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Deficits in memory are seen as a canonical sign of aging and a prodrome to dementia in older adults. However, our understanding of age-related cognition and brain morphology occurring throughout a broader spectrum of adulthood remains limited. We quantified the relationship between cognitive function and brain morphology (sulcal width, SW) using three cross-sectional observational datasets (PISA, AIBL, ADNI) from mid-life to older adulthood, assessing the influence of age, sex, amyloid (Aβ) and genetic risk for dementia. The data comprised cognitive, genetic and neuroimaging measures of a total of 1570 non-clinical mid-life and older adults (mean age 72, range 49-90 years, 1330 males) and 1365 age- and sex-matched adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). Among non-clinical adults, we found robust modes of co-variation between regional SW and multidomain cognitive function that differed between the mid-life and older age range. These cortical and cognitive profiles derived from healthy cohorts predicted out-of-sample AD and MCI. Furthermore, Aβ-deposition and educational attainment levels were associated with cognition but not SW. These findings underscoring the complex interplay between factors influencing cognition and brain structure from mid-life onwards, providing valuable insights for future research into neurodegeneration and the development of future screening algorithms., (© 2024. The Author(s).)

Background: Plasma phospho-tau 217 (pTau217) assays can accurately detect Alzheimer's disease (AD) pathology, but clinical application is limited by the need for specialised equipment. This study tests the performance of a plasma pTau217 assay performed on the Lumipulse-G® platform, that is in widespread clinical use, for selecting patients for therapy based on β-amyloid (Aβ) status and tau staging., Methods: Participants included 388 individuals with 18 F-NAV4694 Aβ-PET and 18 F-MK6240 tau-PET. Association of pTau217 with PET was examined using Spearman's correlation. Discriminative performance for Aβ and tau PET status as well as tau staging was assessed using Receiver Operating Characteristic analysis., Findings: Plasma pTau217 had a high correlation with both Aβ Centiloid (r = 0.76) and tau SUVR meta-temporal (r = 0.78). Area under curve (AUC) was 0.93 for Aβ- vs Aβ+ and 0.94 for tau- vs tau+. Applying one threshold (Youden's index), pTau217 was 87% accurate in classification of participants to Aβ- vs Aβ+. Applying two thresholds to classify participants into Low, Indeterminate, and High zones, 17.8% had Indeterminate results and among Low/High zone participants, 92% were correctly classified as Aβ- or Aβ+. The assay accurately discriminated moderate/high neocortical tau from no tau or tau limited to mesial-temporal lobe (AUC 0.97) and high neocortical tau from all others (AUC 0.94)., Interpretation: Plasma pTau217, measured by the widely-available, fully-automated Lumipulse®, was a strong predictor of both Aβ and tau PET status and demonstrated strong predictive power in identifying individuals likely to benefit the most from anti-Aβ treatments., Funding: NHMRC grants 1132604, 1140853, 1152623 and AbbVie., Competing Interests: Declaration of interests CCR has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Cerveau Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. VLV has received a grant from NIA and is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, and BRI Japan. ES and AWB are employees of Abbvie. SML is a scientific advisor for Cytox Ltd. SA has received grants from NHMRC, MRFF, and NIH and consulting fees from Eisai Australia. SRS has received grants from NHMRC, Alzheimer's Association (USA), Alzheimer's Drug Discovery Foundation, and Bright Focus Foundation and had a paid role in MRFF Grant Assessment Committee. The other authors did not report any conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The profile of autoantibodies is dysregulated in patients with Alzheimer's disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET - CN, 169 Aβ-PET + cognitively normal subjects (preclinical AD), and 31 Aβ-PET + cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD., (© 2024. The Author(s).)

Impaired clearance of amyloid β (Aβ) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aβ clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aβ-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aβ-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aβ levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aβ-binding monocytes may play a role in CNS Aβ clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring., (© 2024. The Author(s).)

Dementia is a burgeoning global problem. Novel magnetic resonance imaging (MRI) metrics beyond volumetry may bring new insight and aid clinical trial evaluation of interventions early in the Alzheimer's disease course to complement existing imaging and clinical metrics. To determine whether: (i) normalized regional sodium-MRI values (Na-SI) are better predictors of neurocognitive status than volumetry (ii) cerebral amyloid PET status improves modelling. Nondemented older adult (>60 years) volunteers of known Alzheimer's Disease Assessment Scale (ADAS-Cog11), Mini-Mental State Examination (MMSE) and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurocognitive test scores, ApolipoproteinE (APOE) e4 +/- cerebral amyloid PET status were prospectively recruited for 3T sodium-MRI brain scans. Left and right hippocampal, entorhinal and precuneus volumes and Na-SI (using the proportional intensity scaling normalization method with field inhomogeneity and partial volume corrections) were obtained after segmentation and co-registration of 3D-T1-weighted proton images. Descriptive statistics, correlation and best-subset regression analyses were performed. In our 76 nondemented participants (mean(standard deviation) age 75(5) years; woman 47(62%); cognitively unimpaired 54/76(71%), mildly cognitively impaired 22/76(29%)), left hippocampal Na-SI, not volume, was preferentially in the best models for predicting MMSE (Odds Ratio (OR) = 0.19(Confidence Interval (CI) = 0.07,0.53), P -value = 0.001) and ADAS-Cog11 (Beta(B) = 1.2(CI = 0.28,2.1), P -value = 0.01) scores. In the entorhinal analysis, right entorhinal Na-SI, not volume, was preferentially selected in the best model for predicting ADAS-Cog11 (B = 0.94(CI = 0.11,1.8), P -value = 0.03). While right entorhinal Na-SI and volume were both selected for MMSE modelling (Na-SI OR = 0.23(CI = 0.09,0.6), P -value = 0.003; volume OR = 2.6(CI = 1.0,6.6), P -value = 0.04), independently, Na-SI explained more of the variance (Na-SI R 2 = 10.3; volume R 2 = 7.5). No imaging variable was selected in the best CERAD models. Adding cerebral amyloid status improved model fit (Akaike Information Criterion increased 2.0 for all models, P -value < 0.001-0.045). Regional Na-SI were more predictive of MMSE and ADAS-Cog11 scores in our nondemented older adult cohort than volume, hippocampal more robust than entorhinal region of interest. Positive amyloid status slightly further improved model fit., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.)

Amyloid-β (Aβ) accumulation in Alzheimer disease (AD) is typically measured using SUV ratio and the centiloid (CL) scale. The low spatial resolution of PET images is known to degrade quantitative metrics because of the partial-volume effect. This article examines the impact of spatial resolution, as determined by the reconstruction configuration, on the Aβ PET quantitation in both cross-sectional and longitudinal data. Methods: The cross-sectional study involved 89 subjects with 20-min [ 18 F]florbetapir scans generated on an mCT (44 Aβ-negative [Aβ-], 45 Aβ-positive [Aβ+]) using 69 reconstruction configurations, which varied in number of iteration updates, point-spread function, time-of-flight, and postreconstruction smoothing. The subjects were classified as Aβ- or Aβ+ visually. For each reconstruction, Aβ CL was calculated using CapAIBL, and the spatial resolution was calculated as full width at half maximum (FWHM) using the barrel phantom method. The change in CLs and the effect size of the difference in CLs between Aβ- and Aβ+ groups with FWHM were examined. The longitudinal study involved 79 subjects (46 Aβ-, 33 Aβ+) with three 20-min [ 18 F]flutemetamol scans generated on an mCT. The subjects were classified as Aβ- or Aβ+ using a cutoff CL of 20. All scans were reconstructed using low-, medium-, and high-resolution configurations, and Aβ CLs were calculated using CapAIBL. Since linear Aβ accumulation was assumed over a 10-y interval, for each reconstruction configuration, Aβ accumulation rate differences (ARDs) between the second and first periods were calculated for all subjects. Zero ARD was used as a consistency metric. The number of Aβ accumulators was also used to compare the sensitivity of CL across reconstruction configurations. Results: In the cross-sectional study, CLs in both the Aβ- and the Aβ+ groups were impacted by the FWHM of the reconstruction method. Without postreconstruction smoothing, Aβ- CLs increased for a FWHM of 4.5 mm or more, whereas Aβ+ CLs decreased across the FWHM range. High-resolution reconstructions provided the best statistical separation between groups. In the longitudinal study, the median ARD of low-resolution reconstructed data for the Aβ- group was greater than zero whereas the ARDs of higher-resolution reconstructions were not significantly different from zero, indicating more consistent rate estimates in the higher-resolution reconstructions. Higher-resolution reconstructions identified 10 additional Aβ accumulators in the Aβ- group, resulting in a 22% increased group size compared with the low-resolution reconstructions. Higher-resolution reconstructions reduced the average CLs of the negative group by 12 points. Conclusion: High-resolution PET reconstructions, inherently less impacted by partial-volume effect, may improve Aβ PET quantitation in both cross-sectional and longitudinal data. In the cross-sectional analysis, separation of CLs between Aβ- and Aβ+ cohorts increased with spatial resolution. Higher-resolution reconstructions also exhibited both improved consistency and improved sensitivity in measures of Aβ accumulation. These features suggest that higher-resolution reconstructions may be advantageous in early-stage AD therapies., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: The standardized uptake value ratio (SUVR) is used to measure amyloid beta-positron emission tomography (Aβ-PET) uptake in the brainDifferences in PET scanner technologies and image reconstruction techniques can lead to variability in PET images across scanners. This poses a challenge for Aβ-PET studies conducted in multiple centers. The aim of harmonization is to achieve consistent Aβ-PET measurements across different scanners. In this study, we propose an Aβ-PET harmonization method of matching spatial resolution, as measured via a barrel phantom, across PET scanners. Our approach was validated using paired subject data, for which patients were imaged on multiple scanners., Methods: In this study, three different PET scanners were evaluated: the Siemens Biograph Vision 600, Siemens Biograph molecular computed tomography (mCT), and Philips Gemini TF64. A total of five, eight, and five subjects were each scanned twice with [ 18 F]-NAV4694 across Vision-mCT, mCT-Philips, and Vision-Philips scanner pairs. The Vision and mCT scans were reconstructed using various iterations, subsets, and post-reconstruction Gaussian smoothing, whereas only one reconstruction configuration was used for the Philips scans. The full-width at half-maximum (FWHM) of each reconstruction configuration was calculated using [ 18 F]-filled barrel phantom scans with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) phantom analysis toolkit. Regional SUVRs were calculated from 72 brain regions using the automated anatomical labelling atlas 3 (AAL3) atlas for each subject and reconstruction configuration. Statistical similarity between SUVRs was assessed using paired (within subject) t -tests for each pair of reconstructions across scanners; the higher the p -value, the greater the similarity between the SUVRs., Results: Vision-mCT harmonization : Vision reconstruction with FWHM = 4.10 mm and mCT reconstruction with FWHM = 4.30 mm gave the maximal statistical similarity (maximum p -value) between regional SUVRs. Philips-mCT harmonization : The FWHM of the Philips reconstruction was 8.2 mm and the mCT reconstruction with the FWHM of 9.35 mm, which gave the maximal statistical similarity between regional SUVRs. Philips-Vision harmonization : The Vision reconstruction with an FWHM of 9.1 mm gave the maximal statistical similarity between regional SUVRs when compared with the Philips reconstruction of 8.2 mm and were selected as the harmonized for each scanner pair., Conclusion: Based on data obtained from three sets of participants, each scanned on a pair of PET scanners, it has been verified that using reconstruction configurations that produce matched-barrel, phantom spatial resolutions results in maximally harmonized Aβ-PET quantitation between scanner pairs. This finding is encouraging for the use of PET scanners in multi-center trials or updates during longitudinal studies., Highlights: Question : Does the process of matching the barrel phantom-derived spatial resolution between scanners harmonize amyloid beta-standardized uptake value ratio (Aβ-SUVR) quantitation? Pertinent findings : It has been validated that reconstruction pairs with matched barrel phantom-derived spatial resolution maximize the similarity between subjects paired Aβ-PET (positron emission tomography) SUVR values recorded on two scanners. Implications for patient care : Harmonization between scanners in multi-center trials and PET camera updates in longitudinal studies can be achieved using a simple and efficient phantom measurement procedure, beneficial for the validity of Aβ-PET quantitation measurements., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 University of Melbourne. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The current study evaluated the relationship between habitual physical activity (PA) levels and brain amyloid beta (Aβ) over 15 years in a cohort of cognitively unimpaired older adults., Methods: PA and Aβ measures were collected over multiple timepoints from 731 cognitively unimpaired older adults participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging. Regression modeling examined cross-sectional and longitudinal relationships between PA and brain Aβ. Moderation analyses examined apolipoprotein E (APOE) ε4 carriage impact on the PA-Aβ relationship., Results: PA was not associated with brain Aβ at baseline (β = -0.001, p = 0.72) or over time (β = -0.26, p = 0.24). APOE ε4 status did not moderate the PA-Aβ relationship over time (β = 0.12, p = 0.73). Brain Aβ levels did not predict PA trajectory (β = -54.26, p = 0.59)., Discussion: Our study did not identify a relationship between habitual PA and brain Aβ levels., Highlights: Physical activity levels did not predict brain amyloid beta (Aβ) levels over time in cognitively unimpaired older adults (≥60 years of age). Apolipoprotein E (APOE) ε4 carrier status did not moderate the physical activity-brain Aβ relationship over time. Physical activity trajectories were not impacted by brain Aβ levels., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Neurofibrillary tangles are present in a proportion of people with dementia with Lewy bodies and may be associated with worse cognition. Recent advances in biomarkers for Alzheimer's disease include second-generation tau positron emission tomography as well as the detection of phosphorylated tau at threonine 181 (p-tau181) in plasma. This study aimed to investigate tau in people with dementia with Lewy bodies using a second-generation tau positron emission tomography tracer as well as plasma p-tau181., Methods: Twenty-seven participants (mean age 74.7 ± 5.5) with clinically diagnosed probable dementia with Lewy bodies underwent comprehensive clinical assessment and positron emission tomography imaging ( 18 F-MK6240 and 18 F-NAV4694). Plasma p-tau181 levels were measured using Simoa technology., Results: Five dementia with Lewy bodies participants (18.5%) had an abnormal tau positron emission tomography (increased tau uptake in the temporal meta-region-of-interest). Higher plasma p-tau181 concentrations correlated with higher tau deposition in the temporal region (ρ = 0.46, 95% confidence interval = [0.10, 0.72]) and classified abnormal tau positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.95 (95% confidence interval = [0.86, 0.99]). Plasma p-tau181 also correlated positively with cortical amyloid-beta binding (ρ = 0.68, 95% confidence interval = [0.40, 0.84]) and classified abnormal amyloid-beta positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.91 (95% confidence interval = [0.79, 0.99]). There was no association found between tau deposition and any of the clinical variables., Conclusions: Tau is a common co-pathology in dementia with Lewy bodies. Plasma p-tau181 correlated with abnormal tau and amyloid-beta positron emission tomography and may potentially be used as a marker to identify co-morbid Alzheimer's disease-related pathology in dementia with Lewy bodies. The clinical implications of tau in dementia with Lewy bodies need to be further evaluated in larger longitudinal studies., Competing Interests: Declaration of Conflicting InterestsChristopher C Rowe has received research grants (to his institution) from Cerveau/Enigma Technologies who supplied the precursor chemicals to make NAV4694 and MK6240, and is on the global advisory boards of Cerveau Technologies (unpaid), Roche and Prothera. All other co-authors have no potential conflicts of interest to disclose.

Traumatic brain injury (TBI) alters brain network connectivity. Structural covariance networks (SCNs) reflect morphological covariation between brain regions. SCNs may elucidate how altered brain network topology in TBI influences long-term outcomes. Here, we assessed whether SCN organisation is altered in individuals with chronic moderate-severe TBI (≥ 10 years post-injury) and associations with cognitive performance. This case-control study included fifty individuals with chronic moderate-severe TBI compared to 75 healthy controls recruited from an ongoing longitudinal head injury outcome study. SCNs were constructed using grey matter volume measurements from T1-weighted MRI images. Global and regional SCN organisation in relation to group membership and cognitive ability was examined using regression analyses. Globally, TBI participants had reduced small-worldness, longer characteristic path length, higher clustering, and higher modularity globally (p < 0.05). Regionally, TBI participants had greater betweenness centrality (p < 0.05) in frontal and central areas of the cortex. No significant associations were observed between global network measures and cognitive ability in participants with TBI (p > 0.05). Chronic moderate-severe TBI was associated with a shift towards a more segregated global network topology and altered organisation in frontal and central brain regions. There was no evidence that SCNs are associated with cognition., (© 2024. The Author(s).)

Background: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer's disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection., Objective: To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies., Methods: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days)., Results: All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum., Conclusions: TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies.

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid-β (Aβ) deposition are early pathological features in Alzheimer's disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed Aβ-PET and serial magnetic resonance imaging scans. Individuals were grouped at baseline according to the presence of cognitive impairment (CU, CI) and Aβ status (Aβ-, Aβ+). Longitudinal volumetric changes in the BF and hippocampus were assessed across groups. The results indicated that high Aβ levels correlated with faster volume loss in the BF and hippocampus, and the effect of Aβ varied within BF subregions. Compared to CU Aβ+ individuals, Aβ-related loss among CI Aβ+ adults was much greater in the predominantly cholinergic subregion of Ch4p, whereas no difference was observed for the Ch1/Ch2 region. The findings support early and substantial vulnerability of the BF and further reveal distinctive degeneration of BF subregions during early AD., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either 18 F-flortaucipir or 18 F-MK-6240 PET scans. Methods: 18 F-flortaucipir ( n = 798) and 18 F-MK-6240 ( n = 216) scans were processed and sampled to obtain regional SUV ratios. Subsamples of the cohorts were based on participant diagnosis, age, amyloid-β status (positive or negative), and neurodegeneration status (positive or negative), creating older-adult (age ≥ 55 y) cognitively unimpaired (amyloid-β-negative, neurodegeneration-negative) and cognitively impaired (mild cognitive impairment/Alzheimer disease, amyloid-β-positive, neurodegeneration-positive) groups, and then were further subsampled via matching to reduce significant differences in diagnostic prevalence, age, and Mini-Mental State Examination score. We used the biostatistical estimation of tau threshold hallmarks (BETTH) algorithm to determine sensitivity and specificity in 6 composite regions. Results: Parametric double receiver operating characteristic analysis yielded the greatest joint sensitivity in 5 of the 6 regions, whereas hierarchic clustering, gaussian mixture modeling, and k-means clustering all yielded perfect joint specificity (2.00) in all regions. Conclusion: When 18 F-flortaucipir and 18 F-MK-6240 are used, Alzheimer disease-related tau status is best assessed using 2 thresholds, a sensitivity one based on parametric double receiver operating characteristic analysis and a specificity one based on gaussian mixture modeling, delimiting an uncertainty zone indicating participants who may require further evaluation., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: The Centiloid (CL) project was developed to harmonize the quantification of amyloid beta (Aβ) positron emission tomography (PET) scans to a unified scale. The CL neocortical mask was defined using 11 C Pittsburgh compound B (PiB), overlooking potential differences in regional distribution among Aβ tracers. We created a universal mask using an independent dataset of five Aβ tracers, and investigated its impact on inter-tracer agreement, tracer variability, and group separation., Methods: Using data from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study (Australian Imaging Biomarkers and Lifestyle + Alzheimer's Disease Neuroimaging Initiative + Open Access Series of Imaging Studies), age-matched pairs of mild Alzheimer's disease (AD) and healthy controls (HC) were selected: 18 F-florbetapir ( N  = 147 pairs), 18 F-florbetaben ( N  = 22), 18 F-flutemetamol ( N  = 10), 18 F-NAV ( N  = 42), 11 C-PiB ( N  = 63). The images were spatially and standardized uptake value ratio normalized. For each tracer, the mean AD-HC difference image was thresholded to maximize the overlap with the standard neocortical mask. The universal mask was defined as the intersection of all five masks. It was evaluated on the Global Alzheimer's Association Interactive Network (GAAIN) head-to-head datasets in terms of inter-tracer agreement and variance in the young controls (YC) and on the ADOPIC dataset comparing separation between HC/AD and HC/mild cognitive impairment (MCI)., Results: In the GAAIN dataset, the universal mask led to a small reduction in the variance of the YC, and a small increase in the inter-tracer agreement. In the ADOPIC dataset, it led to a better separation between HC/AD and HC/MCI at baseline., Discussion: The universal CL mask led to an increase in inter-tracer agreement and group separation. Those increases were, however, very small, and do not provide sufficient benefits to support departing from the existing standard CL mask, which is suitable for the quantification of all Aβ tracers., Highlights: This study built an amyloid universal mask using a matched cohort for the five most commonly used amyloid positron emission tomography tracers.There was a high overlap between each tracer-specific mask.Differences in quantification and group separation between the standard and universal mask were small.The existing standard Centiloid mask is suitable for the quantification of all amyloid beta tracers., Competing Interests: Chris Rowe has received research grants from Piramal Imaging, GE Healthcare, Cerveau, Astra Zeneca, and Biogen. Victor Villemagne is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Piramal Imaging, Life Molecular Imaging, GE Healthcare, Abbvie, Lundbeck, Shanghai Green Valley Pharmaceutical Co Ltd, IXICO, and Hoffmann La Roche. The other authors have nothing to disclose., (© 2023 Commonwealth of Australia. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale., Method: One thousand forty-five participants underwent tau scans with either 18 F-flortaucipir, 18 F-MK6240, 18 F-PI2620, 18 F-PM-PBB3, 18 F-GTP1, or 18 F-RO948. The universal mask was generated from cognitively unimpaired amyloid beta (Aβ)- subjects and Alzheimer's disease (AD) patients with Aβ+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauR z , was constructed., Results: None of the regions known to display off-target signal were included in the masks. The CenTauR z allows robust discrimination between low and high levels of tau deposits., Discussion: We constructed several tau-specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at https://www.gaain.org/centaur-project., Competing Interests: Victor Villemagne has received research grants from NHMRC (GNT2001320), the Aging Mind Foundation (DAF2255207) and NIH (2P01AG025204‐16) and is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, and IXICO. Sandra Sanabria Bohorquez and Robby Weimer are a full‐time employees and stock owners of Roche. Santiago Bullich and Andrew Stephen are full‐time employees of Life Molecular Imaging GmbH. Hitoshi Shimada and Makoto Higuchi hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie. He is on the scientific advisory board for Cerveau Technologies and consulted for Prothena, Eisai, Roche, and Biogen Australia. Oskar Hansson has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. The other authors did not report any conflict of interest., (© 2023 CSIRO and The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes., Methods: Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions., Results: This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (β = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (β = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02)., Discussion: TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period., (© 2023 American Academy of Neurology.)

Introduction: The current study investigated the association between objectively measured physical activity and cognition in older adults over approximately 8 years., Methods: We utilized data from 199 cognitively unimpaired individuals from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, aged ≥60. Actigraphy was used to measure physical activity (intensity, total activity, and energy expenditure) at baseline. Cognition was assessed using a comprehensive cognitive battery every 18-months., Results: Higher baseline energy expenditure predicted better episodic recall memory and global cognition over the follow-up period (p = 0.031; p = 0.047, respectively). Those with higher physical activity intensity and greater total activity also had better global cognition over time (both p = 0.005). Finally, higher total physical activity predicted improved episodic recall memory over time (p = 0.022)., Discussion: These results suggest that physical activity can preserve cognition and that activity intensity may play an important role in this association., Highlights: Greater total physical activity predicts preserved episodic memory and global cognition. Moderate intensity physical activity (>3.7 metabolic equivalents of task [MET]) predicts preserved global cognition. Expending > 373 kilocalories per day may benefit episodic memory and global cognition., (© 2023 the Alzheimer's Association.)

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, β-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent β-amyloid ( 18 F-Florbetaben), tau ( 18 F-Flortaucipir), and fluorodeoxyglucose ( 18 F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. β-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in β-amyloid or tau levels or 18 F-FDG uptake between the TBI and control groups before and after controlling for covariates. The β-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Introduction: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions., Methods: In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses., Results: We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts., Conclusion: Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking., Methods: Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)-negative cognitively unimpaired (CU Aβ-, n = 81) and mild cognitive impairment (MCI Aβ-, n = 26) participants were compared with Aβ-PET-positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aβ-PET load were assessed over a 7 to 10-year duration., Results: Lower plasma Aβ1-42/Aβ1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ- and MCI Aβ-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aβ-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1-42/Aβ1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ-/+ status across the AD continuum. Longitudinally, plasma Aβ1-42/Aβ1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aβ1-42/Aβ1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1-42/Aβ1-40, and higher p-tau181 and GFAP were associated with increased Aβ-PET load prospectively., Discussion: These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aβ-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aβ-/+ status across the AD continuum, a panel of biomarkers may have superior Aβ-/+ status predictive capability across the AD continuum., Highlights: Area under the curve (AUC) of p-tau181 ≥ AUC of Aβ42/40, GFAP, NfL in predicting PET Aβ-/+ status (Aβ-/+).  AUC of Aβ42/40+p-tau181+GFAP panel ≥ AUC of Aβ42/40/p-tau181/GFAP/NfL for Aβ-/+.  Longitudinally, Aβ42/40, p-tau181, and GFAP were altered in MCI versus CU.  Longitudinally, GFAP and NfL were altered in AD versus CU.  Aβ42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline.  Aβ42/40, p-tau181, and GFAP are associated with increased PET Aβ load prospectively., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Amyloid-beta often co-exists in dementia with Lewy bodies, but its clinical relevance in dementia with Lewy bodies remains unclear. This study aimed to investigate the clinical and imaging correlates of amyloid-beta deposition in dementia with Lewy bodies, particularly its relationship with cortical thickness in Alzheimer's disease-prone regions and hippocampal volume., Methods: Twenty-four participants with probable dementia with Lewy bodies underwent high-resolution magnetic resonance imaging and amyloid-beta positron emission tomography imaging using the radiotracer 18 F-NAV4694. Amyloid-beta deposition was quantified and reported using the Centiloid method., Results: Amyloid-beta positivity, defined as Centiloid > 50, was present in 45.8% of dementia with Lewy bodies participants. There were no statistically significant differences in clinical characteristics between Aβ+ and Aβ- dementia with Lewy bodies. Compared with the Aβ- group, Aβ+ dementia with Lewy bodies exhibited greater global cortical thinning as well as in the Alzheimer's disease-prone region of interest, adjusted for age, sex and years of education. A mean cortical thickness of 5.12 mm across a combined meta-region of interest has a sensitivity of 88.9% and specificity of 90.0% in discriminating Aβ+ from Aβ- dementia with Lewy bodies. Hippocampal volume was not different between groups., Conclusion: Early structural changes in cortical thickness, but not hippocampal volume, were observed in dementia with Lewy bodies with significant amyloid-beta burden. This may represent an early Alzheimer's disease-related neurodegenerative process.

Background: The positron emission tomography (PET) radiotracer [ 18 F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [ 18 F]MK-6240 use to identify and stage AD subjects versus non-AD and controls., Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed., Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature., Discussion: This four-class [ 18 F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use., Highlights: A visual read method has been developed for [ 18 F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [ 18 F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature., Competing Interests: J. Shuping is a consultant to Enigma Biomedical Group. C. Wilde was a consultant to Cerveau Technologies. J. Evelhoch, W. Kreisl, K. Johnson, C. Rowe, and K. Van Laere are consultants/advisors to Cerveau Technologies. D. Matthews, A. Lukic, and R. Andrews are employees of ADM Diagnostics, Inc. D. Scott, K. Adamczuk, J. Barakos, and D. Purcell are employees of Clario. C. Rowe is an employee of Austin Health, Melbourne and University of Melbourne, Australia. S. Johnson is an employee of the University of Wisconsin Madison. W. Kreisl, A. Brickman, D. Devanand, J. Luchsinger, Y. Stern, and P. Lao are employees of Columbia University. P. Rosa‐Neto is an employee of McGill University. K. Van Laere is an employee of UZ Leuven. K. Johnson and J. Price are employees of Massachusetts General Hospital and Harvard University. A. Boxer is an employee of the University of California San Francisco. W. Klunk is an employee of the University of Pittsburgh. C. Sur was an employee of Merck & Co., Inc. L. Cordes is an employee of StatKing Clinical Services. L. Ward is an employee of Florey Department of Neuroscience and Mental Health and University of Melbourne. S. Mathotaarachchi is an employee of Enigma Biomedical Group. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Lifestyle factors such as physical activity and optimal sleep are associated with better cognition and lower levels of Alzheimer's disease (AD) biomarkers, including brain beta-amyloid (Aβ) burden., Objective: We utilised cross-sectional data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study to determine whether self-reported physical activity (measured via the International Physical Activity Questionnaire) moderates the relationship between self-reported sleep (measured via the Pittsburgh Sleep Quality Index), cognition, and brain Aβ., Methods: Participants were 349 community-dwelling cognitively normal older adults (75.3 ± 5.7 years), all of whom underwent comprehensive cognitive assessment. Data from a subset of participants (n = 201) were used for analyses with brain Aβ burden (measured by positron emission tomography) as the outcome., Result: Physical activity moderated the relationship between sleep duration and episodic memory (β = -0.10, SE =0.03, p = .005), and sleep efficiency and episodic memory (β = -0.09, SE =0.04, p = .011), such that greater amounts of physical activity mitigated the impact of suboptimal sleep duration and efficiency on episodic memory. Physical activity also moderated the relationship between sleep duration and brain Aβ (β = -0.13, SE =0.06, p = .031), and overall sleep quality and brain Aβ (β = 0.13, SE =0.06, p = .027)., Conclusion: Our findings suggest that physical activity may play an important role in the relationship between sleep and cognitive function, and brain Aβ., Competing Interests: Conflict of interest KRS, SRRS, JP, HRS, KT, DA, KIE and BMB report no disclosures. VLV is a consultant for IXICO and Life Molecular Imaging, and has received speaker honoraria from GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. PM is a full-time employee of Cogstate Ltd. SML has previously been a paid consultant to Alzhyme. CLM is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. CCR has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca, has received speaker honoraria from Bayer Pharma and GE Healthcare, and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. RNM is founder of, and owns stock in, Alzhyme, and is a co-founder of the KaRa Institute of Neurological Diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). 18 F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change., Methods: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aβ-), 44 CU Aβ+, 51 cognitively impaired Aβ+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up 18 F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter., Findings: CU Aβ- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aβ+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aβ+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aβ+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels., Interpretation: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD., Funding: NHMRC; Cerveau Technologies., Competing Interests: Declaration of interests CCR was the recipient of a research grant from Cerveau (institution), who supplied the MK6240 tau tracer precursor for research use. CCR has received consulting fees from Prothera and Merck (scientific advisory panels) and Biogen (for preparation of educational material). CCR has received support for attending meetings and/or travel from Cerveau and the Alzheimer's Association. VLV has received consulting fees from IXICO, Eli Lilly, Life molecular imaging and has received payment/honoraria from ACE Barcelona. VLV has participated on the data safety monitoring/advisory board of Eli Lilly. JF was the recipient of a research grant from the National Health and Medical Research Council (NHMRC), grant numbers APP1132604 and APP1140955. NK, VD, JR, LW, CF, PB, and CLM do not report any disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD., Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers., Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest., Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG., Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

Background: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-β (Aβ) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aβ and tau in predicting cognitive decline are unknown., Objectives: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aβ (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aβ (A+) and tau (T+) with and without p217+tau pre-screening., Design: A prospective observational cohort study., Setting: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT)., Participants: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals., Measurements: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aβ-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years., Results: In CI, p217+tau was a significant predictor of change in MMSE (β = -0.55, p < 0.001) and CDR-SB (β =0.61, p < 0.001) with an effect size similar to Aβ Centiloid (MMSE β = -0.48, p = 0.002; CDR-SB β = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: β = -0.62, p < 0.001; CDR-SB: β = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (β = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU., Conclusions: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing., Competing Interests: Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Cerveau Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. Victor L. Villemagne is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, GE Healthcare, IXICO, Abbvie, Lundbeck, Shanghai Green Valley Pharmaceutical Co Ltd, and Hoffmann La Roche. Ashley I. Bush is a shareholder in Alterity Ltd, Cogstate Ltd and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in Collaborative Medicinal Development Pty Ltd. He has received lecture fees from Biogen P/L. Paul Maruff was a full-time employee of Cogstate. Ziad S. Saad, Gallen Triana-Baltzer, Randy Slemmon and Hartmuth C. Kolb are employees of Janssen Pharmaceuticals. The other authors did not report any conflict of interest.

In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia's leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national Registry for Mild Cognitive Impairment and dementia with 55 participating clinical sites, an extensive map of memory clinic services, national Memory and Cognition Clinic Guidelines and specialized screening for trials sites in five states. This paper provides an overview of ADNeT's achievements to date and future directions. With the increase in dementia cases expected over coming decades, and with recent advances in plasma biomarkers and amyloid lowering therapies, the nationally coordinated initiatives and partnerships ADNeT has established are critical for increased national prevention efforts, co-ordinated implementation of emerging treatments for Alzheimer's disease, innovation of early and accurate diagnosis, driving continuous improvements in clinical care and patient outcome and access to post-diagnostic support and clinical trials. For a heterogenous disorder such as dementia, which is now the second leading cause of death in Australia following cardiovascular disease, the case for adequate investment into research and development has grown even more compelling.

Objectives: Longitudinal tau quantification may provide a useful marker of drug efficacy in clinical trials. Different tau PET tracers may have different sensitivity to longitudinal changes, but without a head-to-head dataset or a carefully designed case-matching procedure, comparing results in different cohorts can be biased. In this study, we compared the tau PET tracers, 18F-MK6240 and 18F-flortaucipir (FTP), both cross-sectionally and longitudinally by case-matching subjects in the AIBL and ADNI longitudinal cohort studies., Methods: A subset of 113 participants from AIBL and 113 from ADNI imaged using 18F-MK6240 and 18F-FTP respectively, with baseline and follow-up, were matched based on baseline clinical diagnosis, MMSE, age and amyloid (Aβ) PET centiloid value. Subjects were grouped as 64 Aβ- cognitively unimpaired (CU), 22 Aβ+ CU, 14 Aβ+ mild cognitive impairment (MCI) and 13 Aβ+ Alzheimer's disease (AD). Tracer retention was measured in the mesial, temporoparietal, rest of the cortex, and a meta-temporal region composed of entorhinal, inferior/middle temporal, fusiform, parahippocampus and amygdala. T-tests were employed to assess group separation at baseline using SUVR Z-scores and longitudinally using SUVR%/Yr., Results: Both tracers detected statistically significant differences at baseline in most regions between all clinical groups. Only 18F-MK6240 showed statistically significant higher rate of SUVR increase in Aβ+ CU compared to Aβ- CU in the mesial, meta-temporal and temporoparietal regions., Conclusion: 18F-MK6240 appears to be a more sensitive tracer for change in tau level at the preclinical stage of AD., Competing Interests: Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie. He is on the scientific advisory board for Cerveau Technologies and consulted for Prothena, Eisai, Roche, and Biogen Australia. Victor Villemagne is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, GE Healthcare, Abbvie, Lundbeck, Shanghai Green Valley Pharmaceutical Co Ltd, and Hoffmann La Roche. The other authors did not report any conflict of interest.

Background: Obstructive sleep apnea (OSA) is associated with an increased risk of amyloid-β (Aβ) burden, the hallmark of Alzheimer's disease, and cognitive decline., Objective: To determine the differential impacts of hypoxemia and slow-wave sleep disruption on brain amyloid burden, and to explore the effects of hypoxemia, slow-wave sleep disruption, and amyloid burden on cognition in individuals with and without OSA., Methods: Thirty-four individuals with confirmed OSA (mean±SD age 57.5±4.1 years; 19 males) and 12 healthy controls (58.5±4.2 years; 6 males) underwent a clinical polysomnogram, a NAV4694 positron emission tomography (PET) scan for Aβ burden, assessment of APOEɛ status and cognitive assessments. Linear hierarchical regressions were conducted to determine the contributions of demographic and sleep variables on amyloid burden and cognition., Results: Aβ burden was associated with nocturnal hypoxemia, and impaired verbal episodic memory, autobiographical memory and set shifting. Hypoxemia was correlated with impaired autobiographical memory, and only set shifting performance remained significantly associated with Aβ burden when controlling for sleep variables., Conclusions: Nocturnal hypoxemia was related to brain Aβ burden in this sample of OSA participants. Aβ burden and hypoxemia had differential impacts on cognition. This study reveals aspects of sleep disturbance in OSA that are most strongly associated with brain Aβ burden and poor cognition, which are markers of early Alzheimer's disease. These findings add weight to the possibility that hypoxemia may be causally related to the development of dementia; however, whether it may be a therapeutic target for dementia prevention in OSA is yet to be determined.

Introduction: Fatty acid-binding protein 3 (FABP3) is a biomarker of neuronal membrane disruption, associated with lipid dyshomeostasis-a notable Alzheimer's disease (AD) pathophysiological change. We assessed the association of cerebrospinal fluid (CSF) FABP3 levels with brain amyloidosis and the likelihood/risk of developing amyloidopathy in cognitively healthy individuals., Methods: FABP3 levels were measured in CSF samples of cognitively healthy participants, > 60 years of age ( n = 142), from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL)., Results: FABP3 levels were positively associated with baseline brain amyloid beta (Aβ) load as measured by standardized uptake value ratio (SUVR, standardized β  = 0.22, P = .009) and predicted the change in brain Aβ load (standardized β  = 0.32, P = .004). Higher levels of CSF FABP3 (above median) were associated with a likelihood of amyloidopathy (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.12 to 4.65, P = .023)., Discussion: These results support inclusion of CSF FABP3 as a biomarker in risk-prediction models of AD., Competing Interests: K.B. has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, BioArctic, 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. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). V.V. is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, GE Healthcare, IXICO, Hospicom, Abbvie, Lundbeck, Shanghai Green Valley Pharmaceutical Co Ltd, and Hoffmann La Roche. S.C. is currently a contracted adviser to Biogen. Other authors have no conflict of interests to disclose. Author disclosures are available in the Supporting Information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: In Alzheimer's disease (AD), plasma amyloid beta (Aβ) 1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown., Methods: Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study., Results: The p-tau181/Aβ 1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86-0.95) and in CN (AUC = 0.873; 0.80-0.94), and symptomatic (AUC = 0.908; 0.82-1.00) adults. Plasma p-tau181/Aβ 1-42 ratio correlated with cerebrospinal fluid (CSF) p-tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74-0.89). The p-tau181/Aβ 1-42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes ( P < 0.0001)., Discussion: Plasma p-tau181/Aβ 1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials., Competing Interests: Eugeen Vanmechelen is cofounder and shareholder of ADx NeuroSciences. Erik Stoops is employee and shareholder of ADx NeuroSciences. Jeroen Vanbrabant, Nele Dewit, and Kimberley Mauroo are employees of ADx NeuroSciences. Paul Maruff is a full‐time employee of Cogstate Ltd. Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie; he is on the scientific advisory board for Cerveau Technologies; and consulted for Prothena, Eisai, Roche, and Biogen Australia. The other authors did not report any conflict of interest. Author disclosures are available in the supporting information, (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: The Centiloid scale was developed to harmonise the quantification of β-amyloid (Aβ) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies., Methods: All Aβ PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer's respective transform. Global Aβ burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11 C-PiB- 18 F-Florbetapir pairs and longitudinal consistency were evaluated., Results: The smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18 F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used., Conclusions: FWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood., Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species., Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively., Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Reactive gliosis, characterized by reactive astrocytes and activated microglia, contributes greatly to neurodegeneration throughout the course of Alzheimer disease (AD). Reactive astrocytes overexpress monoamine oxidase B (MAO-B). We characterized the clinical performance of 18 F-( S )-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ( 18 F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. Methods: Seventy-seven participants-53 who were elderly and cognitively normal, 7 with mild cognitive impairment, 7 with AD, and 10 who were young and cognitively normal-were recruited for the different aspects of the study. Older participants underwent 3-dimensional magnetization-prepared rapid gradient-echo MRI and amyloid-β, tau, and 18 F-SMBT-1 PET. To ascertain 18 F-SMBT-1 selectivity to MAO-B, 9 participants underwent 2 18 F-SMBT-1 scans, before and after receiving 5 mg of selegiline twice daily for 5 d. To compare selectivity, 18 F-THK5351 studies were also conducted before and after selegiline. Amyloid-β burden was expressed in centiloids. 18 F-SMBT-1 outcomes were expressed as SUV, as well as tissue ratios and binding parameters using the subcortical white matter as a reference region. Results: 18 F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate retention in cortical regions, and the lowest retention in cerebellum and white matter, which tightly follows the known regional brain distribution of MAO-B ( R 2 = 0.84). More than 85% of 18 F-SMBT-1 signal was blocked by selegiline across the brain, and in contrast to 18 F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low nonspecific binding. 18 F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (∼2.6%/y) similar to the in vitro rates of change (∼1.9%/y). Quantitative and semiquantitative measures of 18 F-SMBT-1 binding were strongly associated ( R 2 > 0.94), suggesting that a simplified tissue-ratio approach could be used to generate outcome measures. Conclusion: 18 F-SMBT-1 is a highly selective MAO-B tracer, with low nonspecific binding, high entry into the brain, and reversible kinetics. Moreover, 18 F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting that 18 F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18 F-SMBT-1 will require examination of a much larger series, including participants with mild cognitive impairment and AD., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Importance: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD)., Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD., Design, Setting, and Participants: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years., Exposures: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness., Main Outcomes and Measures: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups., Results: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable., Conclusions and Relevance: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.

A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). 18 F-( S )-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ( 18 F-SMBT-1) is a novel 18 F PET tracer highly selective for MAO-B. We characterized the clinical performance of 18 F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis. Methods: We assessed 18 F-SMBT-1 PET regional binding in 77 volunteers (76 ± 5.5 y old; 41 women, 36 men) across the AD continuum: 57 who were cognitively normal (CN) (44 amyloid-β [Aβ]-negative [Aβ-] and 13 Aβ-positive [Aβ+]), 12 who had mild cognitive impairment (9 Aβ- and 3 Aβ+), and 8 who had AD dementia (6 Aβ+ and 2 Aβ-). All participants also underwent Aβ and tau PET imaging, 3-T MRI, and neuropsychologic evaluation. Tau imaging results were expressed in SUV ratios using the cerebellar cortex as a reference region, whereas Aβ burden was expressed in centiloids. 18 F-SMBT-1 outcomes were expressed as SUV ratio using the subcortical white matter as a reference region. Results: 18 F-SMBT-1 yielded high-contrast images at steady state (60-80 min after injection). When compared with the Aβ- CN group, there were no significant differences in 18 F-SMBT-1 binding in the group with Aβ- mild cognitive impairment. Conversely, 18 F-SMBT-1 binding was significantly higher in several cortical regions in the Aβ+ AD group but also was significantly lower in the mesial temporal lobe and basal ganglia. Most importantly, 18 F-SMBT-1 binding was significantly higher in the same regions in the Aβ+ CN group as in the Aβ- CN group. When all clinical groups were considered together, 18 F-SMBT-1 correlated strongly with Aβ burden and much less with tau burden. Although in most cortical regions 18 F-SMBT-1 did not correlate with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and gray matter volumes, whereas the occipital lobe was directly associated with white matter hyperintensity. 18 F-SMBT-1 binding was inversely correlated with Mini Mental State Examination and the Australian Imaging Biomarkers and Lifestyle's Preclinical Alzheimer Cognitive Composite in some neocortical regions such as the frontal cortex, lateral temporal lobe, and supramarginal gyrus. Conclusion: Cross-sectional human PET studies with 18 F-SMBT-1 showed that Aβ+ AD patients, but most importantly, Aβ+ CN individuals, had significantly higher regional 18 F-SMBT-1 binding than Aβ- CN individuals. Moreover, in several regions in the brain, 18 F-SMBT-1 retention was highly associated with Aβ load. These findings suggest that increased 18 F-SMBT-1 binding is detectable at the preclinical stages of Aβ accumulation, providing strong support for its use as a surrogate marker of astrogliosis in the AD continuum., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objectives: Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimer disease (AD). There is evidence of elevated β-amyloid (Aβ) and tau, the pathologic hallmarks of AD, immediately following TBI. It is not clear whether Aβ and tau remain elevated in the chronic period. To address this issue, we assessed Aβ and tau burden in long-term TBI survivors and healthy controls using PET imaging., Methods: Using a cross-sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18 F-NAV4694 (Aβ) and 18 F-MK6240 (tau) tracers. Aβ deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in 4 regions of interest (ROIs). As a secondary measure, PET scans were also visually read as positive or negative. We examined PET data in relation to time since injury and age at injury. PET data were analyzed in a series of regression analyses., Results: The sample comprised 87 individuals with TBI (71.3% male; 28.7% female; mean 57.53 years, SD 11.53) and 59 controls (59.3% male; 40.7% female; mean 60.34 years, SD 11.97). Individuals with TBI did not have significantly higher 18 F-NAV4694 Centiloid values ( p = 0.067) or 18 F-MK6240 tau SUVRs in any ROI ( p ≤ 0.001; SUVR greater for controls). Visual assessment was consistent with the quantification; individuals with TBI were not more likely than controls to have a positive Aβ ( p = 0.505) or tau scan ( p = 0.221). No associations were identified for Aβ or tau burden with time since injury ( p = 0.057 to 0.332) or age at injury., Discussion: A single moderate to severe TBI was not associated with higher burden of Aβ or tau pathologies in the chronic period relative to healthy controls. Aβ and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury., (© 2022 American Academy of Neurology.)

Purpose: Cancer-related cognitive impairment (CRCI) is a recognised adverse consequence of cancer and its treatment. This study assessed the feasibility of collecting longitudinal data on cognition in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent via self-report, neuropsychological assessment, peripheral markers of inflammation, and neuroimaging. An exploration and description of patterns of cancer-related cognitive impairment over the course of treatment and recovery was also undertaken and will be reported separately., Methods: Eligible participants completed repeated measures of cognition including self-report and neuropsychological assessment, and correlates of cognition including blood cell-based inflammatory markers, and neuroimaging at three pre-specified timepoints, time 1 (T1) - pre-treatment (treatment naïve), time 2 (T2) - mid-treatment, and time 3 (T3) - 6 to 8 weeks post-completion of treatment., Results: 30/33 eligible patients (91%, 95% CI: 76%, 97%) were recruited over 10 months. The recruitment rate was 3 patients/month (95% CI: 2.0, 4.3 patients/month). Reasons for declining included feeling overwhelmed and rapid treatment commencement. Mean age was 57 years (SD = 17 years) and 16/30 (53%) were male. Most patients (20/30, 67%) had diffuse large B cell lymphoma or Hodgkin lymphoma (4/30, 13%). The neuroimaging sub-study was optional, 11/30 participants (37%) were eligible to take part, and all agreed. The remaining 19 participants were ineligible as their diagnostic PET/CT scan was completed prior. Retention and compliance with all assessments were 89 to 100% at all timepoints. Only one participant was withdrawn due to disease progression., Conclusions: Findings from this study including excellent recruitment, retention, and compliance rates demonstrate it is feasible to longitudinally assess cognition in people with newly diagnosed aggressive lymphoma during their initial treatment and recovery to inform the development of future research to improve patient experiences and cognitive outcomes., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12619001649101., (© 2022. The Author(s).)

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings., (Copyright © 2022. Published by Elsevier Inc.)

The COVID-19 pandemic has revealed long-standing deficiencies with existing nurse recruitment and retention approaches, resulting in critical shortages of nursing capacity that are set to worsen without appropriate action. Decades of evidence and experience suggest that a multi-pronged approach that fosters an enabling and supportive work environment for nurses across all stages of their working lifespan will be required to build a more sustainable nursing workforce. This paper demonstrates Nova Scotia's innovation in creating a comprehensive, evidence-informed approach to nursing workforce planning and management, including key strategic areas of action related to (1) facilitating entry into the workforce, (2) investing in the active workforce and (3) enhancing support for and managing attrition of the workforce. This paper also offers nursing leaders a series of reflections on current learnings in the implementation of this innovative and person-centred approach to nursing workforce sustainability. Recognizing the pressing need for action, Nova Scotia Health and provincial leaders have and are implementing strategic innovations to enhance the nursing workforce. These include: (1) investment in organizational capacity for evidence-based innovation, (2) development of collaborative relationships between both internal stakeholders and community partners and (3) creation of mechanisms for meaningful engagement and co-design of locally relevant innovative solutions., (Copyright © 2022 Longwoods Publishing.)

In Alzheimer's disease, the molecular pathogenesis of the extracellular Aβ-amyloid (Aβ) instigation of intracellular tau accumulation is poorly understood. We employed a high-resolution PET scanner, with low detection thresholds, to examine the Aβ-tau association using a convolutional neural network (CNN), and compared results to a standard voxel-wise linear analysis. The full range of Aβ Centiloid values was highly predicted by the tau topography using the CNN (training R 2  = 0.86, validation R 2  = 0.75, testing R 2  = 0.72). Linear models based on tau-SUVR identified widespread positive correlations between tau accumulation and Aβ burden throughout the brain. In contrast, CNN analysis identified focal clusters in the bilateral medial temporal lobes, frontal lobes, precuneus, postcentral gyrus and middle cingulate. At low Aβ levels, information from the middle cingulate, frontal lobe and precuneus regions was more predictive of Aβ burden, while at high Aβ levels, the medial temporal regions were more predictive of Aβ burden. The data-driven CNN approach revealed new associations between tau topography and Aβ burden., (© 2022. Crown.)

Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18 F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings., Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ ( 18 F-NAV4694) and tau ( 18 F-MK6240) PET scans were included. Centiloid <25 defined negative Aβ PET (Aβ-). The presence of neocortical tau was defined quantitatively and visually., Results: Aβ- PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2 , and MAPT genes did not identify relevant functional mutations., Discussion: Discordant cases were infrequent (1.4% of all Aβ- participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present., Competing Interests: This work was supported by the National Health and Medical Research Council (NHMRC) (grant numbers APP1140853, APP1132604). Natasha Krishnadas was supported by a cofunded PhD scholarship from Australian Rotary Health and the Estate of Bartolina Peluso. Simon M. Laws has received institutionally administered grants as follows: NHMRC APP1151854, APP1161706, APP1191535, APP2001320, APP2007656; Department of Health (Government of Western Australia) ‐ Multiple Sclerosis Western Australia ‐ Australian Alzheimer's Research Foundation ‐ Edith Cowan University, Strategic Research Centre Support ‐ Florey Institute of Neuroscience and Mental Health. Simon M. Laws has participated on the Cytox Group Ltd ‐ Scientific Advisory Board (pro bono). Victor L Villemagne has received consulting fees from IXICO, Eli Lilly, Life molecular imaging, and Hospicom, and has received payment/honoraria from ACE Barcelona. Christopher C. Rowe has received grants from Cerveau Technologies (institution), Eisai (institution), and Biogen (institution). Christopher C. Rowe has received consulting fees from Nutricia (speaker fee), Prothera, and Biogen (for preparation of educational material). Christopher C. Rowe has participated on a data safety board/advisory board for Cerveau Technologies (unpaid). Vincent Doré, Tenielle Porter, Fiona Lamb, and Svetlana Bozinovski do not report any disclosures., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

This prospective controlled study examined long-term trajectories of neuropsychological performance in individuals with traumatic brain injury (TBI) compared to healthy controls, and the impact of IQ, age at injury, time since injury, and injury severity on change over time. Fifty-three individuals with moderate to severe TBI (60.37% male; M  = 59.77 yrs, SD   = 14.03), and 26 controls (46.15% male; M  = 63.96 yrs, SD   = 14.42) were studied prospectively ( M = 12.72 yrs between assessments). Participants completed measures of premorbid IQ (Weschler Test of Adult Reading), processing speed (Digit Symbol Coding Test), working memory (Digit Span Backwards), memory (Rey Auditory Verbal Learning Test) and executive function (Trail Making Test Part B; Hayling Errors), at a mean of 10.62 yrs (Initial) and 23.91 yrs (Follow-Up) post injury. Individuals with TBI did not show a significantly greater decline in neuropsychological performance over time compared with demographically similar controls. There was no association between change over time with IQ, time since injury or injury severity. Being older at injury had a greater adverse impact on executive function at follow-up. In this small sample, a single moderate to severe TBI was not associated with ongoing cognitive decline up to three decades post injury. Changes in cognitive function were similar between the groups and likely reflect healthy aging.

Background: Recent reports raise the possibility of cerebral amyloid angiopathy (CAA) leading to intracerebral hemorrhage in young adults following childhood neurosurgery, suggesting transmission of amyloid-β (Aβ) through neurosurgical procedures including dura mater grafting. Parenchymal Aβ deposition, and to a lesser extent tau aggregation, similar to that seen in Alzheimer disease, have also been described., Methods: We conducted a database review of 634 consecutive intracerebral hemorrhage patients aged <65 years at a tertiary stroke center over 20 years to identify such patients., Results: We identified 3 patients aged in their thirties who presented with spontaneous lobar intracerebral hemorrhage, with imaging or neuropathology consistent with CAA, and a history of childhood neurosurgery. Two of these patients had undergone a dural repair using cadaveric dura mater (Lyodura). In addition to CAA, both patients had neuropathologically confirmed parenchymal Aβ and tau deposits, characteristic of Alzheimer disease., Conclusions: Our findings support the concept of neurosurgical Aβ transmission but suggest that such cases are rare in standard clinical practice.