Sid E. O’Bryant

Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores: A Texas Alzheimer's Research Consortium Study

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. OBJECTIVE To investigate the effectiveness of CDR-SOB scores in staging dementia severity compared with the global CDR score. DESIGN Retrospective study. SETTING Texas Alzheimers 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 1.0, 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, kappa 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.

The future of blood-based biomarkers for Alzheimer's disease

Treatment of Alzheimers 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.

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.

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.

Specificity of malingering detection strategies in older adults using the CVLT and WCST.

Strategies for the detection of possible malingering have largely taken two forms. First is the development and validation of domain-specific measures of malingering designed specifically for the detection of malingering (e.g., Test Of Memory Malingering, Word Memory Test, and Word Completion Memory Test). The second has been the development and evaluation of performance patterns and cutoff scores applicable to commonly used neuropsychological instruments. Two such instruments that have been examined are the Wisconsin Card Sorting Test (WCST) and the California Verbal Learning Test (CVLT). While several studies propose possible cutoff scores and actuarial judgement strategies for these tests, the specificity of these strategies within older, nonimpaired adults has not been established. Without proper evaluation of potential age-related effects within these strategies, the actual utility of the strategies within suspected malingerers who are older adults is unknown. Therefore, the present study was conducted to evaluate the specificity of the proposed strategies for detecting possible malingering with the WCST and the CVLT in a sample of older, community-dwelling, nonimpaired adults. The results suggest that the currently existing WCST formulas may have limited utility for the detection of malingering with older adults while the CVLT strategies do appear to have potential clinical utility. The potential of these formulas for use with older adults is discussed.

The impact of GPX1 on the association of groundwater selenium and depression: a project FRONTIER study

BackgroundPrior 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.MethodsWe 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).ResultsSelenium 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.ConclusionOur 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.

Arsenic exposure, AS3MT polymorphism, and neuropsychological functioning among rural dwelling adults and elders: a cross-sectional study.

BackgroundThe 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.MethodsData 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.ResultsWithin 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).ConclusionsLow-level arsenic exposure is associated with cognitive functioning; however, this association is modified by an AS3MT gene.

Normative performance on the Brief Smell Identification Test (BSIT) in a multi-ethnic bilingual cohort: a Project FRONTIER study.

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.

A Depressive Endophenotype of Mild Cognitive Impairment and Alzheimer’s Disease

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.

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

BACKGROUND The 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. OBJECTIVE The 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. METHODS AND RESULTS Analyses 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] = 3.008; 95% CI = 1.358-6.667), age (OR = 1.138; 95% CI = 1.093-1.185), and education (OR = 0.915; 95% CI = 0.852-0.982) 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 (OR = 18.795; 95% CI = 2.229-158.485) and Mexican Americans (OR = 8.417; 95% CI = 2.967-23.878). Finally, results in the FRONTIER cohort showed that in elderly Mexican Americans, comorbidity (OR = 2.754; 95% CI = 1.084-6.995) and age (OR = 1.069; 95% CI = 1.023-1.118) significantly increased risk of MCI. In non-Hispanic whites, comorbidity did not significantly increase risk of MCI. CONCLUSIONS Among 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.