Cognitive Impairment and Dementia After Stroke: Design and Rationale for the DISCOVERY Study

Abstract

Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID's overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.

Keywords: Alzheimer disease; biomarker; cognition; dementia; risk factor.

Figure 1.. Brain susceptibility to post-stroke cognitive impairment and dementia.

A complex interaction between life-course exposures to multiple vascular risks and socio-demographic factors, pre-existing burden of cerebral small vessel disease and Alzheimer’s and related neurodegenerative pathology in the brain, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation contribute to brain susceptibility (or resilience) to cognitive decline after stroke. An acute stroke event, whether ischemic or hemorrhagic, likely initiates or exacerbates/accelerates a series of pathological events leading to post-stroke cognitive impairment or dementia.

Figure 2.. The DISCOVERY Network.

The network is comprised of four study cores (Administrative, Recruitment and Retention, Statistical, and Repository) and thirty clinical performance sites across the United States.

Figure 3.. The DISCOVERY Study schema.

Patients diagnosed with acute ischemic stroke, intracranial hemorrhage, and aneurysmal subarachnoid hemorrhage will be enrolled during the index stroke admission (Inpatient Phase), undergo baseline cognitive and functional outcomes assessments, and will be followed for ≥2 years through a series of in-person and phone research visits (Outpatient Phase). During the outpatient phase, all surviving subjects will be seen in two clinic follow-up visits (at 3-6 months and 18 months). All clinic follow-up visits will occur at the DISCOVERY Network Clinical Sites that will be designated as Tier 1, 2, or 3 based on infrastructure, resources, and proficiency to perform in-depth neurocognitive assessments, advanced 3T protocol MRI scans, and PET imaging. Every DISCOVERY subject will have serial centralized phone-based cognitive and functional outcomes assessments at 12 months post-stroke, and annually thereafter for the study’s duration.

Figure 4.. The DISCOVERY Network Fluid Biomarker Strategy.

All enrolled subjects (Tier 1) will undergo a baseline measure of circulating biomarkers in the proposed pathogenic categories influencing post-stroke cognitive impairment/dementia. Tier 2 subjects will participate in longitudinal biomarker assessment using emerging biomarkers including several biomarker kits established by the MarkVCID Consortium.