Allison Caban-Holt

University of Kentucky Sanders-Brown Healthy Brain Aging Volunteers: Donor Characteristics, Procedures and Neuropathology

Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.

A randomized controlled Alzheimer’s disease Prevention trial’s evolution into an exposure trial: The Preadvise trial

OBJECTIVES To summarize the ongoing prevention of Alzheimers disease (AD) by vitamin E and selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. DESIGN PREADViSE was designed as a double blind randomized controlled trial (RCT). SETTING SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. PARTICIPANTS In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. INTERVENTION In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2x2 factorial structure. MEASUREMENTS In the RCT, participants completed the memory impairment screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a modified telephone interview of cognitive status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. RESULTS While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. CONCLUSION Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.

Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE)

Importance Oxidative stress is an established dementia pathway, but it is unknown if the use of antioxidant supplements can prevent dementia. Objective To determine if antioxidant supplements (vitamin E or selenium) used alone or in combination can prevent dementia in asymptomatic older men. Design, Setting, and Participants The Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) trial began as a double-blind randomized clinical trial in May 2002, which transformed into a cohort study from September 2009 to May 2015. The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized clinical trial of the same antioxidant supplements for preventing prostate cancer, which closed in 2009 owing to findings from a futility analysis. The PREADViSE trial recruited 7540 men, of whom 3786 continued into the cohort study. Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites, and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms. Interventions Participants were randomized to vitamin E, selenium, vitamin E and selenium, or placebo. While taking study supplements, enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen. During the cohort study, men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment. Main Outcomes and Measures Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information, including a functional assessment screen. Results The mean (SD) baseline age of the 7540 participants was 67.5 (5.3) years, with 3936 (52.2%) reporting a college education or better, 754 (10.0%) reporting black race, and 505 (6.7%) reporting Hispanic ethnicity. Dementia incidence (325 of 7338 men [4.4%]) was not different among the 4 study arms. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% CI, 0.64-1.20) for vitamin E, 0.83 (0.60-1.13) for selenium, and 1.00 (0.75-1.35) for the combination compared with placebo. Conclusions and Relevance Neither supplement prevented dementia. To our knowledge, this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.

Self-reported head injury and risk of late-life impairment and AD pathology in an AD Center cohort

Aims: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimers disease (AD)-type pathological changes. Methods: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. Results: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 for the transition from MCI to dementia. Without respect to age, head injury increased the odds of mortality (OR = 1.54). Moreover, it increased the odds of a pathological diagnosis of AD for men (OR = 1.47) but not women (OR = 1.18). Men with a head injury had higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without. Conclusions: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes.

Practice effects in a longitudinal, multi-center Alzheimer's disease prevention clinical trial

BackgroundPractice effects are a known threat to reliability and validity in clinical trials. Few studies have investigated the potential influence of practice on repeated screening measures in longitudinal clinical trials with a focus on dementia prevention. The current study investigates whether practice effects exist on a screening measure commonly used in aging research, the Memory Impairment Screen (MIS).MethodsThe PREADViSE trial is a clinical intervention study evaluating the efficacy of vitamin E and selenium for Alzheimer’s disease prevention. Participants are screened annually for incident dementia with the MIS. Participants with baseline and three consecutive follow-ups who made less than a perfect score at one or more assessments were included in the current analyses (N=1,803). An additional subset of participants with four consecutive assessments but who received the same version of the MIS at baseline and first follow-up (N=301) was also assessed to determine the effects of alternate forms on mitigating practice. We hypothesized that despite efforts to mitigate practice effects with alternate versions, MIS scores would improve with repeated screening. Linear mixed models were used to estimate mean MIS scores over time.ResultsAmong men with four visits and alternating MIS versions, although there is little evidence of a significant practice effect at the first follow-up, mean scores clearly improve at the second and third follow-ups for all but the oldest participants. Unlike those who received alternate versions, men given the same version at first follow-up show significant practice effects.ConclusionWhile increases in the overall means were small, they represent a significant number of men whose scores improved with repeated testing. Such improvements could bias case ascertainment if not taken into account.

Frontal white matter integrity in adults with Down syndrome with and without dementia

Adults with Down syndrome (DS) are at high risk for developing Alzheimers disease after the age of 40 years. To detect white matter (WM) changes in the brain linked to dementia, fractional anisotropy (FA) from diffusion tensor imaging was used. We hypothesized that adults with DS without dementia (DS n = 10), DS with dementia (DSAD n = 10) and age matched non-DS subjects (CTL n = 10) would show differential levels of FA and an association with scores from the Brief Praxis Test and the Severe Impairment Battery. WM integrity differences in DS compared with CTL were found predominantly in the frontal lobes. Across all DS adults, poorer Brief Praxis Test performance correlated with reduced FA in the corpus callosum as well as several association tracts, primarily within frontoparietal regions. Our results demonstrate significantly lower WM integrity in DS compared with controls, particularly in the frontal tracts. DS-related WM integrity reductions in a number of tracts were associated with poorer cognition. These preliminary results suggest that late myelinating frontal pathways may be vulnerable to aging in DS.

Diagnostic accuracy and practice effects in the National Alzheimer's Coordinating Center Uniform Data Set neuropsychological battery

The Uniform Data Set (UDS) neuropsychological battery is frequently used in clinical studies. However, practice effects, effectiveness as a measure of global cognitive functioning, and detection of mild cognitive impairment have not been examined.

CERAD practice effects and attrition bias in a dementia prevention trial.

BACKGROUND The Consortium to Establish a Registry for Alzheimers Disease (CERAD) set of tests is frequently used for tracking cognition longitudinally in both clinical and research settings. Repeated cognitive assessments are an important component in measuring such changes; however, practice effects and attrition bias may obscure significant clinical change over time. The current study sought to examine the presence and magnitude of practice effects and the role of attrition bias in a sample of cognitively normal older men enrolled in a prevention trial. METHOD Participants were grouped according to whether they completed five years of follow-up (n = 182) or less (n = 126). Practice effects were examined in these participants as a whole (n = 308) and by group. RESULTS Findings indicate that moderate practice effects exist in both groups on the CERAD T-score and that attrition bias likely does not play a contributing role in improved scores over time. CONCLUSION The current study provides additional evidence and support for previous findings that repeated cognitive assessment results in rising test scores in longitudinally collected data and demonstrates that these findings are unlikely to be due to attrition.

A Survey of Affective Computing for Stress Detection: Evaluating technologies in stress detection for better health.

As we become more aware of the connection between emotional states and physical health, affective computing continues to rise as a field of interest. Affective computing uses both hardware and software technology to detect the affective state of a person. It is an active research area that has seen much growth in technology geared toward affective state analysis. Its origin is credited to Dr. Rosalind Picard of the Massachusetts Institute of Technology (MIT) when she published her 1995 article on affective computing [1]. It has since become a modern branch of computer science for human-computer interfaces [2], [3]. This stem of computer science has two main veins: 1) detection and recognition of emotional information and 2) simulation of emotion in computational devices. The focus of the current survey is the detection and recognition of emotions as affective states.

Antioxidants for the prevention of dementia: Overview of the preadvise trial

important in the regulation of a variety of cellular functions, including inflammation. We previously found that overexpressing the M-CSF receptor (M-CSFR; encoded by c-fms) on microglia leads to rescue of neurons from NMDA-induced excitotoxicity. Objectives: We sought to determine if Src signaling mediates M-CSFR-induced neuroprotection. Methods: We examined the effects of M-CSFR overexpression on Src kinase levels and activity. We also tested whether LPS, a potent inflammatory stimulus, activated Src. To determine the specificity of M-CSFR activation of Src, we quantified the activity of the Src-family kinase Lyn. A mutagenesis approach was used to block M-CSFR-induced Src activation, and the effects on microglial neuroprotection were examined. We also tested whether a Src dominant negative (DN) construct would block M-CSFRinduced neuroprotection. Results: Western analysis showed that microglial M-CSFR activation resulted in a greater than 2 fold increase in Src expression, whereas an enzymatic assay showed a greater than 3.5 fold increase in Src kinase activity. Microglia treatment with LPS did affect Src activity. M-CSFR activation had no effect on Lyn activity. In the M-CSFR, tyrosine position c-fms binds Src and induces activation by phosphorylation. Position c-fms, the global c-fms activation site, indirectly affects Src activation. Using co-cultures consisting of microglia overexpressing the M-CSFR and rat organotypic hippocampal cultures subjected to NMDA-induced excitotoxicity, overexpression of the Y559F or Y807F c-fms mutant constructs in microglia resulted in a loss of neurprotection. Similarly, microglial expression of a Src DN form resulted in loss of M-CSFR-induced neuroprotection, and also inhibited microglial proliferation. Increasing the number of microglia expressing the Src DN form in co-culture only partially restored neuroprotection. Adding exogenous MCSF also partially restored neuroprotection by Src DN-treated microglia in co-cultures. Conclusions: Our results show that the Src signal transduction pathway is important in microglial neuroprotection. Identification of downstream Src kinase targets in microglia could lead to new pharmacological treatments for AD (Funding: Alzheimer’s Association and NIH MH57833).