Search

Beginning in the early stages of Alzheimer's disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a metric of the overlap between the rostral and caudal hippocampal functional networks, across the clinical spectrum of AD. We predicted a decline in rostral-caudal hippocampal convergence in the early stages of the disease. Using fMRI, we generated resting-state hippocampal functional networks across 56 controls, 48 early MCI (EMCI), 35 late MCI (LMCI), and 31 AD patients from the Alzheimer's Disease Neuroimaging Initiative cohort. For each diagnostic group, we performed a conjunction analysis and compared the rostral and caudal hippocampal network changes using a mixed effects linear model to estimate the convergence and differences between these networks, respectively. The conjunction analysis showed a reduction of rostral-caudal hippocampal convergence strength from early MCI to AD, independent of hippocampal atrophy. Our results demonstrate a parallel between the functional convergence within the hippocampus and disease stage, which is independent of brain atrophy. These findings support the concept that network convergence might contribute as a biomarker for connectivity dysfunction in early stages of AD. [ABSTRACT FROM AUTHOR]

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis., Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale., Results: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach., Discussion: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification., Highlights: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) phenotypes might result from differences in selective vulnerability. Evidence from preclinical models suggests that tau pathology has cell-to-cell propagation properties. Therefore, here, we tested the cell-to-cell propagation framework in the amnestic, visuospatial, language, and behavioral/dysexecutive phenotypes of AD. We report that each AD phenotype is associated with a distinct network-specific pattern of tau aggregation, where tau aggregation is concentrated in brain network hubs. In all AD phenotypes, regional tau load could be predicted by connectivity patterns of the human brain. Furthermore, regions with greater connectivity displayed similar rates of longitudinal tau accumulation in an independent cohort. Connectivity-based tau deposition was not restricted to a specific vulnerable network but was rather a general property of brain organization, linking selective vulnerability and transneuronal spreading models of neurodegeneration. Together, this study indicates that intrinsic brain connectivity provides a framework for tau aggregation across diverse phenotypic manifestations of AD.

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1-3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology., (© 2022. The Author(s).)

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β 42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

Background: Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase METHODS: We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([ 18 F]AZD4694) and tau ([ 18 F]MK6240) position emission tomography (PET) and clinical assessment FINDINGS: All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached INTERPRETATION: We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application FUNDING: Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec., Competing Interests: Declaration of interests EVM is the Chief scientific officer in ADx Neurosciences. ES and CF are employees of ADx NeuroSciences. SG has served as a consultant for TauRx, Biogen Canada Member and Roche Canada. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, and has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen. Alzheimer's Association Global Biomarker Standardization Consortium chair and cofounder of Brain Biomarker Solutions in gothenburg AB (BBS) which is a part of the GU ventures Incubator program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. CF, and ES and are employee of ADx NeuroSciences, Gent, Belgium, EVM is a co-founder of ADx NeuroSciences. The other authors declare no competing interest., (Copyright © 2022. Published by Elsevier B.V.)

Recent studies suggest a framework where white-matter (WM) atrophy plays an important role in fronto-temporal dementia (FTD) pathophysiology. However, these studies often overlook the fact that WM tracts bridging different brain regions may have different vulnerabilities to the disease and the relative contribution of grey-matter (GM) atrophy to this WM model, resulting in a less comprehensive understanding of the relationship between clinical symptoms and pathology. Using a common factor analysis to extract a semantic and an executive factor, we aimed to test the relative contribution of WM and GM of specific tracts in predicting cognition in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). We found that semantic symptoms were mainly dependent on short-range WM fibre disruption, while damage to long-range WM fibres was preferentially associated to executive dysfunction with the GM contribution to cognition being predominant for local processing. These results support the importance of the disruption of specific WM tracts to the core cognitive symptoms associated with FTD. As large-scale WM tracts, which are particularly vulnerable to vascular disease, were highly associated with executive dysfunction, our findings highlight the importance of controlling for risk factors associated with deep WM disease, such as vascular risk factors, in patients with FTD in order not to potentiate underlying executive dysfunction., Competing Interests: MS, TP, SS, TD, YI, MK, PV, JT, SM, AB, SG, PR No competing interests declared, (© 2022, Savard et al.)

Tracking longitudinal tau tangles accumulation across the Alzheimer's disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-β-negative, 22 cognitively unimpaired elderly amyloid-β-positive, 21 mild cognitive impairment amyloid-β-positive and 17 Alzheimer's disease dementia amyloid-β-positive individuals) with baseline amyloid-β 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90-110 min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer's disease dementia who died after the PET scans. We found that the cognitively unimpaired amyloid-β-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-β-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer's dementia amyloid-β-positive exhibited tau accumulation in Braak regions III-VI but not I-II. Cognitively impaired amyloid-β-positive individuals that were Braak II-IV at baseline displayed a 4.6-7.5% annual increase in tau accumulation in the Braak III-IV regions, whereas those who were cognitively impaired amyloid-β-positive Braak V-VI at baseline showed an 8.3-10.7% annual increase in the Braak regions V-VI. Neuropathological assessments confirmed PET-based Braak stages V-VI in the two brain donors. Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer's disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual's baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer's disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ-). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the AD-vulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials., (© 2020. The Author(s).)

Objective: To investigate the relationship between the topography of amyloid-β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia., Methods: We evaluated 154 individuals who were assessed with amyloid-β PET with [ 18 F]AZD4694, tau-PET with [ 18 F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid-β PET with [ 18 F]Florbetapir, tau-PET with [ 18 F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel-wise linear regressions between amyloid-PET, tau-PET, and their interaction with cognitive function, correcting for age, sex, and years of education., Results: In both cohorts, we observed that tau-PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR-SoB) scores independently of local amyloid-PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau-PET and clinical function were dependent on local amyloid-PET (FWE corrected at p < 0.001)., Interpretation: In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid-β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid-β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau's relationship with cognitive dysfunction was dependent on local amyloid-β concentrations. Our results provide evidence that amyloid-β in Alzheimer's disease influences cognition by potentiating the deleterious effects of tau pathology., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer's disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the other major proteinopathy of Alzheimer's disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer's disease subjects: (1) 211 participants who underwent tau-PET with [ 18 F]MK6240 and amyloid-PET with [ 18 F]AZD4694, (2) 264 individuals who underwent tau-PET with [ 18 F]Flortaucipir and amyloid-PET with [ 18 F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [ 18 F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer's disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies., (© 2020. The Author(s).)

Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([ 11 C]PBR28), amyloid-β (Aβ) ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [ 11 C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Alzheimer's disease is the leading cause of dementia worldwide and is characterized by a long preclinical phase in which amyloid-β and tau accumulate in the absence of cognitive decline. In vivo biomarkers for Alzheimer's disease are expensive, invasive and inaccessible, yet are critical for accurate disease diagnosis and patient management. Recent ultrasensitive methods to measure plasma phosphorylated tau 181 (p-tau181) display strong correlations with tau positron emission tomography, p-tau181 in CSF, and tau pathology at autopsy. The clinical utility of plasma-based p-tau181 biomarkers is unclear. In a longitudinal multicentre observational study, we assessed 1113 non-demented individuals (509 cognitively unimpaired elderly and 604 individuals with mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative who underwent neuropsychological assessments and were evaluated for plasma p-tau181. The primary outcome was a memory composite z-score. Mixed-effect models assessed rates of memory decline in relation to baseline plasma p-tau181, and whether plasma p-tau181 significantly predicted memory decline beyond widely available clinical and genetic data (age, sex, years of education, cardiovascular and metabolic conditions, and APOE ε 4 status). Participants were followed for a median of 4.1 years. Baseline plasma p-tau181 was associated with lower baseline memory (β estimate: -0.49, standard error: 0.06, t -value: -7.97), as well as faster rates of memory decline (β estimate: -0.11, standard error: 0.01, t -value: -7.37). Moreover, the inclusion of plasma p-tau181 resulted in improved prediction of memory decline beyond clinical and genetic data (marginal R 2 of 16.7-23%, χ 2  < 0.00001). Elevated baseline plasma p-tau181 was associated with higher rates of clinical progression to mild cognitive impairment (hazard ratio = 1.82, 95% confidence interval: 1.2-2.8) and from mild cognitive impairment to dementia (hazard ratio = 2.06, 95% confidence interval: 1.55-2.74). Our results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer's disease biomarker.P  < 0.00001). Elevated baseline plasma p-tau181 was associated with higher rates of clinical progression to mild cognitive impairment (hazard ratio = 1.82, 95% confidence interval: 1.2-2.8) and from mild cognitive impairment to dementia (hazard ratio = 2.06, 95% confidence interval: 1.55-2.74). Our results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer's disease biomarker., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The apolipoprotein E gene ( APOE ) is the most important genetic risk factor for sporadic Alzheimer disease, with the ε4 allele being associated with increased cerebral amyloid-β and tau pathologies. Although APOE has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of APOE and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and APOE , yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the APOE- by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [ 18 F]AZD4694 and [ 18 F]MK6240 were used to assess amyloid-β and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between APOE and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female APOEε4 carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [ 18 F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of APOE and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both APOEε4 carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Alzheimer's disease biomarkers are primarily evaluated through MRI, PET and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible and minimally invasive tools with diagnostic and prognostic value for Alzheimer's disease. Most recently, plasma phosphorylated tau181 has shown excellent performance. The relationship between plasma phosphorylated tau181 and cerebral metabolic dysfunction assessed by [ 18 F]fluorodeoxyglucose PET in Alzheimer's disease is still unknown. This study was performed on 892 older individuals (297 cognitively unimpaired; 595 cognitively impaired) from the Alzheimer's Disease Neuroimaging Initiative cohort. Plasma phosphorylated tau181 was assessed using single molecular array technology and metabolic dysfunction was indexed by [ 18 F]fluorodeoxyglucose PET. Cross-sectional associations between plasma and CSF phosphorylated tau181 and [ 18 F]fluorodeoxyglucose were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by β-amyloid status. Associations between baseline plasma phosphorylated tau181 and longitudinal (24 months) rate of brain metabolic decline were also assessed in 389 individuals with available data using correlations and voxelwise regression models. Plasma phosphorylated tau181 was elevated in β-amyloid positive and cognitively impaired individuals as well as in apolipoprotein E ε4 carriers and was significantly associated with age, worse cognitive performance and CSF phosphorylated tau181. Cross-sectional analyses showed strong associations between plasma phosphorylated tau181 and [ 18 F]fluorodeoxyglucose PET in cognitively impaired and β-amyloid positive individuals. Voxelwise longitudinal analyses showed that baseline plasma phosphorylated tau181 concentrations were significantly associated with annual rates of metabolic decline in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes. The associations between plasma phosphorylated tau181 and reduced brain metabolism, primarily in cognitively impaired and in β-amyloid positive individuals, supports the use of plasma phosphorylated tau181 as a simple, low-cost, minimally invasive and accessible tool to both assess current and predict future metabolic dysfunction associated with Alzheimer's disease, comparatively to PET, MRI and CSF methods., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers., Methods: We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by [ 18 F]flurodeoxyglucose ([ 18 F]FDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model., Results: A total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional [ 18 F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the [ 18 F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [ 18 F]FDG uptake in DIAD mutation non-carriers., Conclusions: The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.

To determine the extent of metabotropic glutamate receptor type 5 (mGluR5) network abnormalities associated with focal cortical dysplasia (FCD), we performed graph theoretical analysis of [ 11 C]ABP688 PET binding potentials (BP ND ), which allows for quantification of mGluR5 availability. Undirected graphs were constructed for the entire cortex in 17 FCD patients and 33 healthy controls using inter-regional similarity of [ 11 C]ABP688 BP ND . We assessed group differences in network integration between healthy controls and the ipsilateral and contralateral hemispheres of FCD patients. Compared to healthy controls, FCD patients showed reduced network efficiency and reduced small-world connectivity. The mGluR5 network of FCD patients was also less resilient to targeted removal of high centrality nodes, suggesting a less integrated network organization. In highly efficient hub nodes of FCD patients, we observed a significant negative correlation between local efficiency and duration of epilepsy only in the contralateral hemisphere, suggesting that some nodes may be more vulnerable to persistent epileptic activity. Our study provides the first in vivo evidence for a widespread reduction in cortical mGluR5 network integration in FCD patients. In addition, we find that ongoing epileptic activity may alter chemoarchitectural brain organization resulting in reduced efficiency in distant regions that are essential for network integration., (Copyright © 2020. Published by Elsevier Inc.)

This article is the second part in our machine learning series. Part 1 provided a general overview of machine learning in nuclear medicine. Part 2 focuses on neural networks. We start with an example illustrating how neural networks work and a discussion of potential applications. Recognizing that there is a spectrum of applications, we focus on recent publications in the areas of image reconstruction, low-dose PET, disease detection, and models used for diagnosis and outcome prediction. Finally, since the way machine learning algorithms are reported in the literature is extremely variable, we conclude with a call to arms regarding the need for standardized reporting of design and outcome metrics and we propose a basic checklist our community might follow going forward., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ε4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Abnormal brain amyloid beta (Aβ) is typically assessed in vivo using global concentrations from cerebrospinal fluid and positron emission tomography (PET). However, it is unknown whether the assessment of the topographical distribution of Aβ pathology can provide additional information to identify, among global Aβ positive individuals, those destined for dementia., Methods: We studied 260 amnestic mild cognitive impairment (MCI) subjects who were Aβ-PET positive with [ 18 F]florbetapir. Using [ 18 F]florbetapir, we assessed the percentage of voxels sowing Aβ abnormality as well as the standardized uptake value ratio (SUVR) values across brain regions. Regressions tested the predictive effect of Aβ on progression to dementia over 2 years., Results: Neither global nor regional [ 18 F]florbetapir SUVR concentrations predicted progression to dementia. In contrast, the spatial extent of Aβ pathology in regions comprising the default mode network was highly associated with the development of dementia over 2 years., Discussion: These results highlight that the regional distribution of Aβ abnormality may provide important complementary information at an individual level regarding the likelihood of Aβ positive MCI to progress to dementia., Competing Interests: All authors report no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Importance: Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial., Objective: To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age., Design, Setting, and Participants: This is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [18F]flortaucipir and amyloid-β PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study., Main Outcomes and Measures: A main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio., Results: The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19; P < .001)., Conclusions and Relevance: Our results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.

The number of cases of dementia has dramatically increased over the last decade. Imaging of the brain with PET has been used for many years, but in the past decade the radiopharmaceuticals and technology available for imaging dementia have vastly improved. In recent years, the U.S. Food and Drug Administration has approved 3 PET radiopharmaceuticals for detecting amyloid in brain, and tau PET radiopharmaceuticals are being investigated in clinical trials for use in dementia imaging. This paper will discuss different forms of dementia that can be imaged with PET, review common radiopharmaceuticals used for imaging dementia, and provide technical recommendations for performing the studies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

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, [ 18 F]AZD4694 β-amyloid-PET, and [ 18 F]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 [ 18 F]AZD4694 retention, [ 18 F]MK6240 retention, and gray matter (GM) volume., Results: Pearson correlations revealed a positive relationship between MBI-C score and global and striatal [ 18 F]AZD4694 standardized uptake value ratios (SUVRs). Voxel-based regression analyses revealed a positive correlation between MBI-C score and [ 18 F]AZD4694 retention. No significant correlations were found between MBI-C score and [ 18 F]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., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Objectives: To study the frequency of suicidal ideation and its association with clinical and neurobiological correlates among cognitively intact autosomal dominant Alzheimer's disease (ADAD) at-risk individuals., Methods/design: In a cross-sectional study of 183 ADAD at-risk individuals (91 mutation carriers and 92 noncarriers), we compared the frequency of suicidal ideation among carriers and noncarriers. Linear mixed-effects models with family-level random effects evaluated the relationships between geriatric depression scale (GDS), neuropsychiatric inventory-questionnaire (NPI-Q), and suicidal ideation scores among all ADAD at-risk individuals. An interaction term was added to the regression models to evaluate the interactions of suicidal ideation and mutation status on neuropsychiatric symptoms., Results: Twenty-six (14.20%) ADAD at-risk individuals (13 [14.28%] carriers and 13 [14.13%] noncarriers) had suicidal ideation. The frequency of suicidal ideation did not differ between carriers and noncarriers. Suicidal ideation was associated with higher GDS among all ADAD at-risk individuals. When stratified into mutation carrier status, noncarriers with suicidal ideation had higher GDS than carriers. There was no statistically significant association between suicidal ideation and NPI-Q among ADAD at-risk individuals. Awareness of mutation status, neuropsychological performances, and cerebrospinal fluid AD biomarkers were not associated with suicidal ideation among carriers and noncarriers., Conclusions: Suicidal ideation is common among cognitively intact ADAD at-risk individuals. While ADAD at-risk individuals with suicidal ideation have greater depressive symptoms, noncarriers with suicidal ideation have higher GDS scores than carriers. Interestingly, awareness of the mutation status was not associated with suicidal ideation in our study. Early identification of suicidal thoughts can facilitate timely interventions to prevent suicidal behaviours. Keywords autosomal dominant Alzheimer's diseasedominantly inherited Alzheimer's networkneuropsychiatric symptomssuicidal ideation., (© 2019 John Wiley & Sons, Ltd.)

Introduction: Neurofilament light chain (NfL) is a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) and other brain disorders. However, there are limited reports of how longitudinal NfL relates to imaging biomarkers. We herein investigated the relationship between blood NfL and brain metabolism in AD., Methods: Voxelwise regression models tested the cross-sectional association between [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) and both plasma and cerebrospinal fluid NfL in cognitively impaired and unimpaired subjects. Linear mixed models were also used to test the longitudinal association between NfL and [ 18 F]FDG in amyloid positive (Aβ+) and negative (Aβ-) subjects., Results: Higher concentrations of plasma and cerebrospinal fluid NfL were associated with reduced [ 18 F]FDG uptake in correspondent brain regions. In Aβ+ participants, NfL associates with hypometabolism in AD-vulnerable regions. Longitudinal changes in the association [ 18 F]FDG-NfL were confined to cognitively impaired Aβ+ individuals., Discussion: These findings indicate that plasma NfL is a proxy for neurodegeneration in AD-related regions in Aβ+ subjects., (© 2019 The Authors.)

Studies of rodent models of Alzheimer's disease (AD) and of human tissues suggest that the retinal changes that occur in AD, including the accumulation of amyloid beta (Aβ), may serve as surrogate markers of brain Aβ levels. As Aβ has a wavelength-dependent effect on light scatter, we investigate the potential for in vivo retinal hyperspectral imaging to serve as a biomarker of brain Aβ. Significant differences in the retinal reflectance spectra are found between individuals with high Aβ burden on brain PET imaging and mild cognitive impairment (n = 15), and age-matched PET-negative controls (n = 20). Retinal imaging scores are correlated with brain Aβ loads. The findings are validated in an independent cohort, using a second hyperspectral camera. A similar spectral difference is found between control and 5xFAD transgenic mice that accumulate Aβ in the brain and retina. These findings indicate that retinal hyperspectral imaging may predict brain Aβ load.

We investigated the association between amyloid-β deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer's disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [ 18 F]FDG and [ 18 F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses. Using voxel-based interaction models at voxel level, we tested whether the regional hypometabolism is associated with FA in the angular bundle and regional amyloid-β deposition. In the AD patients, [ 18 F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [ 18 F]Florbetapir standard uptake value ratios (SUVR) in these regions and low FA in the angular bundle. We found that the interaction between, rather than the independent effects of, high levels of amyloid-β deposition and WM integrity disruption determined limbic hypometabolism in patients with AD. This finding highlights a more integrative model for AD, where the interaction between partially independent processes determines the glucose hypometabolism.

The link between brain amyloid-β (Aβ), metabolism, and dementia symptoms remains a pressing question in Alzheimer's disease. Here, using positron emission tomography ([ 18 F]florbetapir tracer for Aβ and [ 18 F]FDG tracer for glucose metabolism) with a novel analytical framework, we found that Aβ aggregation within the brain's default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aβ aggregation is associated with subsequent cognitive decline. These results were also observed in transgenic Aβ rats that do not form neurofibrillary tangles, which support these findings as an independent mechanism of cognitive deterioration. These results suggest a model in which distant Aβ induces regional metabolic vulnerability, whereas the interaction between local Aβ with a vulnerable environment drives the clinical progression of dementia.

In Mendelian randomization (MR), inference about causal relationship between a phenotype of interest and a response or disease outcome can be obtained by constructing instrumental variables from genetic variants. However, MR inference requires three assumptions, one of which is that the genetic variants only influence the outcome through phenotype of interest. Pleiotropy, that is, the situation in which some genetic variants affect more than one phenotype, can invalidate these genetic variants for use as instrumental variables; thus a naive analysis will give biased estimates of the causal relation. Here, we present new methods (constrained instrumental variable [CIV] methods) to construct valid instrumental variables and perform adjusted causal effect estimation when pleiotropy exists and when the pleiotropic phenotypes are available. We demonstrate that a smoothed version of CIV performs approximate selection of genetic variants that are valid instruments, and provides unbiased estimates of the causal effects. We provide details on a number of existing methods, together with a comparison of their performance in a large series of simulations. CIV performs robustly across different pleiotropic violations of the MR assumptions. We also analyzed the data from the Alzheimer's disease (AD) neuroimaging initiative (ADNI; Mueller et al., 2005. Alzheimer's Dementia, 11(1), 55-66) to disentangle causal relationships of several biomarkers with AD progression., (© 2019 The Authors. Genetic Epidemiology Published by Wiley Periodicals, Inc.)

This article, the first in a 2-part series, provides an introduction to machine learning (ML) in a nuclear medicine context. This part addresses the history of ML and describes common algorithms, with illustrations of when they can be helpful in nuclear medicine. Part 2 focuses on current contributions of ML to our field, addresses future expectations and limitations, and provides a critical appraisal of what ML can and cannot do., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: [ 18 F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [ 18 F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD., Objectives: To test the hypothesis that the MAO-B inhibitor, rasagiline reduces [ 18 F]THK5351 uptake in PSP., Methods: Six individuals (4: PSP; 2: cognitively unimpaired, CU) underwent [ 18 F]THK5351 and [ 18 F]AZD4694 to quantify baseline tau and amyloid deposition, respectively. Following a 10-day course of 1 mg rasagiline, all participants received a post-challenge [ 18 F]THK5351 scan. The baseline and post-rasagiline challenge standardized uptake value (SUV) were generated normalized for patient weight and injected radioactivity., Results: The post-rasagiline regional SUV was reduced on average by 69-89% in PSP, and 53-81% in CU. The distributions of post-rasagiline [ 18 F]THK5351 SUV among PSP individuals were not consistent with the typical pattern of tau aggregates in PSP., Conclusions: Similar to AD, the interpretation of [ 18 F]THK5351 uptake in PSP is likely confounded by off-target binding to MAO-B binding sites. [ 18 F]THK5351 is not sufficient in quantifying tau aggregates in PSP using the proposed rasagiline dosing regimen., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [ 18 F]MK-6240., Methods: In vitro properties of [ 18 F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [ 18 F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [ 18 F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging., Results: In vitro [ 18 F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [ 18 F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time-activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates., Conclusions: This evaluation shows an [ 18 F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [ 18 F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions.

Purpose: We aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer's disease (AD) - related metabolic decline in cognitively normal individuals., Methods: A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) as a function of [ 18 F]florbetapir Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel., Results: The combination of [ 18 F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years., Conclusions: These results highlight the new concept that combined Aβ and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of disease-modifying therapies on [ 18 F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD.

Objective: To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment., Methods: We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [ 18 F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [ 18 F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia., Results: We found that participants with impaired awareness had lower [ 18 F]fluorodeoxyglucose uptake and increased [ 18 F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [ 18 F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame., Conclusions: Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts., Methods: A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [ 18 F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts., Results: Analysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ ( p = 0.003) and Aβ/p-tau ratio ( p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load ( p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ., Conclusions: Together, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.

Identifying individuals destined to develop Alzheimer's dementia within time frames acceptable for clinical trials constitutes an important challenge to design studies to test emerging disease-modifying therapies. Although amyloid-β protein is the core pathologic feature of Alzheimer's disease, biomarkers of neuronal degeneration are the only ones believed to provide satisfactory predictions of clinical progression within short time frames. Here, we propose a machine learning-based probabilistic method designed to assess the progression to dementia within 24 months, based on the regional information from a single amyloid positron emission tomography scan. Importantly, the proposed method was designed to overcome the inherent adverse imbalance proportions between stable and progressive mild cognitive impairment individuals within a short observation period. The novel algorithm obtained an accuracy of 84% and an under-receiver operating characteristic curve of 0.91, outperforming the existing algorithms using the same biomarker measures and previous studies using multiple biomarker modalities. With its high accuracy, this algorithm has immediate applications for population enrichment in clinical trials designed to test disease-modifying therapies aiming to mitigate the progression to Alzheimer's disease dementia., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The clinical significance of ventriculomegaly in cognitively normal elderly individuals remains unclear., Methods: We selected cognitively normal individuals (n = 425) from the Alzheimer's Disease Neuroimaging Initiative database and calculated Evans index (EI) based on the ratio of the frontal horn and skull diameter. We defined ventriculomegaly as EI ≥ 0.30, and the participants were stratified into EI ≥ 0.30 group and EI < 0.30 group. Neuropsychological, imaging, and fluid biomarker profiles between the two groups were then compared using regression models., Results: A total of 96 (22.5%) individuals who had ventriculomegaly performed worse on the cognitive tests; showed smaller hippocampal volume but larger caudate, cingulate, and paracentral gyrus volumes; and displayed lower positron emission tomography [ 18 F]fluorodeoxyglucose standardized uptake value ratio but higher amyloid burden represented by higher [ 18 F]florbetapir standardized uptake value ratio and lower cerebrospinal fluid amyloid β 1-42 levels compared to those without ventriculomegaly., Discussion: Asymptomatic ventriculomegaly might be an early imaging signature of preclinical Alzheimer's disease and/or normal pressure hydrocephalus.

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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD)., Methods: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET., Results: Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction., Conclusions: The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: 18 F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18 F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18 F-THK5351 brain uptake using PET and autoradiography., Methods: Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline 18 F-AZD4694 and 18 F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18 F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18 F-THK5351 scan 9-28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18 F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18 F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline., Results: At baseline, 18 F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18 F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9-28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18 F-THK5351 uptake., Conclusions: These results indicate that the interpretation of 18 F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18 F-THK5351 scans using reference region methods.

Introduction: The prevalence and detailed biomarkers' characteristic of rapidly progressive Alzheimer's disease (rpAD) remain incompletely understood., Methods: A total of 312 mild AD patients from the Alzheimer's Disease Neuroimaging Initiative database were chosen and dichotomized into rpAD and non-rpAD groups. We performed the prevalence and comprehensive biomarker evaluation., Results: The prevalence of rpAD was 17.6% in mild AD. Compared with non-rpAD, there were no differences in APOE ε4/ε4, APOE ε3/ε4, and APOE ε2/ε4 genotype distribution, cerebrospinal fluid tau, phosphorylated tau (p-tau), amyloid-β, hippocampus volume, and amyloid deposition in rpAD. Yet, a lower p-tau/tau ratio was observed in rpAD ( P  = .04). rpAD showed region-specific hypometabolism ([18F]fluorodeoxyglucose-positron emission tomography [FDG-PET]) ( P  = .001). Receiver-operating characteristic analysis of FDG-PET demonstrated that left angular and left temporal cortices were the regions with higher area under the curve and predictive value for identifying clinical at-risk rpAD., Discussion: We identified that rpAD commonly existed in mild AD. Cerebral hypometabolism could provide potential clinical differential value for rpAD in the short-term follow-up period.