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The author comments on a study on the association of neuroinflammation with Alzheimer's disease, obesity and depression in older adults.

Abstract: Paid media are important resources used to recruit subjects in clinical trials. An index for evaluating which advertising resource has minimal cost and time requirement for patient accrual, for a given study design, has not been previously introduced. In this communication the authors present a new index, the Cost–Time Index, which represents a measure of the average amount of money and time spent, simultaneously, on a given advertising resource to recruit one analyzable subject. This index can be calculated using retrospective data and may be a useful tool for comparing recruitment efficiencies among various resources. The authors demonstrate the utility of the Cost–Time Index and recommend its use as an additional variable in future studies regarding recruitment strategies in clinical trials. [Copyright &y& Elsevier]

In this review, evidence is provided that apolipoprotein E (apoE) genotype accounts for the majority of Alzheimer’s disease (AD) risk and pathology. The three major human isoforms, apoE2, apoE3, and apoE4, are encoded by different alleles (#x03B5;2, #x03B5;3, #x03B5;4) and regulate lipid metabolism and redistribution. ApoE isoforms differ in their effects on AD risk and pathology. Clinical and epidemiological data have indicated that the #x03B5;4 allele may account for 50% of AD in the United States. Further, the rarity of AD among carriers of the #x03B5;2 allele suggests that allelic variations in the gene encoding this protein may account for over 95% of AD cases. ApoE4 disrupts memory function in rodents. Further studies have indicated that fragments of apoE may contribute to both plaque and tangle formation. Thus, the epidemiologic and basic science evidence suggest that apoE genotype accounts for the vast majority of AD risk and pathology. [Copyright &y& Elsevier]

Many Veterans of the 1990–1991 Gulf War report symptoms of Gulf War Illness, a condition involving numerous chronic symptoms including pain, fatigue, and mood/cognition symptoms. Little is known about this condition's etiology and treatment. This study reports outcomes from a randomized controlled single-blind trial comparing yoga to cognitive behavioral therapy for chronic pain and other symptoms of Gulf War Illness. Participants were Veterans with symptoms of GWI: chronic pain, fatigue and cognition-mood symptoms. Seventy-five Veterans were randomized to treatment via selection of envelopes from a bag (39 yoga, 36 cognitive behavioral therapy), which consisted of ten weekly group sessions. The primary outcomes of pain severity and interference (Brief Pain Inventory- Short Form) improved in the yoga condition (Cohen's d =.35, p = 0.002 and d = 0.69, p < 0.001, respectively) but not in the CBT condition (d = 0.10, p = 0.59 and d = 0.25 p = 0.23). However, the differences between groups were not statistically significant (d = 0.25, p = 0.25; d = 0.43, p = 0.076), though the difference in an a-priori -defined experimental outcome variable which combines these two variables into a total pain variable (d = 0.47, p = 0.047) was significant. Fatigue, as indicated by a measure of functional exercise capacity (6-min walk test) was reduced significantly more in the yoga group than in the CBT group (between-group d =.27, p = 0.044). Other secondary outcomes of depression, wellbeing, and self-reported autonomic nervous system symptoms did not differ between groups. No adverse events due to treatment were reported. Yoga may be an effective treatment for core Gulf War Illness symptoms of pain and fatigue, making it one of few treatments with empirical support for GWI. Results support further evaluation of yoga for treating veterans with Gulf War Illness. clinicaltrials.gov Registration Number NCT02378025. [ABSTRACT FROM AUTHOR]

A valid, reliable, accessible measurement for the early detection of cognitive decline in patients with Parkinson's disease (PD) is in urgent demand. The objective of the study is to assess the clinical utility of the MemTrax Memory Test in detecting cognitive impairment in patients with PD. The MemTrax, a fast on-line cognitive screening tool based on continuous recognition task, and Montreal Cognitive Assessment (MoCA) were administered to 61 healthy controls (HC), 102 PD patients with normal cognition (PD-N), 74 PD patients with mild cognitive impairment (PD-MCI) and 52 PD patients with dementia (PD-D). The total percent correct (MTx- %C), average response time (MTx-RT), composite score (MTx-Cp) of MemTrax and the MoCA scores were comparatively analyzed. The MoCA scores were similar between HC and PD-N, however, MTx- %C and MTx-Cp were lower in PD-N than HC(p < 0.05). MTx- %C, MTx-Cp and the MoCA scores were significantly lower in PD-MCI versus PD-N and in PD-D versus PD-MCI (p ≤ 0.001), while MTx-RT was statistically longer in PD-D versus PD-MCI (p ≤ 0.001). For PD groups, the MemTrax performance correlated with the MoCA scores. To detect PD-MCI, the optimal MTx- %C and MTx-Cp cutoff were 75 % and 50.0, respectively. To detect PD-D, the optimal MTx- %C, MTx-RT and MTx-Cp cutoff were 69 %, 1.341s and 40.6, respectively. The MemTrax provides rapid, valid and reliable metrics for assessing cognition in PD patients which could be useful for identifying PD-MCI at early stage and monitoring cognitive function decline during the progression of disease. • Early detection of cognitive decline in patients with PD is important. • The MemTrax is a simple and effective cognitive assessment which provides reliable metrics for assessing cognition in PD patients. • MemTrax can be used to identify PD-MCI at early stage and potentially monitor cognitive decline during disease progression. [ABSTRACT FROM AUTHOR]

Atrophy of the hippocampus and surrounding temporal regions occurs in Alzheimer's disease (AD). APOE ε4, the major genetic risk factor for late-onset AD, has been associated with smaller volume in these regions before amyloidosis can be detected by AD biomarkers. To examine APOE ε4 effects in relation to aging, we performed a longitudinal magnetic resonance imaging study involving cognitively normal adults (25 APOE ε4 carriers and 31 ε3 homozygotes), initially aged 51–75 years. We used growth curve analyses, which can provide information about APOE ε4-related differences initially and later in life. Hippocampal volume was the primary outcome; nearby medial temporal regions were secondary outcomes. Brain-derived neurotrophic factor, val66met was a secondary covariate. APOE ε4 carriers had significantly smaller initial hippocampal volumes than ε3 homozygotes. Rate of hippocampal atrophy was not greater in the APOE ε4 group, although age-related atrophy was detected in the overall sample. The findings add to the growing evidence that effects of APOE ε4 on hippocampal size begin early in life, underscoring the importance of early interventions to increase reserve. [ABSTRACT FROM AUTHOR]

Highlights: [•] MA-ergic neurons send extensive projections to the rest of the brain. [•] These neurons exert strong modulatory influence on hippocampal cells. [•] MA-ergic systems are characterized by scarce number of cell bodies and long axons. [•] These neurons retrogradely transport and are dependent on supply of growth factors. [•] This might explain vulnerability of MA-ergic neurons in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: The apolipoprotein (APOE) ɛ4 allele is associated with cognitive deficits and hippocampal atrophy in nondemented middle-aged and older adults. It is not known to what extent this genetic risk factor for Alzheimer''s disease (AD) impacts performance in late middle-aged and older workers in cognitively demanding occupations. This cross-sectional analysis examines brain–cognitive–genetic relationships in actively flying general aviation pilots, half of whom are APOE ɛ4 carriers. Fifty pilots were studied with structural MRI and memory tasks. Average visual paired associate memory recall performance was lower in APOE ɛ4 carriers than non-carriers. Memory performance correlated positively with hippocampal volume, but no structural differences were found in hippocampal or frontal volumes with respect to APOE ɛ4 allele. These results were evident in healthy professionals without any presenting memory problems and without selection for a family history of AD. These findings point to basic memory testing as a sensitive tool for detecting APOE ɛ4-related influences on memory in aging workers. [Copyright &y& Elsevier]

Abstract: We have previously demonstrated that Leptin reduces extracellular amyloid β (Aβ) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer''s disease (AD), may be GSK-3β, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3β in mediating Leptin''s ability to reduce tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3β. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3β inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3β, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3β. These studies provide further insight into Leptin''s mechanism of action in suppressing AD-related pathways. [Copyright &y& Elsevier]

Aims: Gulf War Illness (GWI) is a chronic, debilitating, multi-symptom condition affecting as many as one-third of the nearly 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War (GW). The treatment of GWI relies on symptom management. A common challenge in studying the efficacy of interventions for symptom management is participant recruitment related to factors such as the burden of travelling to study sites and the widespread dispersion of Veterans with GWI. The goal of this study is to assess the efficacy of a novel low-risk therapeutic agent, Bacopa monnieri , for cognitive function in Veterans with GWI and to evaluate the utility of a remote patient-centric study design developed to promote recruitment and minimize participant burden. Main Methods: To promote effective participant recruitment, we developed a remote patient-centric study design. Participants will be recruited online through social media and through a web-based research volunteer list of GW Veterans. An online assessment platform will be used, and laboratory blood draws will be performed at clinical laboratory sites that are local to participants. Furthermore, the assigned intervention will be mailed to each participant. Significance: These study design adaptations will open participation to Veterans nearly nationwide and reduce administrative costs while maintaining methodologic rigor and participant safety in a randomized, placebo-controlled phase II clinical trial. [ABSTRACT FROM AUTHOR]

Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990–91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI. [ABSTRACT FROM AUTHOR]

There is an inadequate portfolio of treatments for Gulf War Illness (GWI), a complex disease involving multiple organ systems, and early-phase clinical trials are hampered by many logistical problems. To address these challenges, the Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC) was formed with the aims of (i) creating a collaborative consortium of clinical and scientific researchers that will rapidly implement rigorous and innovative phase I and II clinical trials for GWI, (ii) perform at least four phase I or II clinical trials, (iii) provide a foundation of scalable infrastructure and management in support of the efficient and successful operation of the GWICTIC, and (iv) partner with the Boston Biorepository, Recruitment & Integrated Network for GWI and other GWI investigators to develop a common data element platform for core assessments and outcomes. The GWICTIC brings together a multidisciplinary team of researchers at several institutions to provide scientific innovation, statistical and computational rigor, and logistical efficiency in the development and implementation of early-phase low-risk clinical trials for GWI. The GWICTIC core trials adhere to a Veteran-centered philosophy and focus on interventions with multiple mechanistic targets to maximize the likelihood of efficacy. To support rapid and efficient study startup and implementation across the GWI research community, the GWICTIC will share infrastructure with investigator-initiated research studies funded under separate mechanisms. The GWICTIC will leverage the efficiencies of centralized research support and innovative trial designs to address several longstanding needs in the GWI interventions research community. [ABSTRACT FROM AUTHOR]