adjusted for age, sex, own education, and parental education, the composite measure of childhood adversity was associated with all facets of neuroticism and accounted for more than 13% of the variance in the composite neuroticism measure. Emotional neglect and parental intimidation had the strongest associations with neuroticism. Childhood adversity was not related to frequency of participation in social activities, but more adversity was associated with having a smaller network (accounting for 3% of the variance) and feeling more emotionally isolated (accounting for 7% of the variance). CONCLUSION: Childhood adversity is associated with less adaptive psychosocial functioning in old age.

Aged↗

PubMed2006

Apolipoprotein E genotype and odor identification in schizophrenia.

The authors examined Apolipoprotein E (ApoE) genotype frequencies and unirhinal odor identification in 28 schizophrenia patients and 26 healthy comparison subjects. No significant associations between ApoE status and olfaction were observed in either diagnostic group. The authors concluded that olfactory deficits in schizophrenia do not appear to be mediated by the ApoE allele.

Adult↗

PubMed2005

Odor identification and decline in different cognitive domains in old age.

The authors examined the association of odor identification with rate of decline in different cognitive systems. Participants are 481 older persons from the Rush Memory and Aging Project. At baseline, the Brief Smell Identification Test was administered. At annual intervals for up to 3 years, a battery of 19 cognitive tests was administered from which previously established composite measures of 5 cognitive domains were derived. In mixed-effects models adjusted for age, sex, and education, lower odor identification score was associated with lower function at baseline in each cognitive domain. Lower score was also associated with more rapid decline in perceptual speed (estimate=0.015, SE=0.006, p=0.013) and episodic memory (estimate=0.012, SE=0.006, p=0.030) but not with rate of decline in semantic memory, working memory, or visuospatial ability. Thus, on average, a person with a low odor identification score (6, 10th percentile) declined more than twice as rapidly in perceptual speed and episodic memory as a person with a high score (11, 90th percentile). Results were unchanged in subsequent analyses that controlled for cigarette smoking or clinically diagnosed stroke. The results indicate that impaired odor identification in old age is associated with impaired global cognition and more rapid decline in perceptual processing speed and episodic memory.

Aged↗

PubMed2005

The use of biomarkers in the elderly: current and future challenges.

Biomarkers are hypothesized but not frequently used in research with the elderly because of a general paucity of supportive scientific data. However, there is an obvious need for greater diagnostic specificity and sensitivity across many diagnoses in the elderly, as well as good targets for therapeutic trials. The authors reviewed the available information in this field as part of a general review of geriatric research for the . Potential biomarkers with pathophysiologic significance have been studied in the field of Alzheimer disease research with some success, especially in the area of genetic markers (apolipoprotein E [APOE] epsilon4 allele), neuroimaging, and cerebrospinal fluid markers (beta-amyloid and tau). While some progress has been made in the search for adequate biomarkers in the elderly, in particular with Alzheimer disease, much more work is needed before these potential biomarkers can be reliably used in clinical practice.

Aged↗

PubMed2005

Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease.

Genes known to contribute to the genetic predisposition to Alzheimer's disease (AD) are active in pathways of neurodegeneration but explain only a minority of the genetic contribution to AD. A protein of importance in cerebral neurodegeneration is the brain-derived neurotrophic factor (BDNF). Variations in two single-nucleotide polymorphisms (SNPs) within the BDNF gene have previously been associated with AD, and one of these SNPs has also been associated with memory loss and affective disorders. We performed a case control study of three BDNF SNPs in 250 neuropathologically confirmed cases of AD and 194 unrelated controls. We did not find a significant association between the three BDNF SNPs studied and AD when evaluated individually or with haplotype analysis. Nor did BDNF genotype appear to affect the APOE epsilon4 association with AD. The three SNPs studied were closely linked (D' = 0.99 across the region). We discuss possible reasons for our failure to confirm the previously reported associations.

Aged↗

PubMed2005

In vivo and in vitro neurogenesis in human olfactory epithelium.

The birth and differentiation of neurons have been extensively studied in the olfactory epithelium (OE) of rodents but not in humans. The goal of this study was to characterize cellular composition and molecular expression of human OE in vivo and in vitro. In rodent OE, there are horizontal basal cells and globose basal cells that are morphologically and functionally distinct. In human OE, however, there appears to be no morphological distinction among basal cells, with almost all cells having round cell bodies similar to rodent globose basal cells. Unlike the case in rodents, human basal cells, including putative neuronal precursors, express p75NGFR, suggesting a distinctive role for p75NGFR in human OE neurogenesis. Molecular expression of neuronal cells during differentiation in human OE grossly follows that in rodents. However, the topographical organization of immature and mature ORNs in human OE differs from that of rodents, in that immature and mature ORNs in humans are dispersed throughout the OE, whereas rodent counterparts have a highly laminar organization. These observations together suggest that the birth and differentiation of neuronal cells in human OE differ from those in rodents. In OE explant culture, neuronal cells derived from human OE biopsy express markers for immature and mature neurons, grossly recapitulating neuronal differentiation of olfactory neurons in vivo. Furthermore, small numbers of cells are doubly label for bromodeoxyuridine and olfactory marker protein, indicating that neuronal cells born in vitro reach maturity. These data highlight species-related differences in OE development and demonstrate the utility of explant culture for experimental studies of human neuronal development.

Adult↗

PubMed2005

A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease?

The prevalence of Alzheimer's disease (AD), a neurodegenerative condition whose greatest risk factor is old age, is expected to rise dramatically during the next five decades, along with the trend for increased longevity. Early diagnosis and intervention with therapies that halt or slow disease progress are likely to represent an important component of effective treatment. Although much progress has been made in this area, there are currently no clinically approved interventions for AD that are classed as disease modifying or neuroprotective. Cholinesterase inhibitors are a drug class used for the symptomatic treatment of AD. Recent evidence from preclinical studies indicates that these agents can attenuate neuronal damage and death from cytotoxic insults, and therefore might affect AD pathogenesis. The mechanisms by which these actions are mediated might or might not be directly related to their primary mode of action.

Alzheimer Disease↗

PubMed2005

Neurodevelopment, neuroplasticity, and new genes for schizophrenia.

Schizophrenia is a complex, debilitating neuropsychiatric disorder. Epidemiological, clinical, neuropsychological, and neurophysiological studies have provided substantial evidence that abnormalities in brain development and ongoing neuroplasticity play important roles in the pathogenesis of the disorder. Complementing these clinical studies, a range of cytoarchitectural, morphometric, ultrastructural, immunochemical, and gene expression methods have been applied in investigations of postmortem brain tissues to characterize the cellular and molecular profile of putative developmental and plastic abnormalities in schizophrenia. While findings have been diverse and many are in need of replication, investigations focusing on higher cortical and limbic brain regions are increasingly demonstrating abnormalities in the structural and molecular integrity of the synaptic complex as well as glutamate-related receptors and signal transduction pathways that play critical roles in brain development, synaptogenesis, and synaptic plasticity. Most exciting have been recent associations of schizophrenia with specific genes, such as neuregulin-1, dysbindin-1, and AKT-1, which are vital to synaptic development, neurotransmission, and plasticity.

Humans↗