Genetics of Cerebral Small Vessel Disease

Cerebral small vessel disease is the second most common endemic entity of the ageing brain following Alzheimer pathology. Its hallmark lesions are leuko-araiosis and lacunar infarctions, which can be non-invasively depicted with brain magnetic resonance imaging. Up to 90% of persons above the age of 65 years present with leuko- araiosis. Lacunes occur less common with a frequency of 6% to 20%. Decreased mobility of the elderly due to disequilibrium and gait abnormalities, and progressive cognitive impairment up to dementia are frequent clinical sequelae of cerebral microangiopathy. Established risk factors are arterial hypertension and advancing age. There does not exist any established treatment yet which allows to modify the evolution of small vessel disease-related brain damage. The heritability of leukoaraiosis volume ranges between 55% and 73%. There are no heritability estimates of other characteristics of white matter lesions such as type and progression are available. Similarly, the heritability of other components of small vessel disease such as lacunes, brain atrophy and microbleeds have not yet been investigated yet. Association studies indicated that the APOE, ACE, eNOS, MTHFR genes might be related to these pathologies. We found positive associations with APOE, PON1 as well as the AGT, with considerable evidence for a causal relationship for the latter. Very recently, the results of the first genome wide scan on white matter lesion volume have been reported by the Framingham Heart Study describing a significant LOD score on chromosome 4 and a suggestive LOD score for linkage on chromosome 17. The aim of our study is to genetically dissect the complexity of cerebral small vessel disease in order to better understand the pathomechanisms leading to these lesions. First we will apply genome wide association as well as fine map the linkage regions on Chr 4 and 17 in the the Austrian Stroke Prevention Study cohort, which is one of the largest community-dwelling studies on cerebral small vessel disease and the study with the longest MRI follow up so far. Second, we will recruit families ascertained through participants of the Austrian Stroke Prevention Study. Family members will undergo the same study protocol including brain MRI as the probands in the population based cohort. In the family based cohort we will estimate heritability of and genetic correlation between different lesion characteristics of cerebral small vessel disease and its major risk factors. We aim to develop a spectrum of possible endophenotypes for cerebral small vessel disease. In the family based cohort we also aim to verify genes associated with cerebral small vessel disease in previous studies. The co-existence of a family and a population based cohort characterized with identical study protocol will offer a unique and outstanding resource to identify genes by allowing for the combined use of linkage and association. Knowledge of genes involved in cerebral small vessel disease will improve our understanding of the pathogenesis of these lesions and will possibly facilitate the development of novel therapeutic targets.

Cerebral small vessel disease represents the 2nd most frequent damage of the aging brain after Alzheimer pathology. Leukoaraiosis and lacunes are the major forms of lesions and can be detected by magnet resonance imaging (MRI) of the brain. Up to 90% of the population above the age of 65 years have some leukoaraiosis of different severity. Lacunes can be seen in 6 to 11% in this age group. Clinical correlates of cerebral small vessel disease are balance and gait disturbances as well as progredient cognitive decline and dementia. Hypertension and age are the major risk factors. There are no therapies available so far to prevent or slow down the progression of small vessel related brain damage. The heritability of leukoaraiosis is in the range of 55-73%. The aim of our study was to dissect the complexity of cerebral aging especially the genetics of cerebral small vessel disease in order to achieve a better understanding of the evolution of such lesions. The project had been conducted in frame of the Austrian Stroke Prevention Study, one of the largest population based studies on brain aging worldwide. First we had performed genome wide association studies (GWAs) which have led to the identification of novel genetic risk factors for stroke, Alzheimer`s dementia and cerebral small vessel disease. Next we sequenced the NOTCH3 gene, which is mutated in CADASIL, an early onset familiar form of stroke and found that this gene is also involved in the common age- related form of cerebral small vessel disease. All these investigations had been conducted according to the international guidelines on a large number of participants and the results had been replicated in independent cohorts. This approach was possible due to the membership of the ASPS in numerous international consortia such as CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ISGC (International Stroke Genetics Consortium) and I-GAP (International Genomic of Alzheimer`s Project). The identification of novel genes improves our limited pathophysiological understanding of cerebral aging and facilitates the development of new therapeutic and preventive approaches to stroke and dementia.