MRI white matter abnormalities in the elderly: Genetic risk factors, rate of progression and neuropsychologic consequences

Focal abnormalities in the deep and subcortical white matter are a common Magnetic Resonance Imaging observation in the elderly. It has been suggested that white matter abnormalities progress gradually over time with the accumulation of vascular risk factors and ultimately may result in subcortical arteriosclerotic encephalopathy with concomitant cognitive decline. It is still unclear which factors besides advancing age and hypertension lead to the development of white matter abnormalities, at what rate and speed these changes progress, and, as to whether lesion progression is indeed paralleled by a decline in cognitive functioning. Recently, genetic factors have been implicated in the etiology of these brain changes. This research proposal is based on a large-scale prospective study on the clinical predictors and consequences of white matter abnormalities in community-dwelling elderly individuals. It represents the only systematic investigation on the natural history of white matter abnormalities worldwide. Study goals: 1. Determine the association between selected genetic polymorphisms and occurrence of MRI white matter abnormalities. Based on clinical studies, known frequencies of the genetic variants and their probable functional importance, gene related with blood pressure regulation (angiotensin converting enzyme, angiotensinogen) , insulin resistence (insulin receptor substrate-1), fibrinogen plasma level (beta-alpha-and gamma fibrinogen), fibrinogen- induced platelet aggregation (glycoprotein IIIa/IIb), oxidative defense mechanisms (manganese superoxide dismutase, paraoxonase) and apolipoproteinE metabolism (VLDL-receptor, LDL-receptor related protein) have been selected. 2.Determine the rate and the extent of white matter abnormality progression over a 3-year observational period. 3.Determine the neuropsychologic consequences of white matter abnormality progression in order to better understand their prognostic significance. Subjects and Methods: The cohort consists of 458 randomly selected participants of the Austrian Stroke Prevention Study without neuropsychiatric disease who underwent baseline MRI scanning between 1991 and 1994. A total of 273 subjects volunteered to have a second MRI study 3-years after the first examination. At each visit subjects underwent a structured clinical interview and examination, extensive laboratory work-up, extensive neuropsychologic testing assessing learning and memory abilities, conceptional reasoning, attention and speed as well as visuopractical skills. DNA has been extracted from the blood of all individuals who gave their informed consent. MRI was performed on 1.5T magnets after careful positioning and the extent of white matter abnormalities at baseline and follow-up will be measured using a semi-automated thresholding technique. Linear and volumetric measurement will be done in selective brain regions as correction for brain atrophy is mandatory when assessing the association between white matter abnormality area and cognitive performance. For genetic testing DNA fragments containing the polymorphisms under investigation will be amplified by PCR, and restriction enzyme digestion or denaturating gradient gel electrophoresis will be used for genotyping. The genetic investigations and MRI measurements are subject of this application. All other clinical and laboratory data needed for our analyses have already been collected.

Magnetic Resonance Imaging of the brains allows to detect small vessel disease related brain lesions even in clinically normal subjects. These abnormalities are a common observation in older persons and are thought to be a cause for cognitive decline, gait disturbances and falls in the elderly. Our project showed that these brain changes progress in approximately one fifth of affected individuals within a relatively short time period of 3 years. Diastolic blood pressure and genetic disposition have an unfavorable effect on the course of the lesions. This is the first longitudinal project assessing the longitudinal course, causes and consequences of cerebral small vessel disease. Ischemia in this vascular territory commonly results in cognitive dysfunction, gait disturbances and falls in the elderly. Research on factors influencing the progression of these abnormalities may have preventive implications. We have shown that small vessel disease related brain lesion progress at a considerable rate in older persons. The diastolic blood pressure and genetic variants which influence blood pressure but may also be directly involved in atherogenesis are important risk factors. Our results suggest that drugs affecting the renin-angiotensin system, i.e angiotensinogen converting enzyme inhibitors are good candidates for future therapeutic trials. In line with our genetic findings such substances may prevent progression of cerebral small vessel disease beyond what can be expected from the reduction of blood pressure alone.