MRI Imaging May Provide Biomarker of Early Vascular changes that Increase Alzheimer’s Risk

Lay Summary

MRI imaging may provide biomarker of early vascular changes that increase Alzheimer’s risk

Accumulating evidence suggests that brain changes associated with Alzheimer’s disease (AD) begin to develop long before AD symptoms become evident. Researchers, therefore, are searching for “biomarkers” that may be indicative of these early changes. Much of the biomarker research to date has focused on ways to detect early deposits of amyloid plaque and tau that accumulate between and within brain cells, respectively, in AD and on later-stage cerebrovascular changes such as microbleeds and lesions in the brain’s white matter. Less attention, in contrast, has focused on stiffening of arteries in the brain. As arteries become stiffer with aging, their “cerebral arterial compliance” decreases. This means that they are less able to accommodate to an increase in blood volume in response to elevated blood pressure, adversely affecting blood flow to and in the brain. The investigators will see whether measures of cerebral arterial compliance are sensitive early indicators of AD-related changes in the brain during the pre-dementia stages.

To do so, they will use a relatively new type of MRI imaging, called “arterial spin labeling” (ASL). This method is a non-invasive way to measure cerebral blood flow in brain tissues. It does not require radioactive dye (as PET imaging does) and can be done simultaneously with MRI imaging of brain structures. The investigators will see whether ASL measures of cerebral arterial compliance are associated with cognitive performance problems in 30 adults with mild cognitive impairment (MCI) compared to 30 healthy adult volunteers.

They also will see whether ASL findings correlate with any other signs of pre-AD, such as early amyloid or tau accumulation or early signs that the brain’s hippocampus is becoming smaller due to loss of brain cells. They anticipate that their findings will support their hypothesis that ASL measures of cerebral arterial compliance are an early sensitive biomarker of neurodegeneration, vascular changes, and poor cognition in older adults with MCI who are at increased risk for AD, and that ASL imaging adds predictive value beyond conventional vascular risk factor measures.

Significance: The study may help to identify the earliest vascular changes associated with development of AD, provide a diagnostic measure of at-risk adults and determine for which individuals to initiate early vascular prevention therapies including lifestyle changes and medications.

Abstract

MRI imaging may provide biomarker of early vascular changes that increase Alzheimer’s risk

The presence of vascular risk factors elevates risk for developing Alzheimer’s disease (AD). Cerebrovascular disease (CVD) commonly co-exists with AD pathology, and influences the clinical expression of AD. Despite growing evidence of the role of CVD in early AD, prevailing models of AD pathogenesis and proposed biomarkers for mild cognitive impairment (MCI), which is often recognized as representing a prodromal stage of AD, do not yet formally integrate vascular biomarkers or risk factors in their models or conceptualizations. Arterial stiffening is a nontraditional vascular risk factor that increases vulnerability to both AD and CVD. When arteries become stiffer, arterial compliance (i.e., the ability of a vessel to distend or increase in volume in response to an increase in blood pressure) decreases. In the “two-hit vascular hypothesis of AD,” Zlokovic (2011) proposed a mechanistic explanation for how vascular risk factors, such as reduced arterial compliance, may influence AD pathophysiology and affect cognition. In this model, the presence of vascular risk factors leads to a reduction in cerebral blood flow (CBF) and blood-brain barrier (BBB) dysfunction (hit one) that precedes amyloid and tau alterations in AD (hit two), which later lead to cognitive decline and ultimately dementia. This model suggests that measures of intracranial vascular dysfunction may offer important markers of vascular pathology in the earliest stages of AD. Indeed, our recent work using an indirect index of arterial stiffening (i.e., brachial pulse pressure) suggests that arterial stiffening is associated with abnormal levels of CSF AD biomarkers and with more rapid progression to dementia. Few options exist for non-invasive estimation of intracranial arterial stiffening; however, recent advances at the University of California San Diego (UCSD) have allowed for assessment of intracranial arterial stiffening using non-invasive and highly novel arterial spin labeling (ASL) magnetic resonance imaging (MRI) methods that estimate cerebral arterial compliance. Since mounting evidence suggests that measuring local arterial compliance in the brain may provide insight into both the development and treatment of AD, we propose to apply ASL MRI to older adults at increased for AD to determine whether cerebral arterial compliance relates to meaningful biological and cognitive correlates of AD. In the proposed study, in a sample of 60 nondemented older adults (30 with MCI and 30 cognitively normal older adults) recruited from the UCSD Alzheimer’s Disease Research Center (ADRC), we will measure cerebral arterial compliance alongside established biomarkers of AD (Aβ42 and structural MRI markers of neurodegeneration [e.g., hippocampal volume]) and CVD (white matter lesions [WMLs], cerebral microbleeds). Our central hypothesis is that the novel ASL MRI measure of cerebral arterial compliance will be a sensitive biomarker of neurodegeneration, vascular changes, and poor cognition in older adults at risk for AD by virtue of having MCI and will have added predictive value beyond conventional vascular risk factors and measures. To our knowledge, this study is the first to examine whether ASL measures of cerebral arterial compliance are sensitive indicators of AD-related neuropathology in the prodromal stages. Development of novel methods capable of detecting insidious cerebrovascular dysfunction prior to the manifestation of these frank lesions would represent a major advancement in early detection and expansion of treatment opportunities in the prodromal stages of AD.