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INTRODUCTION: Hearing loss is identified as one of the largest modifiable risk factors for cognitive impairment and dementia. Studies evaluating this relationship have yielded mixed results. METHODS: We investigated the longitudinal relationship between self‐reported hearing loss and cognitive/functional performance in 695 cognitively normal (CN) and 941 participants with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Within CN participants with hearing loss, there was a significantly greater rate of cognitive decline per modified preclinical Alzheimer's cognitive composite. Within both CN and MCI participants with hearing loss, there was a significantly greater rate of functional decline per the functional activities questionnaire (FAQ). In CN and MCI participants, hearing loss did not significantly contribute to the risk of progression to a more impaired diagnosis. DISCUSSION: These results confirm previous studies demonstrating a significant longitudinal association between self‐reported hearing loss and cognition/function but do not demonstrate an increased risk of conversion to a more impaired diagnosis. CLINICAL TRIAL REGISTRATION INFORMATION: NCT00106899 (ADNI: Alzheimer's Disease Neuroimaging Initiative, clinicaltrials.gov), NCT01078636 (ADNI‐GO: Alzheimer's Disease Neuroimaging Initiative Grand Opportunity, clinicaltrials.gov), NCT01231971 (ADNI2: Alzheimer's Disease Neuroimaging Initiative 2, clinicaltrials.gov), NCT02854033 (ADNI3: Alzheimer's Disease Neuroimaging Initiative 3, clinicaltrials.gov). Highlights: Hearing loss is a potential modifiable risk factor for dementia.We assessed the effect of self‐reported hearing loss on cognition and function in the ADNI cohort.Hearing loss contributes to significantly faster cognitive and functional decline.Hearing loss was not associated with conversion to a more impaired diagnosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials. METHODS: Unbiased analysis of tandem‐mass tag mass spectrometry (TMT‐MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARC cohort (NCT03493282). Comparative analyses and a meta‐analysis with the interim SHINE cohort (NCT03507790; SHINE‐A) followed by network analysis (weighted gene co‐expression network analysis [WGCNA]) were used to understand the biological impact of CT1812. RESULTS: CT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta‐analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment‐associated networks driven by S2R. DISCUSSION: Early clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development. Highlights: This exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282)Comparative analyses identified biomarkers replicating across trials/cohortsTwo independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE‐A]) were used in a meta‐analysisAmyloid beta (Aβ) & synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment‐related correlates emergeNetwork analyses revealed sigma‐2 receptor (S2R)‐interacting proteins that may be "drivers" of changes [ABSTRACT FROM AUTHOR]

Objectives: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. Methods: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo‐controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. Results: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6‐month follow‐up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow‐up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post‐baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. Conclusions: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment. Key points: Methylphenidate (MPH) use in Alzheimer's Disease (AD) patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population.The ADMET2 trial found that participants with AD treated with MPH for apathy experienced a modest but statistically significant greater weight loss compared to placebo group over 6 months, emphasizing the need for clinicians to monitor weight change during treatment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Tau phosphorylated at threonine‐217 (pT217‐tau) is a novel fluid‐based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217‐tau arises in the brain, as soluble pT217‐tau is dephosphorylated post mortem in humans. METHODS: We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early‐stage pT217‐tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217‐tau levels in plasma. RESULTS: pT217‐tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217‐tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These data help to explain why pT217‐tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double‐blind phase 3 DIAN‐TU‐001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid‐no‐change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid‐reduction class exhibited reductions in the annual decline rates compared to the amyloid‐growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. Highlights: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker.Despite similar baseline characteristics, the amyloid‐reduction class exhibited remarkably better outcomes compared to the amyloid‐growth class across multiple measures.LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects. [ABSTRACT FROM AUTHOR]

Background: Mixed model repeated measures (MMRM) is the most common analysis approach in clinical trials for Alzheimer's disease. The model treats time as a categorical variable, which can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. Since MMRM entails a mean parameter for each group and visit, the model can be inefficient for longer trials of Preclinical Alzheimer's. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Method: We use model selection techniques to compare the predictive value of spline models to slope models, MMRM, and models that assume a proportional treatment effect using data from several completed trials. These trials include the ADCS trial of donepezil in MCI, trials of intranasal insulin and a fyn kinase inhibitor in mild Alzheimer's dementia, and the A4 trial of solanezumab in Preclinical Alzheimer's. Simulation studies assess the power and Type I error of these models for trials in Preclinical Alzheimer's, MCI, and mild dementia. Result: The spline model with ADAS‐Cog version effect attained the best predictive value for the trials in mild dementia. The proportional model was preferred for the trial in MCI, but the proportional effect assumption was violated, and the treatment effect estimate was in the wrong direction. Considering that the spline with two degrees of freedom and version effect provide fits that are similar to MMRM in Figure 1, we concluded that two degrees of freedom appear to be sufficient to capture enough of the general trend to assess the treatment effect. AIC results from the A4 Study will be considered and included after the study is completed in Spring 2023. Conclusion: The spline model is shown to have better predictive value and precision in real datasets and has better power and Type I error control in a variety of simulation scenarios. [ABSTRACT FROM AUTHOR]

Introduction: Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Results: Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages. [ABSTRACT FROM AUTHOR]

Previous research reported an age‐related decline in brain norepinephrine transporter (NET) using (S, S)‐[11C]O‐methylreboxetine ([11C]MRB) as a radiotracer. Studies with the same tracer have been mixed in regard to differences related to body mass index (BMI). Here, we investigated potential age‐, BMI‐, and gender‐related differences in brain NET availability using [11C]MRB, the most selective available radiotracer. Forty‐three healthy participants (20 females, 23 males; age range 18–49 years), including 12 individuals with normal/lean weight, 15 with overweight, and 16 with obesity were scanned with [11C]MRB using a positron emission tomography (PET) high‐resolution research tomograph (HRRT). We evaluated binding potential (BPND) in brain regions with high NET availability using multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. Brain regions were delineated with a defined anatomic template applied to subjects' structural MR scans. We found a negative association between age and NET availability in the locus coeruleus, raphe nucleus, and hypothalamus, with a 17%, 19%, and 14% decrease per decade, respectively, in each region. No gender or BMI relationships with NET availability were observed. Our findings suggest an age‐related decline, but no BMI‐ or gender‐related differences, in NET availability in healthy adults. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6‐month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms. [ABSTRACT FROM AUTHOR]

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical‐time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios. [ABSTRACT FROM AUTHOR]

Background: While the spread of tau throughout the brain is well‐characterized in amnestic Alzheimer's disease (AD), tau staging remains less clear for those suffering from clinically heterogeneous variants including logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). We created a method to identify local maxima of tau SUVR ("epicenters") in participants with early‐stage clinically heterogeneous AD with the goal of classifying participant subtypes based on the functional connectivity of these epicenters. Method: We obtained 18F‐MK‐6240 tau PET scans from 10 participants with diagnoses of early‐stage clinically heterogeneous AD (5 lvPPA, 5 PCA, Clinical Dementia Rating 0.5‐1.0). We identified three local maxima of tau SUVR with a minimum specified distance of 20mm between them for each participant (Fig. 1). We then derived each epicenter's functional connectivity in 1000 healthy controls using Neurosynth and sorted participants into subtypes based on the overlap of these functional connectivity maps. Result: Participants with lvPPA showed highest tau burden in the posterior temporoparietal and temporoocciptal regions, left side predominant, and participants with PCA displayed highest tau burden in the bilateral parietooccipital cortex, frontal eye fields, and fusiform gyrus. We identified nine distinct subtypes of functional connectivity and most participants' epicenters participated in more than one subtype. All subtypes highlight functional connectivity networks that have been associated with language and, or visuospatial processing. The most common subtype (seen in 7 of the 10 participants and 11 of the 30 epicenters) features connectivity within the bilateral occipital lobule, fusiform gyrus, and superior parietal lobule (Fig. 2). Conclusion: We used a novel method to identify tau "epicenters" in the brains of participants with early‐stage clinically heterogeneous AD. Using these epicenters, we derived functional connectivity maps, which we then grouped into nine subtypes across participants. We will shortly begin collecting longitudinal tau PET in these clinically heterogeneous individuals with AD, allowing us to assess the extent to which tau spreads along the functional connectivity maps predicted by each participant's epicenters and whether individually tailored epicenters outperform subtype classification. This work could serve as the basis for patient‐specific biomarkers of expected disease spread in clinically heterogeneous AD. [ABSTRACT FROM AUTHOR]

Introduction: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. Methods: We examined the relationship between synaptic density measured by [11C]UCB‐J PET and neuropsychological test performance in 45 participants with early AD. Results: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. Conclusion: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD. [ABSTRACT FROM AUTHOR]

Background: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer’s disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy in limited brain regions, largely at the moderate to severe stages of disease. With the recent advent of synaptic positron emission tomography (PET) imaging, we have begun to evaluate synaptic alterations in vivo. In this study we examined the relationship between synaptic density and cognitive performance in early AD using [11C]UCB‐J PET and an extensive neuropsychological test battery. Method: Using [11C]UCB‐J binding to SV2A, synaptic density was measured in 45 amyloid positive participants with AD (17 amnestic mild cognitive impairment and 28 mild dementia) and 20 amyloid negative cognitively normal (CN) participants aged 50‐85 years. Synaptic density was calculated as the distribution volume ratio (DVR) in a composite region of interest (ROI) of AD‐affected regions (prefrontal, lateral temporal, medial temporal, lateral parietal, anterior cingulate, posterior cingulate, precuneus, and lateral occipital) using cerebellum as reference region. A neuropsychological test battery assessed performance in five cognitive domains. Domain scores were generated for each AD participant by averaging z‐scores within the domain, and global cognitive scores averaged the domain scores. Result: In a multiple linear regression model controlling for age, sex, and education, synaptic density ([11C]UCB‐J DVR) was a significant predictor of global cognitive performance in participants with AD (β=3.21, η2=0.29, P=0.0001; Figure 1A), as well as Verbal Memory (P=0.022; Figure 1B), Language (P=0.001; Figure 1C), Executive Function (P=0.001; Figure 1D), Processing Speed (P=0.001; Figure 1E), and Visuospatial Ability (P=0.001; Figure 1F). The association between synaptic density and global cognition survived partial volume correction (PVC; β=2.16, η2=0.23, P=0.001), and synaptic density was a stronger predictor of cognitive performance than gray matter volume. Figure 2 shows correlation maps of global cognitive performance with regional synaptic density (DVR; without and with PVC) and gray matter volume. Conclusion: These results confirm neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD. [ABSTRACT FROM AUTHOR]

Introduction: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking. Methods: Recruitment for EXERT, a multisite randomized controlled 18‐month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants. Results: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age‐ and geo‐targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations. Discussion: Age‐ and geo‐targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18‐month exercise trial. [ABSTRACT FROM AUTHOR]

Purpose: Positron emission tomography (PET) imaging with various tracers is increasingly used in Alzheimer's disease (AD) studies. However, access to PET scans using new or less‐available tracers with sophisticated synthesis and short half‐life isotopes may be very limited. Therefore, it is of great significance and interest in AD research to assess the feasibility of generating synthetic PET images of less‐available tracers from the PET image of another common tracer, in particular 18F‐FDG. Methods: We implemented advanced deep learning methods using the U‐Net model to predict 11C‐UCB‐J PET images of synaptic vesicle protein 2A (SV2A), a surrogate of synaptic density, from 18F‐FDG PET data. Dynamic 18F‐FDG and 11C‐UCB‐J scans were performed in 21 participants with normal cognition (CN) and 33 participants with Alzheimer's disease (AD). Cerebellum was used as the reference region for both tracers. For 11C‐UCB‐J image prediction, four network models were trained and tested, which included 1) 18F‐FDG SUV ratio (SUVR) to 11C‐UCB‐J SUVR, 2) 18F‐FDG Ki ratio to 11C‐UCB‐J SUVR, 3) 18F‐FDG SUVR to 11C‐UCB‐J distribution volume ratio (DVR), and 4) 18F‐FDG Ki ratio to 11C‐UCB‐J DVR. The normalized root mean square error (NRMSE), structure similarity index (SSIM), and Pearson's correlation coefficient were calculated for evaluating the overall image prediction accuracy. Mean bias of various ROIs in the brain and correlation plots between predicted images and true images were calculated for ROI‐based prediction accuracy. Following a similar training and evaluation strategy, 18F‐FDG SUVR to 11C‐PiB SUVR network was also trained and tested for 11C‐PiB static image prediction. Results: The results showed that all four network models obtained satisfactory 11C‐UCB‐J static and parametric images. For 11C‐UCB‐J SUVR prediction, the mean ROI bias was −0.3% ± 7.4% for the AD group and −0.5% ± 7.3% for the CN group with 18F‐FDG SUVR as the input, −0.7% ± 8.1% for the AD group, and −1.3% ± 7.0% for the CN group with 18F‐FDG Ki ratio as the input. For 11C‐UCB‐J DVR prediction, the mean ROI bias was −1.3% ± 7.5% for the AD group and −2.0% ± 6.9% for the CN group with 18F‐FDG SUVR as the input, −0.7% ± 9.0% for the AD group, and −1.7% ± 7.8% for the CN group with 18F‐FDG Ki ratio as the input. For 11C‐PiB SUVR image prediction, which appears to be a more challenging task, the incorporation of additional diagnostic information into the network is needed to control the bias below 5% for most ROIs. Conclusions: It is feasible to use 3D U‐Net‐based methods to generate synthetic 11C‐UCB‐J PET images from 18F‐FDG images with reasonable prediction accuracy. It is also possible to predict 11C‐PiB SUVR images from 18F‐FDG images, though the incorporation of additional non‐imaging information is needed. [ABSTRACT FROM AUTHOR]

Background: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate (MPH) was modestly efficacious is treating apathy in Alzheimer's disease (AD) with 66% response (> = 4 point decrease on Neuropsychiatric Inventory – apathy (NPI‐A). Here, we evaluated if blood‐based biomarkers potentially associated with treatment‐limiting neuronal damage predicted the probability of treatment response. Method: ADMET 2 participants with baseline and endpoint (6 month) NPI‐A and baseline concentrations of (i) neuronal damage: neurofilament light (NFL) and S‐100B, (ii) inflammation: interleukin (IL)‐6, IL‐10, Tumor Necrosis Factor‐alpha (TNFα), and (iii) oxidative stress: lipid hydroperoxide (LPH), 4‐hydroxynonenal (4‐HNE), 8‐isoprostane (8‐ISO) were included. Biomarkers were normalized by log transformation and pareto scaling. Univariate models examined whether each biomarker interacted with the treatment condition to predict a change of at least 2 points on the NPI‐A. Next, biomarkers with significant associations were included in a multivariate logistical regression model that was used to predict treatment response to MPH and placebo. The index score (difference between response probabilities for MPH and placebo) of each participant indicated their favourability for MPH treatment. Participants were grouped into quartiles by their index score with confidence intervals estimated using non‐parametric bootstrapping. Result: Forty‐nine participants (placebo = 26, MPH = 23, age = 75.4 years (standard deviation [SD] = 7.6), 57% males, Mini Mental State Examination = 19.7 [SD = 4.6]) were included. MPH was more efficacious than placebo in those with higher baseline NFL (‐5.8, t = ‐3.1, p = 0.003), and less efficacious in those with higher LPH (2.0, t = 1.48, p = 0.15). Apathy worsened in participants with high TNFα (2.71, t = 1.94, p = 0.06) in both MPH and placebo groups. Participants in the top quartile of the biomarker index score (66.7% on MPH) were more likely to respond to MPH than placebo (index score = 0.58, 95%CI: 0.48, 0.69). Conclusion: Individuals with greater neuronal injury were more likely to respond to MPH, suggesting that MPH supplementation provides more benefit when neuronal injury is more severe. Combining blood biomarkers yielded a prediction score where participants with high NFL and low LPH levels were more likely to respond to MPH. This approach utilizes biomarkers to address heterogeneity in treatment response to MPH. [ABSTRACT FROM AUTHOR]

Background: Tau pathology in Alzheimer's Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to "seed" pathology throughout the neuronal network affecting the dorsolateral prefrontal cortex (dlPFC) with advanced neurodegeneration. Recent discoveries indicate that phosphorylated tau (pT217‐tau) can be captured in CSF and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixed monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in ERC and dlPFC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space. Method: We used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐33 years) to localize pT217‐tau in ERC layer II, which show the earliest signatures of tau pathology in AD and dlPFC layer III critical for working memory. Result: pT217‐tau immunolabeling was predominantly observed in postsynaptic compartments and accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy. Conclusion: pT217‐tau accumulates in ERC and dlPFC subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to "seed" tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD. [ABSTRACT FROM AUTHOR]

Introduction: The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non‐invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection. Methods: In this small cross‐sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline. Results: The four participants from the A4 trial showed a greater number of retinal spots compared to the four participants from the LEARN study. We observed a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). Discussion: The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally. [ABSTRACT FROM AUTHOR]

Background: Synaptic loss is a primary pathology in Alzheimer's disease (AD) and correlates best with cognitive impairment as found in postmortem studies. Previously, we observed in vivo synaptic density loss with [11C]UCB‐J PET (radiotracer for synaptic vesicle protein 2A, SV2A) in hippocampus and throughout the cortex. Here, we used independent component analysis (ICA), a data‐driven method that identifies independent sources (networks) by linearly unmixing the observed signal into maximally independent components. The aim is to apply ICA, which does not use subject group information, to synaptic density PET data to identify brain networks associated with cognitive deficits in AD. Method: [11C]PIB PET was performed to determine brain amyloid status. A structural T1‐weighted MR was acquired to exclude structural abnormalities and for PET co‐registration and analysis. [11C]UCB‐J binding to SV2A was measured in 38 AD (24 dementia, 14 mild cognitive impairment) and 19 cognitively normal (CN) participants. [11C]UCB‐J distribution volume ratio values were calculated using SRTM2 (population‐fixed k2') with whole cerebellum as reference, registered into MNI space and smoothed (8‐mm Gaussian). Based on previous SV2A ICA, 18 independent components (IC) were extracted. Subject loadings per IC were compared between groups using unpaired t‐tests. Pearson's correlations were used to assess relationships between loading weights and cognitive measures: logical memory II (LMII), Rey auditory verbal learning test (RAVLT‐delay), clinical dementia rating sum of boxes (CDR‐sob), mini‐mental state examination (MMSE). Result: For 8 ICs, we observed significant differences in loading weights between CN and AD groups, including a component (IC01) located in hippocampus and temporal lobe (Figure 1). Within the AD/MCI group, loading weights for IC02, located in the right parietal‐temporal lobe (Figure 2), correlated with LMII (R2: 0.13, p=0.025), and RAVTL‐delay (R2: 0.13, p=0.027). For IC03, located in the left parietal hemisphere (Figure 3), loading weights correlated with CDR‐sob (R2: 0.23, p=0.0028) and MMSE (R2: 0.13, p=0.024). Conclusion: We demonstrated that ICA could define coherent spatial patterns of synaptic density. Furthermore, commonly used cognitive measures correlate significantly with loading weights for two of such networks within only the AD/MCI group. Further studies will explore whether ICA‐based networks might be more sensitive than conventional ROI‐based analysis. [ABSTRACT FROM AUTHOR]

The article entitled "Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials" was published in 2019 by Andrews et al. in I Alzheimer's & Dementia i .[1] This study has emerged as perhaps the most influential investigation on the subject of minimal clinically important differences (MCID) in the key outcome measures used in therapeutic trials for Alzheimer's disease (AD). [Extracted from the article]

Background: Alterations to the retina manifest in patients diagnosed with neurodegenerative diseases such as Alzheimer's disease (AD). Retinal imaging techniques open the possibility for non‐invasive evaluation of AD pathology. Clinically AD diagnosed patients exhibit retinal spots that may be amyloid deposits. Few studies monitoring preclinical individuals exist, limiting the assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection. Method: We compared extent and distribution of retinal fluorescent spots and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from participants from both studies to determine retinal amyloid deposition at baseline. Result: Participants from the A4 trial exhibited a greater number of retinal spots compared to those from the LEARN study. We report a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). Conclusion: The results of this study support the use of retinal fundus imaging for and assessing relationships with brain amyloid PET SUVr. Further work is needed to determine the nature of retinal spots and their relationship with actual amyloid plaques cross‐sectionally and longitudinally. [ABSTRACT FROM AUTHOR]

Background: Synaptic density PET is an emerging technology with potential as a biomarker for tracking disease progression and therapeutic efficacy in studies of Alzheimer's disease (AD). Simplified methods of image acquisition and quantification would facilitate the use of synaptic density imaging in multicenter longitudinal studies. Therefore, we validated a simplified tissue‐to‐reference ratio method using standardized uptake value ratios (SUVR) for estimating synaptic density using [11C]UCB‐J PET. Method: [11C]UCB‐J binding was measured in 31 participants with early AD and 16 cognitively normal (CN) participants aged 55‐85 years. All participants underwent 90 minute dynamic PET scans on the HRRT after bolus injection of [11C]UCB‐J. Parametric images of binding potential (BPND) were generated using SRTM2 (0‐60 minutes) with a centrum semiovale reference region and converted to distribution volume ratios (DVR) with a cerebellum reference region. Parametric images of SUVR were generated by summing frames from 30‐60 or 60‐90 minutes and normalizing to the cerebellum. Regional group differences were assessed using unpaired t tests and Cohen's d, while associations between DVR and SUVR were assessed using Pearson's correlation. Result: Widespread reductions in cortical and subcortical synaptic density were observed in AD (vs. CN) participants using measures of DVR, SUVR30‐60min, and SUVR60‐90min. In the entire sample, stronger regional correlations between measures of DVR and SUVR60‐90min(r=0.97, p<0.00001) were observed compared to DVR and SUVR30‐60min(r=0.91, p<0.00001; Figure 1). The correlation between DVR and SUVR60‐90minwas also stronger for within‐group correlations (DVR vs. SUVR60‐90minrCN=0.97, rAD=0.97; DVR vs. SUVR30‐60minrCN=0.90, rAD=0.91). The within‐region correlation between measures of DVR and SUVR60‐90minranged from 0.77 to 0.97 (p<0.00001) in the entire sample. Effect sizes to determine group differences in SV2A binding across all regions were highly correlated between both DVR and SUVR60‐90min(r=0.93, p<0.00001) and DVR and SUVR30‐60min(r=0.93, p<0.00001; Figure 2). Conclusion: A simplified method of quantifying synaptic density with SUVR using a shortened (60‐90 minute) scan window and cerebellum reference region is highly correlated with measures of DVR generated with SRTM2 kinetic modeling. This simplified tissue‐to‐reference ratio methodology may be of practical use for multicenter and longitudinal studies seeking to measure synaptic density in AD. [ABSTRACT FROM AUTHOR]

Introduction: An animal model of late‐onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration. Methods: We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays. Results: Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young‐adult entorhinal cortex with protein kinase A‐phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex. Discussion: The aging rhesus macaque provides the long‐sought animal model for exploring the etiology of late‐onset Alzheimer's disease and for testing preventive strategies. Highlights: Aging rhesus macaques exhibit tau and amyloid pathology.Tau phosphorylation precedes in the entorhinal cortex and spreads to the association cortex.Phosphorylated tau fibrillates into classic paired helical filaments in tangles.Concurrent phosphorylation of ryanodine receptors suggests calcium involvement.The aging rhesus macaque could model late‐onset Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: CT1812 is an investigational therapeutic that can displace toxic amyloid‐beta oligomers from neuronal receptors and is currently in development for Alzheimer's disease (AD). SPARC (COG0105; NCT03493282), was a randomized double‐blinded placebo‐controlled clinical trial designed to test the impact of the small molecule sigma‐2 receptor (S2R) modulator CT1812 on safety and synaptic density. Exploratory analyses included discovery proteomics for pharmacodynamic biomarker identification and to understand the impact of CT1812 on CSF proteins detected in mild to moderate AD patients. Method: Unbiased quantification, using tandem‐mass tag mass spectrometry (TMT‐MS), of proteomes from AD patients given the S2R modulator CT1812 or placebo (N=18) was performed on baseline and end of study CSF to test two doses (100 mg, 300 mg) of CT1812 given once daily for 6 months in participants with mild‐moderate AD. Individual CSF proteomes were compared to within‐study pooled AD and non‐demented control CSF reference standards from the Emory ADRC to benchmark protein levels in SPARC participant CSF at baseline and to assess treatment effects, via differential expression analysis (one‐way ANOVA; p<0.05) and pathway analyses. Result: A total of 2,760 CSF proteins were detected across all CSF samples. Strong correlations (r>|0.70|) between TMT‐MS values and clinically validated ELISAs for canonical AD biomarker levels (Tau, NFL) were observed across participants and timepoints, confirming previous findings of TMT‐MS as a quantitative method. Differential expression analyses identified 327 proteins altered (one‐way ANOVA; p<0.05) in CT1812 vs placebo CSF. From a curated list of previously published AD biomarkers representing distinct pathways, a subset of proteins were found to be significantly altered by treatment with CT1812 compared to placebo (p<0.05), and included some proteins known to be genetically linked to AD. Pathway analysis identified statistically significant pathways (p<0.05) altered by CT1812, including that tied to inflammation, amyloid biology, and synaptic function. Conclusion: This study enabled the identification of candidate pharmacodynamic biomarkers that may reflect target/pathway engagement or disease modification, and extends proteomics CSF learnings from previous clinical trials with CT1812. Overall, this data suggest CT1812 may impact key proteins and pathways in AD and provides additional support for CT1812 to be further evaluated as a promising therapy for AD. [ABSTRACT FROM AUTHOR]

Background: Diffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer's Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology. Method: Thirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses. Results: AxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group. Conclusion: We found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss. [ABSTRACT FROM AUTHOR]

Background: Traditionally, [18F]FDG PET has been used in Alzheimer's disease (AD) as a surrogate marker of disease progression and is highly correlated with cognitive and functional decline. Synaptic loss is an early pathological event and a major structural correlate with cognitive impairment, although this is based on limited post‐mortem studies at more severe disease stages. Recently, we have confirmed these neuropathologic studies in vivo, using [11C]UBC‐J PET to demonstrate significant correlations between synaptic density and cognitive performance in early AD. In this study, we examined the relationship between synaptic density, glucose metabolism, and cognitive performance in early AD using [11C]UCB‐J PET, [18F]FDG PET, and an extensive neuropsychological battery. Method: [11C]UCB‐J and [18F]FDG binding was measured in 46 amyloid+ participants with AD (18 aMCI and 28 mild dementia) and 17 amyloid‐ cognitively normal participants aged 50‐85 years. Synaptic density was calculated as DVR and glucose metabolism as SUVR in a composite of AD‐affected regions, using a whole cerebellum reference region for both tracers. A validated neuropsychological battery assessed performance across six cognitive domains. Domain scores were calculated for each participant by averaging z‐scores within that domain, and global cognition scores averaged the domain scores. Result: In a multiple linear regression model controlling for age, sex, and education, glucose metabolism was a stronger predictor of global cognitive performance compared to synaptic density in participants with AD (beta=2.90,eta2=0.38,P=0.000005 vs. beta=2.48,eta2=0.22,P=0.001), as well as executive function, language, processing speed, visual memory, and visuospatial ability. Synaptic density was a stronger predictor of verbal memory compared to glucose metabolism (beta=1.68,eta2=0.22,P=0.001 vs. beta=1.02,eta2=0.10,P=0.03). Using William's tests, exploratory analyses demonstrated stronger correlations between medial temporal synaptic density and performance across all cognitive domains. In neocortical ROIs, glucose metabolism was more strongly correlated with cognitive performance across all domains with the exception of verbal memory, which demonstrated stronger correlations with synaptic density across all analyzed ROIs. Conclusion: Consistent with a hypothesis of divergent synaptic loss and hypometabolism in early AD, these results demonstrate synaptic density is more strongly correlated with cognitive decline in medial temporal regions, while cerebral hypometabolism is more strongly correlated with cognitive decline in neocortical regions. [ABSTRACT FROM AUTHOR]

Background: Tau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown. Methods: Cross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and sub‐threshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT. Results: There were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or sub‐threshold levels of amyloid. Conclusions: Tau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease. [ABSTRACT FROM AUTHOR]

Background: Tau pathology in Alzheimer's Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to "seed" pathology throughout the neuronal network. Recent discoveries indicate that tau phosphorylated at threonine 217 (pT217‐tau) can be captured in cerebrospinal fluid (CSF) and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixation of monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in layer II ERC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space. Method: We used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐31 years) to localize pT217‐tau in the stellate cell islands in ERC layer II, which show the earliest signatures of tau pathology in AD. Result: pT217‐tau immunolabeling was predominantly observed in postsynaptic compartments in macaque ERC layer II. pT217‐tau accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies in ERC layer II, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy. Conclusion: pT217‐tau accumulates in ERC layer II subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to "seed" tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD. [ABSTRACT FROM AUTHOR]

Background: Tau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown. Methods: Cross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and subthreshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT. Results: There were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or subthreshold levels of amyloid. Conclusions: Tau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease. [ABSTRACT FROM AUTHOR]

Background: Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment. Method: In this multicenter, randomized, placebo‐controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty‐one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)‐apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect. Result: Of the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (‐3.1, 95% CI ‐5.7 ‐ ‐0.5, p = 0.023) or agitation (‐3.6, 95% CI ‐6.1 ‐ ‐1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (‐4.1, 95% CI ‐6.7 ‐ ‐1.3, p = 0.004), taking at least one AD medication (‐4.0, 95% CI ‐6.9 ‐ ‐1.1, p = 0.008), highly educated (‐2.1, 95% CI ‐5.4 – 1.3, p = 0.231), and low functional capacity (‐2.6, 95% CI ‐5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale. Conclusion: Individuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer's disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation. [ABSTRACT FROM AUTHOR]

Background: EXERT, a multisite 18‐month RCT, is testing the effects of aerobic exercise vs. stretching on cognition and AD biomarkers in sedentary adults with MCI. In the first 12 months, participant exercise 2x/week under the supervision of YMCA trainers, and 2x/week on their own. In months 13‐18, participants continue to exercise 4x/week but without supervision. Here we describe the impact of the COVID‐19 pandemic on delivery of this support‐intensive intervention that involved many challenges but also opportunities for innovation. Method: In February 2020, EXERT met the recruitment goal with 296 enrolled. In March 2020 when COVID‐19 incidence rates began to climb in the US, study assessments and per‐protocol intervention delivery were paused. During the pause, all YMCAs were closed, and the majority of study‐certified YMCA trainers were furloughed. Result: At the time of the pause (March 23), 153 participants were in the supervised phase of the study, and 65 participants were in the unsupervised phase. To keep participants engaged and encourage adherence to the intervention, sites initiated weekly calls with active participants to provide support, address barriers to exercise and collect self‐report adherence data. By September, 7 of 14 sites resumed study activities. Weekly call completion rates during the pause exceeded 85%, and participants reported completing a mean of 3.3 40‐minute exercise sessions per week. On these calls, participants frequently expressed gratitude for the regular contact. By February 2021, all sites resumed activities despite COVID infection rates that have continued to climb across the US. In response, supervised exercise for the majority of participants was transitioned from in‐person to web‐conferencing. Even with this change that can be challenging for MCI, supervised session adherence rates are 72% for the aerobic group and 79% for the stretching group. Retention has remained high at 87%. Conclusion: The COVID‐19 pandemic presented unprecedented challenges, but it also provided unique opportunities to adapt intervention delivery so that a community‐based exercise trial could continue – even during a debilitating global health crisis. EXERT's adaptations may ultimately impact resilience of the intervention to even the most challenging of circumstances that older adults with MCI will face now and in the future. [ABSTRACT FROM AUTHOR]

Background: Apathy is one of the most common and debilitating neuropsychiatric symptoms of Alzheimer's Disease (AD). Two previous trials that suggested methylphenidate was safe and efficacious involved only 60 participants each, followed for 6 weeks. A larger, longer‐lasting trial was required to confirm those promising findings. Methods: ADMET 2 was a phase III, placebo‐controlled, 6‐month, multi‐center, randomized (1:1, 20 mg methylphenidate per day or placebo) clinical trial that randomized 200 participants with AD and apathy. Primary outcomes included: (1) the mean difference on the Neuropsychiatric Inventory Apathy (NPI‐A) subscale scores measured as change from baseline to 6 months, and/or (2) the odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC) at month 6 compared with baseline. Secondary outcomes included change in cognition, safety, and cost‐effectiveness measured monthly for up to 6 months. Results: 200 individuals were randomized (65.8% were males; 34.2% were females; avg age=76 years; 75.3% had some college education or greater; mean Mini‐Mental State Examination score at baseline was 18.9). There was a larger difference in the methylphenidate group compared with the placebo group in NPI‐A score from baseline to 6 months using a mixed model (Mean difference = ‐1.25; 95% CI: ‐2.03, ‐0.47, p = 0.002) with the largest change observed during the first two months. At 6 months, the ADCS‐CGIC showed that 43.8% (39/89) of participants in the methylphenidate group improved compared with 35.2% (32/91) of study participants in the placebo group (odds ratio 1.90 (95% CI: 0.95, 3.84), favoring methylphenidate, but not reaching statistical significance (p = 0.071)). There were no significant differences in other assessments. The safety profile was similar between the two groups. Conclusion: ADMET 2 showed a small to medium benefit for methylphenidate in the treatment of apathy in AD. The effect was observed at 2 months and was sustained throughout the 6 months of the study. Adverse events were mild. These results support previous observations in smaller studies. Methylphenidate offers a viable treatment for patients suffering from apathy in AD. [ABSTRACT FROM AUTHOR]

Background: Synaptic loss is linked with Alzheimer's disease (AD) progression and provides a novel target for exploration with fluid and imaging biomarkers. Studies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early AD. The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. This study examined the association between a SV2A measured with brain [11C]UCB‐J–PET and cerebrospinal fluid (CSF) levels of SV2A. Method: Using [11C]UCB‐J binding to SV2A, synaptic density was measured in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT after a bolus injection of [11C]UCB‐J. Synaptic density was calculated as the distribution volume ratio (DVR) using SRTM2 with a cerebellum reference region. CSF SV2A was measured by an in‐house ELISA method. Result: As previously demonstrated, synaptic density measured with SV2A PET was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. CSF SV2A was also reduced in participants with AD (762 ± 148) pg/mL) compared to CN participants (935 ± 134 pg/mL, P = 0.01, Figure 1). Within the AD group (n = 21), CSF SV2A was significantly correlated with synaptic density measured with [11C]UCB‐J–PET in a composite of AD‐affected regions (r = 0.65, P = 0.001, Figure 2). A regional analysis showed that CSF and PET measures of SV2A were significantly correlated broadly in the neocortex, but not in medial temporal regions such as the hippocampus, entorhinal cortex, and amygdala. Conclusion: This study supports a previous report of decreased CSF SV2A in AD. In the primary analysis, SV2A measured in CSF and SV2A measured with brain PET were strongly correlated within a group of individuals with AD, indicating that decreases in both measures may reflect synaptic loss during disease progression. Further studies will focus on longitudinal changes in CSF and PET measures of SV2A, as well as other CSF measures of synaptic and neuronal damage to investigate the neurobiology of AD. [ABSTRACT FROM AUTHOR]

Background: Tau pathology emerges in a distinct spatial and temporal pattern in Alzheimer's Disease (AD). Anatomical studies in AD subjects and rhesus macaques show earliest signs of tau pathology in the stellate cell islands in entorhinal cortex (ERC) layer II. However, the molecular mechanisms that confer vulnerability to ERC layer II cells early in the disease course is unknown. Our previous research in monkeys showed early calcium dysregulation in layer II ERC, where phosphorylated tau accumulated on the calcium‐storing smooth endoplasmic reticulum (SER) under glutamatergic synapses, and PKA‐phosphorylated ryanodine receptors on the SER showed evidence of calcium leak. cAMP‐PKA magnification of calcium release has been seen in prefrontal cortex, associated with HCN channel opening to dynamically regulate synaptic strength. This process is regulated by phosphodiesterases (PDE), regulation that is lost with age. The current study examined whether this "signature of flexibility" could also be seen in layer II ERC, underlying vulnerability to tau pathology with advancing age. Method: We used high‐spatial resolution immunoEM to localize PDE4D and HCN1 in young rhesus macaque (7‐10y) ERC layer II. Result: PDE4D and HCN1 were primarily observed in postsynaptic compartments in macaque ERC layer II. In dendritic spines, PDE4D was concentrated on the SER spine apparatus and in postsynaptic density, and HCN1 expressed in the membrane near excitatory synapses. Within dendritic shafts, PDE4D labeling was observed along microtubules and near mitochondria, whereas HCN1 was organized in discrete clusters along the plasma membrane. PDE4D immunolabeling was also observed in astroglial leaflets ensheathing excitatory asymmetric synapses. Conclusion: PDE4D is optimally positioned to modulate cAMP microdomains and control calcium extrusion from the SER. HCN1 channels are localized in subcompartments to facilitate dynamic physiological representation of sensory experience and visual space governed by cAMP‐PKA signaling. The anatomical patterns in ERC layer II corroborate our findings in vulnerable glutamatergic circuits in prefrontal cortex, suggesting conserved molecular features in association cortices most susceptible in AD. These data suggest that PDE4D and HCN1 are positioned to provide a signature of flexibility in postsynaptic compartments in ERC layer II stellate cells, which becomes a signature of vulnerability when abrogated by advancing age. [ABSTRACT FROM AUTHOR]

Background: Results from the first Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) clinical trial showed Gantenerumab reduces amyloid‐β deposition in autosomal dominant Alzheimer disease individuals. However, it is uncertain whether these initial findings from [11C]PiB PET generalize to other amyloid‐β PET radiotracers. Method: We acquired [11C]PiB and [18F]AV45 PET in mutation positive DIAN‐TU participants in the gantenerumab (n=30) and placebo drug arms (n=19). Participants were assessed at baseline and Year 4; at each visit, [11C]PiB and [18F]AV45 PET were acquired, with at most 28 days between imaging sessions. Regional standardized uptake value ratios (SUVRs) were quantified using the PET Unified Pipeline. Annualized SUVR percent change between baseline and Year 4 for both radiotracers in both drug arms were calculated. Differences in SUVR change between radiotracers/drug arms were assessed using the Wilcoxon signed‐rank/rank‐sum test. Each test statistic is reported as a rank‐biserial correlation r accompanied by p‐values adjusted for false discovery control by the Benjamini‐Hochberg procedure at level q=0.20. Result: We observed a decrease from baseline to Year 4 SUVR in the gantenerumab arm, which was larger when studied with [11C]PiB than with [18F]AV45 PET in several regions, including the striatum and cingulate gyrus (r=[‐0.79,‐0.31], FDR‐adjusted p‐values=[0.00086,0.19], Figure 1). In contrast, we observed an increase in SUVR in the placebo arm, comparable in magnitude between [11C]PiB and [18F]AV45 PET (r=[‐0.15,0.68], FDR‐adjusted p‐values=[0.29,0.86]). Conclusion: Differences seen between the effects of gantenerumab in [11C]PiB versus [18F]AV45 PET suggest several regions, such as the striatum and cingulate gyrus, may be inappropriate for radiotracer harmonization in studies involving gantenerumab. More practically, the finding that anti‐amyloid‐β therapies may have different effects on signal across radiotracers suggests multi‐site studies of anti‐amyloid‐β treatments should agree on a single radiotracer for best results. Follow‐up postmortem studies will be conducted to determine the binding affinity of various amyloid‐β radiotracers to amyloid‐β plaques in this cohort. [ABSTRACT FROM AUTHOR]

Objective Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. Methods The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. Results AZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD. Ann Neurol 2015;77:953-971 [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer’s disease. Cognitive measures were also obtained. Methods: In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer’s disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer’s Disease Assessment Scale–cognitive portion was administered. Results: Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ1–40 and Aβ1–42 in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ1–40 and Aβ1–42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ1–40 in CSF (P < .01), but increased unbound Aβ1–42 in CSF in a dose-dependent manner. The Alzheimer’s Disease Assessment Scale–cognitive portion was unchanged after the 12-week antibody administration. Conclusions: Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ1–42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ1–42 from amyloid plaques. [Copyright &y& Elsevier]

Background: Calcium dysregulation may be an important etiological event in Alzheimer's Disease (AD). The presenilins (PS1/PS2) are components of the calcium‐storing smooth endoplasmic reticulum (SER), and PS1/PS2 mutations that cause autosomal dominant AD cause calcium leak from the SER. Recent studies of medial temporal lobe from animal models and patients with late‐onset AD have also found evidence of calcium leak from SER through PKA‐phosphorylated ryanodine receptors (pS2808RyR2). Thus, the SER may be a nexus for AD pathology. The current research used immunoelectron microscopy to visualize the SER in the aging rhesus monkey dorsolateral prefrontal cortex (dlPFC), a newly evolved brain region which subserves higher cognition and is vulnerable in AD. As aging increases calcium‐PKA signaling in dlPFC, we looked for evidence of pS2808RyR2, as well as PKA‐phosphorylated tau (pS214Tau), and for changes in the cAMP‐PKA regulatory protein, PDE4Ds. Finally, we examined the location of TREM2, a genetic risk factor for late‐onset AD that is linked to microglia, but was also observed on neuronal SER in the current study. Method: We used high‐spatial resolution immunoEM to localize PDE4D, pS2808RyR2, pS214Tau and TREM2 in aging rhesus monkey dlPFC. Result: The data show that the SER is a focus of age‐related pathology in association cortex, with loss of PDE4D from the SER in spines and dendrites, and increased PKA phosphorylation of pS2808RyR2, which causes calcium "leak". We also find evidence of increased PKA phosphorylation of pS214tau aggregating on the SER and microtubules, an important step that causes tau to detach from microtubules and aggregate, and primes tau for hyperphosphorylation and neurofibrillary tangle formation. Finally, we found TREM2 focused on the SER in spines and dendrites in neurons in addition to its expected location in glia. Thus, early‐onset (PS1/PS2), late‐onset (TREM2) and aging, all target the SER in the association cortical synapses most vulnerable to AD pathology. Conclusion: This nexus of genetic risks supports the hypothesis that calcium dysregulation is a key factor in AD neurodegeneration, an underappreciated mechanism in the AD field. Regulating internal calcium signaling in the aging cortex may provide an opportunity for therapeutic intervention at early stages of pathology. [ABSTRACT FROM AUTHOR]

Background: EXERT is a large multi‐site randomized controlled trial testing the effects of aerobic exercise vs. stretching (control) on cognition and biomarkers of brain health in sedentary adults with MCI. Here, we describe challenges and successes of strategies used to recruit the EXERT cohort. Method: EXERT recruited sedentary adults 65‐89 years old who were willing to exercise 4 days/week at the YMCA with trainer supervision for 12 months, and unsupervised for an additional 6 months. The trial is conducted at 14 clinical sites that include 30 corresponding YMCAs. The ADCS serves as the Coordinating Center, and intervention oversight is provided by Wake Forest School of Medicine in partnership with the YMCA. Result: EXERT recruitment occurred over 43 months and several strategies were deployed to address recruitment challenges. The most notable challenge was that EXERT aimed to recruit adults with a cognitive impairment that is mentally/physically taxing given the expectations of an intensive exercise intervention study. For these individuals, transportation to the YMCA was also often a barrier to participation. Early recruitment methods relied on memory clinic patient rosters and electronic health records, which yielded only a few enrollments. Use of other common strategies (e.g., newspaper advertising) was only minimally successful in identifying candidates. Recruitment gained momentum only after geotargeted mailings of pictorial postcards and brochures were initiated. After the first mailing at 3 sites, the rate of in‐person screenings increased by more than 100% (Figure 1). In total, 500,000 geotargeted mailings across all sites were sent from which more than 50% of all randomized participants were recruited. Recruitment also benefited from high‐profile media coverage (Maria Shriver video, NPR) in 2018 and 2019. Early in 2019, the ADCS established centralized telephone prescreening to reduce burden on site staff. A total of 692 mailing responders were prescreened by the ADCS, of whom 228 were referred to sites. As of January 2020, 984 study candidates completed in‐person screening and 278 participants were enrolled into EXERT. Conclusion: Age and geotargeted mass mailings combined with centralized telephone prescreening and national media campaigns proved to be effective strategies for enrolling people with MCI in a long‐term exercise trial. [ABSTRACT FROM AUTHOR]

Background: The study of neuroimmune function in Alzheimer's disease (AD) has been challenging, partly because the underlying mechanisms are still incompletely understood. Here we present the results of a novel imaging study in human subjects to assess microglial activity in cognitively normal (CN) participants compared to participants with mild cognitive impairment (MCI) or mild dementia (MD) due to AD. Method: This pilot study used positron emission tomography (PET) imaging with the radioligand 11C‐PBR28, which is specific for the 18 kDa‐translocator protein (TSPO), a marker sensitive to acute immune effects of lipopolysaccharide (LPS). The 11C‐PBR28 volume of distribution (VT) was measured from two scans, one at baseline and a second at 180 minutes after intravascular administration of lipopolysaccharide (LPS‐ 0.4 ng/Kg). We calculated microglia activation reserve index (MARI) as the proportional increase in binding of 11C‐PBR28, 180 minutes after the administration of the LPS: MARI = [(VT,LPS‐VT,Baseline)/ VT,Baseline] x 100. Results: CN participants had a significantly higher global cerebral MARI of 35% (SD 13%, n=5) compared to the AD group (MARI=15%, SD 15%, n=5, p=0.030). We found no significant differences between global 11C‐PBR‐28 VT at baseline in CN participants compared to the AD group. MARI values correlated with clinical dementia rating (CDR) ‐ sum of boxes (CDR‐SB) score (R2=0.55, p=0.013), but not with MOCA scores. Conversely baseline 11C‐PBR‐28 VT correlated with MOCA scores (R2=0.44, p=0.025) but not CDR‐SB. TSPO gene polymorphism (high vs. medium affinity binding) did not make a difference in the response pattern. Measurements of serum cytokines indicated that the response differences between the two groups were central and not related to the peripheral immune response. Conclusion: Our experiment presents preliminary human data on reduced brain microglial activity in AD.. Our novel method provides a unique opportunity to test the dynamic response of microglia in vivo. However, further investigations with larger sample sizes are required for better understanding of the role of microglia in AD. [ABSTRACT FROM AUTHOR]

Background: Early onset forms of Alzheimer's disease (AD) are driven by rare dominantly inherited genes; however, the predominant form of the disease is sporadic and occurs later in life through an unknown etiology. Sporadic AD emerges after age 60‐65 and preferentially afflicts the association cortex. Thus, a better understanding of how age‐related changes in vulnerable brain regions relate to AD pathology is crucial to developing novel treatments for the disease. AD is characterized by two main pathological hallmarks, tau neurofibrillary tangles and amyloid‐beta plaques. Tau pathology correlates with cognitive decline while amyloid pathology does not. Thus, we focused on the role of age‐related signaling changes on tau pathology. Dysregulated calcium signaling has long been hypothesized to play a major role in age‐related vulnerability to AD1. Thus, we investigated the impact of aging on calcium signaling in the vulnerable dorsolateral prefrontal cortex (dlPFC) of rhesus monkeys, focusing on regulation of and by cAMP‐PKA signaling in relationship to tau pathology. Monkeys provide a unique opportunity to study higher order cognitive circuits unique to primates while still being able to probe molecular networks to a degree that is not possible in human post‐mortem samples. Overall, we found a significant age‐related dysregulation of calcium‐cAMP‐PKA signaling that strongly associated with early stage tau pathology in rhesus monkey dlPFC. (1) Khachaturian, Z. S. C Alzheimer's & Dementia13, 178‐182.e17 (2017) Method: Patterns of molecular signaling were assessed via western blot and immuno‐electron microscopy of monkey dlPFC in animals ranging from 8 to 28 years of age. Mechanistic studies of the relationship between intracellular calcium and tau phosphorylation were performed in rat primary cortical cultures. Result: We observed a consistent pattern of calcium‐cAMP‐PKA dysregulation in the vulnerable dlPFC region of rhesus monkeys. We found a highly significant association between leaky ryanodine receptor calcium channels and early stage tau phosphorylation (pS214 and pS356). The link between these phosphorylation sites and intracellular calcium was validated through in vitro mechanistic studies. Conclusion: Age‐related dysregulation of calcium‐cAMP in the dlPFC is associated with early stage tau pathology and may explain the vulnerability of these circuits to degeneration. [ABSTRACT FROM AUTHOR]

Background: The study of neuroimmune function in Alzheimer's disease (AD) has been challenging, partly because the underlying mechanisms are still incompletely understood. Here we present the results of a novel imaging study in human subjects to assess microglial activity in cognitively normal (CN) participants compared to participants with mild cognitive impairment (MCI) or mild dementia (MD) due to AD. Method: This pilot study used positron emission tomography (PET) imaging with the radioligand 11C‐PBR28, which is specific for the 18 kDa‐translocator protein (TSPO), a marker sensitive to acute immune effects of lipopolysaccharide (LPS). The 11C‐PBR28 volume of distribution (VT) was measured from two scans, one at baseline and a second at 180 minutes after intravascular administration of lipopolysaccharide (LPS‐ 0.4 ng/Kg). We calculated microglia activation reserve index (MARI) as the proportional increase in binding of 11C‐PBR28, 180 minutes after the administration of the LPS: MARI = [(VT,LPS‐VT,Baseline)/ VT,Baseline] x 100. Results: CN participants had a significantly higher global cerebral MARI of 35% (SD 13%, n=5) compared to the AD group (MARI=15%, SD 15%, n=5, p=0.030). We found no significant differences between global 11C‐PBR‐28 VT at baseline in CN participants compared to the AD group. MARI values correlated with clinical dementia rating (CDR) ‐ sum of boxes (CDR‐SB) score (R2=0.55, p=0.013), but not with MOCA scores. Conversely baseline 11C‐PBR‐28 VT correlated with MOCA scores (R2=0.44, p=0.025) but not CDR‐SB. TSPO gene polymorphism (high vs. medium affinity binding) did not make a difference in the response pattern. Measurements of serum cytokines indicated that the response differences between the two groups were central and not related to the peripheral immune response. Conclusion: Our experiment presents preliminary human data on reduced brain microglial activity in AD. Our novel method provides a unique opportunity to test the dynamic response of microglia in vivo. However, further investigations with larger sample sizes are required for better understanding of the role of microglia in AD. [ABSTRACT FROM AUTHOR]

Background: Using [11C]UCB‐J–PET we have shown significant reductions in hippocampal SV2A specific binding as a marker of synaptic density in participants with early Alzheimer's disease (AD). However, postmortem studies have suggested more widespread neocortical reductions in synaptic density that are associated with fibrillary tau accumulation. Methods: We measured SV2A binding with [11C]UCB‐J‐PET in 34 participants with early AD (MMSE=23.1±4.1, CDR=0.5‐1.0) and 19 cognitively normal (CN) participants (MMSE=29.3±1.1, CDR=0). Amyloid status was confirmed by [11C]PiB‐PET. For [11C]UCB‐J‐PET, we calculated the distribution volume ratio (DVR) using a cerebellum reference. In a subset of 10 CN and 10 AD participants, we measured tau accumulation using [18F]flortaucipir‐PET. [18F]Flortaucipir standardized uptake value ratios (SUVRs) were calculated using an inferior cerebellum reference. Results: Our primary analysis of group differences in SV2A binding demonstrated a significant effect of group (F(1,51)=33.4, P<0.00001) and group*region (F(10,510)=2.4, P=0.01) as predictors of SV2A binding (DVR). Post‐hoc comparisons revealed significant group differences in all medial temporal regions and more broadly in neocortical regions (Figure 1). SV2A reductions in AD were most pronounced in the hippocampus (DVR–17.3%, P<0.00001; BPND–19.8%) and entorhinal cortex (DVR–15.7%, P<0.00001; BPND–17.6%), but also present in parahippocampal, amygdala, lateral temporal, prefrontal, posterior cingulate/precuneus, lateral parietal, and pericentral regions. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. In a smaller sample of participants with tau PET, AD participants demonstrated significantly higher entorhinal cortical (ERC) [18F]flortaucipir binding compared to CN participants (CN SUVR=1.11±0.12, AD SUVR=1.68±0.16, p<0.00001). ERC‐tau was inversely associated with hippocampal synaptic density (r=‐0.63, P=0.005). Synaptic density and tau were inversely associated in regions of early and later Braak stages (r=‐0.45 to ‐0.59, P<0.05). Conclusion: We observed widespread reductions of synaptic density with [11C]UCB‐J‐PET in medial temporal and neocortical regions in early AD. ERC tau accumulation was associated with lower hippocampal synaptic density. This inverse association may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus. Further longitudinal studies are needed to elucidate the chronology and topography of tau accumulation and synaptic loss in AD and their relationship. [ABSTRACT FROM AUTHOR]

Human postmortem studies have reported decreases with age in high-affinity nicotine binding in brain. We have been investigating in vivo the availability of the β2-containing nicotinic acetylcholine receptor (β2-nAChR) in healthy nonsmokers (18–85 years of age) using [123I]5-IA-85380 SPECT imaging. Age and regional β2-nAChR availability (VT,) have been observed to be inversely correlated in all brain regions analyzed, with decline ranging from 21% (cerebellum) to 36% (thalamus), or by up to 5% per decade of life. Preliminary results have confirmed postmortem reports of age-related decline in high-affinity nicotine binding with age and may elucidate the role of β2-nAChRs in the cognitive decline associated with aging. [ABSTRACT FROM AUTHOR]