Diagnosis of mixed dementia by double dichotomy. (20th December 2022) - Rosenberg, Gary A
Abstract: Background: Proper classification of patients with dementia is critical in clinical trials. Dual Alzheimer's disease (AD) and vascular pathology (mixed dementia‐MX) is the most common form of dementia estimated to be as high as 70% in pathological series. However, separation clinically is difficult, which has led to use of biomarkers. A biological definition of AD based on biomarkers has been proposed for research studies with identification of amyloid and tau in CSF or PET. Including in the ATN formula, biomarkers for vascular disease (V), obtained from MRI, separates MX subjects, improving diagnosis of AD and vascular cognitive impairment (VCI). Methods: We used vascular disease biomarkers from MRI and AD biomarkers from CSF with a double dichotomy statistical approach to more precisely define four major groups of patients in the UNM and Alzheimers's Disease Neuroimaging Initiative (ADNI) cohorts. We compared the UNM dataset (N=80) with subjects from ADNI (N=538). Diffusion tensor imaging (DTI) biomarkers (mean free water and PSMD) were combined with CSF amyloid (A) and tau (T) to identify MX patients. We formed a composite vascular disease score (cVDS) with DTI, and a composite AD score (cADS) with CSF amyloid and phosphoTau181 . Results: Plotting cVDS on the x‐axis and cADS on the y‐axis placed subjects in one of four biologically defined quadrants: bAD (biological AD) in the upper left, bSIVD (biological subcortical ischemic vascular disease) in the lower right, bMX (biological mixed dementia) in the upper right, and bCN (biological controls) in the lower left quadrant (Figure). We identified MX, using a double dichotomy statistical method. The UNM cohort had 25% MX, while in ADNI there were 11.5% (Table). The ADNI group had a higher percentage of bCN (43%) and bAD (35%) than the UNM cohort; this was because UNM was one of 7 sites in the MarkVCID consortium with enriched VCI subjects and ADNI excluded vascular disease subjects. Conclusions: Our results show that adding a vascular factor (V) to the ATN formula creates a MX group, improving classification of patients by creating a more homogeneous AD group, which permits AD clinical trials with fewer subjects