Sharpening the tools for the assessment of vascular cognitive impairment

Alzheimer's & DementiaEarly View LETTEROpen Access Sharpening the tools for the assessment of vascular cognitive impairment This article relates to: Response to van den Berg et al. letter: ''Sharpening the tools for assessment of vascular cognitive impairment'' Emilia Salvadori, Leonardo Pantoni, , Alzheimer's & Dementia First Published online: November 23, 2022 Esther van den Berg, Esther van den Berg Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the NetherlandsSearch for more papers by this authorMeike W. Vernooij, Meike W. Vernooij Department of Radiology & Nuclear Medicine and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the NetherlandsSearch for more papers by this authorFrancesco U.S. Mattace-Raso, Francesco U.S. Mattace-Raso Department of Geriatrics and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the NetherlandsSearch for more papers by this authorFrank J. Wolters, Corresponding Author Frank J. Wolters f.j.wolters@erasmusmc.nl Department of Radiology & Nuclear Medicine and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the Netherlands Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands Correspondence Frank J. Wolters, Erasmus MC University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: f.j.wolters@erasmusmc.nlSearch for more papers by this author Esther van den Berg, Esther van den Berg Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the NetherlandsSearch for more papers by this authorMeike W. Vernooij, Meike W. Vernooij Department of Radiology & Nuclear Medicine and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the NetherlandsSearch for more papers by this authorFrancesco U.S. Mattace-Raso, Francesco U.S. Mattace-Raso Department of Geriatrics and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the NetherlandsSearch for more papers by this authorFrank J. Wolters, Corresponding Author Frank J. Wolters f.j.wolters@erasmusmc.nl Department of Radiology & Nuclear Medicine and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, the Netherlands Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands Correspondence Frank J. Wolters, Erasmus MC University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: f.j.wolters@erasmusmc.nlSearch for more papers by this author First published: 23 November 2022 https://doi.org/10.1002/alz.12847AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat TO THE EDITOR For decades, cognitive neuroscientists have attempted to unveil brain pathology through studying cognitive dysfunction in specific cognitive domains. In their recent article, Salvadori et al. venture further down this path. They summarize the current literature to conclude that there is "incomplete evidence" that a single cognitive test could differentiate underlying cerebral small-vessel disease from other causes of cognitive impairment.1 While we support the utility of clinical signs to indicate potential underlying disease etiology, for example, by differentiating types of primary progressive aphasia, we believe the diagnosis of vascular cognitive impairment warrants an approach that extends beyond cognitive testing. In the vast majority of patients, cerebral small vessel disease is accompanied by other types of neurodegenerative pathology. The co-occurrence of pathology increases rapidly with age. At the time of death, 78% of community-dwelling individuals have multiple types of pathology present in their brains, at least one of which often is of a vascular nature.2 As a consequence, distinguishable clinical phenotypes merge into a more generalized cognitive deficit in older individuals. Patients who seek health advice for memory complaints are generally well into their seventies or eighties, rendering an etiological diagnosis on the basis of clinical phenotypes in these patients challenging at the very least. This notion led to the concept of "vascular cognitive impairment" (VCI), which replaced the different monocausal classifications, diagnoses, and terminologies that were used prior to describe cognitive impairment due to cerebrovascular disease. Prior descriptions, such as "multi-infarct dementia," "subcortical dementia," or "vascular cognitive disorders," had mainly focused on the most severe end of the spectrum (i.e., dementia), whereas VCI captures the full range of cognitive changes due to cerebrovascular disease.3 Moreover, the concept of VCI allows for concomitant contributions of other diseases, like Alzheimer's disease (AD), to the phenotype of an individual patient with vascular brain injury. This is especially relevant in light of the expanding evidence for a reciprocal interaction of cerebrovascular disease and neurodegeneration.4 Involvement of the neurovascular unit, the blood–brain barrier, and vascular clearance mechanisms are just three examples of mechanisms illustrating the broad interface between vascular and AD pathology. In light of these developments, we believe that assigning monocausal etiological diagnoses does not serve a patient well if multiple different types of pathologies are contributing to their cognitive complaints in concert. For example, a 75-year-old patient with cognitive impairment that is due both to AD and cerebral small-vessel disease might inadvertently be withheld (symptomatic or disease-modifying) treatment against either cause, while targeting both may be crucial for optimal treatment. Indeed, consensus guidelines for diagnostic assessment of VCI stress that "the order of the descriptive phenotypic terms relevant to patients should attempt to reflect the relative contribution of phenotypes present" (e.g., cognitive impairment due to small vessel disease and AD).5, 6 This requires specific and easily obtainable markers of the different types and manifestations of vascular brain injury (e.g., through brain imaging), accompanied ideally by reference values from unselected age-matched populations. This process can be facilitated by existing and new collaborations that make use of comprehensive data from well-characterized representative cohorts.7 Only when markers of vascular brain injury are appreciated in the context of other neuropathology can we come to the correct diagnosis and tailored management for the majority of patients.8 The challenge before us is not only to identify patients with VCI, but also to determine the extent to which their overall cognitive deficits are due to vascular pathology. This will require further studies to establish the contribution of small-vessel disease, relative to other pathologies within the same individual. Neuropsychological assessment will be an important part of this diagnostic process, but the review by Salvadori et al. shows us that cognitive assessment is unlikely to achieve this on its own . CONFLICTS OF INTEREST Dr. Wolters received research funding from the Dutch Research Council (NWO), the Alzheimer's Association, and the Brain & Behavior Research Foundation, outside of this published work, and has been consultant for the PGGM Pension Fund (fees paid to institution). Dr. Vernooij received research funding from ZonMw and HealthHolland, outside of this published work. Drs. Van den Berg and Mattace-Raso report no disclosures. Author disclosures are available in the supporting information. Supporting Information Filename Description alz12847-sup-0001-SuppMat.pdf271.7 KB SUPPORTING INFORMATION alz12847-sup-0002-SuppMat.docx34 KB SUPPORTING INFORMATION alz12847-sup-0003-SuppMat.docx32.3 KB SUPPORTING INFORMATION alz12847-sup-0004-SuppMat.docx32.8 KB SUPPORTING INFORMATION alz12847-sup-0005-SuppMat.docx32.3 KB SUPPORTING INFORMATION Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Salvadori E, Brambilla M, Maestri G, et al. The clinical profile of cerebral small vessel disease: toward an evidence-based identification of cognitive markers. Alzheimer's Dement. 2022; 1- 17. https://doi.org/10.1002/alz.12650 2Boyle PA, Yu L, Wilson RS, Leurgans SE, Schneider JA, Bennett DA. Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol. 2018; 83(1): 74- 83. https://doi.org/10.1002/ana.25123 3Hachinski V, Iadecola C, Petersen RC, et al. National institute of neurological disorders and stroke-canadian stroke network vascular cognitive impairment harmonization standards. Stroke. 2006; 37(9): 2220- 2241. 4Hachinski V, Einhäupl K, Ganten D, et al. Preventing dementia by preventing stroke: the berlin manifesto. Alzheimers Dement. 2019; 15(7): 961- 984. 5Skrobot OA, Black SE, Chen C, et al. Progress toward standardized diagnosis of vascular cognitive impairment: guidelines from the vascular impairment of cognition classification consensus study. Alzheimers Dement. 2018; 14(3): 280- 292. 6Skrobot OA, O'Brien J, Black S, et al. The vascular impairment of cognition classification consensus study. Alzheimers Dement. 2017; 13(6): 624- 633. 7Khachaturian ZS, Kuller LH, Khachaturian AS. Strategic goals and roadmap for dementia prevention by stroke prevention. Alzheimers Dement. 2019; 15(7): 865- 869 8Wolters FJ, Ikram MA. Epidemiology of vascular dementia: nosology in a time of epiomics. Arterioscler Thromb Vasc Biol. 2019; 39(8): 1542- 1549. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation