[Abstract] 773. A progressive increase in brain microhemorrhages correlates with sporadic late-onset dementia development

Objectives:  Our goal is to define the pathogenesis of sporadic late-onset dementias studying brain microvasculature with new minimally invasive technologies.

Methods:  For the past 5.5 years we have monitored the cognitive course of 76 mildly cognitively impaired (MCI) and 28 cognitively normal elderly individuals applying new MR contrast (Susceptibility Weighted Imaging, SWI) and proteomic tools (‘carrier protein stripping’). The protein discovery tools are novel and are yielding previously unknown blood proteins and peptides considered to be of very low abundance. Low molecular weight fragments in the range of 40 kDa or less are being detected. Validation of these biomarkers has been conducted using antibodies raised against the candidates. The SWI sequence at 1.5T is at least fourfold more sensitive than conventional 1.5T GE-T2* for the detection of brain microbleeds (BMB). SWI is a 3-dimensional velocity compensated gradient echo sequence combining magnitude information with phase information that enhances contrast of magnetic field inhomogeneities combing phase and magnitude information permits shorter echo times, improves signal to noise ratio and detection of subvoxel susceptibility scores.

Results:  SWI at 1.5T revealed an unanticipated association of cognitive loss with increasing BMB typical for ‘cerebral amyloid angiopathy (CAA).’ SWI is superior to conventional gradient echo T2* (GE-T2*) for BMB detection. Nine of 26 MCI participants followed to dementia have significant MH and unique serum proteins, peptides from the heme degradation pathway. Our human experiment is the first prospective evidence for CAA microvasculopathy in the pathogenesis of late onset dementia.

Conclusions:  As a result of the association between cerebral MH and progression to dementia, 3 key endpoints have been added to our study:

(a)

quantifying the location of MH by 3T SWI during the course of dementia,

(b)

proteomic studies of peripheral blood to complement SWI BMB detection to develop a clinical test for CAA and

(c)

determine the role of CAA hypoxic and apoptotic mechanisms responsible for neuronal and cognitive loss in an appropriate transgenic mouse model.

Defining the role of microvasculopathies in the pathogenesis of sporadic late-onset dementia may result in new therapeutic strategies.

This research was funded by NIH grant AG20948.