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1.  Executive Functioning as a Mediator of the Relationship Between Premorbid Verbal Intelligence and Health Risk Behaviors in a Rural-Dwelling Cohort: A Project FRONTIER Study 
Limited research is available regarding the impact of neuropsychological functioning on health risk behaviors in rural-dwelling elderly populations. This cross-sectional study examined the relationships between estimated premorbid verbal IQ (AMNART), executive functioning impairment (EXIT25), and health risk behaviors including alcohol use (AUDIT), smoking, compliance with recommended cancer screenings, and obesity (BMI). The total sample included 456 English-speaking adults and older adults of non-Hispanic White and Hispanic origin seen as part of an ongoing study of rural cognitive aging, Project FRONTIER. Regression analyses revealed significant independent effects of AMNART and EXIT25 on most health risk behaviors, and supported the hypothesized mediating role of EXIT25 on the relationships between AMNART and smoking, cancer screenings, and BMI in both cognitively impaired and healthy subgroups. This study clarifies the relationships between executive functioning, premorbid IQ, and health risk behaviors in diverse groups, and confirms that premorbid IQ represents an important determinant of health behaviors and neurocognitive outcomes.
doi:10.1093/arclin/acs102
PMCID: PMC3569949  PMID: 23192834
Executive functioning; Diversity; Cognition; Health risk behaviors; Premorbid verbal IQ; geriatrics
2.  Characterization of Mexican Americans with Mild Cognitive Impairment and Alzheimer’s Disease 
Objective
To provide characterization of Mexican Americans who meet criteria for Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI).
Methods
1069 participants ages 40 and above who self-identified as either non-Hispanic white (n=633) or Mexican American (n=436); were recruited using a community-based participatory research (CBPR) approach. Global cognition was assessed via the Mini Mental State Exam (MMSE), dementia severity by the Clinical Dementia Rating Scale (CDR) and depression via the Geriatric Depression Scale 30-item version. Age, gender, education, ApoEε4 allele frequency and diabetic diagnoses were also analyzed.
Results
Mexican Americans (normal controls, MCI and AD) were younger, less highly educated, performed more poorly on the MMSE, endorsed more symptoms of depression, were more likely to be diagnosed with diabetes, and possessed the ApoEε4 allele less frequently. Age was the only significant risk factor for cognitive dysfunction (AD/MCI) among Mexican Americans (OR=1.06, 95% CI = 1.03–1.09). Age (B=0.07, std=0.02, p<0.001) and ApoEε4 presence (B=0.9, std=0.4, p=0.02) were significantly related to increased disease severity.
Conclusions
Given the rapidly growing and aging Mexican American population, there is a substantial need for research into cognitive aging, MCI and AD among this ethnic group. The current findings hold important implications for both clinic and research settings and point to additional research needs.
doi:10.3233/JAD-2012-121420
PMCID: PMC3524411  PMID: 22976076
Mild Cognitive Impairment; Alzheimer’s disease; Mexican American; Hispanic; cognition; depression; diabetes
3.  The Link between C-Reactive Protein and Alzheimer’s Disease Among Mexican Americans 
Background
The aim of this study is to evaluate the link between CRP and Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) among Mexican Americans.
Methods
Non-fasting serum CRP levels, MMSE scores and CDR scores were analyzed from 1,066 participants (Mexican American n=471, non-Hispanic n=595) of the Texas Alzheimer’s Research & Care Consortium (TARCC).
Results
Among the total cohort, CRP levels among AD cases were significantly decreased as compared to normal controls (p<0.001) and MCI cases (p=0.002). CRP levels among MCI cases were decreased relative to controls (p=0.03). Among Mexican American and non-Hispanic AD cases, CRP levels were significantly decreased among AD cases as compared to controls. CRP levels were only associated with disease severity (CDR scores) among non-Hispanics (p=0.03) AD cases.
Conclusions
These results show that, while CRP levels are decreased among Mexican American AD cases, CRP appears to not be related to clinical variables as it is among non-Hispanic whites.
doi:10.3233/JAD-122071
PMCID: PMC3608400  PMID: 23254637
C-Reactive Protein; Alzheimer’s disease; Mexican American; Neuropsychology
4.  Biomarkers of Alzheimer’s Disease Among Mexican Americans 
Background
Mexican Americans are the fastest aging segment of the U.S. population yet little scientific literature exists regarding the Alzheimer disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American.
Methods
Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer’s Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses.
Results
The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g. FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve (AUC), sensitivity (SN) and specificity (SP) of 0.77, 0.92 and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of SN and SP.
Conclusion
The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted.
doi:10.3233/JAD-122074
PMCID: PMC3608404  PMID: 23313927
Biomarkers; Mexican American; Alzheimer’s disease; Neuropsychology
5.  Biomarkers of Vascular Risk, Systemic Inflammation and Microvascular Pathology and Neuropsychiatric Symptoms in Alzheimer’s Disease 
Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer’s disease. The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild Alzheimer’s disease. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable Alzheimer’s disease. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview with caretakers/family members using the Neuropsychiatric Inventory. For total sample IL15, VCAM (Vascular Adhesion Molecule) and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in Alzheimer’s disease supporting a vascular and inflammatory component of psychiatric disorders found in Alzheimer’s disease. Gender differences suggest distinct impact of specific risks with total cholesterol a measure of cardiovascular risk being the strongest marker for males and IL-15 a marker of inflammation being the strongest for females.
doi:10.3233/JAD-122359
PMCID: PMC3631280  PMID: 23403534
Alzheimer’s Disease; neuropsychiatric symptoms; biomarkers; gender
6.  Diagnostic Accuracy of the MMSE in Detecting Probable and Possible Alzheimer's Disease in Ethnically Diverse Highly Educated Individuals: An Analysis of the NACC Database 
Background.
To validate and extend the findings of a raised cut score of O’Bryant and colleagues (O’Bryant SE, Humphreys JD, Smith GE, et al. Detecting dementia with the mini-mental state examination in highly educated individuals. Arch Neurol. 2008;65(7):963–967.) for the Mini-Mental State Examination in detecting cognitive dysfunction in a bilingual sample of highly educated ethnically diverse individuals.
Methods.
Archival data were reviewed from participants enrolled in the National Alzheimer's Coordinating Center minimum data set. Data on 7,093 individuals with 16 or more years of education were analyzed, including 2,337 cases with probable and possible Alzheimer's disease, 1,418 mild cognitive impairment patients, and 3,088 nondemented controls. Ethnic composition was characterized as follows: 6,296 Caucasians, 581 African Americans, 4 American Indians or Alaska natives, 2 native Hawaiians or Pacific Islanders, 149 Asians, 43 “Other,” and 18 of unknown origin.
Results.
Diagnostic accuracy estimates (sensitivity, specificity, and likelihood ratio) of Mini-Mental State Examination cut scores in detecting probable and possible Alzheimer's disease were examined. A standard Mini-Mental State Examination cut score of 24 (≤23) yielded a sensitivity of 0.58 and a specificity of 0.98 in detecting probable and possible Alzheimer's disease across ethnicities. A cut score of 27 (≤26) resulted in an improved balance of sensitivity and specificity (0.79 and 0.90, respectively). In the cognitively impaired group (mild cognitive impairment and probable and possible Alzheimer's disease), the standard cut score yielded a sensitivity of 0.38 and a specificity of 1.00 while raising the cut score to 27 resulted in an improved balance of 0.59 and 0.96 of sensitivity and specificity, respectively.
Conclusions.
These findings cross-validate our previous work and extend them to an ethnically diverse cohort. A higher cut score is needed to maximize diagnostic accuracy of the Mini-Mental State Examination in individuals with college degrees.
doi:10.1093/gerona/gls006
PMCID: PMC3403860  PMID: 22396476
Alzheimer's disease; Dementia diagnosis; Ethnicity; Language; Mini-Mental State Examination
7.  A Depressive Endophenotype of Mild Cognitive Impairment and Alzheimer’s Disease 
PLoS ONE  2013;8(7):e68848.
Background
Alzheimer’s disease (AD) is a devastating public health problem that affects over 5.4 million Americans. Depression increases the risk of Mild Cognitive Impairment (MCI) and AD. By understanding the influence of depression on cognition, the potential exists to identify subgroups of depressed elders at greater risk for cognitive decline and AD. The current study sought to: 1) clinically identify a sub group of geriatric patients who suffer from depression related cognitive impairment; 2) cross validate this depressive endophenotype of MCI/AD in an independent cohort.
Methods and Findings
Data was analyzed from 519 participants of Project FRONTIER. Depression was assessed with the GDS30 and cognition was assessed using the EXIT 25 and RBANS. Five GDS items were used to create the Depressive endophenotype of MCI and AD (DepE). DepE was significantly negatively related to RBANS index scores of Immediate Memory (B=-2.22, SE=.37, p<0.001), visuospatial skills (B=-1.11, SE=0.26, p<0.001), Language (B=-1.03, SE=0.21, p<0.001), Attention (B=-2.56, SE=0.49, p<0.001), and Delayed Memory (B=-1.54, SE = 037, p<0.001), and higher DepE scores were related to poorer executive functioning (EXIT25; B=0.65, SE=0.19, p=0.001). DepE scores significantly increased risk for MCI diagnosis (odds ratio [OR] = 2.04; 95% CI=1.54-2.69). Data from 235 participants in the TARCC (Texas Alzheimer’s Research & Care Consortium) were analyzed for cross-validation of findings in an independent cohort. The DepE was significantly related to poorer scores on all measures, and a significantly predicted of cognitive change over 12- and 24-months.
Conclusion
The current findings suggest that a depressive endophenotype of MCI and AD exists and can be clinically identified using the GDS-30. Higher scores increased risk for MCI and was cross-validated by predicting AD in the TARCC. A key purpose for the search for distinct subgroups of individuals at risk for AD and MCI is to identify novel treatment and preventative opportunities.
doi:10.1371/journal.pone.0068848
PMCID: PMC3708919  PMID: 23874786
8.  Diagnostic Validity of Age- And Education-Corrections for the Mini-Mental State Examination (MMSE) in African American Elders 
Objectives
To investigate whether demographic (age and education) adjustments for the Mini-Mental State Examination (MMSE) attenuate mean score discrepancies between African American and Caucasian adults, and to determine whether demographically-adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African American adults when compared to unadjusted MMSE scores.
Design
Cross-sectional study.
Setting
Community-dwelling adults participating in the Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR) and Alzheimer’s Disease Research Center (ADRC).
Participants
Three thousand two hundred fifty-four adults (2819 Caucasian, 435 African American) aged 60 and older.
Measurements
MMSE at study entry.
Results
African American adults obtained significantly lower unadjusted MMSE scores (23.0 ± 7.4) compared to Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly-derived weights. However, controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. Among African American adults, an age- and education-adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia.
Conclusion
Age, dementia severity at study entry, and quality of educational experience are important explanatory factors to understand the existing discrepancies in MMSE performance between Caucasian and African American adults. Our findings support the use of unadjusted MMSE scores when screening African American elders for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.
doi:10.1111/j.1532-5415.2011.03766.x
PMCID: PMC3288600  PMID: 22150301
MMSE; African American; ethnicity; dementia; cognition
9.  The Relation between Inflammation and Neuropsychological Test Performance 
Background. Considerable research documents an association between pro- and anti-inflammatory markers and Alzheimer's disease (AD), yet the differential relation between these markers and neuropsychological functioning in AD and nondemented controls has received less attention. The current study sought to evaluate the relationship between peripheral markers of inflammation (both pro- and anti-inflammatory) and neuropsychological functioning through the Texas Alzheimer's Research and Care Consortium (TARCC) cohort. Methods. There were 320 participants (Probable AD n = 124, Controls n = 196) in the TARCC Longitudinal Research Cohort available for analysis. Regression analyses were utilized to examine the relation between proinflammatory and anti-inflammatory markers and neuropsychological functioning. Follow-up analyses were conducted separately by case versus control status. Results. Proinflammatory and anti-inflammatory markers were found to be associated with neuropsychological testing. Third tertile proinflammatory markers were negatively associated with measures of attention and language, and anti-inflammatory markers were positively associated with measures of immediate verbal memory and delayed verbal and visual memory. Conclusions. These findings support the link between peripheral inflammatory markers and neuropsychological functioning and suggest the utility of examining profiles of inflammatory markers in the future.
doi:10.1155/2012/703871
PMCID: PMC3449133  PMID: 23008797
10.  A Blood-Based Algorithm for the Detection of Alzheimer's Disease 
Background
We previously created a serum-based algorithm that yielded excellent diagnostic accuracy in Alzheimer's disease. The current project was designed to refine that algorithm by reducing the number of serum proteins and by including clinical labs. The link between the biomarker risk score and neuropsychological performance was also examined.
Methods
Serum-protein multiplex biomarker data from 197 patients diagnosed with Alzheimer's disease and 203 cognitively normal controls from the Texas Alzheimer's Research Consortium were analyzed. The 30 markers identified as the most important from our initial analyses and clinical labs were utilized to create the algorithm.
Results
The 30-protein risk score yielded a sensitivity, specificity, and AUC of 0.88, 0.82, and 0.91, respectively. When combined with demographic data and clinical labs, the algorithm yielded a sensitivity, specificity, and AUC of 0.89, 0.85, and 0.94, respectively. In linear regression models, the biomarker risk score was most strongly related to neuropsychological tests of language and memory.
Conclusions
Our previously published diagnostic algorithm can be restricted to only 30 serum proteins and still retain excellent diagnostic accuracy. Additionally, the revised biomarker risk score is significantly related to neuropsychological test performance.
doi:10.1159/000330750
PMCID: PMC3169374  PMID: 21865746
Algorithm, blood-based; Alzheimer's disease; Diagnosis
11.  Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores 
Archives of neurology  2008;65(8):1091-1095.
Background
The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established.
Obiective
To investigate the effectiveness of CDRSOB scores in staging dementia severity compared with the global CDR score.
Design
Retrospective study.
Setting
Texas Alzheimer's Research Consortium minimum data set cohort.
Participants
A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis.
Main Outcome Measures
Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample.
Results
Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.O, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, κ scores ranged from 0.86 to 0.94 (P <.001 for all), with 93.0% of the participants falling within the new staging categories.
Conclusions
The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.
doi:10.1001/archneur.65.8.1091
PMCID: PMC3409562  PMID: 18695059
12.  Serum Brain-Derived Neurotrophic Factor Levels Are Specifically Associated with Memory Performance among Alzheimer's Disease Cases 
Aims
Our purpose was to study the link between serum brain-derived neurotrophic factor (BDNF) levels and neuropsychological functioning through the Texas Alzheimer's Research Consortium cohort.
Methods
A total of 399 participants [probable Alzheimer's disease (AD) n = 198, controls n = 201] were available for analysis. The BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels and neuropsychological functioning.
Results
There were no significant mean differences in BDNF levels between cases and controls. In the AD group, the BDNF levels were significantly negatively associated with the scores on immediate [B = −0.07 (0.02), t = −3.55, p = 0.001] and delayed [B = −0.05 (0.02), t = −2.79, p = 0.01] verbal memory and immediate [B = −0.12 (0.05), t = −2.70, p = 0.01] visual memory. No other neuropsychological variables were significantly related to the BDNF levels. The BDNF levels were not significantly related to the neuropsychological test scores in the control group.
Conclusions
Increased serum BDNF levels were associated with poorer visual and verbal memory, but only among AD cases. The current findings point toward an upregulation of serum BDNF as one possible mechanism linked to memory disturbances in AD though it does not appear to be linked to disease severity.
doi:10.1159/000321980
PMCID: PMC3019366  PMID: 21135555
Alzheimer's disease; Biomarkers; Brain-derived neurotrophic factor; Cognition; Neuropsychology; Aging
13.  The RBANS Effort Index: Base rates in geriatric samples 
Applied neuropsychology  2011;18(1):11-17.
The Effort Index (EI) of the RBANS was developed to assist clinicians in discriminating patients who demonstrate good effort from those with poor effort. However, there are concerns that older adults might be unfairly penalized by this index, which uses uncorrected raw scores. Using five independent samples of geriatric patients with a broad range of cognitive functioning (e.g., cognitively intact, nursing home residents, probable Alzheimer’s disease), base rates of failure on the EI were calculated. In cognitively intact and mildly impaired samples, few older individuals were classified as demonstrating poor effort (e.g., 3% in cognitively intact). However, in the more severely impaired geriatric patients, over one third had EI scores that fell above suggested cut-off scores (e.g., 37% in nursing home residents, 33% in probable Alzheimer’s disease). In the cognitively intact sample, older and less educated patients were more likely to have scores suggestive of poor effort. Education effects were observed in 3 of the 4 clinical samples. Overall cognitive functioning was significantly correlated with EI scores, with poorer cognition being associated with greater suspicion of low effort. The current results suggest that age, education, and level of cognitive functioning should be taken into consideration when interpreting EI results and that significant caution is warranted when examining EI scores in elders suspected of having dementia.
doi:10.1080/09084282.2010.523354
PMCID: PMC3074382  PMID: 21390895
symptom validity testing; RBANS; geriatric assessment
14.  A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI 
PLoS ONE  2011;6(12):e28092.
Context
There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's 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 Alzheimer's disease (AD) participants and 199 control participants from the Texas Alzheimer's Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimer's 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
Alzheimer's 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) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49–14.47), the likelihood ratio of not having AD based on the algorithm (LR−) = 3.55 (SE = 1.15; 2.22–5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86–69.47).
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.
doi:10.1371/journal.pone.0028092
PMCID: PMC3233542  PMID: 22163278
15.  Decreased C-Reactive Protein Levels in Alzheimer Disease 
C-reactive protein (CRP) is an acute-phase reactant that has been found to be associated with Alzheimer disease (AD) in histo-pathological and longitudinal studies; however, little data exist regarding serum CRP levels in patients with established AD. The current study evaluated CRP levels in 192 patients diagnosed with probable AD (mean age = 75.8 ± 8.2 years; 50% female) as compared to 174 nondemented controls (mean age = 70.6 ± 8.2 years; 63% female). Mean CRP levels were found to be significantly decreased in AD (2.9 µg/mL) versus controls (4.9 µg/mL; P = .003). In adjusted models, elevated CRP significantly predicted poorer (elevated) Clinical Dementia Rating Scale sum of boxes (CDR SB) scores in patients with AD. In controls, CRP was negatively associated with Mini-Mental State Examination (MMSE) scores and positively associated with CDR SB scores. These findings, together with previously published results, are consistent with the hypothesis that midlife elevations in CRP are associated with increased risk of AD development though elevated CRP levels are not useful for prediction in the immediate prodrome years before AD becomes clinically manifest. However, for a subgroup of patients with AD, elevated CRP continues to predict increased dementia severity suggestive of a possible proinflammatory endophenotype in AD.
doi:10.1177/0891988709351832
PMCID: PMC3204581  PMID: 19933496
Alzheimer disease; C-reactive protein; inflammation; treatment; primary prevention
16.  A Serum Protein-Based Algorithm for the Detection of Alzheimer's Disease 
Archives of neurology  2010;67(9):1077-1081.
Background
Alzheimer's disease (AD) is the most common form of age-related dementia and one of the most serious health problems in the industrialized world. Biomarker approaches to diagnostics would be more time and cost effective and may also be useful for identifying endophenotypes within AD patient populations.
Methods
We analyzed serum protein-based multiplex biomarker data from 197 patients diagnosed with AD and 203 controls from a longitudinal study of Alzheimer's disease being conducted by the Texas Alzheimer's Research Consortium to develop an algorithm that separates AD from controls. The total sample was randomized equally into training and test sets and random forest methods were applied to the training set to create a biomarker risk score.
Findings
The biomarker risk score had a sensitivity and specificity of 0.80 and 0.91, respectively and an AUC of 0.91 in detecting AD. When age, gender, education, and APOE status were added to the algorithm, the sensitivity, specificity, and AUC were 0.94, 0.84, and 0.95, respectively.
Interpretation
These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD. Of note, a disproportionate number of inflammatory and vascular markers were weighted most heavily in analyses. Additionally, these markers consistently distinguished cases from controls in SAM, logistic regression and Wilcoxon analyses, suggesting the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients.
doi:10.1001/archneurol.2010.215
PMCID: PMC3069805  PMID: 20837851
17.  Depressive Symptom Clusters and Neuropsychological Performance in Mild Alzheimer's and Cognitively Normal Elderly 
Objectives. Determine the relationship between depressive symptom clusters and neuropsychological test performance in an elderly cohort of cognitively normal controls and mild Alzheimer's disease (AD). Design. Cross-sectional analysis. Setting. Four health science centers in Texas. Participants. 628 elderly individuals (272 diagnosed with mild AD and 356 controls) from ongoing longitudinal study of Alzheimer's disease. Measurements. Standard battery of neuropsychological tests and the 30-item Geriatric Depression Scale with regressions model generated on GDS-30 subscale scores (dysphoria, apathy, meaninglessness and cognitive impairment) as predictors and neuropsychological tests as outcome variables. Follow-up analyses by gender were conducted. Results. For AD, all symptom clusters were related to specific neurocognitive domains; among controls apathy and cognitive impairment were significantly related to neuropsychological functioning. The relationship between performance and symptom clusters was significantly different for males and females in each group. Conclusion. Findings suggest the need to examine disease status and gender when considering the impact of depressive symptoms on cognition.
doi:10.1155/2011/396958
PMCID: PMC3166565  PMID: 21904674
18.  Diagnostic Accuracy of the RBANS in Mild Cognitive Impairment: Limitations on Assessing Milder Impairments 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has demonstrated adequate sensitivity in detecting cognitive impairment in a number of neuropsychiatric conditions, including Alzheimer's disease. However, its ability to detect milder cognitive deficits in the elderly has not been examined. The current study examined the clinical utility of the RBANS by comparing two groups: Patients with Mild Cognitive Impairment (MCI; n = 72) and cognitively intact peers (n = 71). Significant differences were observed on the RBANS Total score, 3 of the 5 Indexes, and 6 of the 12 subtests, with individuals with MCI performing worse than the comparison participants. Specificity was very good, but sensitivity ranged from poor to moderate. Areas under the receiver operating characteristic curves for the RBANS Immediate and Delayed Memory Indexes and the Total Scale score were adequate. Although significant differences were observed between groups and the areas under the curves were adequate, the lower sensitivity values of the RBANS suggests that caution should be used when diagnosing conditions such as MCI.
doi:10.1093/arclin/acq045
PMCID: PMC2904671  PMID: 20570820
Mild Cognitive Impairment; Diagnostic accuracy; Repeatable Battery for the Assessment of Neuropsychological Status
19.  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.
doi:10.3390/ijerph8030861
PMCID: PMC3083674  PMID: 21556183
arsenic; chronic exposure; environmental exposure; cognition; rural health
20.  Brain-Derived Neurotrophic Factor Levels in Alzheimer's Disease 
Objective:
The current search for biomarkers that are diagnostic and/or prognostic of Alzheimer's disease (AD) is of vital importance given the rapidly aging population. It was recently reported that brain derived neurotrophic factor (BDNF) fluctuated according to AD severity, suggesting that BDNF might have utility for diagnostics and monitoring of therapeutic efficacy. The current study sought to examine whether BDNF levels varied according to AD severity, as previously reported.
Method:
There were 196 participants (Probable AD n = 98, Controls n = 98) in the Texas Alzheimer's Research Consortium (TARC) Longitudinal Research Cohort available for analysis. BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels, MMSE, and CDR scores adjusting for age and gender.
Results:
In adjusted models, BDNF levels did not distinguish between AD patients and normal controls and did not significantly predict AD severity or global cognitive functioning.
Conclusions:
These findings do not support the notion that BDNF serves as a diagnostic marker for AD or disease severity. It is likely that the most accurate approach to identifying biomarkers of AD will be through an algorithmic approach that combines multiple markers reflective of various pathways.
doi:10.3233/JAD-2009-1051
PMCID: PMC2787708  PMID: 19363274
Alzheimer's disease; Biomarkers; BDNF; Dementia Severity; Clinical Dementia Rating
21.  Utility of the RBANS in detecting cognitive impairment associated with Alzheimer’s disease: Sensitivity, specificity, and positive and negative predictive powers 
Although initially developed as a brief dementia battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has not yet demonstrated its sensitivity, specificity, and positive and negative predictive powers in detecting cognitive impairment in patients with Alzheimer’s disease (AD). Therefore, the current study examined the clinical utility of the RBANS by comparing two age-, education-, and gender-matched groups: patients with AD (n=69) and comparators (n=69). Significant differences (p<0.001) were observed on the RBANS Total score, all five Indexes, and all twelve subtests, with patients performing worse than the comparison participants. An optimal balance between sensitivity and specificity on RBANS scores was obtained when cutoffs of one and one and a half standard deviations below the mean of the comparison sample were implemented. Areas under the Receiver Operating Characteristic curves for all RBANS Indexes were impressive though Immediate and Delayed Memory Indexes were excellent (0.96 and 0.98, respectively). Results suggest that RBANS scores yield excellent estimates of diagnostic accuracy and that the RBANS is a useful screening tool in detection of cognitive deficits associated with AD.
doi:10.1016/j.acn.2008.06.004
PMCID: PMC2570647  PMID: 18639437
Alzheimer’s disease; dementia; diagnostic accuracy; Repeatable Battery for the Assessment of Neuropsychological Status
22.  Utility of the RBANS in detecting cognitive impairment associated with Alzheimer's disease: Sensitivity, specificity, and positive and negative predictive powers 
Abstract
Although initially developed as a brief dementia battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has not yet demonstrated its sensitivity, specificity, and positive and negative predictive powers in detecting cognitive impairment in patients with Alzheimer's disease (AD). Therefore, the current study examined the clinical utility of the RBANS by comparing two age-, education-, and gender-matched groups: patients with AD (n=69) and comparators (n=69). Significant differences (p<0.001) were observed on the RBANS Total score, all 5 Indexes, and all 12 subtests, with patients performing worse than the comparison participants. An optimal balance between sensitivity and specificity on RBANS scores was obtained when cutoffs of one and one and a half standard deviations below the mean of the comparison sample were implemented. Areas under the Receiver Operating Characteristic curves for all RBANS Indexes were impressive though Immediate and Delayed Memory Indexes were excellent (0.96 and 0.98, respectively). Results suggest that RBANS scores yield excellent estimates of diagnostic accuracy and that the RBANS is a useful screening tool in detection of cognitive deficits associated with AD.
doi:10.1016/j.acn.2008.06.004
PMCID: PMC2570647  PMID: 18639437
Alzheimer's disease; Dementia; Diagnostic accuracy; Repeatable Battery for the Assessment of Neuropsychological Status
23.  Detecting Dementia with the Mini-Mental State Examination (MMSE) in Highly Educated Individuals 
Archives of neurology  2008;65(7):963-967.
Objectives
To evaluate the utility of Mini-Mental State Examination (MMSE) scores in detecting cognitive dysfunction in a sample of highly educated individuals.
Design
Archival data were reviewed on 4248 participants enrolled in the Mayo Clinic Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Patient Registry (ADPR).
Patients
1141 primarily Caucasian (93%) individuals with 16 or more years of self-reported education were identified. These included 307 (164 males and 143 females) dementia cases (any type), 176 patients with Mild Cognitive Impairment (106 males and 70 females), and 658 nondemented controls (242 males and 416 females).
Setting
Mayo Clinic ADRC and ADPR cohort.
Main Outcome Measures
Diagnostic accuracy estimates (sensitivity, specificity, positive and negative predictive power) of MMSE cut-scores in detecting cognitive dysfunction.
Results
In this sample of highly educated, largely Caucasian older adults, the standard MMSE cut-score of 24 (23 or below) yielded a sensitivity of .66, specificity of .99 and an overall correct classification rate of 89% in detecting dementia. A cut score to 27 (26 or below) resulted in an optimal balance of sensitivity and specificity (.89 and .91, respectively) with an overall correct classification rate of 90%. In a cognitively impaired group (dementia and MCI), a cut-score of 27 (sensitivity = .69, specificity = .91) or 28 (sensitivity and specificity = .78) might be more appropriate.
Conclusion
Elderly patients with college education who present with complaints of cognitive decline (self- or other-report) and score below 27 on the MMSE are at greater risk of being diagnosed with dementia and should be referred for a comprehensive dementia evaluation, including formal neuropsychological testing.
doi:10.1001/archneur.65.7.963
PMCID: PMC2587038  PMID: 18625866
Alzheimer's disease; dementia; Mini-Mental State Examination; diagnosis
24.  The impact of GPX1 on the association of groundwater selenium and depression: a project FRONTIER study 
BMC Psychiatry  2013;13:7.
Background
Prior animal model and human-based studies have linked selenium concentrations to decreased risk for depression; however, this work has not focused on household groundwater levels or specific depressive symptoms. The current study evaluated the link between groundwater selenium levels and depression. We also sought to determine if a functional polymorphism in the glutathione peroxidase 1 (GPX1) gene impacted this link.
Methods
We used a cross-sectional design to analyze data from 585 participants (183 men and 402 women) from Project FRONTIER, a study of rural health in West Texas. Residential selenium concentrations were estimated using Geospatial Information System (GIS) analyses. Linear regression models were created using Geriatric Depression Scale (GDS-30) total and subfactor scores as outcome variables and selenium concentrations as predictor variables. Analyses were re-run after stratification of the sample on GPX1 Pro198Leu genotype (rs1050454).
Results
Selenium levels were significantly and negatively related to all GDS and subfactor scores accounting for up to 17% of the variance beyond covariates. Selenium was most strongly protective against depression among homozygous carriers of the C allele at the Pro198Leu polymorphism of the GPX1 gene. Analyses also point towards a gene-environmental interaction between selenium exposure and GPX1 polymorphism.
Conclusion
Our results support the link between groundwater selenium levels and decreased depression symptoms. These findings also highlight the need to consider the genetics of the glutathione peroxidase system when examining this relationship, as variation in the GPX1 gene is related to depression risk and significantly influences the protective impact of selenium, which is indicative of a gene-environment interaction.
doi:10.1186/1471-244X-13-7
PMCID: PMC3566946  PMID: 23289525
Aging; Depression; Environmental factors; Selenium; GPX1
25.  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.
doi:10.1159/000341780
PMCID: PMC3457029  PMID: 23012618
Granulocyte colony-stimulating factor; Alzheimer's disease; Inflammation; Serum proteins; Mini-Mental State Examination; Clinical Dementia Rating-Sum of Boxes

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