Dataset Information

Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease.

ABSTRACT: Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models' performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.

SUBMITTER: Kim HR

PROVIDER: S-EPMC7963115 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease.

Kim Hang-Rai HR Lee Peter P Seo Sang Won SW Roh Jee Hoon JH Oh Minyoung M Oh Jungsu S JS Oh Seung Jun SJ Kim Jae Seung JS Jeong Yong Y

Cerebral cortex (New York, N.Y. : 1991) 20190901 10

Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph the ...[more]

PMID: 30566579

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Project description:With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation.

Project description:Alzheimer's disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount of evidence supports the amyloid cascade hypothesis, which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles, and these aggregates lead to inflammation, synaptic impairment, neuronal loss, and thus to cognitive decline and behavioral abnormalities. The poor correlation found between cognitive decline and amyloid plaques, have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer's disease. The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and, although amyloid-beta may initiate the cascade of events, tau impairment is likely the effector molecule of neurodegeneration. Recently, it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and, more importantly, that downregulation of tau partially reverses transcriptional perturbations. Despite mounting evidence points to an interplay between amyloid-beta and tau, some factors could independently affect both pathologies. Thus, the dual pathway hypothesis, which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed. Among others, the immune system seems to be strongly involved in amyloid-beta and tau pathologies. Other factors, as the apolipoprotein E ε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials. Likewise, it has been shown that tau-immunotherapy also reduces amyloid-beta levels. Thus, even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy, combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer's disease.

Project description:Amyloid-beta deposition is one of the hallmark pathologies in both sporadic Alzheimer's disease and autosomal-dominant Alzheimer's disease, the latter of which is caused by mutations in genes involved in amyloid-beta processing. Despite amyloid-beta deposition being a centrepiece to both sporadic Alzheimer's disease and autosomal-dominant Alzheimer's disease, some differences between these Alzheimer's disease subtypes have been observed with respect to the spatial pattern of amyloid-beta. Previous work has shown that the spatial pattern of amyloid-beta in individuals spanning the sporadic Alzheimer's disease spectrum can be reproduced with high accuracy using an epidemic spreading model which simulates the diffusion of amyloid-beta across neuronal connections and is constrained by individual rates of amyloid-beta production and clearance. However, it has not been investigated whether amyloid-beta deposition in the rarer autosomal-dominant Alzheimer's disease can be modelled in the same way, and if so, how congruent the spreading patterns of amyloid-beta across sporadic Alzheimer's disease and autosomal-dominant Alzheimer's disease are. We leverage the epidemic spreading model as a data-driven approach to probe individual-level variation in the spreading patterns of amyloid-beta across three different large-scale imaging datasets (2 sporadic Alzheimer's disease, 1 autosomal-dominant Alzheimer's disease). We applied the epidemic spreading model separately to the Alzheimer's Disease Neuroimaging initiative (n = 737), the Open Access Series of Imaging Studies (n = 510) and the Dominantly Inherited Alzheimer's Network (n = 249), the latter two of which were processed using an identical pipeline. We assessed inter- and intra-individual model performance in each dataset separately and further identified the most likely subject-specific epicentre of amyloid-beta spread. Using epicentres defined in previous work in sporadic Alzheimer's disease, the epidemic spreading model provided moderate prediction of the regional pattern of amyloid-beta deposition across all three datasets. We further find that, whilst the most likely epicentre for most amyloid-beta-positive subjects overlaps with the default mode network, 13% of autosomal-dominant Alzheimer's disease individuals were best characterized by a striatal origin of amyloid-beta spread. These subjects were also distinguished by being younger than autosomal-dominant Alzheimer's disease subjects with a default mode network amyloid-beta origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most autosomal-dominant Alzheimer's disease patients express amyloid-beta spreading patterns similar to those of sporadic Alzheimer's disease, but that there may be a subset of autosomal-dominant Alzheimer's disease patients with a separate, striatal phenotype.

Dataset Information

Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease.

Publications

Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease.

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