O1‐01‐05: Brain microvascular fragility is a major cause of Alzheimer's disease

Background: We have found with serial iron sensitive MRI (susceptibility weighted imaging - SWI) that a progressive increase in small brain micro-bleeds (BMB) correlates with a dementing course in elderly subjects. Our prospective study of sporadic late-onset dementia extended over a five and a half year period enabled the simultaneous detection of both BMB and regional iron levels. BMB are radiologic biomarkers for microvascular fragility. Methods: A community-based cohort of 103 participants; 75 mildly cognitively impaired (MCI) and 28 cognitively normal subjects have been studied for a five and a half year period with serial head SWI and serum proteomic tests. SWI is a high resolution, 3D gradient echo sequence that takes advantage of phase information present in every MR image to produce images of BMB. SWI is far more sensitive for BMB detection than the commonly used clinical sequence - gradient echo T2* (GE-T2*). There is a six-fold increase in number of BMB detectable by SWI at 1.5 T than GE-T2*. Changes in cognitive status monitored by comprehensive psychometric evaluations have been correlated with BMB, regional iron levels, serum proteomics and post-mortem brain studies. Results: Counts of BMB when increasing and clustered are correlated with cognitive loss. BMB clustering, as well as radiologic-neuropathological studies of cadaver brains show progressive fragility of proximate small blood vessels. Serial proteomic studies have identified complementary serum biomarkers related to hemoglobin degradation. Conclusions: BMB once initiated activate a cascade of cellular and genetic events that by a positive feedback mechanism further weaken the vasculature, promote additional BMB, with neuronal death. Once BMB appearance has been observed, lesions then avalanche in a domino-effect with clustering and increasing cognitive loss. These observations lead to a conclusion that brain microvascular fragility is a major cause for Alzheimer's disease. This research was funded by NIH Grant #AG20948.