Abstract
Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing.
Highlights
The need to identify patients with dementia and to determine the cause of cognitive decline during life has greatly increased as a consequence of the increase in dementia due to the aging of the world’s populations
Since vascular cognitive impairment and dementia (VCID) includes a number of forms of vascular disease, we focused on the small vessel form, subcortical ischemic vascular disease (SIVD), which can be detected by MRI and has a progressive course, making it more amenable to clinical trials (Pantoni, 2010)
Using the biological diagnosis to diagnose Alzheimer’s disease (AD) and MRI white matter injury to indicate vascular disease, we identified during life a group of cognitively impaired patients with dual pathology
Summary
The need to identify patients with dementia and to determine the cause of cognitive decline during life has greatly increased as a consequence of the increase in dementia due to the aging of the world’s populations. Biological criteria for diagnosing AD have been published in the National Institute of Aging-Alzheimer’s Association (NIA-AA) research framework, which is based on the use of pathological proteins, amyloid-β (Aβ) and phosphorylated tau (pTau) in either the CSF or brain as shown by positron emission tomography (PET) along with evidence of neurodegeneration; the authors predicted that other pathological processes, such as vascular disease, could be added to the formula at a later time as new biomarkers are discovered (Jack et al, 2018) We adopted this approach to diagnose patients with MX involving dual pathology by combining white matter injury on MRI with the biological diagnosis of AD obtained from CSF. We demonstrated that the important variables had clinical relevance by correlating them with neuropsychological test results
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