Melissa Edwards

A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI

Context There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimers disease (AD) at the population level. Objective To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma. Design, Setting, Participants Analysis of serum biomarker proteins were conducted on 197 Alzheimers disease (AD) participants and 199 control participants from the Texas Alzheimers Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). The full algorithm was derived from a biomarker risk score, clinical lab (glucose, triglycerides, total cholesterol, homocysteine), and demographic (age, gender, education, APOE*E4 status) data. Major Outcome Measures Alzheimers disease. Results 11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUCu200a=u200a0.70, sensitivity (SN)u200a=u200a0.54 and specificity (SP)u200a=u200a0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUCu200a=u200a0.92). However, the full algorithm yielded excellent accuracy (AUCu200a=u200a0.88, SNu200a=u200a0.75, and SPu200a=u200a0.91). The likelihood ratio of having AD based on a positive test finding (LR+)u200a=u200a7.03 (SEu200a=u200a1.17; 95% CIu200a=u200a4.49–14.47), the likelihood ratio of not having AD based on the algorithm (LR−)u200a=u200a3.55 (SEu200a=u200a1.15; 2.22–5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR)u200a=u200a28.70 (1.55; 95% CIu200a=u200a11.86–69.47). Conclusions It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses.

Long-Term Low-Level Arsenic Exposure Is Associated with Poorer Neuropsychological Functioning: A Project FRONTIER Study

Exposure to elements in groundwater (toxic or beneficial) is commonplace yet, outside of lead and mercury, little research has examined the impact of many commonly occurring environmental exposures on mental abilities during the aging process. Inorganic arsenic is a known neurotoxin that has both neurodevelopmental and neurocognitive consequences. The aim of this study was to examine the potential association between current and long-term arsenic exposure and detailed neuropsychological functioning in a sample of rural-dwelling adults and elders. Data were analyzed from 434 participants (133 men and 301 women) of Project FRONTIER, a community-based participatory research study of the epidemiology of health issues of rural-dwelling adults and elders. The results of the study showed that GIS-based groundwater arsenic exposure (current and long-term) was significantly related to poorer scores in language, visuospatial skills, and executive functioning. Additionally, long-term low-level exposure to arsenic was significantly correlated to poorer scores in global cognition, processing speed and immediate memory. The finding of a correlation between arsenic and the domains of executive functioning and memory is of critical importance as these are cognitive domains that reflect the earliest manifestations of Alzheimer’s disease. Additional work is warranted given the population health implications associated with long-term low-level arsenic exposure.

Comorbid Depression and Diabetes as a Risk for Mild Cognitive Impairment and Alzheimer’s Disease in Elderly Mexican Americans

BACKGROUNDnThe links between diabetes, depression, and Alzheimers disease (AD) has been established, but they are still poorly understood. However, little research has examined the effect that comorbidity of depression and diabetes has on cognitive impairment in an ethnically diverse sample.nnnOBJECTIVEnThe purpose of this study was to investigate the relationship between comorbid diabetes and depression on cognitive dysfunction; and examine the relationship in an ethnically diverse population.nnnMETHODS AND RESULTSnAnalyses of data from 2,436 participants (914 men and 1,522 women) of three separate cohorts: HABLE, FRONTIER, and TARCC. In the HABLE cohort, comorbidity (odds ratio [OR]u200a=u200a3.008; 95% CIu200a=u200a1.358-6.667), age (ORu200a=u200a1.138; 95% CIu200a=u200a1.093-1.185), and education (ORu200a=u200a0.915; 95% CIu200a=u200a0.852-0.982) increased the risk of mild cognitive impairment (MCI) diagnosis among elderly Mexican American. In the TARCC cohort, results showed an increase risk of MCI in both non-Hispanic whites (ORu200a=u200a18.795; 95% CIu200a=u200a2.229-158.485) and Mexican Americans (ORu200a=u200a8.417; 95% CIu200a=u200a2.967-23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (ORu200a=u200a2.754; 95% CIu200a=u200a1.084-6.995) and age (ORu200a=u200a1.069; 95% CIu200a=u200a1.023-1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI.nnnCONCLUSIONSnAmong elderly Mexican Americans, comorbid depression and diabetes significantly increased risk for MCI and AD across cohorts. Effects of comorbid diabetes and depression on MCI were inconclusive. Our results support the link between comorbid diabetes and depression and risk for cognitive decline among Mexican Americans. This finding is of critical importance as the Hispanic population is at higher risk of developing AD.

A depressive endophenotype of poorer cognition among cognitively healthy community‐dwelling adults: results from the Western Australia memory study

The objective was to evaluate in a cognitively normal population the utility of an endophenotype of the depression–cognition link previously shown to be related to cognitive functioning in mild cognitive impairment and Alzheimers disease.

The Link between Sleep Disturbance and Depression among Mexican Americans: A Project FRONTIER Study

OBJECTIVEnTo examine the link between disturbed sleep and depression scores in Mexican Americans and non-Hispanic Whites.nnnMETHODSnData were analyzed for 566 participants (45% Mexican Americans) who were part of a rural healthcare study, Project FRONTIER. Mean age was 55.5 years for Mexican Americans (70% female) and 65.6 years for non-Hispanic Whites (69% female). Self-reported sleep disturbance was entered as the predictor, GDS-30 total and factor scores as the outcome variables, and age, sex, education, BMI, and medical diagnoses (hyperlipidemia, diabetes mellitus, and hypertension) entered as covariates.nnnRESULTSnMexican Americans reported higher rates of sleep disturbances (25%) than non-Hispanic whites (17%). Sleep disturbances were significantly associated with GDS-30 total scores and the factors Dysphoria and Cognitive Impairment in both Mexican Americans and non-Hispanic whites.nnnCONCLUSIONSnIn this study, Mexican Americans reported higher rates of sleep disturbances than non-Hispanic whites. Disturbed sleep was positively associated with depression and the factor scores for Dysphoria and Cognitive Impairment in both groups. Given the paucity of research on sleep disorders in Mexican Americans, identifying what sleep disorders are present and the impact treating these sleep disorders have on depression warrant further investigation.

Serum-based protein profiles of Alzheimer's disease and mild cognitive impairment in elderly Hispanics

AIMnTo describe the biomarker profiles in elderly Panamanians diagnosed with Alzheimers disease (AD), mild cognitive impairment (MCI) or no impairment using serum-based biomarkers.nnnMETHODSnTwenty-four proteins were analyzed using an electrochemiluminescence-based multiplex biomarker assay platform. A biomarker profile was generated using random forest analyses.nnnRESULTSnTwo proteins differed among groups: IL-18 and T-lymphocyte-secreted protein I-309. The AD profile was highly accurate and independent of age, gender, education and Apolipoprotein E ε4 status. AD and MCI profiles had substantial overlap among the top markers, suggesting common functions in AD and MCI but differences in their relative importance.nnnCONCLUSIONnOur results underscore the potential influence of genetic and environmental differences within Hispanic populations on the proteomic profile of AD.

Serum granulocyte colony-stimulating factor and Alzheimer's disease.

Background: Granulocyte colony-stimulating factor (G-CSF) promotes the survival and function of neutrophils. G-CSF is also a neurotrophic factor, increasing neuroplasticity and suppressing apoptosis. Methods: We analyzed G-CSF levels in 197 patients with probable Alzheimer’s disease (AD) and 203 cognitively normal controls (NCs) from a longitudinal study by the Texas Alzheimer’s Research and Care Consortium (TARCC). Data were analyzed by regression with adjustment for age, education, gender and APOE4 status. Results: Serum G-CSF was significantly lower in AD patients than in NCs (β = –0.073; p = 0.008). However, among AD patients, higher serum G-CSF was significantly associated with increased disease severity, as indicated by lower Mini-Mental State Examination scores (β = –0.178; p = 0.014) and higher scores on the global Clinical Dementia Rating (CDR) scale (β = 0.170; p = 0.018) and CDR Sum of Boxes (β = 0.157; p = 0.035). Conclusions: G-CSF appears to have a complex relationship with AD pathogenesis and may reflect different pathophysiologic processes at different illness stages.

Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer’s disease

IntroductionThere has been a significant increase in the use of testosterone in aging men, but little investigation into its impact on men with Alzheimer’s disease (AD). The findings of the few studies that have been done are inconsistent. In the present study, we investigated the relationship between total testosterone (TT) and neuropsychiatric symptoms (NPS) in a well-characterized sample of elderly men with mild to moderate AD.MethodsThe sample, which was drawn from the Texas Alzheimer’s Research Care Consortium Longitudinal Research Cohort, included 87 men who met the criteria for mild to moderate AD. The occurrence of NPS was gathered from caregivers and/or family members with the Neuropsychiatric Inventory. TT was analyzed, and the sample was divided into a low-testosterone group (TT ≤2.5xa0ng/ml; nu2009=u200944) and a borderline/normal group (TT ≥2.6xa0ng/ml; nu2009=u200943).ResultsTT was correlated with symptoms of hallucinations, delusions, agitation, irritability and motor activity. The borderline/normal group was significantly more likely to have hallucinations (odds ratio (OR)u2009=u20095.56), delusions (ORu2009=u20093.87), motor activity (ORu2009=u20093.13) and irritability (ORu2009=u20092.77) than the low-testosterone group. Health status and apolipoprotein E ε4 status were not significant factors.ConclusionsThe findings of the present study have implications for the use of testosterone replacement therapy in men with AD or the prodromal stage of the disease.

Vitamin C supplementation, APOE4 genotype and cognitive functioning in a rural-dwelling cohort

ObjectiveApolipoprotein E4 (APOE4) genotype has been implicated as a moderating factor in cognitive function studies. Although prior studies have suggested that vitamin C is associated with better cognitive function in elders, link between the two has been mixed. Limited data exist as to whether the APOE4 genotype influences these associations. Therefore, this study sought to determine whether the association between vitamin C and cognition in a rural community dwelling cohort differs by the APOE4 genotype.Design and ParticipantsData were analyzed on 582 participants (n=183 men; n=399 women) from a rural community-based cohort. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status and The Executive Interview. APOE genotyping was ascertained by standard methods. The relation between vitamin C supplementation and cognition were analyzed first with ANOVA and then ANCOVA with age, gender, education as covariates. Analyses were initially run in the full sample and then split by APOE4 presence (yes/no).ResultsOverall, Vitamin C supplementation was associated with significantly better immediate memory (p=0.04), visuospatial skills (p=0.002), language (p=0.01), and global cognitive functioning (p=0.006). Among APOE4 non-carriers, vitamin C supplementation was positively associated with immediate memory (F[1,392] =6.7, p=0.01), visuospatial skills (F[1,391]=10.6, p=0.001), language (F[1,392]=13.0, p<0.001), attention (F[1,386]=7.9, p=0.005, and global cognition (F[1,382]=11.0, p=0.001. However, there was no significant link between vitamin C supplementation and cognition among APOE4 carriers.ConclusionVitamin C supplementation was found to be positively associated with cognition among this rural-dwelling community-based sample; however, the associations appeared to differ by APOE4 status. These data may suggest that targeted genotype-specific cognitive enhancement studies are needed to clarify the potential benefits of vitamin C supplementation.

Serum-based biomarker algorithms of neuropsychological functioning

Sid O’Bryant, Guanghua Xiao, Robert Barber, Melissa Edwards, James Hall, University of North Texas Health Science Center, Lubbock, Texas, United States; UT Southwestern Medical Center, Dallas, Texas, United States; UNTHSC, Fort Worth, Texas, United States; Texas Tech University, Lubbock, Texas, United States; 5 University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, United States.