Abstract Body

Vascular Components of Cognitive Decline

Ralph L. Sacco, MD, Miami, FL USA

Cognitive Decline and Dementia are rising threats to our aging populations. There are multiple plausible models for pathophysiological relationships between vascular disease and dementia. Threats to brain health comprise a broader range of conditions and clinical outcomes, including stroke, dementia, vascular cognitive impairment, and cognitive aging. Subclinical markers of vascular brain injury detected by MRI (white matter hyperintensities, covert brain infarctions, cerebral microbleeds, perivascular spaces, cortical atrophy) are determinants of stroke, cognitive impairment, and dementia. Reports from the Northern Manhattan Study have demonstrated that multiple vascular risk factors are predictors for stroke, cognitive impairment, and subclinical markers of vascular injury. Key risk factors for stroke include blood pressure, glucose, cholesterol, as well as behaviors such as smoking, physical activity, obesity, and diet and define ideal cardiovascular health. Inflammatory and immune pathways may also be novel determinants of impaired brain health. The broader concept of brain health has resulted in a conceptual shift from vascular risk factors to a multi-dimensional view of the determinants of brain health. Enhanced adherence to the goals recommended by national and international organizations to shift more of the population to ideal cardiovascular health will be necessary to successfully prevent stroke and maintain brain health for our aging populations. Our neurological profession needs to fully embrace the importance of preventive neurology as a critical opportunity to improve the lives of our patients, families and the communities we serve.

Abstract Body

Vascular cognitive impairment (VCI) is a broad concept covering the full spectrum of severity from mild cognitive impairment (MCI) to vascular dementia (VaD), including purely vascular and mixed (vascular/Alzheimer) pathologies. Vascular cognitive impairment is frequent after stroke and is at least as frequent in patients free of any history of stroke who attend memory clinics. There is increasing evidence that targeting vascular risk factors may help preventing or postponing cognitive impairment.

The first studies on stroke-associated cognitive decline emphasized the role of multiple large infarcts. Nowadays, there are more focus on small strokes including (infarcts and haemorrhages), and on associated brain modifications. VCI can be related to different types of small strokes: multiple small subcortical infarcts due to large-vessel occlusion, strategic infarcts, multiple lacunar infarcts due to small-vessel occlusion (related to vascular risk factors or genetic disorders), white matter changes, enlarged perivascular spaces, and brain microbleeds (with or without superficial siderosis). More recently, microinfarcts have been identified as potential contributors to VCI: they are small ischaemic lesions that cannot be visible to the naked eye, but are detected microscopically at the pathological examination. Small strokes lead to loss of structural and functional connectivity and compromise of functional networks.

Small strokes can also induce secondary neurodegenerative changes in remote cerebral areas, such as loss of microstructural integrity on diffusion tensor imaging, reduction in cortical thickness and alterations in sulcal morphology. These changes lead to brain atrophy, the morphological change the most associated with cognitive impairment.

Abstract Body

A number of monogenic forms of cerebral small vessel disease (SVD) cause early onset lacunar stroke and dementia. By far the most common of these is CADASIL due to NOTCH3 mutations, although other underlying genes causing similar diseases include HTRA1 and COL4A1/2. Characteristic MRI features include white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. The pattern of cognitive impairment usually shows prominent executive dysfunction and information processing speed. Diagnosis depends on family history, characteristic clinical features, and characterised MRI markers, and is confirmed by genetic testing, made much simpler with newer gene arrays. Although there is little evidence based management, recent European Neurological Association guidelines provide a useful management framework. Increasing evidence has implicated a key role of disruption in the matrisome and extracellular matrix (ECM) of the small perforating arteries within the brain in disease pathogenesis, with disruption in different genes converging on shared pathways. Recent evidence suggests that more common variants in the same genes can predispose to sporadic younger onset stroke and dementia. Interestingly study of community cohorts has demonstrated that the mutations causing familial SVD are much commoner in the general population than would be expected from familial SVD prevalence. Why mutations sometimes result in early onset disease and on other occasions do not is still being investigated. However these population variants have also been associated with an increased risk of sporadic stroke and sporadic vascular dementia.