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Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

Introduction The etiology of sporadic Alzheimer's disease (AD) requires non‐genetically modified animal models. Methods The relationship of tau phosphorylation to calcium‐cyclic adenosine monophosphate (cAMP)‐protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno‐electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques. Results Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808‐RyR2). Calcium also regulated early tau phosphorylation in vitro. Age‐related reductions in the calcium‐binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques. Discussion Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.

Introduction Synaptic loss is an early pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in the medial temporal and neocortical regions of participants with AD, using in vivo positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A), a promising biomarker of synaptic density. Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in AD however, have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivothe association between fibrillar Aβ deposition and synaptic density in early AD using [11C]PiB and [11C]UCB-J PET. We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI, a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). Methods [11C]UCB-J (for SV2A) and [11C]PiB (Aβ deposition) binding were measured in 14 participants with aMCI due to AD, 24 participants with mild AD dementia, and 19 cognitively normal (CN) participants aged 55-85 years. For [11C]PiB data analysis, parametric images of binding potential (BPND) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, BPNDwas computed using SRTM2 with a shrunken centrum semiovale reference region and converted to DVR with a cerebellum reference region. For the primary analysis of the association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI and dementia, separate univariate regression analyses were performed for each diagnostic group with Pearson r and associated two-tailed P values reported for each model. Fisher z-transformation assessed significant differences in correlation coefficients between the aMCI and dementia groups, with one-tailed P values reported. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Global Aβ deposition was determined for a composite of regions commonly affected by Aβ deposition in AD which included: prefrontal, lateral temporal, posterior cingulate/precuneus, and lateral parietal ROIs. Results The AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in the medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = -0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z= -1.80, P = 0.04; Figure 2).This stronger association was observed to survive partial volume correction (aMCI r= -0.56, P= 0.04; dementia r= -0.01, P= 0.96; Fisher z= -1.67, P= 0.047). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a nominal inverse association in the dementia group between local Aβ deposition and SV2A binding in medial occipital cortex and a more compelling, larger positive correlation between local Aβ accumulation and synaptic density in hippocampus (Table 1). Conclusions To our knowledge, we have conducted the first in vivo study investigating the relationship between Aβ deposition and synaptic alterations in participants with AD. We observed significant inverse associations between measures of global Aβ deposition and hippocampal synaptic density within participants with aMCI but not with dementia. Our findings lend support to a model in which fibrillar Aβ may still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research shouldinvestigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers. Funding P50-AG047270 (CHvD), P30-AG066508 [CHvD], K23-AG057794 (APM), R01-AG052560 (REC, CHV), R01-AG062276 (CHvD), Dana Foundation (MKC), T32-MH019961 (RSO), and Thomas P. Detre Fellowship (RSO).

11C-UCB-J is a PET tracer for synaptic vesicle glycoprotein 2A which may be a marker of synaptic density. To simplify the scan protocol, standardized uptake value ratios (SUVR) were compared to model-based binding potential (BPND) to select the optimal time window in healthy and neuropsychiatric subjects. Methods: A total of 141 scans were acquired for 90 min. Arterial blood sampling and metabolite analysis were conducted. SUVR-1 (centrum semiovale reference region) was computed for six 30-min windows and compared with 1-tissue compartment model BPND. Simulations were performed to assess the time dependency of SUVR-1. Results: Greater correlation and less bias were observed for SUVR-1 at later time windows for all subjects. Simulations showed that the agreement between SUVR-1 and BPND is time-dependent. Conclusion: The 60-90 min period provided the best match between SUVR-1 and BPND (-1±7%), thus, a short scan is sufficient for accurate quantification of 11C-UCB-J specific binding.

Introduction Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density. Methods We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11C]UCB‐J PET and a cerebellar reference region for calculation of the distribution volume ratio. Results We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. Conclusion We were able to measure widespread synaptic loss due to AD using [11C]UCB‐J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.

HMG-CoA reductase inhibitors (statins) have been proposed to both positively and negatively alter the cognitive trajectory of older adults. To further investigate the disparate findings (provided by the FDA black box warning, adverse event reports, case-control studies, observational studies, and randomized controlled trials) that have led to such proposals, this study explored the association between statin use and longitudinal cognitive change, as well as time to diagnostic conversion, using prospective longitudinal (i.e., 24 months follow-up) cohort data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). No associations between statin use and cognitive change were found for participants with cognitively normal status, late mild cognitive impairment, or dementia due to Alzheimer’s disease. However, there was an association between statin use and slower decline on a memory composite in participants with early mild cognitive impairment. Lastly, results did not support an association between statin use and conversion to a more severe diagnostic category for any diagnostic group. Thus, these findings do not provide support for the FDA black box warning that claims statin use causes cognitive deficits, but rather, suggest that additional randomized trials investigating statin use in participants in the prodromal early mild cognitive impairment stage of Alzheimer’s disease may be warranted. OBJECTIVE: To investigate associations between statin use and cognitive change, as well as diagnostic conversion, in individuals with cognitively normal (CN) status, mild cognitive impairment (MCI), and dementia due to Alzheimer’s disease (AD-dementia). METHODS: A multi-center cohort study with 1629 adults 48 to 91 years-old with CN status, early MCI (EMCI), late MCI (LMCI), or AD-dementia at baseline followed prospectively for 24 months. Statin use was assessed at baseline, and cognition was measured over time with a composite memory score, a composite executive function score, and a global cognition score (Alzheimer’s Disease Assessment Scale). Conversion to a more impaired diagnostic category was determined by clinician assessment. Repeated measures linear mixed effects models were used to evaluate associations between statin use and change in cognition over time. Cox proportional hazards models were used to evaluate associations between statin use and time to diagnostic conversion. All models were stratified by baseline diagnostic group. RESULTS: Statin use was not associated with change in cognitive measures for CN, LMCI, or AD-dementia participants. Among EMCI participants, statin use was associated with a significantly slower rate of decline on the memory composite, but no other cognitive measure. Statin use was not associated with time to conversion for any diagnostic group. CONCLUSIONS: This study did not support an association between statin use and diagnostic conversion but suggested a possible association between statin use and cognitive change in EMCI. Additional randomized clinical trials of statins may be warranted in the prodromal EMCI stage of AD.

Background Metabotropic glutamate subtype 5 receptors (mGluR5) modulate synaptic transmission and may constitute an important therapeutic target in Alzheimer’s disease (AD) by mediating the synaptotoxic action of amyloid-β oligomers. We utilized the positron emission tomography (PET) radioligand [18F]FPEB to investigate mGluR5 binding in early AD. Methods Sixteen individuals with amnestic mild cognitive impairment (MCI) due to AD or mild AD dementia who were positive for brain amyloid were compared to 15 cognitively normal (CN) participants who were negative for brain amyloid. Diagnostic groups were well balanced for age, sex, and education. Dynamic PET scans were acquired for 60 min, starting at 60 min after the initial administration of up to 185 MBq of [18F]FPEB using a bolus-plus-constant-infusion method (Kbol = 190 min). Equilibrium modeling with a cerebellum reference region was used to estimate [18F]FPEB binding (BPND) to mGluR5. Analyses were performed with and without corrections for gray matter atrophy and partial volume effects. Results Linear mixed model analysis demonstrated a significant effect of group (p = 0.011) and the group × region interaction (p = 0.0049) on BPND. Post hoc comparisons revealed a significant reduction (43%) in mGluR5 binding in the hippocampus of AD (BPND = 0.76 ± 0.41) compared to CN (BPND = 1.34 ± 0.58, p = 0.003, unpaired t test) participants, and a nonsignificant trend for a reduction in a composite association cortical region in AD (BPND = 1.57 ± 0.25) compared to CN (BPND = 1.86 ± 0.63, p = 0.093) participants. Exploratory analyses suggested additional mGluR5 reductions in the entorhinal cortex and parahippocampal gyrus in the AD group. In the overall sample, hippocampal mGluR5 binding was associated with episodic memory scores and global function. Conclusions [18F]FPEB-PET revealed reductions in hippocampal mGluR5 binding in early AD. Quantification of mGluR5 binding in AD may expand our understanding of AD pathogenesis and accelerate the development of novel biomarkers and treatments.

Sites of early neuropathologic change provide important clues regarding the initial clinical features of Alzheimer's disease (AD). We have shown significant reductions in hippocampal synaptic density in participants with AD, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to hippocampus via the perforant path. In this study, [11C]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A) and [18F]flortaucipir binding to tau were measured via PET in 10 participants with AD (5 mild cognitive impairment, 5 mild dementia) and 10 cognitively normal participants. In the overall sample, ERC tau was inversely associated with hippocampal synaptic density (r=-0.59, P=0.009). After correction for partial volume effects, the association of ERC tau with hippocampal synaptic density was stronger in the overall sample (r=-0.61, P=0.007) and in the AD group where the effect size was large, but not statistically significant (r=-0.58, P=0.06). This inverse association of ERC tau and hippocampal synaptic density may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus.

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 (18)F-FDG. METHODS: We implemented advanced deep learning methods using the U-Net model to predict (11)C-UCB-J PET images of synaptic vesicle protein 2A (SV2A), a surrogate of synaptic density, from (18)F-FDG PET data. Dynamic (18)F-FDG and (11)C-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 (11)C-UCB-J image prediction, four network models were trained and tested, which included 1) (18)F-FDG SUV ratio (SUVR) to (11)C-UCB-J SUVR, 2) (18)F-FDG K(i) ratio to (11)C-UCB-J SUVR, 3) (18)F-FDG SUVR to (11)C-UCB-J distribution volume ratio (DVR), and 4) (18)F-FDG K(i) ratio to (11)C-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, (18)F-FDG SUVR to (11)C-PiB SUVR network was also trained and tested for (11)C-PiB static image prediction. RESULTS: The results showed that all four network models obtained satisfactory (11)C-UCB-J static and parametric images. For (11)C-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 (18)F-FDG SUVR as the input, −0.7% ± 8.1% for the AD group, and −1.3% ± 7.0% for the CN group with (18)F-FDG K(i) ratio as the input. For (11)C-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 (18)F-FDG SUVR as the input, −0.7% ± 9.0% for the AD group, and −1.7% ± 7.8% for the CN group with (18)F-FDG K(i) ratio as the input. For (11)C-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 (11)C-UCB-J PET images from (18)F-FDG images with reasonable prediction accuracy. It is also possible to predict (11)C-PiB SUVR images from (18)F-FDG images, though the incorporation of additional non-imaging information is needed.

Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

Tauopathy is a hallmark pathology of Alzheimer’s disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer’s disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer’s disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer’s disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-β, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer’s disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-β. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-β was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer’s disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer’s disease.

Objective Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain mGluR5 availability. Methods Cognitively normal participants (n = 45), aged 18 to 84 years, underwent [18F]FPEB positron emission tomography scans to quantify brain mGluR5. Distribution volume (VT) was computed using a venous or arterial input function and equilibrium modeling from 90 to 120 minutes. In the primary analysis, the association between age and VT in the hippocampus and association cortex was evaluated using a linear mixed model. Exploratory analyses assessed the association between age and VT in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined. Results In the primary analysis, older age was associated with lower [18F]FPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction. Conclusion Reductions in mGluR5 availability with age appear to be largely mediated by tissue loss. Quantification of [18F]FPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss.

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.

Background Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer’s disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). Methods We measured SV2A binding ([11C]UCB-J) and Aβ deposition ([11C]PiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios (DVR) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Results We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = − 0.55, P = 0.04), but not mild dementia (r = 0.05, P = 0.82; difference statistically significant by Fisher z = − 1.80, P = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a “paradoxical” positive association between local Aβ deposition and SV2A binding in the hippocampus. Conclusions Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.

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.

Positron Emission Tomography (PET) is an important tool for studying Alzheimer’s disease (AD). PET scans can be used as diagnostics tools, and to provide molecular characterization of patients with cognitive disorders. However, multiple tracers are needed to measure glucose metabolism (\(^{18}\)F-FDG), synaptic vesicle protein (\(^{11}\)C-UCB-J), and \(\beta \)-amyloid (\(^{11}\)C-PiB). Administering multiple tracers to patient will lead to high radiation dose and cost. In addition, access to PET scans using new or less-available tracers with sophisticated production methods and short half-life isotopes may be very limited. Thus, it is desirable to develop an efficient multi-tracer PET synthesis model that can generate multi-tracer PET from single-tracer PET. Previous works on medical image synthesis focus on one-to-one fixed domain translations, and cannot simultaneously learn the feature from multi-tracer domains. Given 3 or more tracers, relying on previous methods will also create heavy burden on the number of models to be trained. To tackle these issues, we propose a 3D unified anatomy-aware cyclic adversarial network (UCAN) for translating multi-tracer PET volumes with one unified generative model, where MR with anatomical information is incorporated. Evaluations on a multi-tracer PET dataset demonstrate the feasibility that our UCAN can generate high-quality multi-tracer PET volumes, with NMSE less than \(15\%\) for all PET tracers. Our code is available at https://github.com/bbbbbbzhou/UCAN.

Age is the largest risk factor for Alzheimer’s disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D). Inhibition of PDE4D is currently under investigation as a therapeutic target for AD based on memory-enhancing effects in rodent hippocampus. Therefore, it is important to understand the role of PDE4D in brain regions particularly vulnerable to disease such as the frontal association cortex (FC), where cAMP signaling can impair working memory via opening of potassium channels. We found that PDE4D protein level was decreased in the FC of both moderately and extremely aged rats, and that PDE4D level was correlated with performance on a FC-dependent working memory task. In extremely aged rats, PDE4D was also inversely correlated with levels of phosphorylated tau at serine 214 (S214), a site phosphorylated by protein kinase A. In vitro studies of the PDE4D inhibitor, GEBR-7b, further illustrated that inhibition of PDE4D activity enhanced phosphorylation of tau. pS214-tau phosphorylation is associated with early AD tau pathology, promotes tau dissociation from microtubules and primes subsequent tau hyperphosphorylation at other critical AD-related sites. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the FC to degeneration in AD, and play a critical role in normal cAMP regulation, cautioning against the use of pan-PDE4D inhibitors as therapeutics.

This study evaluated the effect of the alpha-2A-adrenoceptor agonist guanfacine on prefrontally mediated cognitive functions, as well as quality of life and global function in healthy older participants. One hundred twenty-three participants aged 75 years and older were randomly assigned to guanfacine 0.5 mg, 0.1 mg, or placebo daily for 12 weeks. The primary outcome measure was the change in z-score for 6 prefrontal executive function tasks over 12 weeks (PEF6). Neither dose of guanfacine improved PEF6 z-score relative to placebo. The rate of mean change (95% confidence interval) in PEF6 z-score over 12 weeks was 0.270 (0.159, 0.380) for placebo, compared with 0.121 (0.011, 0.232) for guanfacine 0.1 mg (p = 0.06, compared to placebo) and 0.213 (0.101, 0.324) for 0.5 mg (p = 0.47). Neither dose of guanfacine improved the quality of life or global function relative to placebo. Among common adverse events, only dry mouth was significantly more frequent on guanfacine compared to placebo. Guanfacine failed to ameliorate prefrontal cognitive function in older individuals, who were cognitively normal for age.

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.

BACKGROUND: To evaluate the role of cortical amyloid deposition as a factor contributing to memory dysfunction and increased risk of dementia associated with late life depression (LLD). METHODS: 119 older adult participants with current diagnosis of Major Depression (LLD) from the ADNI Depression study and 119 non-depressed (ND) cognitively unimpaired participants matched on age, gender, and APOE genotype obtained from the ADNI database. RESULTS: Thirty-three percent of LLD participants met ADNI criteria for MCI. Compared to ND individuals, the LLD group exhibited less global amyloid (Aβ) accumulation (p = 0.05). The proportion of amyloid positivity in the LLD group was 19.3% compared to 31.1% for the ND participants (p =0.02). Among LLD participants, global Aβ was not associated with lifetime number of depressive episodes, lifetime length of depression, length of lifetime SSRI use, or lifetime length of untreated depression (p > 0.21 for all). Global Aβ was associated with worse memory performance (p = 0.05). Similar results were found in secondary analyses restricting comparisons to the cognitively unimpaired LLD participants and also when comparing the LLD group to a ND group which included MCI participants. CONCLUSIONS: Contrary to expectation, the LLD group showed less Aβ deposition than ND and Aβ deposition was not associated with depression history characteristics. Aβ was associated with memory but this relationship did not differ between LLD and ND. Our results suggest that memory deficits and accelerated cognitive decline reported in previous studies of late life depression is not due to greater cortical Aβ accumulation.

Introduction Synaptic loss has been cited as an early pathological event and major structural correlate of cognitive impairment in Alzheimer's disease (AD). However, this observation is based on limited neuropathological studies. Here, we examined the in vivo relationship between synaptic density and cognitive performance in early AD using [11C]UCB-J PET and an extensive neuropsychological battery. We used principal components analysis (PCA) to identify regional patterns of variance in synaptic density and then assessed the association between principle components (PC) scores with cognitive performance in AD. Methods [11C]UCB-J binding was measured in 45 amyloid+ participants with AD (17 amnestic MCI and 28 mild dementia) and 19 amyloid– cognitively normal participants aged 50-85. Synaptic density was calculated as the distribution volume ratio (DVR) in a composite of AD-affected regions, using the whole cerebellum as reference region. A validated neuropsychological battery assessed performance across five cognitive domains, and an estimate of global cognition was made by averaging z-scores from each of these domains. PCA was applied to the pooled population (n=64) using DVR values centered and standardized by region from each of 42 bilateral cortical and subcortical regions of interest (ROI). Pearson's correlations were used to determine relationships between principle component subject scores and measures of cognitive functioning. Results After application of PCA, parallel analysis determined three significant PCs explaining 75.2% of the total variance (PC1=58.1%, PC2=11.4%, PC3=5.7%). PC1 was characterized by only positive loadings of equally low contributions across the majority of ROIs (Figure 1A, Figure 2AB Table 1) with the exception of verbal memory (Pearson r=0.24, P=0.11), as well as with a measure of global synaptic density (Pearson r=0.97, P Conclusions We present the first in vivo evidence confirming previous neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance. Our findings reinforce synaptic density as a robust biomarker of disease severity and suggest this correlation extends to the early stages of AD. Without the use of diagnostic identifiers, a data-driven approach defined specific spatial patterns of synaptic density, which were in turn correlated with unique participant characteristics within the AD group. Funding P50-AG047270 (CHvD), P30-AG066508 [CHvD], K23-AG057794 (APM), R01-AG052560 (REC, CHV), R01-AG062276 (CHvD), Dana Foundation (MKC), T32-MH019961 (RSO), and Thomas P. Detre Fellowship (RSO).

Importance Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. Objective To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. Design, Setting, and participants This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included. Interventions Ten milligrams of methylphenidate, twice daily, vs matching placebo. Main Outcomes and Measures The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life. Results Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, −1.25; 95% CI, −2.03 to −0.47;P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91;P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84;P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04;P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups. Conclusions and Relevance This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease. Trial Registration ClinicalTrials.gov Identifier:NCT02346201

Epidemiological surveys suggest that excessive drinking is associated with higher risk of Alzheimer's disease (AD). The present study utilized data from the National Alzheimer's Coordinating Center to examine cognition as well as gray/white matter and ventricular volumes among participants with AD and alcohol use disorder (AD/AUD, n = 52), AD only (n = 701), AUD only (n = 67), and controls (n = 1283). AUD diagnosis was associated with higher Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in AD than in non-AD. AD performed worse on semantic fluency and Trail Making Test A + B (TMT A + B) and showed smaller total GMV, WMV, and larger ventricular volume than non-AD. AD had smaller regional GMV in the inferior/superior parietal cortex, hippocampal formation, occipital cortex, inferior frontal gyrus, posterior cingulate cortex, and isthmus cingulate cortex than non-AD. AUD had significantly smaller somatomotor cortical GMV and showed a trend towards smaller volume in the hippocampal formation, relative to non-AUD participants. Misuse of alcohol has an additive effect on dementia severity among AD participants. Smaller hippocampal volume is a common feature of both AD and AUD. Although AD is associated with more volumetric deficits overall, AD and AUD are associated with atrophy in largely distinct brain regions.

Purpose 11C-UCB-J PET imaging, targeting synaptic vesicle glycoprotein 2A (SV2A), has been shown to be a useful indicator of synaptic density in Alzheimer's disease (AD). For SV2A imaging, a decrease in apparent tracer uptake is often due to the combination of gray-matter (GM) atrophy and SV2A decrease in the remaining tissue. Our aim is to reveal the true SV2A change by performing partial volume correction (PVC). Methods We performed two PVC algorithms, Muller-Gartner (MG) and ‘iterative Yang’ (IY), on 17 AD participants and 11 cognitive normal (CN) participants using the brain-dedicated HRRT scanner. Distribution volume VT, the rate constant K1, binding potential BPND (centrum semiovale as reference region), and tissue volume were compared. Results In most regions, both PVC algorithms reduced the between-group differences. Alternatively, in hippocampus, IY increased the significance of between-group differences while MG reduced it (VT, BPND and K1 group differences: uncorrected: 20%, 27%, 17%; MG: 18%, 22%, 14%; IY: 22%, 28%, 17%). The group difference in hippocampal volume (10%) was substantially smaller than any PET measures. MG increased GM binding values to a greater extent than IY due to differences in algorithm assumptions. Conclusion 11C-UCB-J binding is significantly reduced in AD hippocampus, but PVC is important to adjust for significant volume reduction. After correction, PET measures are substantially more sensitive to group differences than volumetric MRI measures. Assumptions of each PVC algorithm are important and should be carefully examined and validated. For 11C-UCB-J, the less stringent assumptions of IY support its use as a PVC algorithm over MG.

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

Introduction Alzheimer's Disease (AD) pathology is traditionally characterized by the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau. However, an equally important pathology, synaptic loss, has been demonstrated to be an early event in the disease process and a major structural correlate of cognitive impairment. Recently, positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a novel biomarker of synaptic density. We have previously demonstrated extensive synaptic loss that is more widespread than reductions in gray matter volume in cortical and subcortical brain regions of participants with AD. The current study further investigates the association of local and global cortical amyloid burden with synaptic density. Methods [11C]UCB-J binding to SV2A and [11C]PiB binding to amyloid were measured in 38 participants with AD (14 amnestic MCI and 24 mild dementia) and 20 cognitively normal (CN) participants aged 55-85?years. For [11C]PiB image analysis, parametric images of the binding potential (BPND) were generated using SRTM2 with whole cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, parametric images of BPND were first computed using SRTM2 with a shrunken (2 mL) centrum semiovale (CS) reference region. BPND was then converted to DVR with a cerebellum reference region. Brain amyloid and synaptic density were measured in frontal, posterior cingulate/precuneus, lateral parietal, lateral temporal, medial temporal, lateral occipital, medial occipital, and pericentral regions of interest (ROIs). For [11C]PiB parametric images, a composite cortical DVR (representative of global amyloid burden) was calculated by combining the frontal, posterior cingulate/precuneus, lateral parietal, and lateral temporal regions. Results The study sample consisted of 58 participants (38 AD and 20 CN) with no group differences observed in sex (p=0.85), age (p=0.46), or education (p=0.06). AD participants had clinical characteristics typical of amnestic MCI and mild AD with CDR-global = 0.74±0.25 (p Conclusions Using [11C]UCB-J PET, widespread reductions of synaptic density in cortical and subcortical regions were observed in AD compared to CN participants. This included regions not traditionally associated with fibrillar amyloid pathology, such as the pericentral cortex. Interestingly, the cortical regions associated with the least robust accumulation of fibrillar amyloid (medial temporal cortex) were associated with the most pronounced reductions in synaptic density. Although significant negative associations between both global and local amyloid burden and regional synaptic density were observed for the pooled sample, this was driven by differences between diagnostic groups and was not significant within the AD group alone. Our findings are therefore consistent with previous postmortem studies describing the patterns of fibrillar amyloid burden and synaptic loss in AD. This research was funded by: NIA (P50AG047270 [CHvD], K23AG057784 [APM], R01AG052560 [REC, CHV], R01AG062276 [CHvD], and The Dana Foundation [MKC]), NIMH R25MH071584 and T32MH019961 (RSO), and the Detre T. Memorial Fellowship (RSO).

Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.

Background: Non-invasive brain stimulation (NIBS) has been widely used to treat mild cognitive impairment (MCI). However, there exists no consensus on the best stimulation sites. Objective: To explore potential stimulation locations for NIBS treatment in patients with MCI, combining meta- and resting state functional connectivity (rsFC) analyses. Methods: The meta-analysis was conducted to identify brain regions associated with MCI. Regions of interest (ROIs) were extracted based on this meta-analysis. The rsFC analysis was applied to 45 MCI patients to determine brain surface regions that are functionally connected with the above ROIs. Results: We found that the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus were the overlapping brain regions between our results and those of previous studies. In addition, we recommend that the temporoparietal junction (including the angular gyrus), which was found in both the meta- and rsFC analysis, should be considered in NIBS treatment of MCI. Furthermore, the bilateral orbital prefrontal gyrus, inferior temporal gyrus, medial superior frontal gyrus, and right inferior occipital gyrus may be potential brain stimulation sites for NIBS treatment of MCI. Conclusion: Our results provide several potential sites for NIBS, such as the DLFPC and inferior frontal gyrus, and may shed light on the locations of NIBS sites in the treatment of patients with MCI.

Collecting multiple modalities of neuroimaging data on the same subject is increasingly becoming the norm in clinical practice and research. Fusing multiple modalities to find related patterns is a challenge in neuroimaging analysis. Canonical correlation analysis (CCA) is commonly used as a symmetric data fusion technique to find related patterns among multiple modalities. In CCA-based data fusion, principal component analysis (PCA) is frequently applied as a preprocessing step to reduce data dimension followed by CCA on dimension-reduced data. PCA, however, does not differentiate between informative voxels from non-informative voxels in the dimension reduction step. Sparse PCA (sPCA) extends traditional PCA by adding sparse regularization that assigns zero weights to non-informative voxels. In this study, sPCA is incorporated into CCA-based fusion analysis and applied on neuroimaging data. A cross-validation method is developed and validated to optimize the parameters in sPCA. Different simulations are carried out to evaluate the improvement by introducing sparsity constraint to PCA. Four fusion methods including sPCA+CCA, PCA+CCA, parallel ICA and sparse CCA were applied on structural and functional magnetic resonance imaging data of mild cognitive impairment subjects and normal controls. Our results indicate that sPCA significantly can reduce the impact of non-informative voxels and lead to improved statistical power in uncovering disease-related patterns by a fusion analysis.

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification.

Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease.We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function.The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group.Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck SharpDohme; ClinicalTrials.gov number, NCT01953601.).

Mild cognitive impairment (MCI) is a transitional state between the cognitive changes in normal aging and Alzheimer’s disease (AD), which induces abnormalities in specific brain regions. Previous studies showed that paired helical filaments Tau (PHF-Tau) protein is a potential pathogenic protein which may cause abnormal brain function and structure in MCI and AD patients. However, the understanding of the PHF-Tau protein network in MCI patients is limited. In this study, 225 subjects with PHF-Tau Positron Emission Tomography (PET) images were divided into four groups based on whether they carried Apolipoprotein E ε4 (APOE 4) or abnormal cerebrospinal fluid Total-Tau (CSF T-Tau). They are two important pathogenic factors that might cause cognitive function impairment. The four groups were: individuals harboring CSF T-Tau pathology but no APOE 4 (APOE 4−T+); APOE 4 carriers with normal CSF T-Tau (APOE 4+T−); APOE 4 carriers with abnormal CSF T-Tau (APOE 4+T+); and APOE 4 noncarriers with abnormal CSF T-Tau (APOE 4−T−). We explored the topological organization of PHF-Tau networks in these four groups and calculated five kinds of network properties: clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Our findings showed that compared with APOE 4−T− group, the other three groups showed different alterations in the clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Simultaneously, voxel-level analysis was conducted and the results showed that compared with APOE 4−T− group, the other three groups were found increased PHF-Tau distribution in some brain regions. For APOE 4+T+ group, positive correlation was found between the value of PHF-Tau distribution in altered regions and Functional Assessment Questionnaire (FAQ) score. Our results indicated that the effects of APOE 4 and abnormal CSF T-Tau may induce abnormalities of PHF-Tau protein and APOE 4 has a greater impact on PHF-Tau than abnormal CSF T-Tau. Our results may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.

Introduction While brain structure during adolescence and early adulthood has been relatively well characterized in bipolar disorder (BD), it is still unclear how the brain's structure is affected by the illness in later life, and whether age of onset may influence age-related changes. Methods High resolution structural magnetic resonance images were acquired at 3 Tesla in 103 individuals with BD and 98 healthy controls (HC), ages 40 to 79 years. Categorical group comparisons (BD vs. HC), and analyses for group differences in age-related patterns, were performed for cortical thickness and grey matter volume. The BD group was also subdivided by age of first mood symptom onset, being either age 25 years and over (adult-onset, n=21) or below age 25 years (adolescent-onset, n=82), and the BD subgroups were compared to controls in a three-way analysis. Results Compared to the HC group, the overall BD group was characterized by lower cortical thickness within the insula and parahippocampus regions (pcorrected= 0.0054), and lower grey matter volume within the hippocampus, thalamus and putamen (pcorrected = 0.001). Significant age-related differences were not detected between the overall BD group and HC group. However, when individuals with BD were divided by those with adolescent or adult onset of the illness, the adult-onset BD subgroup showed significant age-related declines in insula and parahippocampal thickness, and hippocampal, thalamic and striatal grey matter volume, compared to the early-onset BD subgroup and HC group (p = 0.021). Conclusions The findings support structural abnormalities within the insula, parahippocampus, hippocampus, thalamus and striatum in adults with BD ages 40-79 years. Age-related decreases within the insula, parahippocampus and hippocampus may occur particularly in individuals with BD with onset after the age of 25 years. The results suggest that individuals with later onset of BD may be at a greater risk for age-related abnormalities in brain structure in brain systems that subserve emotional and cognitive processes. Funding Funding for the project was awarded by the National Institute of Mental Health.

ImportanceClinical guidelines currently recommend against amyloid imaging for cognitively unimpaired persons. The goal of Alzheimer's disease (AD) prevention, together with advances in understanding the pathophysiology of AD, however, has led to trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Assuming the eventual success of such trials, millions of patients will be affected. There is a need to understand the effects of biomarker disclosure on those individuals.DesignThe Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) involved 2 semi-structured telephone interviews with individuals who received amyloid PET scan results as part of screening for research participation. Post-disclosure interviews were conducted at 4 to 12 weeks and again 1 year later. Data were collected from November 5, 2014 to November 30, 2016. Interviews were transcribed and coded in NVivo 12.0.Participants80 adults aged 65 and older: 50 who received "elevated" and 30 who received "not-elevated" amyloid PET scan results.Main outcomesInterviews examined four domains: (1) comprehension of the amyloid PET scan result; (2) implications of the result for sense of self, memory, and future; (3) sharing of results with others; and (4) AD risk-reduction behaviors.ResultsParticipants who received an elevated amyloid PET scan result viewed the result as more serious and sensitive than other medical test results given its unique implications for identity, self-determination, and stigma. In contrast, participants who received a not-elevated amyloid PET scan result described feeling relief and reinterpreted perceived memory impairments as normal aging. Participants with elevated amyloid reported contemplating and making more changes to health behaviors and future plans than their peers with not-elevated amyloid.ConclusionsClinical practice in the diagnosis and treatment of persons with preclinical AD, a stage of the disease defined by the presence of biomarkers in the absence of cognitive impairment, will need to address matters of identity, stigma, and life-planning.

Objective To investigate optimal cutoff scores and the effects of normative adjustments on the performance of the Montreal Cognitive Assessment (MoCA) as a screening instrument for Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease (AD-dementia). Methods 499 adults 48 to 91 years-old enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and were administered the MoCA during baseline. Participants were classified as either cognitively normal (CN), MCI, or AD-dementia by clinical assessment. Receiver operating characteristic (ROC) analyses were performed using raw MoCA scores, education-adjusted MoCA scores, and a regression-based adjustment derived from the National Alzheimer's Coordinating Center data (NACC). Test performance characteristics were calculated for various cutoffs after each normative correction method. Results Areas under the curve (AUC) were similar for raw, education-adjusted, and NACC-adjusted MoCA scores, and demonstrated minimal improvement when adjustments of increasing complexity were applied. Our results suggest that the optimal cutoff score for distinguising MCI is 24 and for distinguising AD-dementia is 22. Conclusions This study adds to the understanding of how normative adjustments affect the sensitivity and specificity of the MoCA. Suggested corrections based on education alone do not yield improved test characteristics, but small improvements are attained when a regression-based correction that accounts for age, sex, and education is applied. Furthermore, optimal cutoffs for distinguishing CN from MCI or CN from AD-dementia were lower than previously reported. Optimal cutoffs to detect MCI and AD-dementia may vary in different populations, and further study is needed to determine appropriate use of the MoCA as a screening tool.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.