PET Imaging of Tau Deposition in the Aging Human Brain.
Ontology highlight
ABSTRACT:
SUBMITTER: Scholl M
PROVIDER: S-EPMC4779187 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
Publications
PET Imaging of Tau Deposition in the Aging Human Brain.
Schöll Michael M Lockhart Samuel N SN Schonhaut Daniel R DR O'Neil James P JP Janabi Mustafa M Ossenkoppele Rik R Baker Suzanne L SL Vogel Jacob W JW Faria Jamie J Schwimmer Henry D HD Rabinovici Gil D GD Jagust William J WJ
Neuron 20160301 5
Tau pathology is a hallmark of Alzheimer's disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory p ...[more]
Similar Datasets
Project description:Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of ?-amyloid (A?). However, the accumulation of A? begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [18F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline A? levels and A? slope in asymptomatic older adults, suggesting a slowing of A? accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of A? predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of A? increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.
| S-EPMC5943976 | biostudies-other
Project description:ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages.
| S-EPMC6831941 | biostudies-literature
Project description:Tau pathology first appears in the transentorhinal and anterolateral entorhinal cortex (alEC) in the aging brain. The transition to Alzheimer's disease (AD) is hypothesized to involve amyloid-β (Aβ) facilitated tau spread through neural connections. We contrasted functional connectivity (FC) of alEC and posteromedial EC (pmEC), subregions of EC that differ in functional specialization and cortical connectivity, with the hypothesis that alEC-connected cortex would show greater tau deposition than pmEC-connected cortex. We used resting state fMRI to measure FC, and PET to measure tau and Aβ in cognitively normal older adults. Tau preferentially deposited in alEC-connected cortex compared to pmEC-connected or non-connected cortex, and stronger connectivity was associated with increased tau deposition. FC-tau relationships were present regardless of Aβ, although strengthened with Aβ. These results provide an explanation for the anatomic specificity of neocortical tau deposition in the aging brain and reveal relationships between normal aging and the evolution of AD.
| S-EPMC6764824 | biostudies-literature
Project description:The tau protein aggregates in aging and Alzheimer disease and may lead to memory loss through disruption of medial temporal lobe (MTL)-dependent memory systems. Here, we investigated tau-mediated mechanisms of hippocampal dysfunction that underlie the expression of episodic memory decline using fMRI measures of hippocampal local coherence (regional homogeneity; ReHo), distant functional connectivity and tau-PET. We show that age and tau pathology are related to higher hippocampal ReHo. Functional disconnection between the hippocampus and other components of the MTL memory system, particularly an anterior-temporal network specialized for object memory, is also associated with higher hippocampal ReHo and greater tau burden in anterior-temporal regions. These associations are not observed in the posteromedial network, specialized for context/spatial information. Higher hippocampal ReHo predicts worse memory performance. These findings suggest that tau pathology plays a role in disconnecting the hippocampus from specific MTL memory systems leading to increased local coherence and memory decline.
| S-EPMC6814780 | biostudies-literature
Project description:IntroductionTau-positron emission tomography (PET) imaging with AV1451 is sensitive to Alzheimer disease (AD)-related tau deposition in the brain. We (1) examined regional variation of average tau-PET standardized uptake value ratios (SUVRs) in a young normal population (30-49 years) and corrected for the regional variability and (2) tested if the standardized values (z-scores) scaled appropriately to capture regional Alzheimer-specific (i.e., amyloid sensitive) tau-PET changes in individuals aged 50+ years.MethodsWe identified 490 individuals (70 between 30-49 years as a reference group and 420 cognitively normal between 50-95 years of age) with tau-PET and amyloid PET scans from the Mayo Clinic Study of Aging.ResultsThere was intrinsic regional variability in average tau-PET SUVR with uptakes higher in some regions than others, even in the younger individuals who would have minimal or no neurofibrillary tangles. We corrected for this using region of interest-specific z-scores based on the reference group. Amyloid and tau-PET uptake were associated throughout the brain after adjusting for age, with the highest correlations in the medial temporal regions.DiscussionRegions with high-average SUVR are not necessarily those with the greatest tau pathology. Standardization is therefore recommended. Standardization of the data "realigns" the data such that the regional tau z-scores are informative of the disease process, that is, regions with high z-scores now coincide with regions correlated with amyloid deposition. Medial temporal structures, specifically entorhinal cortex-tau, may be useful as an AD-specific tau-PET signature due to its sensitivity to amyloid.
| S-EPMC5257031 | biostudies-literature
Project description:BackgroundMicrotubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer's disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging. The contribution of MT instability in AD remains unknown, though it may be more proximal to neuronal dysfunction than tau accumulation. Our lab reported the first brain-penetrant MT-based PET ligand, [11C]MPC-6827, and its PET imaging with this ligand in normal rodents and non-human primates demonstrated high brain uptake and excellent pharmacokinetics. Target engagement and mechanism of action using in vitro, in vivo, and ex vivo methods were evaluated here.MethodsIn vitro cell uptake assay was performed in SH-SY5Y neuronal cells with [11C]MPC-6827, with various MT stabilizing and destabilizing agents. To validate the in vitro results, wild type (WT) mice (n = 4) treated with a brain-penetrant MT stabilizing drug (EpoD) underwent microPET/CT brain imaging with [11C]MPC-6827. To determine the influence of tau protein on radiotracer binding in the absence of protein accumulation, we utilized tau knockout (KO) mice. In vivo microPET imaging, ex vivo biodistribution, and autoradiography studies were performed in tau KO and WT mice (n = 6/group) with [11C]MPC-6827. Additionally, α, β, and acetylated tubulin levels in both brain samples were determined using commercially available cytoskeleton-based MT kit and capillary electrophoresis immunoblotting assays.ResultsCell uptake demonstrated higher radioactive uptake with MT destabilizing agents and lower uptake with stabilizing agents compared to untreated cells. Similarly, acute treatment with EpoD in WT mice decreased [11C]MPC-6827 brain uptake, assessed with microPET/CT imaging. Compared to WT mice, tau KO mice expressed significantly lower β tubulin, which contains the MPC-6827 binding domain, and modestly lower levels of acetylated α tubulin, indicative of unstable MTs. In vivo imaging revealed significantly higher [11C]MPC-6827 uptake in tau KOs than WT, particularly in AD-relevant brain regions known to express high levels of tau. Ex vivo post-PET biodistribution and autoradiography confirmed the in vivo results.ConclusionsCollectively, our data indicate that [11C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [11C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies.
| S-EPMC9325934 | biostudies-literature
Project description:Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.
| S-EPMC6219464 | biostudies-literature
Project description:Imaging biomarkers support the diagnosis of Alzheimer's disease (AD). We aimed to determine whether combining automated brain volumetry on MRI and quantitative measurement of tau deposition on [18F] THK-5351 PET can aid discrimination of AD spectrum. From a prospective database in an IRB-approved multicenter study (NCT02656498), 113 subjects (32 healthy control, 55 mild cognitive impairment, and 26 Alzheimer disease) with baseline structural MRI and [18F] THK-5351 PET were included. Cortical volumes were quantified from FDA-approved software for automated volumetric MRI analysis (NeuroQuant). Standardized uptake value ratio (SUVR) was calculated from tau PET images for 6 composite FreeSurfer-derived regions-of-interests approximating in vivo Braak stage (Braak ROIs). On volumetric MRI analysis, stepwise logistic regression analyses identified the cingulate isthmus and inferior parietal lobule as significant regions in discriminating AD from HC and MCI. The combined model incorporating automated volumes of selected brain regions on MRI (cingulate isthmus, inferior parietal lobule, hippocampus) and SUVRs of Braak ROIs on [18F] THK-5351 PET showed higher performance than SUVRs of Braak ROIs on [18F] THK-5351 PET in discriminating AD from HC (0.98 vs 0.88, P = 0.033) but not in discriminating AD from MCI (0.85 vs 0.79, P = 0.178). The combined model showed comparable performance to automated volumes of selected brain regions on MRI in discriminating AD from HC (0.98 vs 0.94, P = 0.094) and MCI (0.85 vs 0.78; P = 0.065).
| S-EPMC8121780 | biostudies-literature
Project description:Alzheimer's disease (AD) patients are known to have heterogeneous clinical presentation and pathologic patterns. We hypothesize that AD dementia can be categorized into subtypes based on multimodal imaging biomarkers such as magnetic resonance imaging (MRI), tau positron emission tomography (PET), and amyloid PET. We collected 3T MRI, 18F-THK5351 PET, and 18F-flutemetamol (FLUTE) PET data from 83 patients with AD dementia [Clinical Dementia Rating (CDR) ≤1] and 60 normal controls (NC), and applied surface-based analyses to measure cortical thickness, THK5351 standardized uptake value ratio (SUVR) and FLUTE SUVR for each participant. For the patient group, we performed an agglomerative hierarchical clustering analysis using the three multimodal imaging features on the vertices (n = 3 × 79,950). The identified AD subtypes were compared to NC using general linear models adjusting for age, sex, and years of education. We mapped the effect size within significant cortical regions reaching a corrected p-vertex <0.05 (random field theory). Our surface-based multimodal framework has revealed three distinct subtypes among AD patients: medial temporal-dominant subtype (MT, n = 44), parietal-dominant subtype (P, n = 19), and diffuse atrophy subtype (D, n = 20). The topography of cortical atrophy and THK5351 retention differentiates between the three subtypes. In the case of FLUTE, three subtypes did not show distinct topographical differences, although cortical composite retention was significantly higher in the P type than in the MT type. These three subtypes also differed in demographic and clinical features. In conclusion, AD patients may be clustered into three subtypes with distinct topographical features of cortical atrophy and tau deposition, although amyloid deposition may not differ across the subtypes in terms of topography.
| S-EPMC6710378 | biostudies-literature
Project description:IntroductionHead injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important.MethodsCognition and tau deposition were compared between 752 individuals with (impaired, n = 302) or without cognitive impairment (CN, n = 450) with amyloid and [18F]flortaucipir positron emission tomography, HI history information, and cognitive testing from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study.ResultsSixty-three (38 CN, 25 impaired) reported a history of HI. Higher neuropsychiatric scores and poorer memory were observed in those with a history of HI. Tau was higher in individuals with a history of HI, especially those who experienced a loss of consciousness (LOC). Results were driven by impaired individuals, especially amyloid beta-positive individuals with history of HI with LOC.DiscussionThese findings suggest biological changes, such as greater tau, are associated with HI in individuals with cognitive impairment. Small effect sizes were observed; thus, further studies should replicate and extend these results.
| S-EPMC8383323 | biostudies-literature