Baseline serum brain-derived neurotrophic factor association with future cognition in community-dwelling older adults undergoing annual memory screening.

OBJECTIVES: It has been shown that peripheral measures of brain-derived neurotrophic factor (BNDF), an important neurotrophin instrumental to the biology of learning, may contribute to predicting cognitive decline. However, the two primary forms of BDNF, mature (mBDNF) and pro (proBDNF), and how they contribute to cognition longitudinally has not been well studied. METHODS: Eighty-two older adults (average age 72.2 ± 6.4 years) provided blood samples at two time points separated on average by 4.2 years while participating in an annual memory screening that included the MoCA (Montreal Cognitive Assessment) and GDS (Geriatric Depression Scale). Both mBDNF and proBDNF from serum were quantified at each time point. Whole blood samples were genotyped for APOE and BDNF Val66Met. RESULTS: Using logistic regression analysis controlling for age, sex, baseline MoCA score, APOE, and BDNF, higher baseline mBDNF was associated with subjects whose screening score was near maximum or maximum (as defined by MoCA score of 29 or 30) at the second collection visit. APOE was a significant contributing factor; however, BDNF Val66Met was not. Using a similar logistic regression analysis, baseline proBDNF was not found to be associated with future cognition. DISCUSSION: This study further supports that mBDNF measured in the serum of older adults may reflect a protective role while proBDNF requires further investigation.

Interleukin 10 (IL10) promoter region polymorphism is associated with IL10 serum concentrations and processing speed in healthy community-dwelling older adults.

Inflammation is repressed by interleukin 10 (IL10), a potent anti-inflammatory cytokine, and unchecked inflammation can have detrimental effects on cognition. In healthy older adults enrolled in the Australian Research Council Longevity Intervention (ARCLI) cohort we explored whether a known functional single nucleotide polymorphism (SNP) in the promoter region of IL10, -1082 G/A (rs1800896), was associated with reaction times on computerized cognitive testing that included elements of processing speed (i.e., reaction time). Participants were aged 60-75 years (240 females, 158 males), free of dementia and psychiatric disorders, and provide a blood sample. Processing speed was measured using the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB), which includes measures of reaction time (in milliseconds, ms) on six tasks. Blood-derived DNA was genotyped for the IL10 rs1800896 SNP and presence of the APOE E4 allele. General linear models for each SUCCAB subtest were fitted, with age, sex, education (years), APOE E4 carrier status, and IL10 genotype as independent variables. Carriers of the IL10 AA genotype had significantly slower reaction times on multiple tests compared to carriers of the minor allele (AG, GG) and lower IL10 serum levels. Although IL10 SNPs have not been detected in Alzheimer's disease genome-wide associated studies, these results support further exploration of IL10 mechanisms as a possible resilience factor.

Bacopa monnieri supplementation has no effect on serum brain-derived neurotrophic factor levels but beneficially modulates nuclear factor kappa B and cyclic AMP response element-binding protein levels in healthy elderly subjects.

Background and Aim: Bacopa monnieri is an Ayurvedic herb that has been used for multiple conditions, most notably to augment cognition, particularly memory and attention. Multiple mechanisms, including raising brain-derived neurotrophic factor (BDNF), have been proposed and investigated in animal models that require translational studies in humans. Methods: Bacopa was administered in an open-labeled study to cognitively healthy controls over a 3-month period. Cognition and mood were assessed using the Montreal Cognitive Assessment (MoCA) and geriatric depression scale (GDS) at the baseline and 3-month visit. Laboratories were assessed for safety and serum levels of mature (mBDNF) and proBDNF were quantified. In a subset of subjects, intracellular signaling processes were assessed using western blot analysis. Results: Bacopa was provided to 35 subjects and was well-tolerated except for 4 (11%) subjects who early terminated due to known, reversible, and gastrointestinal side effects (i.e., nausea, diarrhea). Over the 3 months, the GDS and the total MoCA did not significantly change; however, the delayed-recall subscale significantly improved (baseline: 3.8 ± 1.2, 3-months: 4.3 ± 0.9; P = 0.032). Serum mBDNF and proBDNF levels did not significantly change. Cyclic AMP response element-binding protein (CREB) phosphorylation significantly increased (P = 0.028) and p65 nuclear factor kappa B (NF-κB) phosphorylation significantly decreased (P = 0.030). Conclusion: These results suggest that Bacopa may exert an anti-inflammatory effect through NF-κB and improve intracellular signaling processes associated with synaptogenesis (CREB). The future placebo-controlled studies are recommended. Relevance for Patients: B. monnieri will require larger, blinded trials to better understand potential mechanisms, interactions, and utilization.

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain.

BACKGROUND: The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD. METHODS: L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS). FINDINGS: Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE ε4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE ε2 carriers relative to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE ε4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies. INTERPRETATION: Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD progression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cerebrovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD.

Characterization of immune profile in an aging multiple sclerosis clinic population.

BACKGROUND: There is limited data regarding adaptive immunity in older persons with Multiple Sclerosis (MS). OBJECTIVE: The aim of the present study was to quantify adaptive immune cells in younger (age less than 50) and older (age greater than 50) with MS in the context of clinical parameters (EDSS, 25-foot walk, SDMT). Subjects were either Untreated (no MS medications in 6 months), taking Injectables (interferons or glatiramer acetate), or Other approved MS treatments. RESULTS: A total of 72 subjects were enrolled (30 younger and 42 older). Older MS patients that were Untreated or taking Injectables had lower CD8 cell counts. Older MS patients demonstrated increased levels of CD4+CD25hi cells and inflammatory serum cytokines (TNF-α, IL-8). There was suggestion that MS treatments modulated IL-10. Cognition as assessed by SDMT was associated with disease duration and IL-10. CONCLUSION: Components of adaptive immunity are influenced by aging in MS which may also impact aspects of cognition as measured by SDMT.

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness.

BACKGROUND: Nearly 250,000 veterans from the 1990-1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. METHODS: Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. RESULTS: An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. CONCLUSION: Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model.

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100µg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.

Effects of a combined transcranial magnetic stimulation (TMS) and cognitive training intervention in patients with Alzheimer's disease.

INTRODUCTION: This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. METHODS: 131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini-Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale-cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. RESULTS: Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ -4 point improvement on ADAS-Cog versus 15.4% in the sham group. DISCUSSION: neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.

A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness.

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and  PER (PB+PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI.

Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment.

BACKGROUND: Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects. METHODS: Seventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1. RESULTS: Compared with healthy control subjects, plasma BACE1 activity (Vmax) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD. CONCLUSIONS: Plasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia.