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Adults with Down syndrome are genetically predisposed to developing Alzheimer's disease after the age of 40. The cholinergic system, which is critical for cognitive functioning, is known to decline in Alzheimer's disease and although first investigated in individuals with Down syndrome 40 years ago, remains relatively understudied. Existing studies suggest individuals with Down syndrome have an intact cholinergic system at birth that declines through adulthood alongside the development of Alzheimer's disease pathology. The present study provides the first description of cholinergic terminals in vivo in non-demented adults with Down syndrome utilizing [18F]-fluoroethoxybenzovesamicol PET imaging. In addition, we investigated age-associated decline in cholinergic terminal density. Sixteen (16) non-demented adults with Down syndrome (mean age 35.5, 8 females) and 20 neurotypically developed individuals (mean age 35.5, 10 females) were studied, comparing radiotracer uptake groupwise and associations with age utilizing a voxel-based approach. Adults with Down syndrome displayed significantly increased [18F]-fluoroethoxybenzovesamicol uptake in the cerebellum, brainstem, thalamus, and numerous cortical regions compared to age-matched controls following an unpaired t-test thresholded at p < 0.001 and minimum cluster size 50. Cholinergic terminal density in numerous cortical regions showed a steeper decline associated with older age in adults with Down syndrome than observed in neurotypically developed adults in the age range tested following a generalized linear model testing the interaction between age and group, thresholded at p < 0.005 and minimum cluster size 50. These data suggest higher cholinergic terminal density in early adulthood in individuals with Down syndrome, with a greater age-related difference than is observed in neurotypically developed individuals. • [18F]-FEOBV uptake is increased in adults with Down syndrome compared to controls. • Adults with Down syndrome display markedly lower [18F]-FEOBV uptake at older ages. • [18F]-FEOBV uptake shows a steeper age-associated decline in adults with DS than controls. [ABSTRACT FROM AUTHOR]

Compared to men, women have a higher risk of developing Alzheimer's disease (AD) in later life. A hypothesized reason for this increased risk may be the change in hormone levels following menopause. Estrogen is important for neurotransmitter systems, such as the cholinergic system, and the loss of estrogen post-menopause may accelerate cholinergic and cognitive decline in some women. Previous studies have examined the effect of cholinergic decline in postmenopausal women, but only in an indirect fashion, often through the use of cholinergic antagonists. The investigational radiotracer [18F]-fluoroethoxybenzovesamicol radiotracer (FEOBV) offers a way to assess cholinergic integrity more directly, as the tracer binds to the presynaptic vesicular cholinergic transporter. Previous studies have shown that FEOBV can quantify cholinergic system decline in AD patients compared to cognitively unimpaired older adults. The present study is an investigation of cholinergic system integrity in a sample of cognitively unimpaired postmenopausal women, who were part of a larger study examining cholinergic compensation following the menopause transition. To explore the effectiveness of using FEOBV to assess in vivo cholinergic activity, we assessed whether higher FEOBV standardized uptake value ratios (SUVR) would be associated with other markers of cholinergic integrity, such as basal forebrain volumes, as well as other risk factors including age and cognitive performance Sixteen healthy postmenopausal women aged 50-70 years completed an FEOBV PET scan (6.5 mCi dose), in addition to structural MRI, EEG recording and cognitive assessments. Co-registration of the FEOBV PET images to the participant's structural MRI data before the SUVR was normalized in reference to the supraventricular white matter. This mask was used as a reference to avoid any partial volume effects from the ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables. Preliminary analyses showed a positive relationship between global FEOBV SUVR and the gray-matter volume of the basal forebrain of both hemispheres. A negative relationship was found between age and FEOBV SUVR, with older adults showing reduced SUVR. Finally, a positive relationship was also seen between global FEOBV SUVR and global cognition, with higher SUVR associated with better cognitive performance. Greater FEOBV SUVR was associated with both basal forebrain volume and cognitive performance in this pilot sample of cognitively unimpaired postmenopausal women. These results highlight the role of cholinergic compensation in postmenopausal women as a potential risk factor for future cognitive decline. Funding Information: This research was supported by NIA grant R01 AG066159, a CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences and funding from the Vanderbilt Trans-Institutional Partnership. [ABSTRACT FROM AUTHOR]

We evaluated the associations of subjective (self-reported everyday cognition [ECog]) and objective cognitive measures with regional amyloid-β (Aβ) and tau accumulation in 86 clinically normal elderly subjects from the Alzheimer's Disease Neuroimaging Initiative. Regression analyses were conducted to identify whether individual ECog domains (Memory, Language, Organization, Planning, Visuospatial, and Divided Attention) were equally or differentially associated with regional [18F]florbetapir and [18F]flortaucipir uptake and how these associations compared to those obtained with objective cognitive measures. A texture analysis, the weighted 2-point correlation, was used as an additional approach for estimating the whole-brain tau burden without positron emission tomography intensity normalization. Although the strongest models for ECog domains included either tau (planning and visuospatial) or Aβ (memory and organization), the strongest models for all objective measures included Aβ. In Aβ-negative participants, the strongest models for all ECog domains of executive functioning included tau. Our results indicate differential associations of individual subjective cognitive domains with Aβ and tau in clinically normal adults. Detailed characterization of ECog may render a valuable prescreening tool for pathological prediction. • The best models for predicting subjective cognitive decline (SCD) domains of memory and organization include amyloid-β. • The best models for SCD domains of planning and visuospatial skills include tau. • Detailed characterization of SCD may help predict the AD pathological designations. [ABSTRACT FROM AUTHOR]

The development of neurotransmitter based cognitive enhancers for Alzheimer's disease have focused recently on allosteric modulation, as a way of reducing potential drug-limiting toxicities that have been the hallmark of earlier orthosteric compounds. VU319 is an investigational positive allosteric modulator of the M1 muscarinic acetylcholine receptor that has recently finished initial testing in healthy volunteers. Cognitive tasks and event-related potentials (ERPs) have been used during the randomized, double-blind, placebo controlled Single Ascending Dose (SAD) study of VU319. This presentation includes both data from the initial SAD study, and the Food Effect substudy. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state. VU319 was given orally to 52 healthy volunteers aged 18-55?years. The SAD study tested 40 participants in five dose escalating cohorts of eight participants, in which six received VU319 and two received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. The five doses for the SAD study were 60, 120, 240, 400 and 600mg. Participants in the Food Effect substudy received VU319 at a single dose of 120mg. For the 5 cohorts of the SAD study, all participants were dosed in a fasted stated. In contrast, all 12 participants in the Food Effect substudy completed were dosed twice; once fasted, and once following breakfast. Cognitive and electrophysiological tasks were examined pre-dosing and at 5?hours post-dose. The tasks were selected for their sensitivity to cholinergic tone. Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Recorded ERP examined auditory and visual discrimination using oddball tasks, and an incidental memory task in which participants passively observed novel and repeated complex images. The analysis showed a trend for improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants on the highest dose of VU319 responded significantly faster to targets on the continuous performance test compared to participants on placebo (p = 0.03, effect size d = 1.2). Additionally, on the incidental memory task, participants who received the higher two doses of VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d > 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that the response time on the continuous performance task decreased in relation to increasing concentration of VU319 in the bloodstream. We conclude that these results demonstrate potential enhancement of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by VU319 and therefore provide a potential framework to examine the cognitive impact of multiple doses of VU319 in AD patients. This research was funded by: This work was supported by the following grants: VKC Hobbs Discovery Grant 4-04-218-9745, Alzheimer's Association PCTR-16-383171; NICHD U54 HD083211, NCATS UL1 TR000445, 2RO1MH082867, R01MH073676, R01MH86601, MH087965, MH093366. [ABSTRACT FROM AUTHOR]

Sensory over-responsivity (SOR) refers to excessively intense and/or prolonged behavioral responses to environmental stimuli typically perceived as non-aversive. SOR is prevalent in several neurodevelopmental disorders, including chronic tic disorders (CTDs) and obsessive-compulsive disorder (OCD). Few studies have examined the extent and clinical correlates of SOR across disorders, limiting insights into the phenomenon's transdiagnostic clinical and biological relevance. Such cross-disorder comparisons are of particular interest for CTDs and OCD given their frequent co-occurrence. We sought to compare the magnitude of SOR between adults with CTD and adults with OCD and to identify the clinical factors most strongly associated with SOR across these disorders. We enrolled 207 age- and sex-matched participants across four diagnostic categories: CTD without OCD (designated "CTD/OCD-"; n = 37), CTD with OCD ("CTD/OCD+"; n = 32), OCD without tic disorder ("OCD"; n = 69), and healthy controls (n = 69). Participants completed a self-report battery of rating scales assessing SOR (Sensory Gating Inventory, SGI), obsessive-compulsive symptoms (Dimensional Obsessive-Compulsive Scale, DOCS), inattention and hyperactivity (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-5), anxiety (Generalized Anxiety Disorder-7), and depression (Patient Health Questionnaire-9). CTD participants were also administered the Yale Global Tic Severity Scale (YGTSS). To examine between-group differences in SOR, we compared SGI score across all groups and between pairs of groups. To examine the relationship of SOR with other clinical factors, we performed multivariable linear regression. CTD/OCD-, CTD/OCD+, and OCD participants were 86.7%, 87.6%, and 89.5%, respectively, more likely to have higher SGI total scores than healthy controls. SGI total score did not differ between CTD/OCD-, CTD/OCD+, and OCD groups. In the regression model of log-transformed SGI total score, OCD diagnosis, DOCS score, and ASRS-5 score each contributed significantly to model goodness-of-fit, whereas CTD diagnosis and YGTSS total tic score did not. SOR is prevalent in adults with CTD and in adults with OCD but does not significantly differ in magnitude between these disorders. Across CTD, OCD, and healthy control adult populations, SOR is independently associated with both obsessive-compulsive and ADHD symptoms, suggesting a transdiagnostic relationship between these sensory and psychiatric manifestations. Future cross-disorder, longitudinal, and translational research is needed to clarify the role and prognostic import of SOR in CTDs, OCD, and other neurodevelopmental disorders. • Sensory over-responsivity (SOR) is prevalent in chronic tic disorders (CTDs) and obsessive-compulsive disorder (OCD). • Magnitude of SOR does not significantly differ between CTD and OCD adult samples. • SOR is associated with both obsessive-compulsive and attention deficit hyperactivity disorder (ADHD) symptoms. [ABSTRACT FROM AUTHOR]

Introduction Subjective cognitive decline (SCD) is increasingly recognized as the initial outward sign of preclinical Alzheimer's disease. The ability to explore associations between individual domains (memory, language, executive function, and visuospatial processing) within SCD and pathological biomarkers of early Alzheimer's disease (AD) would provide an important tool to understand the pathological basis of SCD and the risk of developing AD. This study utilizes multiple data analysis strategies to characterize the severity of tau and amyloid burden in clinically normal elderly adults (CN) and early mild cognitive impairment (EMCI) subjects in association with their subjective cognitive decline. Methods All subject data were downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. These included [18F]flortaucipir tau and [18F]florbetapir amyloid positron emission tomography (PET) images as well as the subjects' SCD scores. For SCD, we used the self- and informant-reported individual items of Everyday Cognition questionnaire, including Everyday Memory, Everyday Language, Everyday Visuospatial abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The severity of the amyloid burden was calculated as the global PET standardized uptake value ratio (SUVR). The severity of the tau burden was assessed with both standard uptake-based approaches (tau SUVR in entorhinal, limbic, and isocortical Braak regions) and with a novel texture analysis tool, the weighted two-point correlation (wS2) analysis, which characterizes the spatial clustering of the tau-PET image as a sensitive early biomarker of abnormal tau accumulation and spread. Using a series of backward-elimination regression models, we identified the combination of predictors (from tau PET, global amyloid-PET, sex, APOE, and age) that constructed the best model to predict each Everyday Cognition item. Results Across the different cognitive tests, the wS2-based tau measures explained more variability, as indicated by p-values and elevated R-squared values, than standardized uptake value ratios from different anatomical regions, including the entorhinal cortex which is believed to be among the first regions to show signs of tau pathology. Our backward-elimination regression analyses (figure 1) suggested that the strongest models for predicting some of the subjective cognitive items (Everyday Memory, Everyday Language, Everyday Organization) were more likely amyloid-related whereas other items (Everyday Visuospatial, Everyday Planning) were more tau-related (together with age and sex). Conclusions Different pathological pathways may influence the manifestation of different subjective cognitive items. In vivo texture analysis techniques may be used as sensitive tools to explore these pathological pathways in association with the earliest signs of cognitive changes. [ABSTRACT FROM AUTHOR]

The development of neurotransmitter based cognitive enhancers for Alzheimer's disease have focused recently on allosteric modulation, as a way of reducing potential drug-limiting toxicities that have been the hallmark of earlier orthosteric compounds. VU319 is an investigational positive allosteric modulator of the M1 muscarinic acetylcholine receptor that has recently finished initial testing in healthy volunteers. Cognitive tasks and event-related potentials (ERPs) have been used during the randomized, double-blind, placebo controlled Single Ascending Dose (SAD) study of VU319. This presentation includes both data from the initial SAD study, and the Food Effect substudy. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state. VU319 was given orally to 52 healthy volunteers aged 18-55 years. The SAD study tested 40 participants in five dose escalating cohorts of eight participants, in which six received VU319 and two received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. The five doses for the SAD study were 60, 120, 240, 400 and 600mg. Participants in the Food Effect substudy received VU319 at a single dose of 120mg. For the 5 cohorts of the SAD study, all participants were dosed in a fasted stated. In contrast, all 12 participants in the Food Effect substudy completed were dosed twice; once fasted, and once following breakfast. Cognitive and electrophysiological tasks were examined pre-dosing and at 5 hours post-dose. The tasks were selected for their sensitivity to cholinergic tone. Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Recorded ERP examined auditory and visual discrimination using oddball tasks, and an incidental memory task in which participants passively observed novel and repeated complex images. The analysis showed a trend for improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants on the highest dose of VU319 responded significantly faster to targets on the continuous performance test compared to participants on placebo (p = 0.03, effect size d = 1.2). Additionally, on the incidental memory task, participants who received the higher two doses of VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d > 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that the response time on the continuous performance task decreased in relation to increasing concentration of VU319 in the bloodstream. We conclude that these results demonstrate potential enhancement of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by VU319 and therefore provide a potential framework to examine the cognitive impact of multiple doses of VU319 in AD patients. This work was supported by funding from the Alzheimer's Association Part the Cloud Initiative PCTR-16-383171. [ABSTRACT FROM AUTHOR]

Introduction The decline of cholinergic functioning is associated with increased cognitive decline and the development of Alzheimer's disease (AD) pathology. At present, there is no pharmacological agent that slows the progression the disease. Muscarinic post positive allosteric modulators (PAMs) are a new class of compounds aiming to restore cholinergic functioning in patients suffering from AD pathology. PAMs of the M1 receptor can potentiate the response of the M1 receptor to acetylcholine, without inducing the harmful side-effects. This is due to the fact that PAMs do not bind at the target site, rather they boost the signal of acetylcholine when is engaged at the orthosteric receptor. The downside of using PAMs is that they have low affinity to radioactive ligands, so this reduces the utility of PET imaging. This creates a challenge in how to establish functional efficacy of the compound in both preclinical and clinical trials. Methods To address this challenge, we plan on using cognitive tasks and electroencephalography (qEEG) to identify dose-depended changes in cholinergic functioning. These functional biomarkers allow us to develop more detailed models of how M 1 PAMs may influence downstream cognitive processing. The cognitive and EEG measures presented have been shown to modulate cholinergic tone, therefore we should be able to identify effective target engagement. Results Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Tasks recorded by EEG tested auditory and visual discrimination using oddball tasks, and incidental memory. Conclusions These cognitive and electrophysiological results will assist in establishing functional targets for future studies using M 1 PAMs. This research was funded by Funding for this research comes from an Alzheimer's Association and the Alzheimer's Drug Discovery Foundation. [ABSTRACT FROM AUTHOR]