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INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aβ) pathology frequently co‐exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate–severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aβ, as assessed by 18F‐AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aβ were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aβ. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aβ‐vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aβ pathology. The pattern of hippocampal atrophy could serve as a disease‐specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We assessed whether macro‐ and/or micro‐structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid‐β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS: Higher global efficiency of the limbic network, as well as free‐water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks. DISCUSSION: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties. Highlights: Aβ and tau were associated with longitudinal memory change over ∼7.5 years.White matter properties attenuated the impact of tau pathology on memory change.Health/risk factors were associated with white matter properties. [ABSTRACT FROM AUTHOR]

Background: White matter changes are hypothesized to be among the earliest changes occurring in the course of Alzheimer's disease (AD). We investigated associations between AD pathology, namely amyloid and tau, and white matter microstructural changes in cognitively unimpaired individuals at risk of AD dementia. We expected higher levels of pathology to be related to lower free‐water‐corrected fractional anisotropy. Method: We studied 223 cognitively normal older adults with PET and multi‐shell diffusion MRI from the PREVENT‐AD cohort. We first measured standardized uptake value ratios (SUVRs) in 40 brain regions for amyloid‐β (Aβ, i.e., lateral and medial prefrontal, parietal, lateral temporal, and cingulate cortical regions in both hemispheres) and 26 brain regions for tau (i.e., Braak stages I, III, and IV). We then used TractSeg, a deep learning framework, to segment 49 well‐established white matter bundles. We mapped free‐water‐corrected fractional anisotropy (FAT) in those bundles. Lastly, to explore the relationships between AD pathology and white matter microstructure across bundles, we applied two separate partial least squares analyses: one for Aβ pathology and one for tau (Figure 1). Result: We found one significant latent variable relating Aβ pathology to FAT. Specifically, higher levels of Aβ pathology were associated with the combination of higher levels of FAT within the rostral body of the uncinate fascicle and superior longitudinal fascicle (Figure 2A). We found two significant latent variables relating tau pathology to FAT for which higher levels of tau pathology were associated with elevated FAT within the uncinate fascicle, thalamo‐occipital bundle, optic radiation, inferior occipitofrontal fascicle, inferior longitudinal fascicle, middle longitudinal fascicle, etc. (Figure 2B). Conclusion: In cognitively unimpaired individuals at risk of AD, increased Aβ and tau pathology were associated with higher levels of FAT in AD‐related bundles. These unexpected findings may suggest an inverted U‐shape pattern between AD pathology and FAT in the preclinical phase of AD for which FAT values would start by increasing before decreasing later in the course of the disease. This first increase might be a marker of early pathological processes such as neuroinflammation or swelling. [ABSTRACT FROM AUTHOR]

Background: Females and individuals with a family history (FH) of Alzheimer's disease (AD) are considered at higher risk of sporadic AD. However, how sex and maternal/paternal heredity affects in vivo AD biomarkers is not well understood. Our objectives were to 1) assess if females or individuals with a first‐degree maternal FH of AD accumulate amyloid‐beta (Aβ) and/or tau faster than males or individuals with a first‐degree paternal FH of AD and 2) assess if both could influence the rate of Aβ driving tau in preclinical AD. Method: Two hundred and thirty‐five older adults (age 68.3 ± 5.1 years, 69.8% female) from the PREVENT‐AD cohort, cognitively unimpaired at baseline, underwent [18F]‐NAV4694 and [18F]‐AV1451 positron emission tomography (PET) scans. Longitudinal PET scans were available for 106 individuals (4.3 ± 0.4 years follow‐up). We extracted and averaged the standard uptake value ratio (SUVr) in fronto‐parietal regions for Aβ and in temporal regions for tau. We performed t‐tests and ANOVA models to assess sex or maternal/paternal FH (FHsex) differences in Aβ and tau burden or annual change. We then performed linear regression models with an interaction term between Aβ and sex (or Aβ and FHsex) on tau burden and annual change, plus additional models to adjust for age and education. Result: Sex and FHsex differences on Aβ and tau burden or annual rate of change did not reach significance although females tended to have higher tau SUVr at baseline (p = 0.053) (Figure 1 & 2). We found an interaction between Aβ and sex (훽 = ‐0.13, p = 0.008), and between Aβ and FHsex (훽 = 0.11, p = 0.03), on tau at baseline (Figure 3) suggesting that, for the same level of Aβ burden, females and individuals with paternal FH of AD had higher tau burden than males and individuals with maternal FH of AD. Results were similar when adjusted for age and education. Conclusion: Females and individuals with a paternal FH of AD might need less Aβ before developing AD‐related tau, but did not accumulate tau faster. Identifying individuals more vulnerable to AD pathology, by disentangling sex‐specific effects, would help to design personalized interventions for AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS: We measured longitudinal changes in plasma amyloid‐beta (Aβ)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. RESULTS: Aβ42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4‐year follow‐up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non‐carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aβ‐PET and tau‐PET positive showed faster plasma pTau181 and GFAP increase compared to PET‐negative individuals. DISCUSSION: Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. Highlights: Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD.Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non‐carriers.Female sex showed accelerated increase in plasma GFAP over time compared to males.Aβ42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden. [ABSTRACT FROM AUTHOR]

Background: To compare the post mortem uptake of [18F]MK6240 and [18F]PI2620 in the brain hemisphere, of A‐T‐ (CN) and A+T+ tissue Method: Autoradiography (ARG) imaging using [18F]MK6240 and [18F]PI2620 was used to assess uptake of CN and AD tissues. One study used sections of whole‐hemisphere of one CN tissue and one AD tissue. The uptake value of [18F]MK6240 was calculated from a regions of interest (ROI) drawn manually from the area of cortex gray matter (GM), cortex white matter (WM), and background (BG). Other study was 24 tissues from the prefrontal cortex (Pfc) (12CN, 12AD), hippocampus (Hip) (12 CN, 12 AD) and cerebellum (Cer) (12 CN, 12 AD) were evaluated with [18F]MK6240, and [18F]PI2620. The uptake value of [18F]MK6240 and [18F]PI2620 was calculated from ROI drawn manually from the area of pfc GM, hip GM and cer GM. Result: The ARG showed greater [18F]MK6240 uptake in AD than in CN tissue. There were significant differences between CN and AD tissue in terms of cortex gray GM distribution and cortex WM, but no significant differences in BG. These results also, there is no correlation between the specific activity of [18F]MK6240 and the uptake value in CN and AD tissues. In a second experiment, based on our findings there was a significant difference between CN and AD groups when assessed by [18F]MK6240 as well as [18F]PI2620 in the pfc_GM and hip_GM. Furthermore, we found no difference between AD and CN tissues when assessed by [18F]MK6240 and [18F]PI2620 in cerebellum GM. Ratio values Pfc/Cer and Hip/Cer assessed by [18F]MK6240 as well as there were significant differences between CN and AD. [18F]MK6240 and [18F]PI2620 were highly correlated in AD but not in CN brain tissues. Conclusion: We also found that [18F]PI2620 and [18F]MK6240 have similar brain uptake in post‐mortem tissue. [ABSTRACT FROM AUTHOR]

Background: To compare the performance of plasma p‐tau181, plasma‐NfL and FDG‐PET in the diagnosis of biological AD. Method: We included 787 participants (cognitively unimpaired (CU, n = 251), mild cognitive impairment (MCI, n = 412), and Alzheimer's dementia (AD, n = 124) from the ADNI database. Participants underwent measures of plasma p‐tau181, plasma‐NfL, CSF P‐tau181, [18F]FDG‐PET, amyloid‐PET and cognitive screening tests. ROC analyses were used to determine diagnostic accuracy of plasma P‐tau181, NfL and [18F]FDG‐PET using clinical diagnosis and core AD biomarkers (amyloid‐PET and CSF P‐tau181) as reference standards. We assessed whether plasma P‐tau181 and [18F]FDG‐PET diagnostic accuracies were significantly different with a bootstrap‐based test (pROC package in R). Second, correlations of [18F]FDG‐PET, plasma‐NfL, plasma P‐tau181 with P‐tau181 CSF, Aβ‐PET, and cognitive performance were evaluated. Correlation coefficients were compared via Cocor package, a statistical framework for comparing associations between intercorrelated measurements. Result: Across the total sample we observed that plasma P‐tau181, plasma‐NfL, and [18F]FDG‐PET were able to identify individuals with CSF evidence of AD as well as participants who are amyloid‐PET+. In the MCI group, plasma P‐tau181 outperformed [18F]FDG‐PET and plasma‐NfL in identifying AD pathophysiology measured via CSF P‐tau181 (p = 0.0007), and amyloid‐PET (p = 0.001). We also observed that both plasma P‐tau181, plasma‐NfL and [18F]FDG‐PET were associated with AD pathophysiology measured by core AD biomarkers (CSF and amyloid‐PET). However, [18F]FDG‐PET was more closely associated with cognitive outcomes than plasma P‐tau181 and plasma NfL (MoCA: p < 0.0001; MMSE: p< 0.0001; CDR‐SB: p < 0.0001) Conclusion: This study investigated the diagnostic properties of plasma P‐tau181 and two neurodegenerative biomarkers (plasma‐NfL and [18F]FDG‐PET) as well as their to identify biological AD. While plasma P‐tau181, plasma‐NfL concentrations and [18F]FDG‐PET were associated with AD pathophysiology measured by core AD biomarkers (CSF and amyloid‐PET), plasma P‐tau181 outperformed [18F]FDG‐PET and plasma‐NfL in identifying individuals with AD pathophysiology. However, we also observed that [18F]FDG‐PET was more strongly associated with neuropsychological assessments than plasma P‐tau181 and plasma‐NfL. Taken together, our study suggests that plasma P‐tau181 may aid in the evaluation of individuals by identifying those with underlying AD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) has been defined as a biological construct that can be determined using in vivo biomarkers. Recent studies confirmed the clinical value of the AT(N) framework when using Aβ and tau positron emission tomography (PET) scans in predicting progression from cognitively unimpaired to MCI. Our study aims to investigate if plasma biomarkers can yield similar predictive performance to PET biomarkers, and to also compare against cerebrospinal fluid (CSF) biomarkers Method: Individuals from the PREVENT‐AD cohort were included in the study. Participants had Aβ and tau plasma measurements and at least one year of clinical follow‐up thereafter (n = 278). A subset of participants had CSF measurements (n = 102) and/or PET scans (n = 133) also with 1‐year clinical follow‐up. Participants were cognitively unimpaired at the time of all biomarker measurements. MCI diagnoses were made by clinical consensus among expert clinical and research staff blind to plasma, CSF, PET, MRI and APOE genotype. We established thresholds of plasma and CSF Aβ and tau positivity based on >80% specificity in identifying individuals with significant levels of Aβ‐PET (plasma Aβ42/40 = 0.057; plasma pTau181 = 7.53 pg/mL; CSF Aβ42 = 961.37; CSF pTau181 = 66.59 pg/mL). Aβ ([18F]NAV4694) and tau ([18F]AV1451)PET thresholds were defined by the mean plus 2 standard deviations from young participants (Aβ SUVR cut‐off = 1.17; tau SUVR cut‐off = 1.24). Result: 36.8% (7/19) of the A+T+ plasma group progressed to MCI, 50% (4/8) of the A+T+ CSF group progressed to MCI, and 46.6% (7/15) A+T+ PET group progressed to MCI (Fig. 1).We found differences in MCI progression status between the A+T+ group compared to the A‐T‐ and A+T‐ groups across all biomarkers' measurements, with the A+T+ group always showing a higher rate of progression than the other two groups (post‐hoc chi‐square analyses; p<0.05). Conclusion: Abnormal levels of Aβ and tau plasma biomarkers can help predict near‐ term progression to MCI. When plasma thresholds are derived based on PET data, however, plasma biomarkers have a slightly lower specificity than PET and CSF biomarkers, and both plasma and CSF biomarkers are less sensitive than PET biomarkers. [ABSTRACT FROM AUTHOR]

Background: The preclinical stage of Alzheimer's disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants' disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) and neurofilament light chain(NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we aimed to evaluate the utility of using changes in plasma p‐tau181 and NfL as surrogate biomarkers for clinical trials targeting preclinical AD. Method: We access 257 CU older individuals that had available Aβ‐PET at baseline, as well as the baseline, up to 24‐month plasma p‐tau181 and NfL measures from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We calculate the estimated sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers. Result: We demonstrated that therapeutical clinical trials of 24‐month follow‐up using p‐tau181 and NfL would require 78% and 63% smaller sample sizes compared with a 12‐month follow‐up(Figure 1). The use of intermediate levels of Aβ(CL20‐40), rather than merely Aβ positivity, as an enrichment strategy reduced the sample size by 73% for p‐tau181 and 59% for NfL over 24 months. As demonstrated in Figure 2A the estimated cost of a clinical trial using only plasma biomarkers is lower than using neuroimaging biomarkers for surrogacy(Figure 2A). However, as showed by Figure 2B a trial including all Aβ positive individuals, the total estimated cost when considering surrogate biomarkers plus other related assessments are numerically higher using plasma than neuroimaging biomarkers; while trials including only individuals with intermediate Aβ levels, the cost was similar using plasma and neuroimaging biomarkers for surrogacy. Conclusion: Our results suggest that to monitor large scale large‐scale population interventions in CU Aβ positive individuals' plasma p‐tau181/ NfL could potentially be used. Furthermore, using a strategy that has been proposed in recent clinical trials, we demonstrated that the use of intermediate levels of Aβ is more cost‐effective than trials using Aβ‐positive individuals in clinical. [ABSTRACT FROM AUTHOR]

Introduction: [18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694. Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2‐year follow‐up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker‐defined groups Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow‐up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti‐amyloid therapies. [ABSTRACT FROM AUTHOR]

Background: Gold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau‐PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals. Method: Using the topographical information from [18F]MK6240 tau‐PET, we applied the Braak tau staging system to 324 living individuals. We used PET‐based Braak stage to model the trajectories of amyloid‐b, phosphorylated tau in cerebrospinal fluid (pTau181, pTau217, pTau231, pTau235) and plasma (pTau181, pTau231), neurodegeneration and cognitive symptoms. Result: PET‐based Braak stages were We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau‐PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III‐IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, while Braak stages V‐VI were incompatible with normal cognition. Follow up tau‐PET scans indicated sequential progression of in vivo Braak stages over time, with progression beyond Braak stage III requiring the presence of amyloid‐beta abnormality. Conclusion: Our results support PET‐based Braak staging as a framework to model the natural history of AD, as well as monitor AD severity from presymptomatic to clinical dementia phases. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [11C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug–occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [11C]martinostat using [11C]methyl triflate in ethanol, as opposed to the originally described synthesis using [11C]methyl iodide and DMSO. [11C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high‐performance liquid chromatography; 1.5–1.8 GBq (41–48 mCi; n = 3) of formulated [11C]martinostat was obtained from solid‐phase extraction using a hydrophilic–lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [11C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [11C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre‐release quality control testing. [ABSTRACT FROM AUTHOR]

Background: The spread of abnormal tau along connectivity‐based networks is a hallmark of Alzheimer's disease (AD). In addition, activated microglia was shown to affect tau spread across networks. However, traditional network approaches using atlas‐defined regions suffer from assuming within‐region homogenous connectivity, as well as abrupt and linear connectivity changes between the regions; while, in fact, brain structure and function exist as complex overlapping axes of connectivity variation. Here, we studied smooth/continuous spatial transitions or 'gradients' of connectivity and their link to gradients of pathology in AD. This work provides novel insights into brain architecture driving pathology spread. Method: We enrolled 220 individuals including 106 cognitively normal Aβ‐negative (A‐) and 37 A+, and 77 MCI/AD A+ (TRIAD). From diffusion‐weighted MRI and fMRI data, we estimated region‐to‐region fiber count and correlated timeseries, respectively, and averaged subject‐wise connectivity matrices to create structural and functional 'template connectomes'. From 18F‐MK6240 and 11C‐PBR28 PET data, we extracted regional tau and neuroinflammation SUVR values, respectively, and created covariance matrices for each disease stage. Next, the template connectomes/covariance matrices were subjected to non‐linear dimensionality reduction to extract embedded components ('gradients'). We correlated the primary gradients of functional or structural connectivity (G1FC/G1SC) with the primary and secondary gradients of tau or neuroinflammation (G1TAU/G2TAU; G1INFLAM/G2INFLAM). We employed three brain atlases for validation: high‐resolution customized Glasser‐atlas (1332 equally‐sized subregions), DKT, and Schaefer‐100. Result: G1FC replicated the previously reported 'uni‐to‐transmodal' functional gradient (Margulies 2016) and correlated strongly with G1TAU in cognitively impaired A+ (Fig.1 A); illustrating a common topographic variation in tau spread and functional connectivity in symptomatic stages. Conversely, G1SC ran between medial‐temporal‐lobe (MTL)/posterior and frontal/anterior regions, and correlated strongly with both G2TAU (Fig.1 B) and G1INFLAM (Fig.1 C) in cognitively (un)impaired A+; illustrating a common topographic variation in tau/microglia and structural connectivity already present at early disease stages. Different brain atlases led to similar results. Conclusion: We identified two gradients of continuous topographic variation in tau and neuroinflammation, potentially reflecting heterogeneity of AD‐subgroups. While microglial activation and early‐stage tau propagation may be largely dominated by structural organisation, later‐stage tau propagation may be more heterogeneously associated with variation in structural and particularly functional connectivity. [ABSTRACT FROM AUTHOR]

Background: It has already been shown that longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) correlate with longitudinal Alzheimer's disease (AD) progression. However, it is unclear whether longitudinal plasma p‐tau181 is a suitable measure to be used as a surrogate variable in clinical trials. This study aims to evaluate the utility of using longitudinal changes in plasma p‐tau181 to monitor drug effects in AD clinical trials. Method: We evaluated 715 individuals (227 cognitively unimpaired (CU) amyloid‐beta (Aβ) negative, 103 CU Aβ positive, 265 mild cognitive impairment (MCI) Aβ positive, and 120 Alzheimer's disease (AD) dementia Aβ positive) from the Alzheimer's Disease Neuroimaging Initiative. Individuals diagnosed with AD or MCI were classified as cognitive impaired (CI). The subjects had [18F]florbetapir Aβ PET at baseline and longitudinal plasma p‐tau181 (up to 4‐year follow‐up duration). We determined the longitudinal rates of change in plasma p‐tau181 concentrations and its effect sizes, calculated as mean change divided by the standard deviation. Logistic regression tested whether the longitudinal change in p‐tau181 status was associated with individuals' clinical deterioration. Result: Plasma p‐tau181 slope of change was positively associated with baseline plasma p‐tau concentrations (Fig 1). Longitudinal increase in plasma p‐tau181 was correlated with longitudinal worsening in cognition. Long‐term increase in plasma p‐tau181 values was more consistent in CU Aβ negative (48‐month effects size=0.4) and CU Aβ positive (48‐month effects size=0.6) than in CI Aβ positive (48‐month effects size=0.2) individuals (Fig 2). Conclusion: Monitoring change in plasma p‐tau181 status from negative to positive can be helpful to identify individuals on the verge of cognitive deterioration in clinical practice. Longitudinal changes in plasma p‐tau181 values can open a new frontier in AD research offering a cost‐effective and scalable alternative to be used as a surrogate variable in large‐scale trials designed to test the effects of population interventions on the natural history of tau pathology in elderly populations. [ABSTRACT FROM AUTHOR]

Background: Idiopathic rapid eye movement sleep behavior disorder is associated with increased risk of neurodegeneration, but the temporal evolution of regional perfusion, a marker of cerebral activity, has not been characterized. The objective of the current study was to study longitudinal regional perfusion in patients with idiopathic rapid eye movement sleep behavior disorder.Methods: Thirty-seven patients and 23 controls underwent high-resolution single-photon emission computed tomography. After 17 months on average, scans were repeated for idiopathic rapid eye movement sleep behavior disorder patients. We compared regional cerebral blood flow between groups and over time.Results: At baseline, patients showed lower relative regional perfusion in the anterior frontal and lateral parietotemporal cortex compared with controls. However, over time, patients showed an increase in relative regional perfusion in the anterior frontal, lateral parietal, and occipitotemporal cortex, reverting toward normal control levels.Conclusions: Patients with idiopathic rapid eye movement sleep behavior disorder showed significant areas of relative regional hypoperfusion, which disappeared over time to finally return to average levels, suggesting possible developing compensation in areas affected by neurodegeneration. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Neuroleptic drug-induced parkinsonism (NIP) is a leading cause of parkinsonism, particularly in aging. Based on abnormal dopamine transporter scan results, individuals displaying chronic NIP are often diagnosed with Lewy-body Parkinson's disease (PD), but this assumption needs further substantiation.Objective: To quantitate the profile of striatal dopaminergic nerve terminal density in NIP relative to PD.Methods: We used the positron emission tomography ligand [11 C](+)-dihydrotetrabenazine targeting vesicular monoamine transporter type 2 (VMAT2) binding sites and collected various clinical parameters (motor ratings, olfaction, polysomnography to document rapid eye movement sleep muscle activity, quantitative sensory testing for pain thresholds) possibly predicting binding results in patients older than age 50 living with schizophrenia spectrum disorders under long-term stable antipsychotic drug treatment, with (N = 11) or without (N = 11) chart documention of chronic NIP, and compared them to healthy volunteers (N = 11) and others medicated for PD (N = 12).Results: Striatal VMAT2 binding was dichotomous in the NIP group between those with spared (N = 5) or low (N = 6) PD-like values. Striatal binding reduction in the low VMAT2-NIP group was asymmetric without the gradient of maximal involvement in the posterior putamen typical of PD. Anosmia was the only nonmotor parameter measured matching the abnormal striatal VMAT2 binding status.Conclusion: These preliminary observations suggest that striatal VMAT2 binding is abnormal in a fraction of chronic NIP cases and differs in spatial distribution from PD. The possibility of a drug-induced axonopathy and resultant synaptopathy, as well as the evolution of the binding deficit, warrant further longitudinal studies in a large cohort. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background and Purpose: Fluorine‐18‐fluoroethoxybenzovesamicol([18F]‐FEOBV) is a PET radiotracer previously used in neurodegenerative diseases to quantify brain cholinergic denervation. The current exploratory study aimed at verifying the reliability of such an approach in Alzheimer's disease (AD) by demonstrating its concordance with MRI volumetry of the cholinergic basal forebrain (ChBF). Methods: The sample included 12 participants evenly divided between healthy volunteers and patients with AD. All participants underwent MRI ChBF volumetry and PET imaging with [18F]‐FEOBV. Comparisons were made between the two groups, and partial correlations were performed in the AD patients between [18F]‐FEOBV uptake in specific cortical regions of interest (ROIs) and volumetry of the corresponding ChBF subareas, which include the nucleus basalis of Meynert (Ch4), and the medial septum/vertical limb of the diagonal band of Broca (Ch1/2). Results: Patients with AD showed both lower ChBF‐Ch4 volumetric values and lower [18F]‐FEOBV cortical uptake than healthy volunteers. Volumes of the Ch4 subdivision were significantly correlated with the [18F]‐FEOBV uptake values observed in the relevant ROIs. Volumes of the Ch1/2, which remains relatively unaffected in AD, did not correlate with [18F]‐FEOBV uptake in the hippocampus, nor in any cortical area. Conclusion: These results suggest that cortical cholinergic denervation as measured with [18F]‐FEOBV PET is proportional to ChBF atrophy measured by MRI‐based volumetry, further supporting the reliability and validity of [18F]‐FEOBV PET to quantify cholinergic degeneration in AD. [ABSTRACT FROM AUTHOR]

Background: Tau pathology can spread through connectivity‐based networks, with certain regions (or epicenters) accumulating more tau than others. Such spatial vulnerabilities may be due to their unique apical position in the cortical hierarchy, which can be elucidated through 'gradients of connectivity' (Margulies 2016 PNAS). Prior work showed that the primary gradient of functional connectivity unveils a uni‐to‐transmodal topography of the healthy neocortex which highly correlates with a cognitive gradient of perception‐to‐abstraction. Here, we hypothesized that the gradients of functional/structural connectivity interact with tau to affect cognitive functions in Alzheimer's disease (AD). Method: We included 213 participants from TRIAD (103 CN Aβ‐, 103 CN Aβ+, and 75 CI Aβ+) with diffusion‐weighted MRI, resting‐state functional MRI, 18F‐MK6240 tau‐PET, and an extensive cognitive battery. We performed non‐linear dimensionality reduction on the individual functional and structural connectomes, and extracted the first components ('gradients') ‐explaining most variance (G1FC and G1SC). First, we compared G1FC_or_SC between diagnostic groups. Second, we investigated the interaction effect of G1FC_or_SC*tauSUVR on cognition (across 9 cognitive domains). Last, we investigated whether the tau‐cognition relationship changed in a topography‐specific manner along the cortical hierarchy, within (equally‐sized) gradient‐derived meta‐ROIs along G1FC_or_SC. Results were compared to Braak‐derived regional associations. Analyses were adjusted for age, sex, APOE, education, and multiple comparisons. Result: We observed reduced segregation of functional networks in AD compared to controls, with unimodal (lower‐order cognitive) and transmodal (higher‐order cognitive) regions moving closer on G1FC. This may indicate loss of network specialization in AD. Participants who had both higher tau and G1FC alterations had more cognitive impairment (Fig.1A; shown for MMSE/language). This interaction‐effect was less pronounced with G1SC (Fig.1B). Last, tau correlated with cognition in a topography‐specific progressive manner (i.e., along the transmodal‐unimodal G1FC axis and anterior‐posterior G1SC axis) (Fig.1C). Notably, tau correlated with delayed memory progressively along the posterior‐anterior G1SC axis (R2 = 0.93 in all and R2 = 0.95 in A+) and BraakI‐VI axis (R2 = 0.77 in all and R2 = 0.28 in A+). Conclusion: Our work supports the contribution of connectome‐driven tau distribution on cognitive impairment in AD. Connectome gradients may provide a spatial framework to study tau spreading along the major axes of brain organization underlying specific cognitive domains. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is associated with abnormal cerebral perfusion at wakefulness, but whether these anomalies evolve over time is unknown. Here, we examined longitudinal changes in regional cerebral blood flow (rCBF) distribution in late middle‐aged and older adults with treated or untreated OSA. Twelve controls (64.8 ± 8.0 years) and 23 participants with newly diagnosed OSA (67.8 ± 6.2 years) were evaluated with polysomnography and cerebral 99mTc‐HMPAO single‐photon emission computed tomography during wakeful rest. OSA participants were referred to a sleep apnea clinic and 13 of them decided to start continuous positive airway pressure (CPAP). Participants were tested again after 18 months. Voxel‐based analysis and extracted relative rCBF values were used to assess longitudinal changes. Untreated OSA participants showed decreased relative rCBF in the left hippocampus and the right parahippocampal gyrus over time, while treated participants showed trends for increased relative rCBF in the left hippocampus and the right parahippocampal gyrus. No changes were found over time in controls. Untreated OSA is associated with worsening relative rCBF in specific brain areas over time, while treated OSA shows the opposite. Considering that OSA possibly accelerates cognitive decline in older adults, CPAP treatment could help reduce risk for cognitive impairment. [ABSTRACT FROM AUTHOR]

Objective: Previous positron emission tomography (PET) studies using [11C]ABP688 show reduced metabotropic glutamate receptor type 5 (mGluR5) allosteric binding site availability in the epileptogenic hippocampus of mesial temporal lobe epilepsy (MTLE) patients. However, the link between mGluR5 abnormalities and postsurgical outcomes remains unclear. Here, we test whether reduced PET [11C]ABP688 binding in cornu ammonis (CA) sectors more vulnerable to glutamatergic excitotoxicity relates to surgical outcomes. Methods: We obtained magnetic resonance imaging (MRI) and [11C]ABP688‐PET from 31 unilateral MTLE patients and 30 healthy controls. MRI hippocampal subfields were segmented using FreeSurfer. To respect the lower PET special resolution, MRI‐derived anatomical subfields were combined into CA1–3, CA4/dentate gyrus, and Subiculum. Partial volume corrected [11C]ABP688 nondisplaceable binding potential (BPND) values were averaged across each subfield, and Z‐scores were calculated. Subfield [11C]ABP688‐BPND was compared between seizure‐free and non‐seizure‐free patients. In addition, we also assessed subfield volumes and [18F]fluorodeoxyglucose (FDG) uptake in each clinical group. Results: MTLE [11C]ABP688‐BPND was reduced in ipsilateral (epileptogenic) CA1–3 and CA4/dentate‐gyrus (p <.001, 95% confidence interval [CI] =.29–.51) compared to controls, with no difference in Subiculum. [11C]ABP688‐BPND and subfield volumes were compared between seizure‐free (Engel IA, n = 13) and non‐seizure‐free patients (Engel IC–III, n = 10). In ipsilateral CA1–3 only, [11C]ABP688‐BPND was lower in seizure‐free patients than in non‐seizure‐free patients (p =.012, 95% CI = 1.46–11.0) independently of volume. A subset analysis of 12 patients with [11C]ABP688‐PET+[18F]FDG‐PET showed no between‐group significant difference in [18F]FDG uptake, whereas CA1–3 [11C]ABP688‐BPND remained significantly lower in the seven of 12 seizure‐free patients (p =.03, 95% CI = −3.13 to −.21). Significance: Reduced mGluR5 allosteric site availability in hippocampal CA1–3, measured in vivo by [11C]ABP688‐PET, is associated with postsurgery seizure freedom independent of atrophy or hypometabolism. Information derived from hippocampal CA1–3 [11C]ABP688‐PET is a promising imaging biomarker potentially impactful in surgical decisions for MRI‐negative/PET‐negative MTLE patients. [ABSTRACT FROM AUTHOR]

Objective: Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [11 C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site.Methods: Thirty-one unilateral MTLE patients and 30 healthy controls underwent [11 C]ABP688 PET. We compared partial volume corrected [11 C]ABP688 nondisplaceable binding potentials (BPND ) between groups using region-of-interest and whole-brain voxelwise analyses. [18 F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [11 C]ABP688 BPND and [18 F]FDG uptake to compare lateralization and localization differences.Results: [11 C]ABP688 BPND was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [11 C]ABP688 BPND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [18 F]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow-up, 13 were seizure-free (Engel Ia) and showed significantly lower [11 C]ABP688 BPND in the ipsilateral entorhinal cortex.Interpretation: [11 C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [18 F]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1-11 ANN NEUROL 2019;85:218-228. [ABSTRACT FROM AUTHOR]

Background: Transentorhinal tau neurofibrillary tangles deposition is a typical finding in cognitively unimpaired (CU) elderly. Thus, how tau tangle spreads over the neocortex, leading to disease progression, is a pressing issue in Alzheimer's disease (AD). Although amyloid is postulated to trigger this spread, the fact that amyloid deposition is present in low concentrations in temporal structures challenges this framework. Here, we tested the hypothesis that brain amyloid burden interacts with medial temporal neuroinflammation unleashing tau spread over the neocortex. To assess neuroinflammation, we used [11C]PBR28 PET, a ligand that binds to the 18‐kDa translocator protein(TSPO), considerate a proxy of inflammation. Methods: TSPO polymorphism (rs6971) was genotyped in 678 participants from the Montreal catchment area (48% presented rs6971 polymorphism of high TSPO binders). Following inclusion/exclusion criteria, we studied 131 high TSPO binders (22 CU young, 63 CU elderly, 28 MCI, 18 AD). All individuals had PET; amyloid [18F]NAV4694, tau [18F]MK6240, and [11C]PBR28,as well as MRI, cognitive and genetic assessments. Structural equation modeling (SEM) tested associations between markers. Results: [11C]PBR28 uptake was progressively higher from CU to AD(Fig.1). [18F]NAV4694,[18F]MK6240, and [11C]PBR28 were correlated (Fig.2); however, analysis of variance suggested that an interaction between [18F]NAV4694and[11C]PBR28 on [18F]MK6240 best explain the association between these markers(P<0.0001). Voxel‐wise analysis, taking into consideration global and local tracer effects, suggests an interaction between global [18F]NAV4694 and medial temporal [11C]PBR28 on medial temporal [18F]MK6240(Fig.3). Stratified analysis revealed that individuals with abnormal amyloid, tau, and neuroinflammation (A+/T+/NI+) had elevated cognitive impairment and hippocampus atrophy(Fig.4). SEM suggests that global amyloid interacts with transentorhinal inflammation leading to tau spread over Braak II‐III(Fig.5). Subsequently, tau hierarchically spread from Braak III to VI. Models inverting the variables mentioned above or the order of Braak regions did not fit the data. Accumulation of tau only in Braak IV‐VI was associated with cognitive symptoms (Fig.6). Conclusion: Our results suggest that an interaction between global amyloid and medial temporal neuroinflammation triggers tau spread over the neocortex. Global amyloid may represent distant amyloid load or amyloid oligomers. Our results suggest individuals with tau deposition confined to transentorhinal cortex as targets for the use of anti‐inflammatory drugs in AD. [ABSTRACT FROM AUTHOR]

Background: Postmortem Braak staging provides an index of disease stage and has therefore been incorporated as a core neuropathological criterion for the diagnosis of Alzheimer's disease (AD). Recent in vivo studies using the tau positron emission tomography agent [18F]flortaucipir have shown low sensitivity to detect tau pathology in early Braak stages. These studies report Braak I‐II or greater in ∼20% of cognitively unimpaired elderly, in contrast to the ∼70‐90% of non‐zero Braak stage reported in postmortem studies. Here, we tested whether the novel high‐affinity tau tangles tracer [18F]MK‐6240 (6 fold > [18F]flortaucipir)can better identify individuals in the early stages of tau accumulation. Method: To this end, we studied 301 individuals (30 young adults, 138 cognitively unimpaired (CU) elderly, 67 mild cognitive impairment (MCI), 54 AD dementia, and 12 frontotemporal dementia (FTD)) with amyloid‐b[18F]NAV4694, tau [18F]MK‐6240, magnetic resonance imaging, and clinical assessments. Results: [18F]MK‐6240 discriminated AD from FTD dementia as well as predicted amyloid‐b positivity with the highest area under the curve in Braak I‐II region (=∼95‐100%)(Fig.1 and 2). [18F]MK‐6240 accumulation hierarchically followed the 6 Braak stages (Fig.3)in 98% of our population (Fig.4).91% of the elderly amyloid‐b positive and 46% of the elderly amyloid‐b negative displayed tau deposition, at least in the transentorhinal cortex (Braak I)(Fig.4). Cognition and amyloid‐b status explained most of the Braak stages variance (P<0.0001, R2=0.75). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid‐b, neurodegeneration, and cognitive impairment (P<0.0001). No single region‐of‐interest accurately segregated individuals into the 6 Braak stages (Fig.5). However, classification decision tree analysis suggested that a composite of transentorhinal, entorhinal, and hippocampal cortices(Braak I‐II) was the region‐of‐interest that best represented [18F]MK‐6240Braak stages (capacity of a region' SUVR cutoff segregating individuals in 7 levels (Braak 0‐VI)) (accuracy=86.2%)(Fig.6). Conclusion: Our results highlight that the hierarchical 6‐stage Braak model using [18F]MK‐6240 provides a robust index of early and late tau accumulation as well as disease stages in preclinical and symptomatic individuals. Tau positron emission tomography Braak staging using high‐affinity tracers has the potential to be incorporated in the diagnosis of living patients with AD. [ABSTRACT FROM AUTHOR]

Background: Preclinical models suggest that tau pathology spreads intracellularly, thought to explain the topographical distribution of tau observed in Alzheimer's disease (AD). However, these findings have yet to be extended to humans. Method: We assessed 131 cognitively unimpaired elderly and 63 AD individuals who underwent amyloid‐PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, fMRI and diffusion‐weighted MRI. Of the subjects with AD, 11 had behavioural/ dysexecutive AD, 18 had PCA and 11 had Logopenic variant PPA, while 23 subjects had an amnestic presentation (all were Ab+/Tau+). A voxelwise multivariate regression model was employed to determine the peak difference in [18F]MK6240 SUVR between each AD variant and CU elderly, with each clinical diagnosis entered as a different categorical variable and correcting for age, gender and MMSE score. Within each AD variant, the peak voxels derived from the regression model were used to compute the correlation between [18F]MK6240 SUVR in the seed voxel and [18F]MK6240 SUVR in every voxel, thus generating an [18F]MK6240 covariance network for each AD group. The same seeds were also employed in functional connectivity and diffusion tractography analyses in the CU elderly group. To determine whether the topographical distribution of tau pathology is related to connectivity properties of the human brain, we applied regression models to assess the relationship between functional/structural connectivity values from the CU population and [18F]MK6240 in each variant of AD. Result: Tau organization differed between AD groups, reflecting clinical phenotypes and organizing within distinct brain networks. Furthermore, structural (Figure 1) and functional (Figure 2) connectivity patterns of the human brain predicted in vivo [18F]MK6240 SUVR across the cerebral cortex in each variant of AD. Conclusion: These results support a framework in which the intrinsic connectivity of the human brain provides a scaffold for tau pathology to spread to anatomically distant regions. [ABSTRACT FROM AUTHOR]

Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTD) have provided evidence‐based dementia guidelines for Canadian clinicians and researchers. We present the results of the 5th CCCDTD, which convened in October 2019, to address topics chosen by the steering committee to reflect advances in the field, and build on previous guidelines. Topics included: (1) utility of the National Institute on Aging research framework for clinical Alzheimer's disease (AD) diagnosis; (2) updating diagnostic criteria for vascular cognitive impairment, and its management; (3) dementia case finding and detection; (4) neuroimaging and fluid biomarkers in diagnosis; (5) use of non‐cognitive markers of dementia for better dementia detection; (6) risk reduction/prevention; (7) psychosocial and non‐pharmacological interventions; and (8) deprescription of medications used to treat dementia. We hope the guidelines are useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence‐based approach to dementia. [ABSTRACT FROM AUTHOR]

Introduction: Mild behavioral impairment (MBI) is characterized by the emergence of neuropsychiatric symptoms in elderly persons. Here, we examine the associations between MBI and Alzheimer's disease (AD) biomarkers in asymptomatic elderly individuals. Methods: Ninety‐six cognitively normal elderly individuals underwent MRI, [18F]AZD4694 β‐amyloid‐PET, and [18F]MK6240 tau‐PET. MBI was assessed using the MBI Checklist (MBI‐C). Pearson's correlations and voxel‐based regressions were used to evaluate the relationship between MBI‐C score and [18F]AZD4694 retention, [18F]MK6240 retention, and gray matter (GM) volume. Results: Pearson correlations revealed a positive relationship between MBI‐C score and global and striatal [18F]AZD4694 standardized uptake value ratios (SUVRs). Voxel‐based regression analyses revealed a positive correlation between MBI‐C score and [18F]AZD4694 retention. No significant correlations were found between MBI‐C score and [18F]MK6240 retention or GM volume. Conclusion: We demonstrate for the first time a link between MBI and early AD pathology in a cognitively intact elderly population, supporting the use of the MBI‐C as a metric to enhance clinical trial enrolment. [ABSTRACT FROM AUTHOR]

Background: Binding in alpha‐synuclein containing brain regions have been described for both Flortaucipir ([18F]AV‐1451) and [18F]MK‐6240. Here we assessed whether alpha‐Synuclein constitutes a target for these tau imaging agents. Method: We used autoradiographic dot blot to validate specific and evaluate off‐target interactions of [18F]MK‐6240 and [18F]AV‐1451 using sarkosyl‐insoluble extracts from PSP, CBD, PiD, and AD cortical tissue which contain fibrillar forms of tau. Tissue concentrations of alpha‐Synuclein are orders of magnitude lower than NFTs leading us to use recombinant alpha‐Synuclein PFFs to evaluate potential off‐target interactions. Briefly, 1:100 dilutions of each preparation were incubated with 82 fmol of mass in a 30uL total volume. Samples were incubated for 90 minutes at 37°C. Reactions were terminated by pipetting the solution in triplicate onto a glass fiber filter held within a 96‐well dot‐blot aspiration device and the samples were immobilized. Unbound ligand was washed three times with ice cold PBS. The glass fiber filters were transferred to a cassette for exposure to autoradiographic film for 90 minutes and the activity in photostimulated luminescence units per mm2 was calculated using ImageJ software v.1.8.0. Result: Disintegrations were corrected for decay and normalized to cerebellar extracts for both ligands. [18F]MK‐6240 demonstrated high specificity, binding in AD extracts and AD extracts subject to trypsin treatment. [18F]AV‐1451 demonstrated similar binding in both native and trypsinized AD extracts, while also showing overlapping binding profiles in human alpha‐synuclein PFFs but not in mouse alpha‐synuclein PFFs. Conclusion: [18F]AV‐1451 binds to recombinant human alpha‐Synuclein PFFs as it does to native AD‐tau PHFs. Future experiments should assess patient derived alpha‐Synuclein aggregates as a potential off target binding to [18F]AV‐1451. [ABSTRACT FROM AUTHOR]

Background: A family of tropomyosin receptor kinases (TrkA/B/C) plays important roles in the regulation of neuronal differentiation, growth, and survival via their interactions with neurotrophins. A growing body of literature suggests the downregulation of Trk in many neurodegenerative conditions of the central nervous system (CNS), including Alzheimer's disease (AD). We recently reported the development of [18F]TRACK, the PET tracers for in vivo imaging of TrkB and its first in‐human study. Here, we wish to report a fully automated GMP‐compliant radiosynthesis of [18F]TRACK at high radiochemical purity (RCP) and molar activity and its preliminary evaluation in wild‐type and a transgenic rat model of AD. Method: Radiosynthesis was performed using Scintomics GRP automated module via copper‐catalyzed 18F‐fluorination of the chiral boron pinacolate precursor. Brain imaging in wild‐type (n = 3) and TgF344‐AD rat models (n = 2) at 23 months was performed on microPET Concord R4 scanner. Result: [18F]TRACK was synthesized with a 5.0±1.4% radiochemical yield not corrected for decay (activity range 95‐154 mCi) with >99% RCP and molar activities of 250 ± 75 GBq/µmol (n = 6). The synthesis was fully automated and all batches passed quality control procedures, including chemical purity, sterility and pyrogenicity. The tracer showed moderate brain uptake in wild‐type rats with the highest accumulation in the thalamus (SUVmax = 1.56 ± 0.28, 10 min post‐injection), consistent with the brain regional distribution in humans acquired in a parallel study. Preliminary data suggests lower tracer uptake in TgF344‐AD rat model of AD in thalamus, striatum and frontal cortex compared to wild‐type animals. Conclusion: This study demonstrated the feasibility of the GMP‐compliant production of [18F]TRACK in sufficient doses and molar activities for scanning multiple subjects per day or long range deliveries. Preliminary biodistribution studies showed moderate brain uptake of the tracer with preferential accumulation in the thalamus across species. These findings warrants further studies of Trk brain expression and its implication in neurodegenerative and psychiatric pathologies using [18F]TRACK. [ABSTRACT FROM AUTHOR]

[18F]MK‐6240 (6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [18F]MK‐6240 was synthesized in one step from its bis‐Boc protected precursor N‐[(tert‐butoxy)carbonyl]‐N‐(6‐nitro‐3‐[1H‐pyrrolo[2,3‐c]pyridin‐1‐yl]isoquinolin‐5‐yl) carbamate in DMSO using [18F] fluoride with TEA HCO3 with step‐wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis‐Boc 18F‐labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single‐use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [18F]MK‐6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies. [18F]MK‐6240, a highly selective positron emission tomography (PET) radiotracer for the in vivo imaging of neurofibrillary tangles, was prepared by a simple one‐step reaction and validated for use in humans. [ABSTRACT FROM AUTHOR]

Molecular imaging techniques using 18F‐fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Understanding the underling pathophysiology of tau burden and its propagation through Braak stages is imperative in Alzheimer's disease (AD) and its clinical trial strategy. This multimodal PET study aimed to reveal the Aβ ([18F]AZD4694) and activated microglia ([11C]PBR28) converges to potentiate the NFTs ([18F]MK6240) deposition in AD in Braak stages. We hypothesized that the NFTs deposition driven by Aβ and neuroinflammation leads to cognitive. Method: A total of 108 participants (70 CN, 25 MCI, and 13 AD) with a high‐affinity binder for TSPO underwent 3 PET scans, MMSE and CDR‐SB. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. A total of 35 anatomical based regions including Braak stage 1 – 6 and its combination, 23 anatomical regions, and local‐to‐local interactive region were used to evaluate the important regional effect of amyloid and neuroinflammation on tau. All analyses were corrected for age, sex, education, APOE, and multiple correction using FDR. Result: We showed a significant synergistic local‐to‐local effect between Aβ and neuroinflammation on NFTs in Precuneus/PCC, basolateral temporal, and medial frontal cortices. Moreover, 3D cross‐regional regressions showed signification interactions between amyloid and neuroinflammation on tau on all Braak stages. Importantly, neuroinflammation in cingulate /precuneus demonstrated the greatest number of interactive effects on tau in the presence of amyloid. Last, global amyloid, cingulate neuroinflammation, and Braak stage 4 tau together led to worse MMSE (p = 0.03) while global amyloid and Braak stage 4 tau together led to worse CDR‐SB (p = 0.003). Conclusion: This study demonstrated the imperative role of microglia on tau propagation in the presence of amyloid. The microglial activation in the cingulate/precuneus, epicenter of the archetypical brain network, showed the most frequent effect together with global amyloid on tau loads on all Braak stages. Last, all 3 major targets of AD clinical trials led to worse cognitive score compared to its independent effect. This study underscores the local and distal effects of neuroinflammation and amyloid on Braak staging in AD, and shows molecular underpinnings for a promising combination therapy in AD. [ABSTRACT FROM AUTHOR]

Background: Increasing attention is being directed to atypical clinical presentations of Alzheimer's disease. The behavioural/dysexecutive variant of Alzheimer's disease is a rare clinical syndrome presenting with behavioural changes, apathy and executive dysfunction, similar to frontotemporal dementia. While initial autopsy studies identified pathology in the frontal cortex, recent studies challenge the notion of frontal involvement in this condition. Method: We assessed 14 cases of behavioural/dysexecutive Alzheimer's disease recruited from a tertiary care memory clinic, all of whom had biologically defined Alzheimer's disease (amyloid and tau positive). They were compared with 24 disease severity‐ and age‐matched amnestic Alzheimer's disease patients and a group of 131 cognitively unimpaired (CU) elderly individuals. All subjects were evaluated with [18F]AZD4694‐PET (amyloid‐b), [18F]MK6240‐PET (tau), MRI, genotyping for apolipoprotein E (APOE) and neuropsychological testing. Result: Voxelwise contrasts against CU elderly identified patterns of frontal cortical tau aggregation in the behavioural/dysexecutive group, with peaks in the anterior cingulate, frontal insula and orbitofrontal cortices. Amnestic Alzheimer's disease patients had larger differences in the lateral temporal, inferior parietal and posterior cingulate cortices. In contrast to tau‐PET, no differences were observed in the distribution of amyloid‐PET between both Alzheimer's disease groups. Finally, voxelwise regressions demonstrated significant relationships between frontal cortical tau load and severity of executive dysfunction (FWE corrected at p<0.001), while memory dysfunction was related to temporal and parietal tau load (FWE corrected at p<0.001). Conclusion: The association between frontal tau pathology and behavioural / dysexecutive clinical presentations provides in vivo support for a "frontal variant" of Alzheimer's disease as initially identified by autopsy studies. Our results also highlight the need for consensus clinical criteria for behavioural/dysexecutive Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: While fluid phosphorylated tau (pTau) epitopes are interpreted to be biomarkers of tau pathology according to the A/T/(N) framework, it is unclear to what extent they are preferentially associated with the defining histopathological hallmarks of Alzheimer's Disease (AD): amyloid‐β plaques and tau neurofibrillary tangles. Method: We studied 171 individuals, including young adults (n=27), cognitively unimpaired elderly (n=85), individuals with mild cognitive impairment (n=36) and individuals with Alzheimer's clinical syndrome (n=23), who were evaluated with [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, four tau phosphorylation sites in CSF (pTau181, pTau217, pTau231, pTau235) and two phosphorylation sites in plasma (pTau181, pTau231). To better understand the role of soluble biomarkers in AD diagnostic and research purposes, we evaluated associations between soluble pTau sites and cerebral amyloid‐PET and tau‐PET concentrations. Voxel‐wise linear regressions between fluid and imaging biomarkers were performed. Results for plasma and CSF pTau181 were replicated in an independent sample of 258 individuals included in the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI). Result: We observed that for all plasma and CSF epitopes, pTau is more closely associated with amyloid‐PET than with tau‐PET. Squared correlation coefficients (Spearman's R2) between CSF pTau epitopes and neocortical [18F]AZD4694 SUVR range from 0.48 to 0.63, while those for the temporal meta‐ROI [18F]MK6240 SUVR vary between 0.33 and 0.45 (p<0.001 for all phosphorylation sites). Using the R package "Cocor", for CSF pTau181, pTau217 and pTau231 the difference in correlation coefficients between both measures of imaging biomarkers appear significant (p<0.01). Voxel‐wise linear regression analyses further support these results, in particular showing sizable associations for CSF pTau231 with amyloid‐PET. In addition, soluble pTau is more closely correlated with medial temporal than with neocortical tau. All soluble pTau concentrations rise significantly with increasing amyloid‐β plaque load. In contrast, soluble pTau plateau as tau‐PET concentrations increase, starting at Braak stage III. These findings were replicated using plasma and CSF pTau181 in the ADNI cohort. Conclusion: Phosphorylated tau epitopes measured in CSF and plasma better reflect cerebral amyloidosis than neurofibrillary tangles in the brain. The current findings support careful interpretation of fluid pTau concentrations when implementing the A/T/(N) framework. [ABSTRACT FROM AUTHOR]

Background: A family of tropomyosin receptor kinases (TrkA/B/C) plays important roles in the regulation of neuronal differentiation, growth, and survival via their interactions with neurotrophins. A growing body of literature suggests the downregulation of Trk in many neurodegenerative conditions of the central nervous system (CNS), including Alzheimer's disease (AD). We recently reported the development of [18F]TRACK, the PET tracers for in vivo imaging of TrkB and its first in‐human study. Here, we wish to report a fully automated GMP‐compliant radiosynthesis of [18F]TRACK at high radiochemical purity (RCP) and molar activity and its preliminary evaluation in wild‐type and a transgenic rat model of AD. Method: Radiosynthesis was performed using Scintomics GRP automated module via copper‐catalyzed 18F‐fluorination of the chiral boron pinacolate precursor. Brain imaging in wild‐type (n = 3) and TgF344‐AD rat models (n = 2) at 23 months was performed on microPET Concord R4 scanner. Result: [18F]TRACK was synthesized with a 5.0±1.4 % radiochemical yield not corrected for decay (activity range 95–154 mCi) with >99% RCP and molar activities of 250 ± 75 GBq/µmol (n = 6). The synthesis was fully automated and all batches passed quality control procedures, including chemical purity, sterility and pyrogenicity. The tracer showed moderate brain uptake in wild‐type rats with the highest accumulation in the thalamus (SUVmax = 1.56 ± 0.28, 10 min post‐injection), consistent with the brain regional distribution in humans acquired in a parallel study. Preliminary data suggests lower tracer uptake in TgF344‐AD rat model of AD in thalamus, striatum and frontal cortex compared to wild‐type animals. Conclusion: This study demonstrated the feasibility of the GMP‐compliant production of [18F]TRACK in sufficient doses and molar activities for scanning multiple subjects per day or long range deliveries. Preliminary biodistribution studies showed moderate brain uptake of the tracer with preferential accumulation in the thalamus across species. These findings warrants further studies of Trk brain expression and its implication in neurodegenerative and psychiatric pathologies using [18F]TRACK. [ABSTRACT FROM AUTHOR]

Introduction Recent literature proposes that amyloid β (Aβ) and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia. Methods We stratified 314 mild cognitive impairment individuals using [ 18 F]florbetapir positron emission tomography Aβ imaging and cerebrospinal fluid p-tau. Regression and voxel-based logistic regression models with interaction terms evaluated 2-year changes in cognition and clinical status as a function of baseline biomarkers. Results We found that the synergism between [ 18 F]florbetapir and p-tau, rather than their additive effects, was associated with the cognitive decline and progression to AD. Furthermore, voxel-based analysis revealed that temporal and inferior parietal were the regions where the synergism determined an increased likelihood of developing AD. Discussion Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between Aβ and p-tau proteins. [ABSTRACT FROM AUTHOR]

A decade of research and development in resting-state functional MRI (RSfMRI) has opened new translational and clinical research frontiers. This review aims to bridge between technical and clinical researchers who seek reliable neuroimaging biomarkers for studying drug interactions with the brain. About 85 pharma-RSfMRI studies using BOLD signal (75% of all) or arterial spin labeling (ASL) were surveyed to investigate the acute effects of psychoactive drugs. Experimental designs and objectives include drug fingerprinting dose-response evaluation, biomarker validation and calibration, and translational studies. Common biomarkers in these studies include functional connectivity, graph metrics, cerebral blood flow and the amplitude and spectrum of BOLD fluctuations. Overall, RSfMRI-derived biomarkers seem to be sensitive to spatiotemporal dynamics of drug interactions with the brain. However, drugs cause both central and peripheral effects, thus exacerbate difficulties related to biological confounds, structured noise from motion and physiological confounds, as well as modeling and inference testing. Currently, these issues are not well explored, and heterogeneities in experimental design, data acquisition and preprocessing make comparative or meta-analysis of existing reports impossible. A unifying collaborative framework for data-sharing and data-mining is thus necessary for investigating the commonalities and differences in biomarker sensitivity and specificity, and establishing guidelines. Multimodal datasets including sham-placebo or active control sessions and repeated measurements of various psychometric, physiological, metabolic and neuroimaging phenotypes are essential for pharmacokinetic/pharmacodynamic modeling and interpretation of the findings. We provide a list of basic minimum and advanced options that can be considered in design and analyses of future pharma-RSfMRI studies. Hum Brain Mapp 38:2276-2325, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Compelling experimental evidence suggests that microglial activation is involved in the spread of tau neurofibrillary tangles over the neocortex in Alzheimer’s disease (AD). Here, we tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak‐like pattern in the human brain. Method: We studied 130 subjects (86 cognitively unimpaired and 44 cognitively impairment elderly) with microglia activation [11C]PBR28 PET, Amyloid [18F]NAV4694 PET, cognitive tests, magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. Participants also had baseline and follow‐up tau [18F]MK6240 PET scans. We used linear regressions and partial correlations to estimate the association between topographical distributions of microglial activation and tau accumulation. Result: (A)Microglial activation (MA) connectivity analysis between regions comprising Braak histopathological stages (Braak I‐VI) across our population demonstrated that MA regions correlated hierarchically with each other, where a Braak‐like stage region only correlates with the previous and subsequent stage. (B)Tau tangles connectivity analysis between regions that comprise Braak stages (Braak I‐VI) across our population demonstrated that tau regions correlated hierarchically with each other, where a Braak stage only correlates with the previous/subsequent stage (C)The scatterplot shows that the elements of the MA‐MA matrix and tau‐tau matrix were highly positively correlated with each other, reinforcing the notion of a joint topographic propagation of MA and tau tangles through Braak stages. (D) Rates of tau propagation over 1‐year hierarchically correlated in Braak stages. (E)Significant Pearson correlation between longitudinal tau propagation and baseline tau network. (F)Significant Pearson correlation between longitudinal tau propagation and baseline microglia network. (G)Partial residuals plots show the results of regression between network of tau propagation over 1‐year and both baseline topographic circuits, MA‐MA and tau‐tau networks. The model suggests that the pathways of longitudinal tau propagation depended on underlying microglia, rather than tau circuits. (H)The figure shows thatmicroglial activation levels in the transentorhinal cortex predicted longitudinal tau spread over the neocortex. Conclusion: Our results support a model in which an interaction between amyloid load and activated microglia set the pace for tau spread across Braak stages, while the simultaneous cerebral presence of these pathologies potentiates the development of dementia. [ABSTRACT FROM AUTHOR]

Background: Deposition of amyloid‐beta (Aβ) plaques and hyperphosphorylated tau are known hallmarks of Alzheimer’s disease (AD). In addition, neuroinflammation or microglia activation plays a role in AD pathophysiology and may be a potential driver of abnormal tau deposition. This study demonstrated the important brain regions where microglia activation, in addition to Aβ, is driving tau positivity in AD. Method: 120 participants from the TRIAD cohort underwent 18F‐AZD4694 amyloid‐PET, 18F‐MK620 tau‐PET, and 11C‐PBR28 neuroinflammation‐PET. All images were normalized to the ADNI template and quantified as SUVR in 35 regions‐of‐interest using cerebellar gray as the reference region. ANCOVA was used to assess the differences in levels of microglia activation between tau‐positive (T+; n=38) vs. tau‐negative (T‐; n=82), corrected for age, sex, APOE‐e4, education, and global Aβ. Tau status was based on both visual rating with elevated uptake in Braak1and2 and quantitative cut‐off of 1.22. In addition, step‐wise logistic regression was conducted to predict T+ in three steps: 1) the covariates, i.e. age, sex, APOEε4, and education, 2) covariates + global Aβ, and 3) covariates + global Aβ + activated microglia in each of the 35 ROIs, corrected for multiple comparisons using FDR. Our prediction model was trained based on a randomly selected 70%/30% training/test set. In order to investigate the stability of our model, this procedure was repeated 500 times. Result: Levels of microglia activation were significantly increased in T+ compared to T‐ in the posterior cingulate (p=0.0001), middle (p=0.02) and inferior (p=0.0005) temporal, fusiform (p=0.0004), and orbitofrontal cortex (p=0.005). Based on logistic regression and a likelihood‐ratio test between each step, we found that the ‘covariates + global Aβ model’ performed significantly better in predicting T+ than the ‘covariates‐only’ model (χ2(1)=72.64, p<0.0001). In the 3‐step model, the addition of activated microglia showed a significant improvement of the model’s performance to predict T+, particularly the activated microglia in the hippocampus (p=0.001), middle (p=0.006) and inferior (p=0.001) temporal, and fusiform (p=0.001) cortex. Receiver operating characteristic curves (ROC) and AUCs are shown in Fig 1. Conclusion: Our study demonstrated that activated microglia in the Braak2 to Braak4 regions play an important role in predicting tau positivity in addition to Aβ. [ABSTRACT FROM AUTHOR]

Background: As the only optically accessible part of the central nervous system, the retina represents an intriguing opportunity for the detection of biomarkers for Alzheimer's disease (AD). This study evaluated the performance of the Retinal Deep PhenotypingTM platform, a digital biomarker platform comprising a hyperspectral retinal camera and image analysis algorithms, for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in older adults. A set of phenotypic features that correlates with the cerebral amyloid status as determined by amyloid PET scan were identified and used to train a classifying algorithm. Method: Hyperspectral retinal images acquired with a Mydriatic Hyperspectral Retinal Camera from 194 participants (age ≥ 50 years), including cognitively normal and cognitively impaired (mild cognitive impairment and dementia) across 5 imaging sites were processed in order to train the model. Of these 194 participants, 73 individuals (38%) were amyloid‐positive, as confirmed by unanimous readings of PET scans by a panel of 3 expert reviewers. The pre‐processed hyperspectral images were segmented into various anatomical sites, and a texture‐based approach was used to extract several thousands of spatial‐spectral features. The most relevant features for the classification task were selected using a minimum redundancy maximum relevance (MRMR) algorithm and used to train a linear support vector machine (SVM) classifier. A nested, cross‐validation technique was used to evaluate the performance of the classifier. Result: The resulting model based on the 17 most significant features showed high performance to discriminate between amyloid positive and negative subjects with an area under the receiver operating curve (AUCROC) of 0.87 (95% CI: 0.83 – 0.92). Conclusion: The Retinal Deep PhenotypingTM platform shows promise for detecting the likely cerebral amyloid PET status in adults 50 years and older from a simple, non‐invasive retinal scan and could provide an accessible means to identify individuals with abnormal cerebral amyloid in a clinical or drug development context. This phenotyping platform provides a flexible approach that could also be used for the detection of multiple biomarkers involved in cognitive decline from the same hyperspectral images of the retina. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[11C]methyl-Ltryptophan (11C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional 11C-AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized 11C-AMT trapping in pre-frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized 11C-AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized 11C-AMT trapping in the brainstem and prefrontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre-existing 5-HT alterations pre-disposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms. [ABSTRACT FROM AUTHOR]

Background: p75‐neurotrophin receptor (p75NTR) plays an important role in cell death in adults and has been associated with age‐related basal forebrain degeneration and in Alzheimer's disease (AD). A recent study demonstrated the reduced pro‐inflammatory response and improvement of the functional outcome by blocking p75NTR following traumatic brain injury. Here, we aimed to test whether a novel p75NTR antagonist, EVT901, reduces neuroinflammation caused by AD pathology in the TgFAD344 rat model (Tg). We hypothesized that chronic administration of EVT901 will reduce the neuroinflammation caused by amyloidosis and hyperphosphorylated tau in the AD rat model. Method: Two parallel longitudinal studies were conducted to characterize the progression of amyloidosis and neuroinflammation in TgFAD344 rat models (WT = 15 & Tg = 22) and the effect of EVT901 on neuroinflammation (Tg = 6). In the first study, animals underwent 60‐minute dynamic PET scans using [18F]AZD4694 for amyloid‐beta and [11C]PBR28 for neuroinflammation at 15 and 22 months. During the intervention study, animals received 1 mg/kg of EVT901 for 7 days via tail vein injection at 22 months. These animals also underwent [11C]PBR28 PET one day before and after the intervention. The 1 mg/ml drug was prepared in a 10% PEG‐400/90% saline solution. All PET images were matched to the respective MRI and normalized to the average template. [18F]AZD4694 BPND and [11C]PBR28 BPND were quantified based on the SRTM method using pons and midbrain as a reference region, respectively. Result: The first study demonstrated a significant increase in [18F]AZD4694 and [11C]PBR28 uptake in both the hippocampus and neocortex in Tg compared to WT at baseline and follow‐up. TgFAD344 rats showed a longitudinal increase in [18F]AZD4694 and [11C]PBR28 binding in similar regions. Our second study demonstrated a significant reduction in [11C]PBR28 binding following the intervention in the hippocampus and parietotemporal cortex. Conclusion: This study demonstrated the amyloid pathology and neuroinflammation in the TgFAD344 rat model is captured by [18F]AZD4694 and [11C]PBR28 in vivo. Furthermore, a novel p75NTR antagonist, EVT901, reduces the neuroinflammation induced by AD pathophysiology. Blocking p75NTR can be considered a novel therapeutic target to reduce neuroinflammation in AD. [ABSTRACT FROM AUTHOR]

Background: Understanding sex dimorphism in neurodevelopment and neurodegeneration is imperative for therapeutic strategy, clinical trial enrichment, and personalized medicine. However, the cellular underpinning of sex dimorphism in Alzheimer's disease (AD) pathophysiology is still poorly understood. Here, we aimed to investigate the effect of sex on microglial activation and its effect on cognition using the major targets of AD clinical trials – amyloid ([18F]AZD4694), tau ([18F]MK6240), and neuroinflammation ([11C]PBR28) – through a multimodal PET study in humans and rats. Method: A total of 108 participants (70 CN, 25 MCI, and 13 AD; 36 M, 72 F) with a high‐affinity binder for TSPO from the TRIAD cohort underwent 3 PET scans and MMSE for cognitive assessment. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. Furthermore, 29 rats (8 WT, 21 Tg; 13 M, 16 F) underwent a 60‐min dynamic [18F]AZD4694 and [11C]PBR28 PET scans. All PET images were normalized to the average template. [18F]AZD4694 and [11C]PBR28 BPND were quantified based on SRTM method using Pons and midbrain as a reference region, respectively. The sex effect on neuroinflammation is evaluated based on a linear regression model in humans and rats. Consequently, sex dimorphism induced neuroinflammation effect on cognition was assessed using MMSE. All the models were corrected for age, APOE, education, amyloid and tau status. Result: In this study, females showed greater [11C]PBR28 binding in basal temporal regions in humans and parietotemporal cortex, hippocampus, and basal forebrain in rats. Consequently, greater neuroinflammation in females showed negative effects on MMSE but not in males, p = 0.033. Conclusion: This study demonstrated the greater microglia activation in females compared to males. Considering the difference in the microglia reaction to amyloidosis in rodents compared to humans, the increased microglial activation effect on cognition was only assessed in humans. Here, microglial sex dimorphism showed deleterious effects on cognition only in females. This study highlights the difference in microglial reactivity leading to greater vulnerability to cognitive decline in females. As such, it is imperative to explore a sex‐specific therapeutic strategy for AD clinical trial. [ABSTRACT FROM AUTHOR]

Background: We have demonstrated in vivo in humans that spatial progression of tau distribution and atrophy in Alzheimer's is largely driven by connectivity (Soucy et al, HAI2020). Nevertheless, local tau accumulation and atrophy should not progress in parallel during disease evolution. Atrophy keeps worsening, while local tau density (SUVRs estimated with PET) initially increases but could then decline because of tissue loss. Therefore, despite the impact of connectivity on progression of both local atrophy and SUVRs, it likely will not remain the same for both over time. This is what we tested in this work. Method: We studied 35 AD subjects from ADNI with 2 PET studies (18F‐florbetapir) at times Ta/Tb (mean elapsed time = 438 days, median = 454), and a T1 MRI at Ta. Eighteen subjects were non‐progressors (NP) and 17 were progressors (P) based on change between Ta/b hippocampal SUVRs values. This criterion was considered to represent how far advanced patients were in their disease. Moran I statistic was used to measure autocorrelations between connectivity and T1 MRI‐defined cortical thickness at Ta or tau PET SUVR values at both times Ta and Tb in NP and P subjects in regions separately analyzed based the "intensity" of their connectivity as defined by a standard connectivity map (Human Connectome Project). We defined 3 groups of regions from thresholds separating poorly connected from moderately connected (0.01) and moderately connected from highly connected ones (0.021). Result: In both NPs and Ps, regions with high connectivity showed higher Z‐score (4.06) of the Moran I value for correlations between regions' cortical thickness than those with low (2.64)/moderate (2.17) connectivity. For SUVR values however, in both NPs and Ps and at both time points, Z‐scores were always lower for the highly connected regions than for those with moderate/low connectivity. Conclusion: The way connectivity influences correlations of atrophy across regions is indeed different from the way it affects correlations of tau deposition, likely for the reasons we hypothesized above to guide the progression of each parameter. Models of tau propagation across the brain will need to factor in ongoing atrophy but reversible accumulation of tau. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests that middle‐aged subjects with early‐onset AD show higher tau burden and more rapid tau accumulation compared to elderly. Here, we aim to investigate the effects of age, the greatest risk factor in AD, on amyloid, tau, and neuroinflammation in late‐onset AD. We hypothesized the independent effect of age on amyloid and neuroinflammation. However, the effect of age on tau would depend on amyloid load in AD. Method: A total of 106 participants (66 A‐T‐, age 20‐86y; 40 A+T‐/A+T+, age 65‐84y) from the TRIAD cohort underwent static 40‐60min 18F‐AZD4694, 90‐110min 18F‐MK620, and 60‐90min 11C‐PBR28 SUVR, as well as MOCA and CDR‐SOB cognitive testing. All images were normalized to the ADNI template, and used cerebellar gray matter as the reference region. The effects of age on amyloid, tau, or neuroinflammation, as well as the interactive effect between age and AT status based on linear regression models. Last, the age‐dependent effect of amyloid, tau, or neuroinflammation on cognition is investigated. All models were corrected for sex, APOE, education, and remaining PET variables. Result: We showed a positive main effect of age on amyloid (p<0.001) or neuroinflammation (p=0.05) while no interactive effect between age and AT status was observed. However, a significant interaction between age and AT status on tau in Braakstage1‐2 (p=0.01), Braakstage3‐4 (p=0.001), and Braakstage5‐6 (p=0.002) were observed (Figure1). In relation to cognition, younger subjects with higher tau load performed worse on cognitive testing as shown by a significant negative interaction between age and tau on MOCA. In contrast, age and amyloid showed a positive interactive effect on cognition. Conclusion: Our study demonstrated that the age and amyloid or neuroinflammation have a positive association irrespective of the disease status. However, the effect of age on tau deposition depends on the amyloid load such that the presence of pathologic Ab leads to greater tau burden at younger age and worse cognition in late‐onset AD. This supports the framework where tau burden depends on amyloid load following the Ab cascade hypothesis. [ABSTRACT FROM AUTHOR]

Background: Translating recent advances in the diagnosis of Alzheimer's disease (AD) and other dementias to clinical practice using biomarker‐based approaches requires accessible, affordable biomarkers. This protocol tested the performance of a Retinal Deep Phenotyping platform for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in human subjects. This platform generates data rich retinal reflectance images captured non‐invasively with a Metabolic Hyperspectral Retinal Camera (MHRC) yielding specific spatial‐spectral features which are analyzed by a machine learning algorithm relatively to a recognized gold standard biomarker (in this case PET amyloid imaging). Methods: 134 subjects (50 years and older) from 3 clinical sites were included, 94 with normal, 40 with abnormal cognition, imaged with the MHRC and amyloid PET (unanimous visual reads from a panel of 3 expert reviewers; 42 amyloid positive, 92 negative). Over 600 spatial‐spectral features were extracted from hyperspectral retinal images obtained at 450‐900 nm. After a feature selection based on F‐score ranking, a classifier was trained on the datasets from 87 patients (2/3 of the cohort) using the most discriminating features. The classification performance was then evaluated with the datasets from the remaining 47 patients. Results: Resubstituting the training set of 87 patients into the classifier yielded sensitivity and specificity values of 88% and 91%, respectively. The training misclassification rate was predicted using the k‐fold loss metric, with a predicted error rate of 19%. To verify this performance, the test set of 47 patients was classified by the model resulting in sensitivity and specificity values of 80% and 81%, respectively. Conclusions: The Retinal Deep Phenotyping platform shows promise for detecting the likely cerebral amyloid PET status in human subjects and could serve as a screening tool to identify subjects in the AD continuum, for instance in a clinical or drug development context. The platform could also be used for the detection of other biomarkers involved in cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Translocator protein (TSPO) is an 18 kDa protein has been considered a target for neuroinflammation. Using multiparametric acquisitions, we tested in a large‐scale cohort the hypothetical framework proposing that neuroinflammation imposes vulnerability to neurofibrillary tangles (NFT) formation and propagation. Methods: We studied cognitive unimpaired and impaired individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort who had a complete baseline clinical and cognitive assessments, structural MRIs, [11C]PBR28, [18F]MK6240 and [18F]AZD4694 (PET proxies for TSPO, NFT and Αβ, respectively). The PET outcome measure was the SUVR. A fraction of these individuals also had CSF cytokines analysed using the Olink Platform. We conducted ROI path analysis and voxel‐based analysis to establish the associations between [11C]PBR28, [18F]MK6240 and [18F]AZD4694. Results: A total of 138 (CN=90; MCI=30=; AD=18) individuals were included in this analysis. We found that brain [11C]PBR28 uptake was correlated with CSF biomarkers of neuroinflammation. We also found an age‐related increase of [11C]PBR28 uptake. [11C]PBR28 was increased brain in AD related areas across the its clinical spectrum. [11C]PBR28 was associated with cognitive deficits in these individuals. In regards to tau aggregates, we found that [18F]MK6240 uptake in the mesial temporal structures derives from local interactions between [18F]AZD4694 and [11C]PBR28. Importantly, path analysis revealed that [11C]PBR28 and [18F]AZD4694 uptake potentiated the propagation of [18F]MK6240 from early to late Braak stages (Figure 1). Conclusions: Our results reveal that TSPO upregulation is part of the repertoire of biomarker alterations in patients within the entire AD clinical spectrum. TSPO is critical for the early and late tangle formation on medial temporal structures as well in advanced Braak stages. Neuroinflammation imaging agents such as [11C]PBR28 provide critical information regarding inflammatory tissue responses amenable of pharmacological interventions. [ABSTRACT FROM AUTHOR]

Background: We have demonstrated in vivo in humans that spatial progression of tau distribution and atrophy in Alzheimer's is largely driven by connectivity (Soucy et al, HAI2020). Nevertheless, local tau accumulation and atrophy should not progress in parallel during disease evolution. Atrophy keeps worsening, while local tau density (SUVRs estimated with PET) initially increases but could then decline because of tissue loss. Therefore, despite the impact of connectivity on progression of both local atrophy and SUVRs, it likely will not remain the same for both over time. This is what we tested in this work. Method: We studied 35 AD subjects from ADNI with 2 PET studies (18F‐florbetapir) at times Ta/Tb (mean elapsed time = 438 days, median = 454), and a T1 MRI at Ta. Eighteen subjects were non‐progressors (NP) and 17 were progressors (P) based on change between Ta/b hippocampal SUVRs values. This criterion was considered to represent how far advanced patients were in their disease. Moran I statistic was used to measure autocorrelations between connectivity and T1 MRI‐defined cortical thickness at Ta or tau PET SUVR values at both times Ta and Tb in NP and P subjects in regions separately analyzed based the "intensity" of their connectivity as defined by a standard connectivity map (Human Connectome Project). We defined 3 groups of regions from thresholds separating poorly connected from moderately connected (0.01) and moderately connected from highly connected ones (0.021). Result: In both NPs and Ps, regions with high connectivity showed higher Z‐score (4.06) of the Moran I value for correlations between regions' cortical thickness than those with low (2.64)/moderate (2.17) connectivity. For SUVR values however, in both NPs and Ps and at both time points, Z‐scores were always lower for the highly connected regions than for those with moderate/low connectivity. Conclusion: The way connectivity influences correlations of atrophy across regions is indeed different from the way it affects correlations of tau deposition, likely for the reasons we hypothesized above to guide the progression of each parameter. Models of tau propagation across the brain will need to factor in ongoing atrophy but reversible accumulation of tau. [ABSTRACT FROM AUTHOR]