Organophosphorus (OP) insecticides are pest‐control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans toOPinsecticides include a well‐defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels ofOPinsecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures toOPinsecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short‐ and long‐term neurological issues that have been associated with acute and subacute exposures of humans toOPinsecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure toOPinsecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity ofOPinsecticides. Most of the discussion will be focused on chlorpyrifos, the top‐sellingOPinsecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain.This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. image

Current hypotheses and theories regarding the pathogenesis of AD heavily implicate brain IR as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs) enriched for neuronal origin, and two-dimensional Magnetic Resonance Spectroscopy measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data) and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance to glycolysis, and the expression of glucose transporters and insulin signaling genes, determine the vulnerability of different brain regions to Tau and/or Aβ pathology and that insulin resistance is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.

Background: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer’s Disease (AD).Objective: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD.Method: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone.Results: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs.Conclusion: The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.

Brain insulin resistance (IR), which depends on insulin‐receptor‐substrate‐1 (IRS‐1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312‐IRS‐1 (ineffective insulin signaling) and lower p‐panTyr‐IRS‐1 (effective insulin signaling) in neural origin‐enriched plasma exosomes of AD patients vs. controls. Here, we hypothesized that these exosomal biomarkers associate with brain atrophy in AD. We studied 24 subjects with biomarker‐supported probable AD (low CSF Aβ₄₂). Exosomes were isolated from plasma, enriched for neural origin using immunoprecipitation for L1CAM, and measured for pSer₃₁₂‐ and p‐panTyr‐IRS‐1 phosphotypes. MPRAGE images were segmented by brain tissue type and voxel‐based morphometry (VBM) analysis for gray matter against pSer₃₁₂‐ and p‐panTyr‐IRS‐1 was conducted. Given the regionally variable brain expression of IRS‐1, we used the Allen Brain Atlas to make spatial comparisons between VBM results and IRS‐1 expression. Brain volume was positively associated with P‐panTyr‐IRS‐1 and negatively associated with pSer₃₁₂‐IRS‐1 in a strikingly similar regional pattern (bilateral parietal‐occipital junction, R middle temporal gyrus). This volumetric association pattern was spatially correlated with Allen Human Brain atlas normal brain IRS‐1 expression. Exosomal biomarkers of brain IR are thus associated with atrophy in AD as could be expected by their pathophysiological roles and do so in a pattern that reflects regional IRS‐1 expression. Furthermore, neural‐origin plasma exosomes may recover molecular signals from specific brain regions. Hum Brain Mapp 38:1933–1940, 2017. © 2017 Wiley Periodicals, Inc.

Objective: Brain glucose hypometabolism is a prominent feature of Alzheimer's disease (AD), and in this case–control study we used Magnetic Resonance Spectroscopy (MRS) to assess AD‐related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites.Methods: J‐modulated Point‐Resolved Spectroscopy (J‐PRESS) and Prior‐Knowledge Fitting (ProFit) software was used to measure glucose and other metabolites in the posterior cingulate/precuneus of 25 AD, 27 older controls, and 27 younger control participants. Clinical assessments for AD participants included cognitive performance measures, insulin resistance metrics and CSF biomarkers.Results: AD participants showed substantially elevated glucose, lactate, and ascorbate levels compared to older (and younger) controls. In addition, the precuneal glucose elevation discriminated well between AD participants and older controls. Myo‐inositol correlated with CSF p‐Tau_181P, total Tau, and the Clinical Dementia Rating (CDR) sum‐of‐boxes score within the AD group.Interpretation: Higher glucose to creatine ratios in the AD brain likely reflect lower glucose utilization. Our findings reveal pronounced metabolic abnormalities in the AD brain and strongly suggest that brain glucose merits further investigation as a candidate AD biomarker.