Cognitive and Cerebrospinal Fluid Alzheimer's Disease-related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls.

BACKGROUND: Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults. METHODS: The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid ß (Aß) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls. RESULTS: The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aß, tau, or p-tau levels, or tau/Aß or p-tau/Aß ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (ß, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up. CONCLUSIONS: During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aß) changes or greater cognitive decline.

Scheltens ratings, clinical white matter hyperintensities and executive functioning in the Cache County Memory Study.

OBJECTIVE: Examine the association between neuropsychologically assessed executive function and clinically identifiable white matter burden from magnetic resonance imaging, using a visual rating system (Scheltens Rating System) applied to the Cache County Memory Study (CCMS) archival database. METHOD: We used the Scheltens Ratings Scale to quantify white matter lesion burden in the CCMS sample and used this metric as a predictor of executive function. The sample included 60 individuals with dementia and 13 healthy controls. RESULTS: Higher Scheltens ratings were associated with poorer task performance on an Executive Function composite score of common neuropsychological tests. This association held true for both controls and dementing cases. CONCLUSIONS: The current findings support extensive prior literature demonstrating the association between brain vascular health determined by white matter burden and clinical outcomes based on neuropsychological assessment of cognitive performance.

Decision making in clinical trials: Interim analyses, innovative design, and biomarkers.

The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease-modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1-2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies.

TOMM40 '523 Genotype Distinguishes Patterns of Cognitive Improvement for Executive Function in APOEɛ3 Homozygotes.

BACKGROUND: TOMM40 '523 has been associated with cognitive performance and risk for developing Alzheimer's disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. OBJECTIVE: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 '523 for genetic risk for conversion to mild cognitive impairment. METHODS: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. RESULTS: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = -0.088, p = 0.034) and for the executive function domain score (B = -0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. CONCLUSIONS: Our results add to the growing body of evidence that TOMM40, in the absence of APOEɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer's disease risk.

Influence of mild cognitive impairment on patient and care partner decision-making for acute ischemic stroke.

GOALS: Evidence suggests that patients with mild cognitive impairment (MCI) receive fewer treatments for acute ischemic stroke and other cardiovascular diseases than patients with normal cognition. Little is known about how patient and care partner preferences for ischemic stroke treatment differ between the patient population with MCI and the population with normal cognition. This study aimed to understand how patient MCI diagnosis influences patient and care partner decision-making for acute ischemic stroke treatments. METHODS: Multi-center qualitative study using in-person semi-structured interviews with 20 MCI and normal cognition patient-care partner dyads using a standard guide. The present study reports results on patient and care partner preferences for a clinical vignette patient to receive three non-invasive treatments (intravenous tissue plasminogen activator, inpatient rehabilitation, and secondary preventive medications) and two invasive treatments (feeding tube and carotid endarterectomy) after acute ischemic stroke. We used qualitative content analysis to identify themes. FINDINGS: We identified three major themes: (1) Patients with MCI desired non-invasive treatments after stroke, similar to patients with normal cognition and for similar reasons; (2) Patients with MCI expressed different preferences than patients with normal cognition for two invasive treatments after stroke: carotid endarterectomy and feeding tube placement; and (3) Patients with MCI expressed more skepticism of the stroke treatment options and less decisiveness in decision-making than patients with normal cognition. CONCLUSIONS: These results suggest that patient MCI diagnosis may contribute to differences in patient and care partner preferences for invasive treatments after stroke, but not for non-invasive treatments.

Feasibility of a standard cognitive assessment in European academic memory clinics.

INTRODUCTION: Standardized cognitive assessment would enhance diagnostic reliability across memory clinics. An expert consensus adapted the Uniform Dataset (UDS)-3 for European centers, the clinician's UDS (cUDS). This study assessed its implementation acceptability and feasibility. METHODS: We developed a survey investigating barriers, facilitators, and willingness to implement the cUDS. With a mixed-methods design, we analyzed data from academic memory clinics. RESULTS: Seventy-eight percent of responding clinicians were experienced neuropsychologists/psychologists and 22% were medical specialists coming from 18 European countries. Sixty-five percent clinicians were willing to implement cUDS. General barriers related to implementation (43%) and clinical-methodological domains (21%). Favorable clinicians reported finances (15%) and digitalization (9%) as facilitating, but unavailability of local norms (23%) as hindering. Unfavorable clinicians reported logistical (23%) and time issues (18%). DISCUSSION: Despite challenges, data showed moderate clinicians' acceptability and requirements to improve feasibility. Nonetheless, these results come from academic clinicians. The next steps will require feasibility evaluation in non-academic contexts.

Remote self-administration of digital cognitive tests using the Brief Assessment of Cognition: Feasibility, reliability, and sensitivity to subjective cognitive decline.

Cognitive impairment is a common and pervasive feature of etiologically diverse disorders of the central nervous system, and a target indication for a growing number of symptomatic and disease modifying drugs. Remotely acquired digital endpoints have been recognized for their potential in providing frequent, real-time monitoring of cognition, but their ultimate value will be determined by the reliability and sensitivity of measurement in the populations of interest. To this end, we describe initial validation of remote self-administration of cognitive tests within a regulatorily compliant tablet-based platform. Participants were 61 older adults (age 55+), including 20 individuals with subjective cognitive decline (SCD). To allow comparison between remote (in-home) and site-based testing, participants completed 2 testing sessions 1 week apart. Results for three of four cognitive domains assessed demonstrated equivalence between remote and site-based tests, with high cross-modality ICCs (absolute agreement) for Symbol Coding (ICC = 0.75), Visuospatial Working Memory (ICC = 0.70) and Verbal Fluency (ICC > 0.73). Group differences in these domains were significant and reflected sensitivity to objective cognitive impairment in the SCD group for both remote and site-based testing (p < 0.05). In contrast, performance on tests of verbal episodic memory suggested inflated performance during unmonitored testing and indicate reliable use of remote cognitive assessments may depend on the construct, as well as the population being tested.

Putting participants and study partners FIRST when clinical trials end early.

Between 2018 and 2019, multiple clinical trials ended earlier than planned, resulting in calls to improve communication with and support for participants and their study partners ("dyads"). The multidisciplinary Participant Follow-Up Improvement in Research Studies and Trials (Participant FIRST) Work Group met throughout 2021. Its goals were to identify best practices for communicating with and supporting dyads affected by early trial stoppage. The Participant FIRST Work Group identified 17 key recommendations spanning the pre-trial, mid-trial, and post-trial periods. These focus on prospectively allocating sufficient resources for orderly closeout; developing dyad-centered communication plans; helping dyads build and maintain support networks; and, if a trial stops, informing dyads rapidly. Participants and study partners invest time, effort, and hope in their research participation. The research community should take intentional steps toward better communicating with and supporting participants when clinical trials end early. The Participant FIRST recommendations are a practical guide for embarking on that journey.

Acoustofluidic multimodal diagnostic system for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative brain disorder that affects tens of millions of older adults worldwide and has significant economic and societal impacts. Despite its prevalence and severity, early diagnosis of AD remains a considerable challenge. Here we report an integrated acoustofluidics-based diagnostic system (ADx), which combines triple functions of acoustics, microfluidics, and orthogonal biosensors for clinically accurate, sensitive, and rapid detection of AD biomarkers from human plasma. We design and fabricate a surface acoustic wave-based acoustofluidic separation device to isolate and purify AD biomarkers to increase the signal-to-noise ratio. Multimodal biosensors within the integrated ADx are fabricated by in-situ patterning of the ZnO nanorod array and deposition of Ag nanoparticles onto the ZnO nanorods for surface-enhanced Raman scattering (SERS) and electrochemical immunosensors. We obtain the label-free detections of SERS and electrochemical immunoassay of clinical plasma samples from AD patients and healthy controls with high sensitivity and specificity. We believe that this efficient integration provides promising solutions for the early diagnosis of AD.

Assessment of Neuropsychological Function in Veterans With Blast-Related Mild Traumatic Brain Injury and Subconcussive Blast Exposure.

Objective: The majority of combat-related head injuries are associated with blast exposure. While Veterans with mild traumatic brain injury (mTBI) report cognitive complaints and exhibit poorer neuropsychological performance, there is little evidence examining the effects of subconcussive blast exposure, which does not meet clinical symptom criteria for mTBI during the acute period following exposure. We compared chronic effects of combat-related blast mTBI and combat-related subconcussive blast exposure on neuropsychological performance in Veterans. Methods: Post-9/11 Veterans with combat-related subconcussive blast exposure (n = 33), combat-related blast mTBI (n = 26), and controls (n = 33) without combat-related blast exposure, completed neuropsychological assessments of intellectual and executive functioning, processing speed, and working memory via NIH toolbox, assessment of clinical psychopathology, a retrospective account of blast exposures and non-blast-related head injuries, and self-reported current medication. Huber Robust Regressions were employed to compare neuropsychological performance across groups. Results: Veterans with combat-related blast mTBI and subconcussive blast exposure displayed significantly slower processing speed compared with controls. After adjusting for post-traumatic stress disorder and depressive symptoms, those with combat-related mTBI exhibited slower processing speed than controls. Conclusion: Veterans in the combat-related blast mTBI group exhibited slower processing speed relative to controls even when controlling for PTSD and depression. Cognition did not significantly differ between subconcussive and control groups or subconcussive and combat-related blast mTBI groups. Results suggest neurocognitive assessment may not be sensitive enough to detect long-term effects of subconcussive blast exposure, or that psychiatric symptoms may better account for cognitive sequelae following combat-related subconcussive blast exposure or combat-related blast mTBI.

Recruitment of a multi-site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial.

INTRODUCTION: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking. METHODS: Recruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants. RESULTS: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age- and geo-targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations. DISCUSSION: Age- and geo-targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18-month exercise trial.

Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. FINDINGS: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. INTERPRETATION: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. FUNDING: Takeda and Zinfandel.

Differentiating among stages of cognitive impairment in aging: Version 3 of the Uniform Data Set (UDS) neuropsychological test battery and MoCA index scores.

INTRODUCTION: Federally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1. METHODS: First, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver-operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests. RESULTS: Some V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants. DISCUSSION: Further efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required.

Metabolic and Neurocognitive Changes Following Lifestyle Modification: Examination of Biomarkers from the ENLIGHTEN Randomized Clinical Trial.

BACKGROUND: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. OBJECTIVE: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. METHODS: ENLIGHTEN participants were randomized using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). RESULTS: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d = 0.48, p = 0.015) and DASH improved metabolic function (d = 0.37, p = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = -2.3 [-4.3, -0.2], p = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7], p = 0.004), associated with increases in Executive Function. CONCLUSION: Changes in neurocognition after lifestyle modification are associated with improved metabolic function.

Racially diverse participant registries to facilitate the recruitment of African Americans into presymptomatic Alzheimer's disease studies.

INTRODUCTION: The Alzheimer's Disease Prevention Registry (ADPR) of the Joseph and Kathleen Bryan Alzheimer's Disease Research Center at Duke University has been successful in achieving a racially diverse and "research ready" cohort of cognitively healthy volunteers. METHODS: The ADPR is based on an infrastructure that includes: (1) an administrative leadership team; (2) a coordinating center; (3) an IT management team; (4) a community engagement team; and (5) collaborations with study partners across disciplines. RESULTS: The ADPR currently has more than 4677 members, 26% of whom are African American. The ADPR has supported 21 studies including 8 biomarker studies, 7 clinical trials, 4 cognitive neuroscience studies, and 2 studies assessing novel computerized measures. DISCUSSION: We describe our experiences establishing and maintaining a diverse ADPR as well as insights on recruitment strategies to increase the representation of African Americans in Alzheimer's disease studies.

The TOMMORROW study: Design of an Alzheimer's disease delay-of-onset clinical trial.

INTRODUCTION: Alzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. METHODS: The TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. RESULTS: The focus of this paper is on the design of the study; study results will be presented in a separate paper. DISCUSSION: The design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials.

Association Between Insulin Resistance, Plasma Leptin, and Neurocognition in Vascular Cognitive Impairment.

BACKGROUND: Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. OBJECTIVE: To examine metabolic mechanisms underlying the association between obesity and neurocognition. METHODS: We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. RESULTS: Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p = 0.043), CRP (p < 0.001), and leptin (p < 0.001) compared with men. Higher BMI levels were associated with worse performance on measures of Executive Function (ß= -0.16, p = 0.024) and Verbal Memory (ß= -0.16, p = 0.030), but not Visual Memory (ß= 0.05, p = 0.500). Worse metabolic biomarker profiles also were associated with lower Executive Function (ß= -0.12, p = 0.050). Mediation analyses suggested leptin was a plausible candidate as a mediator between BMI and Executive Function. CONCLUSIONS: In overweight and obese adults with vascular CIND, the association between greater weight and poorer executive function may be mediated by higher leptin resistance.

Effects of pioglitazone on mnemonic hippocampal function: A blood oxygen level-dependent functional magnetic resonance imaging study in elderly adults.

INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. METHODS: Using a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face-name pairs. RESULTS: Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face-name pairs at day 7 and day 14, relative to baseline. DISCUSSION: Our exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.