Tau PET Imaging Research Articles

Fast accumulators of tau have higher levels of plasma pTau and stronger associations with amyloid in later Braak regions at baseline

AbstractBackgroundAccumulation of tau neurofibrillary tangles in Alzheimer’s disease (AD) follows a stereotypical pattern, known as Braak staging. As individuals show different rates of tau accumulation, depending on their initial stage, this potentially biases drug effects on tau pathology over time. We hypothesized that amyloid would be a driving force behind tau deposition in later Braak regions for those that were at earlier stages of the disease.Method79 individuals (CU: 57, MCI: 21, AD: 1) were recruited from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort. All individuals underwent baseline and 2‐year follow‐up amyloid ([18F]AZD4694) and tau ([18F]MK6240) PET imaging, as well as baseline plasma pTau181, pTau217, and pTau231 assessments. Differences in standardized uptake value ratios between the two timepoints in Braak I‐IV were used to separate fast accumulators of tau from slow accumulators, using the standard deviation of a Young group (n = 13).Pearson R’s were calculated between tau deposition in Braak regions IV‐VI and the neocortical amyloid load at baseline, within both these groups. Furthermore, a voxelwise analysis was performed to identify specific regional differences in amyloid SUVR between slow and fast progressors, while correcting for age, sex, ApoE4 carriership, as well as the individual’s Braak stage. In addition, an independent t‐test was performed to compare the levels of each pTau species at baseline.ResultFast accumulators had stronger increases (p < 0.01) in tau accumulation in Braak region V and VI, compared to slower accumulators. Furthermore, the level of tau deposition in Braak region IV and V was positively associated (p < 0.01) with the amyloid load in the neocortex, but only in the fast accumulator group (figure 1). The voxelwise analysis confirmed that faster progressors had stronger associations with amyloid‐PET (figure 2). Furthermore, those who accumulated tau at a faster rate also had higher levels of plasma pTau at baseline (figure 3).ConclusionTau deposition in later Braak regions is associated with a higher amyloid load and increased values of pTau181, pTau217 and pTau231 at baseline in individuals in early Braak stages that accumulate tau at a more rapid rate.

Regional cerebral blood flow is associated with PET and plasma biomarkers of tau pathology in middle age

AbstractBackgroundCerebrovascular dysfunction and vascular brain injury are associated with risk and progression of clinical Alzheimer’s disease (AD), but it is unclear whether they contribute directly to disease pathogenesis. Animal models of small vessel cerebrovascular disease suggest that transient cerebral hypoperfusion may promote tau pathology independent of amyloidosis. In the current study, we used pulsed arterial spin labeling (PASL) magnetic resonance imaging (MRI) to examine the association of regional cerebral blood flow (CBF) with two biomarkers of tau pathology, plasma phosphorylated tau 181 (ptau181) concentrations and PET MK6240 SUVR, in middle aged adult participants from the Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease.MethodAt the time of analysis, 469 Offspring Study participants (54.0±10.6‐years‐old; 64% women; 67% Latinx, 22% non‐Latinx Black, 6% non‐Latinx white) had available PASL and ptau181 plasma concentrations (Quanterix Simoa HDx platform). Sixty‐four participants (59.9±5.4‐years‐old age; 67% women; 64% Latinx, 22% non‐Latinx Black, 8% Latinx white) with PASL CBF data received tau PET imaging with MK6240 and mean SUVR was computed across all grey matter regions for each participant. Voxelwise correlational analyses were run to examine the relationship between ptau181 concentrations and regional CBF and between tau PET SUVR and regional CBF.ResultIncreased ptau181 concentrations were associated with clusters of decreased CBF in frontal grey matter, striatum, hippocampus, and periventricular white matter. These correlations were asymmetrical, with the largest clusters found in the left hemisphere. Higher PET SUVR was associated with clusters of lower CBF in frontal, parietal, and occipital grey matter.ConclusionThese findings demonstrate a codependency between regional blood flow and tau pathology, indexed by fluidic and imaging biomarkers. Future studies will clarify the directionality and possible causality of these associations, but these cross‐sectional findings are consistent with a hypothesis that subtle diminished blood flow gives rise to tau abnormalities.

A CenTauR scale based on 18F‐MK6240

AbstractBackgroundA standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.Method375 18F‐MK6240 PET & T1w scan pairs (HC Aß‐ = 179/MCI Aß+ = 98/AD Aß+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aß‐ (<10CL) and AD Aß+ (>25CL) individuals younger than 75y, with MMSE = 20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aß‐ and 29 AD Aß+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.ResultThe mean and standard deviation (std) for the HC and AD groups are reported in Table 1. Using a single transformation resulted in the following equation: Ct = 100x(SUVR‐0.97)/2.26 Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.ConclusionThe region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.

A CenTauR scale based on 18F‐MK6240

AbstractBackgroundA standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.Method375 18F‐MK6240 PET & T1w scan pairs (HC Aβ‐ = 179/MCI Aβ+ = 98/AD Aβ+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aβ‐ (<10CL) and AD Aβ+ (>25CL) individuals younger than 75y, with MMSE ≥20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aβ‐ and 29 AD Aβ+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.ResultThe mean and standard deviation (std) for the HC and AD groups are reported in Table 1.Using a single transformation resulted in the following equation:Ct = 100x(SUVR‐0.97)/2.26Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.ConclusionThe region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.

Radiopharmaceutical selection for tau PET imaging

AbstractBackgroundThe accumulation of pathologically misfolded tau is a feature that is shared by a group of neurodegenerative disorders that are collectively referred to as tauopathies. AD is the most prevalent of these tauopathies. Neurofibrillary tangles are characterized by the presence of hyperphosphorylated protein (tau), and senile plaques are characterized by the presence of amyloid peptide aggregates. PET imaging is fully quantitative and enables accurate spatial assessment. However, as a result of non‐specific binding and the limited spatial resolution of PET scanners, this technique requires not only the presence of tau inclusions in a brain region but also sufficient density and spatial extent of those inclusions in order to generate a sufficient signal‐to‐noise ratio. With the development of tau‐specific ligands for use with PET, it is now possible to investigate the role that tau pathology plays in the development and progression of these disorders. The purpose of this study is to analyze, compare, and rank the currently available tau PET tracers for imaging in research and routine clinical settings.MethodWe proposed using the fuzzy Preference Ranking Organization Method for Enrichment of Evaluations (PROMETHEE), a multicriteria decision‐making (MCDM) tool. First‐generation tau PET tracers ([18F]AV1451, [11C]PBB3, [18F]THK5117, [18F]THK5351, [18F]THK5317, and [18F]THK5105) and second‐generation compounds ([18F]MK‐6240, [18F]JNJ‐067, [18F] PI‐2620, [18F]RO‐948 (previously referred to as [18F]RO69558948), [18F]PM‐PBB3, [18F]GTP1, [18F]JNJ‐64349311 ([18F]JNJ311), [11C]RO‐6931643, and [11C]RO‐6924963) were selected to investigate in this study. The evaluation is based on relative parameters, such as specificity, target binding accuracy, neocortical uptake, radiation exposure, brain penetration, free fraction in plasma, defluorination, and adverse reactions, and the importance that is placed on each of these parameters is weighted differently.ResultThe results from this study show that [18F]RO‐948 is the most favorable tau PET ligand, while[18F]THK5105 is the least favorable one based on the considered weighted criteria in this study.ConclusionFuzzy PROMETHEE can be used as a decision‐aid system to select the proper radiopharmaceuticals for tau PET imaging. This study can be extended to include more tracers and criteria and might help researchers and concerned readers to select the optimal tau PET tracer.

Amyloid and Tau PET Positivity in Progressive Agrammatic Aphasia and Apraxia of Speech.

The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer's disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers.

NCOG-34. BRAIN PET IMAGING OF PAIRED HELICAL FILAMENT TAU IN OLDER ADULTS WITH CANCER: PILOT STUDY TO IDENTIFY MECHANISMS OF COGNITIVE IMPAIRMENT AFTER CANCER THERAPY

Abstract BACKGROUND Cancer-related cognitive impairment (CRCI) occurs in up to 75% of patients treated with chemotherapy for systemic cancer, and older patients treated for CNS cancer receiving brain radiation therapy (RT) and chemotherapy are particularly at risk. The mechanisms of injury and CRCI remain unknown. In neurodegenerative disorders, deposition of paired helical filament tau (PHFTau) is correlated with nature and extent of cognitive symptoms. The role of PHFTau in CRCI has not been elucidated. We conducted a pilot study to determine whether CRCI is associated with PHFTau. METHODS Patients (age >60) diagnosed with mild cognitive impairment (MCI) or dementia after chemotherapy and/or brain RT underwent Tau PET imaging using [F18]Flourtaucipir. Cortical [F18]Flourtaucipir binding was quantified by standard uptake value ratio (SUVR) in 68 regions of interest (ROIs) and compared to a control group (n=22). SUVR in each ROI for each subject was considered significantly elevated when it was >2SD above the control group (p< 0.05). Neuropsychological test scores were correlated with PHFTau distribution. RESULTS Five patients with MCI/Dementia following cancer therapy participated. Two patients with prior chemo-RT for CNS cancer and prominent executive dysfunction had no significant F[18]T807 uptake. However, three patients treated with systemic chemotherapy for non-CNS cancer and neuropsychological profiles dominated by episodic memory impairment showed F[18]T807 uptake in patterns typical of AD dementia in temporal, parietal and cingulate ROI’s (n=2), or uptake in the entorhinal and inferior temporal ROIs (n=1). DISCUSSION In this pilot study, [F18]Flourtaucipir imaging of patients with cancer and MCI/Dementia showed that executive dysfunction after RT was not associated with abnormal PHFTau whereas amnestic declines after chemotherapy were associated with PHFTau in medial temporal lobes and beyond. Given the cross-sectional study, timing of tau accumulation in relation to cancer/treatment is unknown. Prospective studies are needed to understand the relevance of PHFTau in CRCI.

26 Religious Stress Coping, Memory, and Markers of Brain Pathology in Individuals with Autosomal Dominant Alzheimer’s Disease from the Colombia-Boston Biomarker Study

Objective:High levels of stress may increase risk for Alzheimer’s disease (AD) dementia. Religious coping practices to deal with stress (i.e., prayer, having faith, attending religious services) may reduce risk of dementia. Studying religious stress coping in cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia later in life, may inform us about the role of religious coping in modifying the clinical trajectory from preclinical to clinical stages of the disease. We examined religious stress coping in cognitively unimpaired mutation carriers from the world’s largest ADAD kindred and its relation to markers of brain pathology and memory.Participants and Methods:16 cognitively unimpaired Presenilin-1 E280A mutation carriers and 19 age and education-matched noncarrier family members from the Colombia-Boston (COLBOS) Biomarker Study were included. A subsample (n=26; 13 cognitively unimpaired carriers) underwent amyloid and tau PET imaging. Participants completed the Coping Strategies Questionnaire (CAE) that includes a subscale used to assess religious stress coping, where a higher score indicates more coping, and underwent memory testing using the Free and Cued Selective Reminding Test (FCSRT). The Geriatric Depression Scale (GDS) was used to assess depression. Mann-Whitney U tests were used to examine group differences in religious stress coping, brain pathology (i.e., cortical amyloid-beta, entorhinal and precuneus tau), memory, and depression. Nonparametric correlations were used to examine associations among religious stress coping, age, education, depression, memory, and pathology.Results:Carriers had poorer FCSRT immediate free recall than noncarriers (U=84.5, p=.024). There was no difference between groups in CAE religious stress coping, other FCSRT memory scores, nor GDS score (all p>.05). Compared to non-carriers, carriers had more cortical amyloid (U=152.0, p<.001) and more precuneus tau (U=123.0, p=.05). In carriers, religious stress coping was positively associated with education (r=.57, p=.022), FCSRT immediate free recall (a=.75, p<.001), FCSRT cued recall (a=.50, p=.047), and FCSRT delayed recall (r=.52, p=.038). After controlling for education, religious stress coping remained positively associated with FCSRT immediate free recall (r=.65, p=.009), but not other FCSRT memory scores (all p>.05). Religious stress coping was not associated with age or GDS score regardless of controlling for education (all p>.05). In carriers, religious stress coping was negatively associated with entorhinal tau (r=-.73, p=.005) and precuneus tau burden (r=-.58, p=.037). The association between religious stress coping and entorhinal tau remained significant after controlling for education (r=-.67, p=.016), but not precuneus tau (p>.05). Religious stress coping was not associated with cortical amyloid regardless of controlling for education in carriers (all p>.05). None of the associations with brain pathology or memory were significant in the non-carrier group.Conclusions:Religious stress coping was associated with better memory performance and a low AD pathology burden in individuals at genetic risk for developing AD dementia. Future studies with independent and larger samples should further examine religious stress coping strategies and their associations with other AD-related biomarkers, as well as with other risk and protective factors to better understand their role at the preclinical and prodromal stages of Alzheimer’s disease.

2 Computerized Cognitive Practice Effects in Relation to Amyloid and Tau in Preclinical Alzheimer's Disease: Results from a Multi-Site Cohort

AbstractObjective:There is a need to identify scalable cognitive paradigms that are sensitive enough to relate to Alzheimer's disease biomarkers (amyloid and tau) in the preclinical stage. Here, we determine whether initial performance and practice effects on the memory-focused Computerized Cognitive Composite (C3) relate to demographic variables, amyloid status [abnormal (A+), normal (A-)], and regional tau in clinically unimpaired (CU) older adults.Participants and Methods:We examined pre-randomization data from CU older adults screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. We focused on participants who completed the C3 (n=3287), most of whom completed an alternate version of the C3 again approximately 51 days later (n=4141), as well as a subset of preclinical AD participants (i.e., A+ CU) who completed the C3 and tau PET imaging with [18]F-flortaucipir (initial C3: n=354; repeat C3: n=343). C3 initial performance and practice effects were examined in relation to amyloid status (A+, A-) and continuous regional tau burden.Results:Initial C3 performance was associated with amyloid status [B(SE) = -0.075 (0.021), p < 0.001] across all participants, as well as tau burden in the medial temporal lobe (MTL) [B (SE) = -0.728 (0.220), p = 0.001], inferior temporal (IT) cortex [B (SE) = -0.782 (0.264), p = 0.003], and inferior parietal (IP) cortex [B (SE) = -0.721 (0.281), p = 0.011] amongst preclinical AD individuals. Short-term practice effects were also associated with reduced tau burden in MTL [B (SE) = -0.471 (0.202), p = 0.020], IT [B (SE) = -0.640 (0.240), p = 0.008], and IP [B( SE) = - 0.584 (0.255), p = 0.023] amongst preclinical AD participants, but were not associated with amyloid status [B (SE) = -0.018 (0.020), p = 0.348]. Critically, these effects with tau were only detected when baseline performance was accounted for presumably due to opposing influence from both practice effects and regression to the mean effects.Conclusions:This is the first study to show that performance on a brief cognitive battery administered in a multisite context is associated with both amyloid and tau among CU older adults. These findings suggest that computerized assessments may be a cost-effective and scalable approach for early detection efforts. Further, diminished practice effects on memory-based measures are associated with elevated tau burden in preclinical AD, suggesting that high-frequency cognitive testing collected over a short follow-up period may provide additional insights regarding early disease processes than single assessments.

Criterion Validation of Tau PET Staging Schemes in Relation to Cognitive Outcomes.

Utilization of NIA-AA Research Framework requires dichotomization of tau pathology. However, due to the novelty of tau-PET imaging, there is no consensus on methods to categorize scans into "positive" or "negative" (T+ or T-). In response, some tau topographical pathologic staging schemes have been developed. The aim of the current study is to establish criterion validity to support these recently-developed staging schemes. Tau-PET data from 465 participants from the Alzheimer's Disease Neuroimaging Initiative (aged 55 to 90) were classified as T+ or T- using decision rules for the Temporal-Occipital Classification (TOC), Simplified TOC (STOC), and Lobar Classification (LC) tau pathologic schemes of Schwarz, and Chen staging scheme. Subsequent dichotomization was analyzed in comparison to memory and learning slope performances, and diagnostic accuracy using actuarial diagnostic methods. Tau positivity was associated with worse cognitive performance across all staging schemes. Cognitive measures were nearly all categorized as having "fair" sensitivity at classifying tau status using TOC, STOC, and LC schemes. Results were comparable between Schwarz schemes, though ease of use and better data fit preferred the STOC and LC schemes. While some evidence was supportive for Chen's scheme, validity lagged behind others-likely due to elevated false positive rates. Tau-PET staging schemes appear to be valuable for Alzheimer's disease diagnosis, tracking, and screening for clinical trials. Their validation provides support as options for tau pathologic dichotomization, as necessary for use of NIA-AA Research Framework. Future research should consider other staging schemes and validation with other outcome benchmarks.

H - 06 Associations between Non-verbal Reasoning Abilities and Brain Pathology in a Colombian Cohort with Autosomal Dominant Alzheimer's Disease.

Declines in non-verbal reasoning abilities have been linked to Alzheimer's disease (ad) progression. Individuals with autosomal dominant ad (ADAD) are genetically determined to develop early-onset dementia. We examined the relation between non-verbal reasoning abilities and brain pathology in a Colombian cohort with ADAD due to the Presenilin-1 (PSEN1) E280A mutation. A total of 25 carriers of the PSEN1 E280A mutation (16 cognitively-unimpaired carriers [x- age = 35.25 +/- 4.04]; 9 with mildly impaired (age = 45.56 +/- 2.60), and 27 non-carriers (age = 36.11 +/- 5.59) were included. A summary non-verbal reasoning score was calculated from performance on the Judgment of Line Orientation and the Spanish WAIS-IV Matrix Reasoning and Visual Puzzles subtests. Participants also completed the Mini-mental State Examination (MMSE) and underwent amyloid and tau PET imaging. Mann-Whitney U test and education-adjusted Spearman partial correlations were used to examine group differences and associations between pathology levels and non-verbal reasoning. Compared to carriers, non-carriers had higher MMSE and non-verbal reasoning scores (p = 0.006). In carriers only, lower non-verbal reasoning was associated with greater mean cortical amyloid (r = -0.427, p = 0.037) and greater precuneus tau (r = -0.516, p = 0.010). No significant associations were observed after excluding the impaired carriers from the analyses. Our findings suggest that changes in non-verbal reasoning abilities are evident in early symptomatic ADAD stages and are related to ad brain pathology. Future longitudinal work is needed to characterize the progression of non-verbal reasoning deficits in ADAD. Future research should also examine performance between older adults and people at risk for sporadic ad.

H - 13 Examining the Cultural Sensitivity of a Novel Neuropsychological Assessment in Distinguishing between Cognitively Unimpaired (CU) and Amnestic Mild Cognitive Impairment (aMCI) in Hispanic Older Adults.

Common neuropsychological measures are not sensitive in capturing early cognitive changes associated with prodromal Alzheimer's Disease (ad) and vary across cultural groups. The Cognitive Stress Test (CST) is a novel assessment with high levels of sensitivity and specificity that measures maximum learning, proactive interference (PSI), retroactive interference, and the ability to recover from PSI (FrPSI). Authors evaluated the utility of the CST in distinguishing between aMCI versus CU Hispanic older adults. 18 aMCI and 15 CU older adults (mean age = 73.06; SD = 7.94, 42.4% male) were compared using the CST. Participants were categorized into the aforementioned groups using the Clinical Dementia Rating and results of neuropsychological evaluation. CST was not used in categorization to avoid circularity. CST includes the presentation of 18 target words from two semantically related wordlists (occupations, household items, and transportation) and assesses FrPSI over repeated trials. Data was analyzed utilizing an ROC curve to measure differences between CU and aMCI. The ROC curve demonstrated an area under the curve of 0.92, indicating that PSI was significant in differentiating participants. Findings suggest that PSI may be an early feature of aMCI groups who are at higher risk of progression to clinical ad. The CST was deemed to be an effective and culturally sensitive memory measurement tool among Hispanic older adults. In future studies, this paradigm may be particularly useful in deconstructing cognitive processes that can be compared to structural and functional MRI, amyloid and tau PET imaging, and emerging plasma biomarkers of ad.

GTP1 metabolic stability assessment: A study of the tau PET tracer [18F]GTP1

Tau PET imaging using the tau specific PET tracer [18F]GTP1 has been and is part of therapeutic trials in Alzheimer's disease to monitor the accumulation of tau aggregates in the brain. Herein, we examined the metabolic processes of GTP1 and assessed the influence of smoking on its metabolism through in vitro assays. The tracer metabolic profile was assessed by incubating GTP1 with human liver microsomes (HLM) and human hepatocytes. Since smoking strongly stimulates the CYP1A2 enzyme activity, we incubated GTP1 with recombinant CYP1A2 to evaluate the role of the enzyme in tracer metabolism. It was found that GTP1 could form up to eleven oxidative metabolites with higher polarity than the parent. Only a small amount (2.6 % at 60 min) of a defluorinated metabolite was detected in HLM and human hepatocytes incubations highlighting the stability of GTP1 with respect to enzymatic defluorination. Moreover, the major GTP1 metabolites were not the product of CYP1A2 activity suggesting that smoking may not impact in vivo tracer metabolism and subsequently GTP1 brain kinetics.

Tau-PET abnormality as a biomarker for Alzheimer's disease staging and early detection: a topological perspective.

Alzheimer's disease can be detected early through biomarkers such as tau positron emission tomography (PET) imaging, which shows abnormal protein accumulations in the brain. The standardized uptake value ratio (SUVR) is often used to quantify tau-PET imaging, but topological information from multiple brain regions is also linked to tau pathology. Here a new method was developed to investigate the correlations between brain regions using subject-level tau networks. Participants with cognitive normal (74), early mild cognitive impairment (35), late mild cognitive impairment (32), and Alzheimer's disease (40) were included. The abnormality network from each scan was constructed to extract topological features, and 7 functional clusters were further analyzed for connectivity strengths. Results showed that the proposed method performed better than conventional SUVR measures for disease staging and prodromal sign detection. For example, when to differ healthy subjects with and without amyloid deposition, topological biomarker is significant with P < 0.01, SUVR is not with P > 0.05. Functionally significant clusters, i.e. medial temporal lobe, default mode network, and visual-related regions, were identified as critical hubs vulnerable to early disease conversion before mild cognitive impairment. These findings were replicated in an independent data cohort, demonstrating the potential to monitor the early sign and progression of Alzheimer's disease from a topological perspective for individual.

Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid

IntroductionNon-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology.Methods122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models.ResultsWe find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants.ConclusionsThe combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer’s Disease-related episodic memory decline, suggesting utility in clinical trials.

Association of Apolipoprotein E ε4 with Tau and Amyloid‐β PET in a memory clinic cohort

AbstractBackgroundThe Apolipoprotein E ε4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). Previous studies have found a link between ApoE4 genotype and tau (T) deposition in the medial temporal lobe (MTL). However, further studies disentangling the influence of genotype on tau deposition and amyloid (A) are still needed. The aim of this study was to assess tau and amyloid deposition depending on subject genotype in a memory clinic cohort.Method89 subjects from the Geneva Memory Center underwent amyloid and tau PET imaging, and ApoE genotyping (ApoE2 carriers, ApoE3 homozygotes, ApoE4 carriers). The remaining subjects were classified as ApoE3. Amyloid uptake has been calculated as centiloid values and tau uptake as standardized uptake value ratio (SUVR), normalized to cerebellar uptake. Positivity for each biomarker was based on thresholds published by previous studies. Correlation between amyloid centiloid and tau SUVR in general and by genotype was calculated. ANOVA with Tuckey correction for multiple comparisons was used to assess differences between tau or amyloid PET uptake across different genotypes.Result85% of the A+T+ subjects were carriers of the ApoE4 gene. The association between neocortical amyloid and MTL tau stratified by genotype showed that these measures are correlated in ApoE4 carriers (r = 0.52, p = 0.001). The correlation was not significant in non‐carriers. MTL tau SUVR was higher in ApoE4 carriers and significantly different when compared to non‐carriers. Furthermore, tau SUVR from lateral and superior temporal lobes were also significantly different in ApoE4 carriers vs. non‐carriers even when not considering the centiloid value, showing an amyloid‐independent association between tau SUVR and genotype is not limited to the MTL. Centiloid values showed similar differences when comparing ApoE4 carriers with non‐carriers.ConclusionApoE4 gene carriers present a significant increase of both tau and amyloid load with respect to non‐carriers. Furthermore, increased tau deposition independent from amyloid load is not limited to the MTL, with the entire temporal lobe showing higher tau pathology in ApoE4 carriers.

Long‐term memory over 1‐week and markers of brain pathology in cognitively unimpaired individuals from a Colombian cohort with autosomal dominant Alzheimer’s disease

AbstractBackgroundLong‐term forgetting (LTF) over days or weeks may be a sensitive early marker of Alzheimer’s disease (AD), useful for preclinical AD trials. We examined associations between LTF and markers of brain pathology in individuals from the world’s largest kindred with autosomal dominant AD due to the Presenilin‐1 (PSEN1) E280A mutation.MethodsA total of 14 cognitively unimpaired PSEN1 mutation carriers (mean age: 35.9 years) and 16 matched non‐carriers (mean age: 32.8 years) from the Colombia‐Boston Biomarker Study of autosomal dominant AD were included. Participants underwent amyloid (11‐C Pittsburgh compound B) and tau (Flortaucipir) PET imaging, and memory tasks (NEUROPSI word list, stories and semi‐complex figure). We examined performance on learning and delayed recall after a 20‐min, 1‐day and 7‐day interval. LTF was calculated for the three tasks as the proportion of material retained at 20 min that was recalled 7 days later. Mann‐Whitney tests were conducted to compare memory performance and LTF between PSEN1 mutation carriers and non‐carriers. Spearman’s correlations were used to examine the association between LTF and brain pathology markers of amyloid burden and regional tau (entorhinal and inferior temporal cortices). Fisher’s exact tests were used to compare correlation coefficients between groups.ResultsLearning did not differ between carriers and non‐carriers. Compared to non‐carriers, carriers had lower 20‐min recall in all three tasks (p&lt;0.05), and lower 1‐day and 7‐day recall of word list and stories. There were no group differences in word list, stories or figure LTF. Further, no group differences were observed in the association of amyloid burden and LTF on any of the tasks. Lower word list LTF was associated with greater entorhinal burden among carriers, and the strength of this association was significantly different between carriers and non‐carriers (p = 0.046; carriers: r = 0.73, p = 0.003; non‐carriers: r = 0.43, p = 0.094).ConclusionsOur preliminary findings show that, while rates of LTF over 7 days did not differ between PSEN1 carriers and non‐carriers, carriers had lower verbal memory recall over 1 and 7 days. Further, LTF was associated with early tau accumulation, suggesting that longer recall intervals may be more sensitive to detect subtle memory changes in cognitively unimpaired individuals at risk for AD.

Neuroimaging biomarkers of the Amyloid, Tau, Neurodegeneration and Vascular framework in association with sleep duration changes over time

AbstractBackgroundBoth short and long sleep duration were previously associated with incident dementia, but underlying mechanisms of this association remains unknown. This project aims to evaluate 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’s disease (AD).MethodWithin the Framingham Heart Study, two samples were studied: 271 participants (age:53.6±8.0 years; 51%M) who underwent 11C‐PiB amyloid (global, precuneus) and 18F‐Flortaucipir tau (several medial cortical limbic structures) PET imaging; and 2165 participants (age:61.3±11.1 years; 45%M) who underwent an MRI. To estimate neurodegeneration, total brain volume was extracted from MRI. Vascular MRI metrics included white matter hyperintensities (continuous, and dichotomous indicator for extensive for age), covert brain infarcts, and average free‐water. Self‐reported sleep duration was assessed both at the time of neuroimaging testing and around 15 years before, and split by categories (≤6h, 7‐8h, ≥9h). Sleep duration change over time was assessed by change between categories and by continuous delta change (split by negative and positive values for decreased or increased respectively). Logistic and linear regression models were tested between self‐reported sleep duration and neuroimaging metrics, adjusted for age and age2, sex, PET camera, APOE4 carrier status, depression, diabetes, hypertension, and prevalent cardiovascular diseases.ResultsNo association was observed between cross‐sectional self‐reported sleep duration and neuroimaging metrics. Transitioning to longer sleep over time (≤6h to ≥9h and 7‐8h to ≥9h as compared to consistently sleeping 7‐8h) was associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:3.50[0.95‐12.92], p = 0.040;ß[SE]:0.25[0.10], p = 0.015) and higher free‐water (ß[SE]:0.021[0.007], p = 0.003;ß[SE]:0.009[0.002], p = 0.0002). When looking at continuous sleep duration change, increasing sleep duration over time was also associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:1.26[1.02‐1.55], p = 0.032;ß[SE]:0.10[0.04], p = 0.007) and higher free‐water (ß[SE]:0.002[0.001], p = 0.031). Self‐reported sleep duration change was not associated with PET amyloid or tau outcomes.ConclusionVascular pathology in the brain as evidenced by higher white matter hyperintensities burden and free‐water is associated with sleep duration that is getting longer over time, thus potentially explaining its association with dementia risk. In fact, elongation of sleep duration may be an early change in the AD trajectory.

The heterogeneity of asymmetric tau distribution is associated with an early age at onset and poor prognosis in Alzheimer’s disease

AbstractBackgroundThis study aimed to investigate whether an asymmetric tau distribution on PET images could be associated with clinical characteristics and prognosis in prodromal and/or clinical Alzheimer’s disease (AD).MethodThe testing cohort consisted of 60 patients with mild cognitive impairment due to AD and AD dementia from the Alzheimer’s Disease Neuroimaging Initiative – who underwent tau PET imaging with the first‐generation tau tracer [18F]flortaucipir. The validation cohort consisted of an independent sample of 67 patients enrolled from the Shanghai Memory Study who underwent PET tau imaging with the second‐generation tau tracer [18F]APN‐1607. Based on the absolute global tau interhemispheric differences, each cohort was divided into two groups (asymmetric versus symmetric tau distribution). The two groups were cross‐sectionally compared in terms of demographic and cognitive characteristics, as well as pathological burden. The cognitive trajectories of cognitive decline were analyzed longitudinally.ResultFourteen patients (23.3%) in the testing cohort and 26 (38.8%) in the validation cohort showed an asymmetric tau distribution. In both cohorts, cross‐sectional results consistently revealed that an asymmetric tau distribution was associated with an earlier age at disease onset and more severe tau and amyloid burden (Fig 1). In longitudinal analyses, patients with an asymmetric tau distribution were characterized by a steeper cognitive decline (Fig 2).ConclusionAn asymmetric tau distribution on PET images was consistently associated with an earlier age at onset and more severe pathological features of AD in two independent cohorts. Additionally, this imaging biomarker was longitudinally associated with a more rapid trajectory of cognitive decline.

Autosomal dominant Parkinson's disease caused by the recently identified LRRK2 N1437D mutation in a Chinese family: Clinical features, imaging findings, and functional impact

IntroductionMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of autosomal dominantly inherited Parkinson's disease (PD). Recently, a novel pathogenic variant (N1437D; c.4309A > G; NM_98578) in the LRRK2 gene has been identified in three Chinese families with PD. In this study, we describe a Chinese family with autosomal dominant PD that segregated with the N1437D mutation. A detailed clinical and neuroimaging characterization of the affected family members is reported. We also sought to investigate the functional mechanisms by which the detected mutation could cause PD. MethodsWe characterized the clinical and imaging phenotype of a Chinese pedigree with autosomal dominant PD. We searched for a disease-causing mutation by targeted sequencing and multiple ligation-dependent probe amplification. The functional impact of the mutation was investigated in terms of LRRK2 kinase activity, guanosine triphosphate (GTP) binding, and guanosine triphosphatase (GTPase) activity. ResultsThe disease was found to co-segregate with the LRRK2 N1437D mutation. Patients in the pedigree exhibited typical parkinsonism (age at onset: 54.0 ± 5.9 years). One affected family member – who had evidence of abnormal tau accumulation in the occipital lobe on tau PET imaging – developed PD dementia at follow-up. The mutation markedly increased LRRK2 kinase activity and promoted GTP binding, without affecting GTPase activity. ConclusionsThis study describes the functional impact of a recently identified LRRK2 mutation, N1437D, that causes autosomal dominant PD in the Chinese population. Further research is necessary to investigate the contribution of this mutation to PD in multiple Asian populations.