Youssef, Hossam

Objectives: To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. Methods: Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm3/year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. Results: In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm3 (IQR: 3.3-28.4 cm3), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm3/year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P<0.001). Conclusions: This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aβ (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients ( n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Introduction: Carotid revascularization is known to prevent stroke in patients with high-grade carotid stenosis, but whether carotid revascularization may slow the progression of hemispheric WMD in patients with carotid stenosis to prevent cognitive decline have not been well described. Methods: We conducted a longitudinal study involving patients age ≥40 years with carotid stenosis on ultrasound from 2011-2015 with serial brain MRI scans at least 1 year apart followed for radiographic and clinical outcomes to 2020. Severity of carotid stenosis was defined as moderate 50-69%, high-grade 70-99%, or occluded. Hemispheric WMD volume was quantified from axial T2 FLAIR images. Patients were stratified by revascularization status. Primary outcome was change in WMD volume per year ipsilateral or contralateral to the index carotid. Hemispheric differences in the annual rate of WMD progression (cc/yr) were compared between revascularized vs not revascularized using multivariable linear regression analysis adjusted for variables that differed between revascularization status. Results: Of the 150 patients, moderate stenosis was present in 37.3%, high-grade stenosis in 42.0%, and carotid occlusion in 20.7%. Mean age was 71±10 years, 36.7% were female. Seventy-three (48.7%) had carotid revascularization with a median follow-up of 5.1 years. Baseline WMD volume was 4.86cc ipsilateral and 4.39cc contralateral to the index carotid. Patients who underwent revascularization trended to have slower WMD progression in the hemisphere ipsilateral to the index carotid compared to those not revascularized (0.32cc/yr vs 0.63 cc/yr, p=0.340). The same trend was not observed in the contralateral hemisphere. In adjusted models, carotid revascularization was associated with a 0.33 cc per year decrease in WMD progression between hemispheres compared to those not revascularized (β= -0.33, p=0.070). Conclusions: In this study with a median follow-up of 5 years, we found that carotid revascularization resulted in a 50% reduction in the annual rate of WMD progression. Intervention trials should test whether carotid revascularization slows WMD progression in patients with cognitive impairment to prevent further cerebrovascular events and cognitive decline.