Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study.

Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-ß deposition in the precuneus region (ß±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal.

Clinically normal females exhibit higher 18F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET.

The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury.

BACKGROUND: Preclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex. METHODS: This exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer's disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined. RESULTS: Participants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (ß ± SE = - 0.12 ± 0.06, p = 0.034 and ß ± SE = 0.08 ± 0.04, p = 0.026, respectively). CONCLUSIONS: Circulating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer's disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.

BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.

Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy.

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022;92:358-363.

Lower novelty-related locus coeruleus function is associated with Aß-related cognitive decline in clinically healthy individuals.

Animal and human imaging research reported that the presence of cortical Alzheimer's Disease's (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC's in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older individuals. We show that LC activity and LC-FC with amygdala and hippocampus was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippocampus and parahippocampus were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC's functional properties as a gauge to identify individuals at-risk for AD-related cognitive decline.

Dual-stream pyramid registration network.

We propose a Dual-stream Pyramid Registration Network (referred as Dual-PRNet) for unsupervised 3D brain image registration. Unlike recent CNN-based registration approaches, such as VoxelMorph, which computes a registration field from a pair of 3D volumes using a single-stream network, we design a two-stream architecture able to estimate multi-level registration fields sequentially from a pair of feature pyramids. Our main contributions are: (i) we design a two-stream 3D encoder-decoder network that computes two convolutional feature pyramids separately from two input volumes; (ii) we propose sequential pyramid registration where a sequence of pyramid registration (PR) modules is designed to predict multi-level registration fields directly from the decoding feature pyramids. The registration fields are refined gradually in a coarse-to-fine manner via sequential warping, which equips the model with a strong capability for handling large deformations; (iii) the PR modules can be further enhanced by computing local 3D correlations between the feature pyramids, resulting in the improved Dual-PRNet++ able to aggregate rich detailed anatomical structure of the brain; (iv) our Dual-PRNet++ can be integrated into a 3D segmentation framework for joint registration and segmentation, by precisely warping voxel-level annotations. Our methods are evaluated on two standard benchmarks for brain MRI registration, where Dual-PRNet++ outperforms the state-of-the-art approaches by a large margin, i.e., improving recent VoxelMorph from 0.511 to 0.748 (Dice score) on the Mindboggle101 dataset. In addition, we further demonstrate that our methods can greatly facilitate the segmentation task in a joint learning framework, by leveraging limited annotations.

Association of cortical microstructure with amyloid-ß and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults.

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-ß and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-ß, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-ß, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-ß, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-ß and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-ß, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

Resting-state functional connectivity and amyloid burden influence longitudinal cortical thinning in the default mode network in preclinical Alzheimer's disease.

Proteinopathies are key elements in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), with the nature and location of the proteinopathy characterizing much of the disease phenotype. Susceptibility of brain regions to pathology may partly be determined by intrinsic network structure and connectivity. It remains unknown, however, how these networks inform the disease cascade in the context of AD biomarkers, such as beta-amyloid (Aß), in clinically-normal older adults.The default-mode network (DMN), a prominent intrinsic network, is heavily implicated in AD due to its spatial overlap with AD atrophy patterns and tau deposition. We investigated the influence of baseline Aß positron emission tomography (PET) signal and intrinsic DMN connectivity on DMN-specific cortical thinning in 120 clinically-normal older adults from the Harvard Aging Brain Study (73 ± 6 years, 58% Female, CDR = 0). Participants underwent11C Pittsburgh Compound-B (PiB) PET, 18F flortaucipir (FTP) PET, and resting-state MRI scans at baselineand longitudinal MRI (3.6 ± 0.96 scans; 5.04 ± 0.8 years). Linear mixed models tested relationships between baseline PiB and DMN connectivity on cortical thinning in a composite of DMN regions. Lower DMN connectivity was associated with faster cortical thinning, but only in those with elevated baseline PiB-PET signal. This relationship was network specific, in that the frontoparietal control network did not account for the observed association. Additionally, the relationship was independent of inferior temporal lobe FTP-PET signal. Our findings provide evidence that compromised DMN connectivity, in the context of preclinical AD, foreshadows neurodegeneration in DMN regions.

Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline.

OBJECTIVE: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. METHODS: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aß-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. RESULTS: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). ß-amyloid (Aß)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aß + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04). INTERPRETATION: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aß were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.