Mark A. Reger

INTRANASAL INSULIN IMPROVES COGNITION AND MODULATES β-AMYLOID IN EARLY AD

Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, β-amyloid, and cortisol. Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42), resulting in an increased Aβ40/42 ratio (p = 0.0207). Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Preserved Cognition in Patients With Early Alzheimer Disease and Amnestic Mild Cognitive Impairment During Treatment With Rosiglitazone A Preliminary Study

OBJECTIVE Insulin resistance (impaired insulin action) has been associated with Alzheimer disease (AD) and memory impairment, independent of AD. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists improve insulin sensitivity and regulate in-vitro processing of the amyloid precursor protein (APP). Authors evaluated the effects of the PPAR-gamma agonist rosiglitazone on cognition and plasma levels of the APP derivative beta-amyloid (Abeta) in humans. METHODS In a placebo-controlled, double-blind, parallel-group pilot study, 30 subjects with mild AD or amnestic mild cognitive impairment were randomized to a 6-month course of rosiglitazone (4 mg daily; N = 20) or placebo (N = 10). Primary endpoints were cognitive performance and plasma Abeta levels. RESULTS Relative to the placebo group, subjects receiving rosiglitazone exhibited better delayed recall (at Months 4 and 6) and selective attention (Month 6). At Month 6, plasma Abeta levels were unchanged from baseline for subjects receiving rosiglitazone but declined for subjects receiving placebo, consistent with recent reports that plasma Abeta42 decreases with progression of AD. CONCLUSIONS Findings provide preliminary support that rosiglitazone may offer a novel strategy for the treatment of cognitive decline associated with AD. Future confirmation in a larger study is needed to fully demonstrate rosiglitazones therapeutic potential.

Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimers disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.

Intranasal Insulin Administration Dose-Dependently Modulates Verbal Memory and Plasma Amyloid-β in Memory-Impaired Older Adults

Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimers disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.

A meta-analysis of the neuropsychological sequelae of HIV infection

This meta-analysis summarizes the broad spectrum of neuropsychological research on HIV disease across a sample of 41 primary studies and an aggregate of 8,616 participants for 10 major neuropsychological ability areas. Analyses of the course of cognitive decline within and across Centers for Disease Control classifications reveals statistically significant cognitive deficits from asymptomatic HIV to AIDS. Effect sizes (Cohen, 1988) were calculated to reflect between-group (asymptomatic, symptomatic, AIDS) differences in each neuropsychological domain. Relatively small effect sizes were obtained for the asymptomatic (0.05-0.21) patients, and generally small to moderate effect sizes were obtained for symptomatic (0.18-0.65) HIV+ patients, with motor functioning exhibiting the greatest effects in this later disease stage. The most notable deficits in cognitive functioning were found in the AIDS group with moderate (attention and concentration) to large (motor functioning) effect sizes with values ranging from 0.42-0.82. Comparison of cognitive functioning as a function of disease progression revealed that motor functioning, executive skills, and information processing speed were among the cognitive domains showing the greatest decline from early to later stages of HIV. These findings indicate that cognitive deficits in the early stages of HIV are small and increase in the later phases of the illness, and that specific patterns of cognitive deficits can be detected with disease progression. These results and their clinical utility are further discussed.

The relationship between neuropsychological functioning and driving ability in dementia: a meta-analysis.

A meta-analysis of 27 primary studies was conducted to examine the relationship between neuropsychological functioning and driving ability for adults with dementia. When studies using a control group were included, the relationship between cognitive measures and on-road or non-road driving measures was significant for all reported domains; mean correlations ranged from.35 to.65. Caregiver reports of driving ability and cognitive variables were correlated significantly only on measures of mental status and visuospatial skills. When studies using a control group were excluded, moderate mean correlations were observed for visuospatial skills and on-road or non-road measures, and for mental status with non-road tests. Other effects were small or nonsignificant. Implications for basing driving recommendations on neuropsychological testing are discussed.

Effects of β-hydroxybutyrate on cognition in memory-impaired adults

Glucose is the brains principal energy substrate. In Alzheimers disease (AD), there appears to be a pathological decrease in the brains ability to use glucose. Neurobiological evidence suggests that ketone bodies are an effective alternative energy substrate for the brain. Elevation of plasma ketone body levels through an oral dose of medium chain triglycerides (MCTs) may improve cognitive functioning in older adults with memory disorders. On separate days, 20 subjects with AD or mild cognitive impairment consumed a drink containing emulsified MCTs or placebo. Significant increases in levels of the ketone body beta-hydroxybutyrate (beta-OHB) were observed 90 min after treatment (P=0.007) when cognitive tests were administered. beta-OHB elevations were moderated by apolipoprotein E (APOE) genotype (P=0.036). For 4+ subjects, beta-OHB levels continued to rise between the 90 and 120 min blood draws in the treatment condition, while the beta-OHB levels of 4- subjects held constant (P<0.009). On cognitive testing, MCT treatment facilitated performance on the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-cog) for 4- subjects, but not for 4+ subjects (P=0.04). Higher ketone values were associated with greater improvement in paragraph recall with MCT treatment relative to placebo across all subjects (P=0.02). Additional research is warranted to determine the therapeutic benefits of MCTs for patients with AD and how APOE-4 status may mediate beta-OHB efficacy.

A meta-analysis of the effects of Internet- and computer-based cognitive-behavioral treatments for anxiety

Internet-and computer-based cognitive-behavioral treatments have been introduced as novel approaches to deliver standard, quality treatment that may reduce barriers to care. The purpose of this review is to quantitatively summarize the literature examining the treatment effects of Internet- or computer-based treatment (ICT) on anxiety. Nineteen randomized controlled ICT trials were identified and subjected to fixed and random effects meta-analytic techniques. Weighted mean effect sizes (Cohens d) showed that ICT was superior to waitlist and placebo assignment across outcome measures (ds=.49-1.14). The effects of ICT also were equal to therapist-delivered treatment across anxiety disorders. However, conclusions were limited by small sample sizes, the rare use of placebo controls, and other methodological problems. In addition, the number of available studies limited the opportunity to conduct analyses by diagnostic group; there was preliminary support for the use of ICT for panic disorder and phobia. Large, well-designed, placebo-controlled trials are needed to confirm and extend the results of this meta-analysis.

Association between number of deployments to Iraq and mental health screening outcomes in US Army soldiers.

OBJECTIVE High rates of mental health concerns have been documented in US Army soldiers deployed in support of Operation Iraqi Freedom. The goal of this study was to compare the postdeployment mental health screening results of US Army soldiers with 1 or 2 deployments to Iraq. METHOD Routine mental health screening data collected from September 7, 2005, to April 27, 2007, in the Soldier Wellness Assessment Program were compared between soldiers evaluated after their first or second deployment to Iraq (n=1322). Standardized measures (Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, Primary Care Posttraumatic Stress Disorder Screen, Alcohol Use Disorders Identification Test) were used to screen for posttraumatic stress disorder (PTSD), panic, other anxiety, major depression, other depression, and hazardous alcohol consumption 90 to 180 days after the soldiers returned from Iraq. RESULTS There was a significant association between number of deployments and mental health screening results such that soldiers with 2 deployments showed greater odds of screening positive for PTSD (odds ratio [OR]=1.64, P=.001). Similar results were observed when the analyses were repeated utilizing a more conservative cut-point for PTSD (OR=1.60, P=.001). After adjustment for demographic characteristics, the results were unchanged. There was no association between the number of deployments and other mental health screening results. CONCLUSIONS These results provide preliminary evidence that multiple deployments to Iraq may be a risk factor for PTSD. However, these cross-sectional data require replication in a longitudinal study.

Suicide risk among 1.3 million veterans who were on active duty during the Iraq and Afghanistan wars

PURPOSE We conducted a retrospective cohort mortality study to determine the postservice suicide risk of recent wartime veterans comparing them with the US general population as well as comparing deployed veterans to nondeployed veterans. METHODS Veterans were identified from the Defense Manpower Data Center records, and deployment to Iraq or Afghanistan war zone was determined from the Contingency Tracking System. Vital status of 317,581 deployed and 964,493 nondeployed veterans was followed from the time of discharge to December 31, 2009. Underlying causes of death were obtained from the National Death Index Plus. RESULTS Based on 9353 deaths (deployed, 1650; nondeployed, 7703), of which 1868 were suicide deaths (351; 1517), both veteran cohorts had 24% to 25% lower mortality risk from all causes combined but had 41% to 61% higher risk of suicide relative to the US general population. However, the suicide risk was not associated with a history of deployment to the war zone. After controlling for age, sex, race, marital status, branch of service, and rank, deployed veterans showed a lower risk of suicide compared with nondeployed veterans (hazard ratio, 0.84; 95% confidence interval, 0.75-0.95). Multiple deployments were not associated with the excess suicide risk among deployed veterans (hazard ratio, 1.00; 95% confidence interval, 0.79-1.28). CONCLUSIONS Veterans exhibit significantly higher suicide risk compared with the US general population. However, deployment to the Iraq or Afghanistan war, by itself, was not associated with the excess suicide risk.