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Is tau in the absence of amyloid on the Alzheimer's continuum?: A study of discordant PET positivity.

ABSTRACT: The amyloid cascade model of Alzheimer's disease posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer's continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is frequently observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled 'primary age-related tauopathy'. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to Alzheimer's disease. We used positron emission tomography imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer's pathogenesis. Five hundred twenty-three individuals from the Alzheimer's Disease Neuroimaging Initiative who had undergone flortaucipir positron emission tomography imaging were selected to derive positron emission tomography positivity thresholds using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. those with normal cognition or mild cognitive impairment) had also undergone florbetapir positron emission tomography imaging within 12 months and were categorized into one of the four groups based on cortical amyloid and Braak stage I/II tau positivity: A-/T-, A+/T-, A-/T+, or A+/T+. Tau positivity in the absence of amyloid beta positivity (i.e. A-/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T-, and the remainder of the sample fell into A-/T- (22%) or A+/T+ (27%) categories. A-/T- and A+/T- groups had the best cognitive performances across memory, language and executive function; the A-/T+ group showed small-to-moderate relative decreases in cognition; and the A+/T+ group had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau values and all cognitive domains only in the A-/T+ and A+/T+ groups, with strongest associations for the A+/T+ group. Among our sample of older adults across the Alzheimer's pathological spectrum, 7-fold fewer individuals have positron emission tomography evidence of amyloid beta pathology in the absence of tau pathology than the converse, challenging prevailing models of amyloid beta's primacy in Alzheimer's pathogenesis. Given that cognitive performance in the A-/T+ group was poorer than in individuals without either pathology, our results suggest that medial temporal lobe tau without cortical amyloid beta may reflect an early stage on the Alzheimer's pathological continuum.

SUBMITTER: Weigand AJ

PROVIDER: S-EPMC7001143 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundConsidering the limited accessibility of amyloid position emission tomography (PET) in patients with dementia, we proposed a deep learning (DL)-based amyloid PET positivity classification model from PET images with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (2-[18F]FDG).MethodsWe used 2-[18F]FDG PET datasets from the Alzheimer's Disease Neuroimaging Initiative and Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease for model development. Moreover, we used an independent dataset from another hospital. A 2.5-D deep learning architecture was constructed using 291 submodules and three axes images as the input. We conducted the voxel-wise analysis to assess the regions with substantial differences in glucose metabolism between the amyloid PET-positive and PET-negative participants. This facilitated an understanding of the deep model classification. In addition, we compared these regions with the classification probability from the submodules.ResultsThere were 686 out of 1433 (47.9%) and 50 out of 100 (50%) amyloid PET-positive participants in the training and internal validation datasets and the external validation datasets, respectively. With 50 times iterations of model training and validation, the model achieved an AUC of 0.811 (95% confidence interval (CI) of 0.803-0.819) and 0.798 (95% CI, 0.789-0.807) on the internal and external validation datasets, respectively. The area under the curve (AUC) was 0.860 when tested with the model with the highest value (0.864) on the external validation dataset. Moreover, it had 75.0% accuracy, 76.0% sensitivity, 74.0% specificity, and 75.0% F1-score. We found an overlap between the regions within the default mode network, thus generating high classification values.ConclusionThe proposed model based on the 2-[18F]FDG PET imaging data and a DL framework might successfully classify amyloid PET positivity in clinical practice, without performing amyloid PET, which have limited accessibility.

Project description:ImportanceAn increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear.ObjectiveTo study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum.Design, setting, and participantsA multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-).ExposuresTau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments.Main outcomes and measuresCross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset).ResultsAmong the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+.Conclusions and relevanceIn this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Project description:BackgroundInconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [18F]florbetaben (FBB) and [18F]florbetapir (FBP) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples.MethodsWe analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer's Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295).ResultsThe FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [18F]FBB: CLwhole cerebellum = 157.15 × SUVRFBB - 151.87; threshold=1.08, 18 CL [18F]FBP: CLwhole cerebellum = 188.22 × SUVRFBP - 189.16; threshold=1.11, 20 CL [18F]FBB: CLcomposite = 244.20 × SUVRFBB - 170.80 [18F]FBP: CLcomposite = 300.66 × SUVRFBP - 208.84 CONCLUSIONS: FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.

Project description:BACKGROUND:The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated ?-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. METHODS:Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine ?-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. RESULTS:Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their ?-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising ?-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. CONCLUSIONS:Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising ?-amyloid load show correlated levels of microglial activation which then later decline when the ?-amyloid load approaches AD levels. Later, as tau tangles form in ?-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Project description:Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-β and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-β/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-β-positive tau-negative participants with respect to the reference amyloid-β-negative tau-negative group. Both amyloid-β and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-β in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-β/tau stages. Taken together, our results show that CSF amyloid-β and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes.

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Is tau in the absence of amyloid on the Alzheimer's continuum?: A study of discordant PET positivity.

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