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We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Between January and August, 2010, 18–26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ1–42, total tau and phospho-tau181 concentrations, and plasma Aβ1–42 concentrations and Aβ1–42:Aβ1–40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ1–42 concentrations (p=0·008) and plasma Aβ1–42 concentrations (p=0·01) than non-carriers. Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ1–42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

Results of previous studies have shown associations between PET imaging of amyloid plaques and amyloid-β pathology measured at autopsy. However, these studies were small and not designed to prospectively measure sensitivity or specificity of amyloid PET imaging against a reference standard. We therefore prospectively compared the sensitivity and specificity of amyloid PET imaging with neuropathology at autopsy. This study was an extension of our previous imaging-to-autopsy study of participants recruited at 22 centres in the USA who had a life expectancy of less than 6 months at enrolment. Participants had autopsy within 2 years of PET imaging with florbetapir (18F). For one of the primary analyses, the interpretation of the florbetapir scans (majority interpretation of five nuclear medicine physicians, who classified each scan as amyloid positive or amyloid negative) was compared with amyloid pathology (assessed according to the Consortium to Establish a Registry for Alzheimer's Disease standards, and classed as amyloid positive for moderate or frequent plaques or amyloid negative for no or sparse plaques); correlation of the image analysis results with amyloid burden was tested as a coprimary endpoint. Correlation, sensitivity, and specificity analyses were also done in the subset of participants who had autopsy within 1 year of imaging as secondary endpoints. The study is registered with ClinicalTrials.gov, number NCT 01447719 (original study NCT 00857415). We included 59 participants (aged 47–103 years; cognitive status ranging from normal to advanced dementia). The sensitivity and specificity of florbetapir PET imaging for detection of moderate to frequent plaques were 92% (36 of 39; 95% CI 78–98) and 100% (20 of 20; 80–100%), respectively, in people who had autopsy within 2 years of PET imaging, and 96% (27 of 28; 80–100%) and 100% (18 of 18; 78–100%), respectively, for those who had autopsy within 1 year. Amyloid assessed semiquantitatively with florbetapir PET was correlated with the post-mortem amyloid burden in the participants who had an autopsy within 2 years (Spearman ρ=0·76; p<0·0001) and within 12 months between imaging and autopsy (0·79; p<0·0001). The results of this study validate the binary visual reading method approved in the USA for clinical use with florbetapir and suggest that florbetapir could be used to distinguish individuals with no or sparse amyloid plaques from those with moderate to frequent plaques. Additional research is needed to understand the prognostic implications of moderate to frequent plaque density. Avid Radiopharmaceuticals.

The pathological underpinnings of Alzheimer disease (AD) are now known to begin up to two decades before manifestation of clinical disease, and intervention during preclinical AD stages is increasingly recognized as key to therapeutic success. Here, Eric Reiman and colleagues discuss strategies to study changes in the brain and bodily fluids that precede clinical AD, focusing in particular on genetic at-risk individuals, who might be suitable candidates for secondary prevention trials. Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. Key Points The pathogenic cascade of Alzheimer disease (AD) is thought to begin at least one to two decades prior to cognitive impairment Disappointing results of several AD drugs in late-stage trials have suggested the need for early therapeutic intervention, calling for development of biomarkers and sensitive cognitive measures of preclinical disease The best established measurements for detection and tracking of preclinical and clinical AD include MRI, fluorodeoxyglucose PET, amyloid PET, and cerebrospinal fluid measures of amyloid-β 42 , total tau, and phospho-tau Studies of individuals with inherited AD can provide insights into cognitive and biomarker changes that precede clinical manifestation of AD, and are suitable candidates for ongoing monitoring and early-intervention strategies We are entering an era of AD prevention research, with a number of preclinical AD treatment trials in the planning stages or under way for several at-risk, cognitively unimpaired populations

Background There is an increasing interest in utilizing tau PET to identify patients early in Alzheimer’s disease (AD). In this work, a temporal lobe composite ( Eτ ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated. Methods A total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (AD signature ) (Devous et al., J Nucl Med 59:937–43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944–51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs ( Eτ+ /AD signature +; Eτ+ /AD signature –; Eτ −/AD signature −). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+ /AD signature − group and B2 NFT scores were created for visual evaluation of uptake. Results Sixty-four out of 390 analyzable subjects were identified as Eτ+ /AD signature –: 84% were Aβ+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+ /AD signature – status reflects an early stage of AD, Eτ+ /AD signature – subjects deteriorated significantly faster than Eτ– /AD signature – subjects, but significantly slower than Eτ+ /AD signature + subjects, on most measures (i.e., change in AD signature SUVr, Eτ ROI cortical thickness, and MMSE). The AD signature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+ /AD signature –. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects. Conclusion The Eτ VOI identified subjects with elevated temporal but not global tau ( Eτ+ /AD signature –) that were primarily Aβ+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+ /AD signature – subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ −/AD signature − subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer’s disease.

This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18 months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups ( p = 9e−17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms. ► Hypometabolic convergence index (HCI) is a FDG-PET based global single index. ► HCI reflects a person's cerebral hypometabolism pattern similarity to that of AD. ► HCI correlated with cognitive measures. ► HCI distinguished AD, MCI who converted to AD in 18 months, MCI who did not, and NC. ► MCIs with high HCI or small hippocampal volume had higher risk to convert to AD.

Abstract The spread of neurofibrillary tau pathology in Alzheimer disease (AD) mostly follows a stereotypical pattern of topographical progression but atypical patterns associated with interhemispheric asymmetry have been described. Because histopathological studies that used bilateral sampling are limited, this study aimed to assess interhemispheric tau pathology differences and the presence of topographically atypical cortical spreading patterns. Immunohistochemical staining for detection of tau pathology was performed in 23 regions of interest in 57 autopsy cases comparing bilateral cortical regions and hemispheres. Frequent mild (82% of cases) and occasional moderate (32%) interhemispheric density discrepancies were observed, whereas marked discrepancies were uncommon (7%) and restricted to occipital regions. Left and right hemispheric tau pathology dominance was observed with similar frequencies, except in Braak Stage VI that favored a left dominance. Interhemispheric Braak stage differences were observed in 16% of cases and were more frequent in advanced (IV–VI) versus early (I–III) stages. One atypical lobar topographical pattern in which occipital tau pathology density exceeded frontal lobe scores was identified in 4 cases favoring a left dominant asymmetry. We speculate that asymmetry and atypical topographical progression patterns may be associated with atypical AD clinical presentations and progression characteristics, which should be tested by comprehensive clinicopathological correlations.

Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.

INTRODUCTION The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O‐GlcNAcylation, an important post‐translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O‐GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O‐GlcNAcase (OGA) catalyzes the removal of O‐GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD. METHODS A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure‐based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O‐GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy. RESULTS Ceperognastat is a potent, central nervous system (CNS)‐penetrant, low‐dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat. DISCUSSION Ceperognastat is an orally available, highly potent, CNS‐penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O‐GlcNAc‐tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program. Highlights Ceperognastat is a highly potent, CNS‐penetrant OGA inhibitor. Ceperognastat is both orally available and CNS‐penetrant even when given at low doses. Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain. Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.

Tensor-based morphometry can recover three-dimensional longitudinal brain changes over time by nonlinearly registering baseline to follow-up MRI scans of the same subject. Here, we compared the anatomical distribution of longitudinal brain structural changes, over 12 months, using a subset of the ADNI dataset consisting of 20 patients with Alzheimer's disease (AD), 40 healthy elderly controls, and 40 individuals with mild cognitive impairment (MCI). Each individual longitudinal change map (Jacobian map) was created using an unbiased registration technique, and spatially normalized to a geometrically-centered average image based on healthy controls. Voxelwise statistical analyses revealed regional differences in atrophy rates, and these differences were correlated with clinical measures and biomarkers. Consistent with prior studies, we detected widespread cerebral atrophy in AD, and a more restricted atrophic pattern in MCI. In MCI, temporal lobe atrophy rates were correlated with changes in mini-mental state exam (MMSE) scores, clinical dementia rating (CDR), and logical/verbal learning memory scores. In AD, temporal atrophy rates were correlated with several biomarker indices, including a higher CSF level of p-tau protein, and a greater CSF tau/beta amyloid 1-42 (ABeta42) ratio. Temporal lobe atrophy was significantly faster in MCI subjects who converted to AD than in non-converters. Serial MRI scans can therefore be analyzed with nonlinear image registration to relate ongoing neurodegeneration to a variety of pathological biomarkers, cognitive changes, and conversion from MCI to AD, tracking disease progression in 3-dimensional detail.

This study examined the large-scale connectivity among multiple resting-state networks (RSNs) in the human brain. Independent component analysis was first applied to the resting-state functional MRI (fMRI) data acquired from 12 healthy young subjects for the separation of RSNs. Four sensory (lateral and medial visual, auditory, and sensory-motor) RSNs and four cognitive (default-mode, self-referential, dorsal and ventral attention) RSNs were identified. Gaussian Bayesian network (BN) learning approach was then used for the examination of the conditional dependencies among these RSNs and the construction of the network-to-network directional connectivity patterns. The BN based results demonstrated that sensory networks and cognitive networks were hierarchically organized. Specially, we found the sensory networks were highly intra-dependent and the cognitive networks were strongly intra-influenced. In addition, the results depicted dominant bottom-up connectivity from sensory networks to cognitive networks in which the self-referential and the default-mode networks might play respectively important roles in the process of resting-state information transfer and integration. The present study characterized the global connectivity relations among RSNs and delineated more characteristics of spontaneous activity dynamics. ► Resting-state networks were hierarchically organized. ► Highly intra-dependent sensory RSNs and strongly intra-influential cognitive RSNs. ► Bottom-up cross-network information processing was intrinsically engaged. ► Default-mode network was pivotal for the resting-state information integration.