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.

Differential Vulnerability of Hippocampal Subfields to Amyloid and Tau Deposition in the Lewy Body Diseases.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) copathologies of ß-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD. METHODS: This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid ß-amyloid (A) and tau (T) were acquired. The association of functional cognition, ß-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models. RESULTS: Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum (F = 6.9, p = 0.002), presubiculum (F = 7.3, p = 0.001), and parasubiculum (F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants (F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 (p = 0.021) and subiculum (p = 0.002) atrophy. DISCUSSION: In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aß does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.

Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology.

BACKGROUND AND OBJECTIVES: Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease. METHODS: Two Framingham Heart Study overlapping samples were studied: participants who underwent 11C-Pittsburg Compound B amyloid and 18F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics. RESULTS: The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average ß [SE] 0.0062 [0.0024], p = 0.009; short to long ß [SE] 0.0164 [0.0076], p = 0.031; average to long ß [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (ß [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (ß [SE] -0.43 [0.20], p = 0.028; ß [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, ß [SE] 0.12 [0.04], p = 0.003; ß [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; ß [SE] 0.24 [0.10], p = 0.019; ß [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes. DISCUSSION: Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.

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.

Impact of motion correction on [18F]-MK6240 tau PET imaging.

Objective. Positron emission tomography (PET) imaging of tau deposition using [18F]-MK6240 often involves long acquisitions in older subjects, many of whom exhibit dementia symptoms. The resulting unavoidable head motion can greatly degrade image quality. Motion increases the variability of PET quantitation for longitudinal studies across subjects, resulting in larger sample sizes in clinical trials of Alzheimer's disease (AD) treatment.Approach. After using an ultra-short frame-by-frame motion detection method based on the list-mode data, we applied an event-by-event list-mode reconstruction to generate the motion-corrected images from 139 scans acquired in 65 subjects. This approach was initially validated in two phantoms experiments against optical tracking data. We developed a motion metric based on the average voxel displacement in the brain to quantify the level of motion in each scan and consequently evaluate the effect of motion correction on images from studies with substantial motion. We estimated the rate of tau accumulation in longitudinal studies (51 subjects) by calculating the difference in the ratio of standard uptake values in key brain regions for AD. We compared the regions' standard deviations across subjects from motion and non-motion-corrected images.Main results. Individually, 14% of the scans exhibited notable motion quantified by the proposed motion metric, affecting 48% of the longitudinal datasets with three time points and 25% of all subjects. Motion correction decreased the blurring in images from scans with notable motion and improved the accuracy in quantitative measures. Motion correction reduced the standard deviation of the rate of tau accumulation by -49%, -24%, -18%, and -16% in the entorhinal, inferior temporal, precuneus, and amygdala regions, respectively.Significance. The list-mode-based motion correction method is capable of correcting both fast and slow motion during brain PET scans. It leads to improved brain PET quantitation, which is crucial for imaging AD.

Measurement of Cerebral Perfusion Indices from the Early Phase of [18F]MK6240 Dynamic Tau PET Imaging.

6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]MK6240) has high affinity and selectivity for hyperphosphorylated tau and readily crosses the blood-brain barrier. This study investigated whether the early phase of [18F]MK6240 can be used to provide a surrogate index of cerebral perfusion. Methods: Forty-nine subjects who were cognitively normal (CN), had mild cognitive impairment (MCI), or had Alzheimer's disease (AD) underwent paired dynamic [18F]MK6240 and [11C]Pittsburgh compound B (PiB) PET, as well as structural MRI to obtain anatomic information. Arterial blood samples were collected in a subset of 24 subjects for [18F]MK6240 scans to derive metabolite-corrected arterial input functions. Regional time-activity curves were extracted using atlases available in the Montreal Neurologic Institute template space and using FreeSurfer. The early phase of brain time-activity curves was analyzed using a 1-tissue-compartment model to obtain a robust estimate of the rate of transfer from plasma to brain tissue, K 1 (mL⋅cm-3⋅min-1), and the simplified reference tissue model 2 was investigated for noninvasive estimation of the relative delivery rate, R 1 (unitless). A head-to-head comparison with R 1 derived from [11C]PiB scans was performed. Grouped differences in R 1 were evaluated among CN, MCI, and AD subjects. Results: Regional K 1 values suggested a relatively high extraction fraction. R 1 estimated noninvasively from simplified reference tissue model 2 agreed well with R 1 calculated indirectly from the blood-based compartment modeling (r = 0.99; mean difference, 0.024 ± 0.027), suggesting that robust estimates were obtained. R 1 measurements obtained with [18F]MK6240 correlated strongly and overall agreed well with those obtained from [11C]PiB (r = 0.93; mean difference, -0.001 ± 0.068). Statistically significant differences were observed in regional R 1 measurements among CN, MCI, and AD subjects, notably in the temporal and parietal cortices. Conclusion: Our results provide evidence that the early phase of [18F]MK6240 images may be used to derive a useful index of cerebral perfusion. The early and late phases of a [18F]MK6240 dynamic acquisition may thus offer complementary information about the pathophysiologic mechanisms of the disease.

Kinetic evaluation and assessment of longitudinal changes in reference region and extracerebral [18F]MK-6240 PET uptake.

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

Extra-pair paternity drives plumage colour elaboration in male passerines.

The elaborate ornamental plumage displayed by birds has largely been attributed to sexual selection, whereby the greater success of ornamented males in attaining mates drives a rapid elaboration of those ornaments. Indeed, plumage elaboration tends to be greatest in species with a high variance in reproductive success such as polygynous mating systems. Even among socially monogamous species, many males are extremely colourful. In their now-classic study, Møller and Birkhead (1994) suggested that increased variance in reproductive success afforded by extra-pair paternity should intensify sexual selection pressure and thus an elaboration of male plumage and sexual dichromatism, but the relatively few measures of extra-pair paternity at the time prevented a rigorous test of this hypothesis. In the nearly three decades since that paper's publication, hundreds of studies have been published on rates of extra-pair paternity and more objective measures of plumage colouration have been developed, allowing for a large-scale comparative test of Møller and Birkhead's (1994) hypothesis. Using an analysis of 186 socially monogamous passerine species with estimates of extra-pair paternity, our phylogenetically controlled analysis confirms Møller and Birkhead's (1994) early work, demonstrating that rates of extra-pair paternity are positively associated with male, but not female, colouration and with the extent of sexual dichromatism. Plumage evolution is complex and multifaceted, driven by phylogenetic, ecological, and social factors, but our analysis confirms a key role of extra-pair mate choice in driving the evolution of ornamental traits.

Association of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-ß and Regional Tau Burden Among Framingham Heart Study Participants Without Dementia.

Importance: Aortic stiffness is associated with clinical hallmarks of Alzheimer disease and related dementias and could be a modifiable target for disease prevention. Objective: To assess associations of aortic stiffness and pressure pulsatility with global amyloid-ß plaques and regional tau burden in the brain of middle-aged and older adults without dementia. Design, Setting, and Participants: The sample for this cross-sectional study was drawn from the Framingham Heart Study Third Generation Cohort at examination 3 (N = 3171; 2016-2019), of whom 3092 successfully underwent comprehensive hemodynamic evaluations. In a supplemental visit (2015-2021), a subset of 270 participants without dementia who represented the spectrum of vascular risk also underwent positron emission tomography. Thirteen participants were excluded for missing covariate data. The final sample size was 257 participants. Exposures: Three measures of aortic stiffness and pressure pulsatility (carotid-femoral pulse wave velocity, central pulse pressure [CPP], and forward wave amplitude [FWA]) were evaluated using arterial tonometry. Main Outcomes and Measures: Global amyloid-ß plaques and regional tau were assessed using 11C-Pittsburgh compound B and 18F-flortaucipir positron emission tomography tracers, respectively. Results: The mean (SD) age of the 257 participants was 54 (8) years, and 126 were women (49%). All participants were White Western European race. In multivariable models, higher CPP (ß per SD = 0.17; 95% CI, 0.00-0.35; P = .045) and FWA (ß per SD = 0.16; 95% CI, 0.00-0.31; P = .04) were associated with greater entorhinal tau burden. In similar models, higher CPP (ß per SD = 0.19; 95% CI, 0.02-0.36; P = .03) and FWA (ß per SD = 0.17; 95% CI, 0.01-0.32; P = .03) were associated with greater rhinal tau burden. Aortic stiffness and pressure pulsatility measures were not associated with amygdala, inferior temporal, precuneus tau burden, or global amyloid-ß plaques. Associations for entorhinal and rhinal tau outcomes were more prominent in older participants (≥60 years). For example, higher levels of all aortic stiffness and pressure pulsatility measures (ß per SD = 0.40-0.92; P = .001-.02) were associated with higher entorhinal tau burden among older but not younger participants in stratified analyses. Conclusions and Relevance: In this cross-sectional study, abnormal central vascular hemodynamics were associated with higher tau burden in specific brain regions. Findings suggest that aortic stiffness, which is potentially modifiable, may be a probable independent target for prevention of tau-related pathologies.

Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-ß Burden.

BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-ß (Aß) burden. OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aß on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aß burden. METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aß on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aß in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS: Participants with higher mean ICA IMT had more Aß in the precuneus (beta±standard error [ß±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (ß±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aß or progression of ICA or CCA IMT and Aß. CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aß burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-ß and Tau Pathology in Middle-Aged Adults: The Framingham Study.

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-ß (Aß) and tau pathology. METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aß, adjusting for potential confounders and multiple comparisons. RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aß or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (ß= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (ß= 2.01±0.47, p < 0.001; ß= 1.60±0.53, p = 0.007, and ß= 1.59±0.47, p = 0.003 and ß= 1.60±0.42, p = 0.001, respectively) and to Aß deposition overall and in the inferior temporal and parahippocampal regions (ß= 1.93±0.47, p < 0.001; ß= 1.59±0.38, p < 0.001, and ß= 1.52±0.54, p = 0.008, respectively). CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

Associations Between Brainstem Volume and Alzheimer's Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study.

The brainstem is among the first regions to accumulate Alzheimer's disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-ß or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

Association of Midlife Depressive Symptoms with Regional Amyloid-ß and Tau in the Framingham Heart Study.

BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-ß (Aß) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aß and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator. METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aß and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (ß= 0.446, SE = 0.155, p = 0.006) and amygdala (ß= 0.350, SE = 0.133, p = 0.012). CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.