Kim HJ, Park S, Cho H, Jang YK, San Lee J, Jang H, Kim Y, Kim KW, Ryu YH, Choi JY, Moon SH, Weiner MW, Jagust WJ, Rabinovici GD, DeCarli C, Lyoo CH, Na DL, Seo SW. Assessment of Extent and Role of Tau in Subcortical Vascular Cognitive Impairment Using 18F-AV1451 Positron Emission Tomography Imaging. JAMA Neurol. 2018 Aug 1;75(8):999-1007. PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is an interesting study with well-characterized patient groups exploring the cross-sectional relationship between subcortical small vessel disease, amyloid, and tau deposits in patients with subcortical vascular cognitive impairment. Using flortaucipir- and florbetaben-PET, Kim and colleagues observed independent contributions of amyloid and small vessel disease with regional tau pathology. These findings are consistent with animal studies noting an association between increased cerebrovascular pathology and tau formation (Amtul et al., 2014; Bennett et al., 2018), and CSF studies have reported both independent and synergistic associations between amyloid pathology and small vessel disease on tau pathology or hippocampal volume (Freeze et al., 2017; Guzman et al., 2013; Kim et al., 2015). It may be that additive or synergistic relationships between pathologies can be detected at different stages of the disease.

    With respect to cognition, it is interesting to note that while the tau patterns in the subcortical vascular cognitive impairment group are similar to what is typically observed in patients with prodromal Alzheimer’s disease (Johnson et al., 2016), the relationships with cognition are different, with tau pathology in subcortical vascular cognitive impairment being primarily related to language and not memory. Given the small sample size, the findings need to be replicated in larger cohorts. The mediation model showing that the relationship between either amyloid burden or small vessel disease on cognition is mediated by distinct patterns of tau pathology is suggestive that this may be the case, though more regions should be explored. However, longitudinal investigations and drug interventions will be necessary to ascertain the temporal and potentially causal relationships.

    This work represents an important piece in the larger discussion on whether cognitive impairment due to Alzheimer’s disease and cerebrovascular pathology share common endpoints with respect to tau, neurodegeneration, and neuronal dysfunction. A rich neuropathological literature that informs us that the co-occurrence of cerebrovascular and AD pathology is quite common (e.g., Schneider et al., 2007), emphasizing that a better understanding of how vascular and AD pathologies interact in vivo is a critically important question going forward. Given that overall lower levels of tau PET signal were seen in SVCI as compared to ADCI, the observations here are consistent with the idea that cerebrovascular disease reduces the threshold at which Alzheimer’s disease pathology (especially tau pathology) leads to cognitive impairment, at least in impaired individuals with some level of increased amyloid burden. The authors in the current article used a visual assessment to define presence of amyloid, but it would be interesting for future studies that use quantitative measurements of amyloid burden to investigate whether there is a dose-response relationship between the magnitude of small vessel disease and the threshold at which amyloid and tau pathologies impact cognition. Ultimately, understanding the link between vascular pathology and Alzheimer’s disease pathology will be important for the implementation of vascular biomarkers in the diagnostic research criteria framework (Vemuri and Knopman, 2015; Jack et al., 2018) and, more broadly, to the success of clinical trials in late-onset AD.  

    References:

    Amtul Z, Nikolova S, Gao L, Keeley RJ, Bechberger JF, Fisher AL, Bartha R, Munoz DG, McDonald RJ, Naus CC, Wojtowicz JM, Hachinski V, Cechetto DF. Comorbid Aβ toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit. Neurobiol Aging. 2014 Jul;35(7):1605-14. Epub 2014 Jan 8 PubMed.

    Bennett RE, Robbins AB, Hu M, Cao X, Betensky RA, Clark T, Das S, Hyman BT. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1289-E1298. Epub 2018 Jan 22 PubMed.

    Freeze WM, Jacobs HI, Gronenschild EH, Jansen JF, Burgmans S, Aalten P, Clerx L, Vos SJ, van Buchem MA, Barkhof F, van der Flier WM, Verbeek MM, Rikkert MO, Backes WH, Verhey FR, LeARN project. White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β. J Alzheimers Dis. 2017;55(1):333-342. PubMed.

    Guzman VA, Carmichael OT, Schwarz C, Tosto G, Zimmerman ME, Brickman AM, . White matter hyperintensities and amyloid are independently associated with entorhinal cortex volume among individuals with mild cognitive impairment. Alzheimers Dement. 2013 Oct;9(5 Suppl):S124-31. PubMed.

    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562. PubMed.

    Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, Mormino E, Chhatwal J, Amariglio R, Papp K, Marshall G, Albers M, Mauro S, Pepin L, Alverio J, Judge K, Philiossaint M, Shoup T, Yokell D, Dickerson B, Gomez-Isla T, Hyman B, Vasdev N, Sperling R. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016 Jan;79(1):110-9. Epub 2015 Dec 15 PubMed.

    Kim GH, Lee JH, Seo SW, Kim JH, Seong JK, Ye BS, Cho H, Noh Y, Kim HJ, Yoon CW, Oh SJ, Kim JS, Choe YS, Lee KH, Kim ST, Hwang JW, Jeong JH, Na DL. Hippocampal volume and shape in pure subcortical vascular dementia. Neurobiol Aging. 2015 Jan;36(1):485-91. Epub 2014 Sep 28 PubMed.

    Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007 Dec 11;69(24):2197-204. PubMed.

    Vemuri P, Knopman DS. The role of cerebrovascular disease when there is concomitant Alzheimer disease. Biochim Biophys Acta. 2015 Sep 25; PubMed.

    View all comments by Jennifer Rabin

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Cerebrovascular Disease: Does Tau Mediate Cognitive Decline?