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1.  Validation of a serum screen for Alzheimer’s disease across assay platforms, species and tissues 
Journal of Alzheimer's disease : JAD  2014;42(4):1325-1335.
Background
There is a significant need for rapid and cost-effective biomarkers of Alzheimer’s disease (AD) for advancement of clinical practice and therapeutic trials.
Objective
The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson’s Disease).
Methods
Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were analyzed from 49 Parkinson’s disease (PD) cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD vs. AD vs. NC. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD.
Results
Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi-marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90–100% of the samples. SVM analyses were highly accurate at distinguishing PD vs. AD vs. NC.
Conclusions
This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers.
doi:10.3233/JAD-141041
PMCID: PMC4400808  PMID: 25024345
Alzheimer’s Disease; blood-based biomarkers; tissue; species; serum
2.  MANUSCRIPT IN PRESS: DEMENTIA & GERIATRIC COGNITIVE DISORDERS 
Background
Prior work on the link between blood-based biomarkers and cognitive status has largely been based on dichotomous classifications rather than detailed neuropsychological functioning. The current project was designed to create serum-based biomarker algorithms that predict neuropsychological test performance.
Methods
A battery of neuropsychological measures was administered. Random forest analyses were utilized to create neuropsychological test-specific biomarker risk scores in a training set that were entered into linear regression models predicting the respective test scores in the test set. Serum multiplex biomarker data were analyzed on 108 proteins from 395 participants (197 AD cases and 198 controls) from the Texas Alzheimer’s Research and Care Consortium.
Results
The biomarker risk scores were significant predictors (p<0.05) of scores on all neuropsychological tests. With the exception of premorbid intellectual status (6.6%), the biomarker risk scores alone accounted for a minimum of 12.9% of the variance in neuropsychological scores. Biomarker algorithms (biomarker risk scores + demographics) accounted for substantially more variance in scores. Review of the variable importance plots indicated differential patterns of biomarker significance for each test, suggesting the possibility of domain-specific biomarker algorithms.
Conclusions
Our findings provide proof-of-concept for a novel area of scientific discovery, which we term “molecular neuropsychology.”
doi:10.1159/000345605
PMCID: PMC4400831  PMID: 24107792
Neuropsychology; Biomarkers; Algorithms; Molecular; Psychology
3.  Risk factors for mild cognitive impairment among Mexican Americans 
Background
While a great deal of literature has focused on risk factors for Mild Cognitive Impairment (MCI), little published work examines risk for MCI among Mexican Americans.
Methods
Data from 1628 participants (non-Hispanic n= 1002; Mexican American n=626) were analyzed from two ongoing studies of cognitive aging and Alzheimer’s disease, Project FRONTIER and TARCC.
Results
When looking at the full cohorts (non-Hispanic and Mexican American), age, education, APOE ε4 status and gender were consistently related to MCI diagnosis across the two cohorts. However, when split by ethnicity advancing age was the only significant risk factor for MCI among Mexican Americans across both cohorts.
Conclusions
The current data suggests that many of the previously established risk factors for MCI among non-Hispanic cohorts may not be predictive of MCI among Mexican Americans and point to the need for additional work aimed at understanding factors related to cognitive aging among this underserved segment of the population.
doi:10.1016/j.jalz.2012.12.007
PMCID: PMC3737282  PMID: 23643456
Mexican American; Mild Cognitive Impairment; cognition; Alzheimer’s disease; ethnicity; cross-cultural; risk factors
4.  A Brief Spanish-English Equivalent Version of the Boston Naming Test: A Project FRONTIER Study 
The Boston Naming Test is a neuropsychological measure of confrontation naming, short forms of which can be advantageous with various populations. The purpose of this study was to establish a Spanish-English equivalent version of the BNT using item response theory. Data were analyzed from 380 Project FRONTIER participants; 27 items differed between groups and were removed from the measure. Additionally, 18 items did not differ between groups but were poor items. The current 15-item Spanish-English equivalent version of the BNT offers significant advantages. Future work is required to validate the diagnostic utility of the instrument in various settings and populations.
doi:10.1080/13803395.2013.825234
PMCID: PMC3789857  PMID: 23998641
Confrontation naming; Item response theory; Language of administration; Boston Naming Test; Hispanic
5.  Normative Performance on the CLOX Task in a Multi-Ethnic Bilingual Cohort: A Project FRONTIER Study 
The CLOX test is a neuropsychological measure intended to aid in the assessment and detection of dementia in elderly populations. Few studies have provided normative data for this measure, with even less research available regarding the impact of socio-demographic factors on test scores. This study presents normative data for the CLOX in a sample of English- and Spanish-speaking Hispanic and non-Hispanic Whites. The total sample included 445 cognitively healthy older adults seen as part of an ongoing study of rural cognitive aging, Project FRONTIER. Unlike previous studies, criteria for “normality” (i.e., unimpaired) for CLOX1 and CLOX2 were based not merely on global impairment, but also on domain-specific impairment of executive functioning on the EXIT25 and/or Trail Making Test B (Trails B), or visuospatial/constructional impairment on the Line Orientation and Figure Copy subtests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. Hierarchical regression analyses revealed that CLOX1 scores require adjustment by Age across ethnicities, while Education and Gender are necessary stratification markers for CLOX1 performance only in non-Hispanic Whites. None of the demographic variables were valid predictors of CLOX2 performance, negating the need for such adjustments. In addition to being the first study to provide separate normative data for CLOX performance in Hispanic and non-Hispanic White samples, the current study offers a novel approach to defining “normal” by cognitive domain. We also highlight the need to directly examine the impact of socio-demographic factors before applying normative corrections based on factors that have negligible impact on test scores.
doi:10.1002/gps.2810
PMCID: PMC4142441  PMID: 22052628
Executive functioning; visuospatial skills; norms; geriatrics; cognition
6.  Normative Performance on the Brief Smell Identification Test (BSIT) in a Multi-Ethnic Bilingual Cohort: A Project FRONTIER Study 
The Clinical neuropsychologist  2013;27(6):946-961.
The Brief Smell Identification Test (BSIT) is a commonly used measure of olfactory functioning in elderly populations. Few studies have provided normative data for this measure, and minimal data are available regarding the impact of sociodemographic factors on test scores. This study presents normative data for the BSIT in a sample of English- and Spanish-speaking Hispanic and non-Hispanic Whites. A Rasch analysis was also conducted to identify the items that best discriminated between varying levels of olfactory functioning, as measured by the BSIT. The total sample included 302 older adults seen as part of an ongoing study of rural cognitive aging, Project FRONTIER. Hierarchical regression analyses revealed that BSIT scores require adjustment by age and gender, but years of education, ethnicity, and language did not significantly influence BSIT performance. Four items best discriminated between varying levels of smell identification, accounting for 59.44% of total information provided by the measure. However, items did not represent a continuum of difficulty on the BSIT. The results of this study indicate that the BSIT appears to be well-suited for assessing odor identification deficits in older adults of diverse backgrounds, but that fine-tuning of this instrument may be recommended in light of its items’ difficulty and discrimination parameters. Clinical and empirical implications are discussed.
doi:10.1080/13854046.2013.796406
PMCID: PMC3742676  PMID: 23634698
Olfactory functioning; norms; geriatrics; cognition
7.  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
8.  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
9.  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
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.  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
14.  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
15.  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
16.  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
17.  Total Cholesterol and Neuropsychiatric Symptoms in Alzheimer's Disease: the Impact of Level and Gender 
Background
Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are a major factor in nursing home placement and a primary cause of stress for caregivers. Elevated cholesterol has been linked to psychiatric disorders and has been shown to be a risk factor for AD and to impact disease progression. The present study investigated the relationship been cholesterol and NPS in AD.
Methods
Data on cholesterol and NPS from 220 individuals (144 females, 76 males) with mild to moderate AD from the TARCC (Texas Alzheimer's Research and Care Consortium) cohort was analyzed. Total number of NPS, symptoms of hyperactivity, psychosis, affect and apathy were evaluated. Groups based on total cholesterol (TC) above and below 200 were compared on NPS. The impact of gender was also assessed.
Results
Individuals with high TC had lower MMSE and significantly more NPS and more symptoms of psychosis. When stratified by gender males with high TC had significantly more NPS than high TC females or low TC males or females.
Discussion
The role of elevated cholesterol in the occurrence of NPS in AD appears gender and symptom specific. Cross validation of these findings has implications for interventions especially for males with high TC.
doi:10.1159/000361043
PMCID: PMC4201880  PMID: 25011444
Cholesterol; Neuropsychiatric Symptoms; Alzheimer's Disease
18.  The Hachinski Ischemic Scale and cognition: the influence of ethnicity 
Age and Ageing  2013;43(3):364-369.
Objective: cardiovascular burden is considered a risk factor for the development of cognitive dysfunction and dementia. While this link is well established in the literature, implementing this work in primary care settings remains a challenge. The goal of this study is to examine the utility of the Hachinski Ischemic Scale (HIS) in identifying cognitive dysfunction and diagnosis of mild cognitive impairment (MCI) in an ethnically diverse sample.
Methods: data were analysed on 517 participants (211 Mexican Americans and 306 non-Hispanic Whites) recruited from Project FRONTIER, a study of rural health. Neuropsychological measures were utilised to assess for cognitive functioning.
Results: among non-Hispanic Whites, HIS scores were significantly related to poorer performance on tasks of global cognition [B (SE) = −0.13 (0.06), P = 0.02], immediate memory [B (SE) = −0.85 (0.26), P < 0.001], attention [B (SE) = −1.6 (0.36), P < 0.001] and executive functioning [B (SE) = 0.46 (0.12), P < 0.001], and significantly predicted diagnosis of MCI [odds ratio (OR) = 1.4; 95% confidence interval (CI) = 1.2–1.6]. For Mexican Americans, HIS scores were significantly related to immediate memory [B (SE) = −0.78 (0.28), P = 0.01], attention [B (SE) = −0.74 (0.36), P = 0.04] and executive functioning [B (SE) = 0.37 (0.14), P = 0.01]; however, HIS scores were not significantly related to diagnosis of MCI in Mexican Americans (OR = 1.2, 95% CI = 0.96–1.4, P = 0.116).
Conclusion: HIS scores were related to cognitive functioning; however, these results differed by ethnicity. It is possible that these findings indicate that vascular factors may increase risk for MCI among non-Hispanic Whites but not for Mexican Americans. These findings are consistent with past research that suggests risk factors for MCI may differ by ethnicity.
doi:10.1093/ageing/aft189
PMCID: PMC4001171  PMID: 24321843
Hachinski Ischemic Scale; Mexican American; Cognition; Ethnic differences; Older people
19.  Total testosterone and neuropsychiatric symptoms in elderly men with Alzheimer’s disease 
Introduction
There 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.
Methods
The 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 ≤2.5 ng/ml; n = 44) and a borderline/normal group (TT ≥2.6 ng/ml; n = 43).
Results
TT 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) = 5.56), delusions (OR = 3.87), motor activity (OR = 3.13) and irritability (OR = 2.77) than the low-testosterone group. Health status and apolipoprotein E ε4 status were not significant factors.
Conclusions
The 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.
doi:10.1186/s13195-015-0107-4
PMCID: PMC4416299  PMID: 25937840
20.  The future of blood-based biomarkers for Alzheimer’s disease 
Treatment of Alzheimer’s disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood– brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
doi:10.1016/j.jalz.2013.01.013
PMCID: PMC4128378  PMID: 23850333
21.  Oxidative stress, testosterone, and cognition among Caucasian and Mexican American men with and without Alzheimer’s disease 
Background
The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy (TRT) have been equivocal.
Objective
Given our prior pre-clinical studies that reported a major influence of oxidative stress (OS) on testosterone’s neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load.
Methods
In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone (LH) correlated with cognition in a subset of the Texas Alzheimer’s Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n=116) and Mexican-American (n=117) men. We also assessed whether OS (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 (SOD), and glutathione S-transferase (GST) varied as a function of circulating testosterone.
Results
In a low OS environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high OS (homocysteine levels >12 μM), testosterone and LH were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans.
Conclusion
While testosterone may be beneficial under conditions of low OS, testosterone appears to have negative consequences under conditions of elevated OS, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.
doi:10.3233/JAD-131994
PMCID: PMC4219556  PMID: 24496073
androgens; homocysteine; Mexican American; antioxidants; luteinizing hormone
22.  Arsenic exposure, AS3MT polymorphism, and neuropsychological functioning among rural dwelling adults and elders: a cross-sectional study 
Environmental Health  2014;13:15.
Background
The aim was to examine the link between low-level arsenic exposure and cognitive functioning, and the potential role of a single nucleotide polymorphism (SNP A35991G, rs10748835) of the AS3MT gene in modifying this link.
Methods
Data were analyzed on 526 participants from Project FRONTIER. Hierarchical linear regressions were created with neuropsychological raw index scores as the outcome variable and arsenic exposure and AS3MT SNP as different predictor variables.
Results
Within the total sample, arsenic exposure was negatively associated with language (p < 0.001) and executive functioning (p < 0.001). Among those with the AA genotype of the AS3MT gene, arsenic levels were negatively associated with language (p < 0.001), attention (p = 0.01), and executive functioning (p = 0.04). Among those with the AG genotype, arsenic levels were positively associated with immediate (p = 0.04) and delayed memory (p < 0.001) and negatively associated with executive functioning (p = 0.03). Among those with the GG genotype, arsenic levels were negatively associated with visuospatial functioning (p = 0.02).
Conclusions
Low-level arsenic exposure is associated with cognitive functioning; however, this association is modified by an AS3MT gene.
doi:10.1186/1476-069X-13-15
PMCID: PMC4234288  PMID: 24621105
Arsenic; AS3MT; Neuropsychology; Cognition
23.  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
24.  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
25.  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

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