. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci. 2018 Mar;21(3):424-431. Epub 2018 Feb 5 PubMed.


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  1. Experimental studies showed that assembled mutant human tau propagates through connectivity, not proximity, in the absence of Aβ deposits (Ahmed et al., 2014). Additional experiments demonstrated that Aβ deposits can enhance the spreading of tau pathology (Pooler et al., 2015He et al., 2018). It is important to relate these animal studies to what may be going on in human brain. The present work, which used PET scanning and DTI, is therefore particularly welcome. Tau assemblies propagated through connectivity, not proximity, in an Aβ-dependent manner. The molecular mechanisms underlying tau aggregate propagation and its enhancement by Aβ remain to be elucidated. One must bear in mind that prion-like spreading of tau aggregates is also believed to be important in sporadic tauopathies that lack Aβ deposits, such as Pick’s disease and progressive supranuclear palsy. Does it follow that the spreading of tau pathology is less effective in those diseases?


    . A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014 May;127(5):667-83. Epub 2014 Feb 16 PubMed.

    . Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease. Acta Neuropathol Commun. 2015 Mar 24;3:14. PubMed.

    . Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018 Jan;24(1):29-38. Epub 2017 Dec 4 PubMed.

    View all comments by Michel Goedert
  2. Heidi Jacobs and colleagues performed a longitudinal multimodal imaging study to assess the relationships between Aβ (PiB-PET) and tau (flortaucipir PET) pathology, hippocampal volumes (T1-weighted MRI), white-matter tracts (DTI), and cognition (memory and executive-function composite scores) in 256 cognitively normal elderly. Using a stepwise approach, they tested a multifactorial hypothetical model flowing from previous imaging work from this group and others, as well as the basic science literature. Among many analyses presented in this excellent paper, I found two of them particularly interesting.

    In the first analysis, the authors tested whether diffusivity of the hippocampal cingulum bundle (HCB) was associated with accumulation of tau pathology in the posterior cingulate cortex (PCC). The HCB is a white-matter tract that connects the hippocampus with the PCC. Studying this tract in conjunction with the uncinate fasciculus (UF, a WM tract that innervates the medial temporal lobe but not the hippocampus) and tau load in the inferior temporal lobe (a region proximate to the hippocampus but less tightly connected to the HCB) as control conditions is of great interest for inferring spreading mechanisms of tau pathology. The authors found that mean baseline diffusivity was associated with increased PCC tau load over time, and that this relationship was absent for UF diffusivity (as predictor) and changes in inferior temporal cortex flortaucipir uptake (as dependent variable). Stratification by Aβ status revealed that this effect was strongly driven by Aβ-positive individuals. These findings provide further support for the hypothesis that propagation of tau pathology occurs through connectivity, rather than just proximity. The employment of DTI in this study provides convergent information to some recent cross-sectional studies in clinical populations that used the functional architecture (task-free fMRI) as a surrogate for the structural connectome (Hoenig et al., 2018; Cope et al., 2018). 

    In the second analysis, the authors assessed the inter-relationships between HCB diffusivity, PCC tau load, and cognitive function. They showed that baseline HCB diffusivity predicted memory decline, but this only reached significance in subjects with high PCC tau load. Further stratification by Aβ status showed that the Aβ-positive subjects in the sample—again—drove this interaction effect. This emphasizes the importance of Aβ deposition as a potential trigger for downstream effects, while tau pathology might be the actual driver of neurodegeneration and subsequent cognitive decline. These findings suggest that Aβ is an important focus for disease-modifying drugs, but is has to be targeted at very early, presymptomatic stages of Alzheimer’s disease to prevent the pathological chain of events from progressing.

    This study is a terrific example of translational neuroscience, in which cellular/molecular perspectives on mechanistic properties of neurodegenerative diseases were used to investigate these mechanisms on a macroscopic scale in living humans. Some debates at the microscopic level unfortunately cannot be broached by human imaging approaches due to some inherent limitations. For example, the perforant pathway (connecting entorhinal cortex with hippocampus) would have been a logical target for studying mechanisms of tau spreading along WM tracts, but this pathway cannot be captured with the current spatial resolution of DTI. Also, tau pathology in the hippocampus itself cannot be reliably measured using the current generation of tau PET tracers (due to off-target binding in proximate choroid plexus). Having said that, this study provides important insights into the spatiotemporal relationships between presence of Aβ, tau accumulation, alterations in white matter tracts, neurodegeneration and cognitive decline in preclinical AD.


    . Networks of tau distribution in Alzheimer's disease. Brain. 2018 Feb 1;141(2):568-581. PubMed.

    . Tau burden and the functional connectome in Alzheimer's disease and progressive supranuclear palsy. Brain. 2018 Feb 1;141(2):550-567. PubMed.

    View all comments by Rik Ossenkoppele

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