Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET

PurposeAlzheimer’s disease (AD) studies revealed that abnormal deposition of tau spreads in a specific spatial pattern, namely Braak stage. However, Braak staging is based on post mortem brains, each of which represents the cross-section of the tau trajectory in disease progression, and numerous studies were reported that does not conform to this model. This study aimed to identify the tau trajectory and additionally quantify the tau progress in a data-driven approach using the continuous latent space learned by variational autoencoder (VAE). Methods1080 [18F]Flortaucipir brain PET images were collected from Alzheimer’s Disease Neuroimaging Initiative database. VAE was built to compress the hidden features from tau images in latent space. Hierarchical clustering and minimum spanning tree were applied to organize the features and calibrate them to the tau progression, thus deriving pseudo-time. The image-level tau trajectory was inferred by continuously sampling across the calibrated latent features. We assessed the pseudo-time with regards to tau standardized uptake value ratio (SUVr) in AD-vulnerable regions, amyloid deposit, glucose metabolism, cognitive scores and clinical diagnosis. ResultsWe identified 4 clusters that plausibly capture certain stages of AD and organized the clusters in the latent space. The inferred tau trajectory agreed with the Braak staging. According to the derived pseudo-time, tau first deposits in the parahippocampal and amygdala, and then spreads to fusiform, inferior temporal lobe, and posterior cingulate. Prior to the regional tau deposition, amyloid accumulates first. ConclusionThe spatiotemporal trajectory of tau progression inferred in this study was consistent with Braak staging, and the profile of other biomarkers in disease progression agreed well with previous findings. We addressed that this approach additionally carries a potential to quantify tau progression as a continuous variable taking a whole-brain tau image into account.

Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

Background To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen’s d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings.

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n=174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p=0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p=0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p<0.0001), but other features including ARTAG (p=0.03) and hippocampal atrophy (p=0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Visit-to-Visit Blood Pressure Variability, Neuropathology, and Cognitive Function

ObjectiveLarge systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration and underlying neuropathological changes.MethodsWe used longitudinal data (between 2005 and 2019) from the National Alzheimer’s Coordinating Center. 13,284 dementia-free participants aged≥50 years were followed over a median of 5.0 (interquartile range: 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia, or from MCI to dementia.ResultsLarger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles: 2.64; 95%CI:2.29-3.04, P <0.001). It was also associated with a higher burden of vascular pathology (including microinfarcts, white matter lesion, atherosclerosis of the circle of Willis and arteriolosclerosis) and with neurofibrillary tangle pathology assessed by Braak staging (All P < 0.05). The association with cognitive deterioration and vascular pathology appeared stronger among those with normal cognition versus MCI at baseline. These findings were observed after adjusting for age, sex, mean SBP and other confounding variables. Similar results were observed for diastolic BP variability.ConclusionLarger visit-to-visit SBP variability was associated with cognitive deterioration. It was also associated with cerebrovascular pathology and neurofibrillary tangles. These results suggest the intertwined role of vascular and Alzheimer's disease pathology in the etiology of dementia.

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.

Tau-PET and in vivo Braak-staging as a prognostic marker in Alzheimer’s disease

ABSTRACTINTRODUCTIONTau pathology in Alzheimer’s disease tracks clinical status more closely than beta-amyloid. Thus, tau-PET may be a promising prognostic marker for cognitive decline. Here, we systematically compared tau-PET and Braak-staging vs. amyloid-PET as predictors of cognitive decline.METHODSWe included 396 cognitively normal to dementia subjects with 18F-Flutemetamol/18F-Florbetapir-amyloid-PET, 18F-Flortaucipir-tau-PET and ~2-year cognitive assessments. Annual cognitive change rates were calculated via linear-mixed models. We determined global amyloid-PET, global tau-PET, and tau-PET-based Braak-stage (Braak0/BraakI+/BraakI-IV+/BraakI-VI+/Braakatypical+). In bootstrapped linear regression, we assessed whether tau-PET outperformed amyloid-PET in predicting cognitive decline. Using ANCOVAs, we tested whether later Braak-stage predicted accelerated cognitive decline and determined Braak-stage-specific conversion risk to MCI or dementia.RESULTSGlobal tau-PET was a better predictor of cognitive decline than global amyloid-PET (p<0.001). Advanced Braak-stage was associated with faster cognitive decline (p<0.001) and elevated clinical conversion risk.DISCUSSIONTau-PET and Braak-staging show promise for predicting patient-specific risk of clinical AD progression.

Braiding Braak and Braak: Staging patterns and model selection in network neurodegeneration

A hallmark of Alzheimer’s disease is the aggregation of insoluble amyloid-beta plaques and tau protein neurofibrillary tangles. A key histopathological observation is that tau protein aggregates follow a clear progression pattern through the brain; characterized by six distinct stages. This so-called ‘Braak staging pattern’ has become the gold standard for Alzheimer’s disease progression. It has also been suggested, via a histopathological analysis, that soluble seed-competent tau seeding precedes tau aggregation in the same manner. Mathematical models such as prion-like propagation on networks have the ability to capture key feature of the dynamics. Here, we study the staging of tau proteins using a model of proteopathy that include both local growth due to autocatalytic effects and diffusion along axonal pathways. We develop new methods to capture the staging patterns and use these as a qualitative criterion to identify the best model for diffusion process on networks and to identify possible parameter regimes. Our analysis provides a systematic way to study Braak staging in neurodegenerative processes.