(1 P30 AG072946) Linda J. Van Eldik, PhD, PI
The UK-ADRC serves as the focal point for all Alzheimer's disease-related activities at UK by providing an environment and core resources to catalyze research, outreach, education, and clinical programs. The major goal of this project is to build on the existing broad-based Alzheimer's disease program to gain an understanding of pathogenic mechanisms in Alzheimer's disease with the eventual goal of prevention and treatment of the disease.

The UK-ADRC operates the Sanders-Brown Center on Aging Clinic, the Minority Gateway Satellite Clinic, and the Telemedicine Cognitive Clinic to diagnose and care for individuals with cognitive problems. Approximately 80,000 Kentuckians and more than 6 million people nationally have Alzheimer's disease.

The brain is one of the most highly perfused organs of the body that requires two large arteries to feed it – the right and left internal carotid and the right and left vertebral arteries. While it only weighs 3lb, the brain receives 15% of the output from the heart.

VCID is a newer term for any damage to the blood vessels of the brain, or any impediment to the blood flow to the brain, that can affect a person’s cognitive performance or decision-making ability. The term was developed in recognition that as we age, the performance of our blood vessels declines, and we can develop a number of pathologies of our vasculature that impacts our brain function. Often times, damage to the small blood vessels of the brain, called cerebral small vessel disease, occurs co-morbid with other neurodegenerative diseases including Alzheimer’s disease (AD), Lewy body dementia (LBD), limbic-predominant TDP-43 encephalopathy (LATE), and Parkinson’s disease (PD).

The term VCID encompasses a number of pathologies that can occur in the brain. Microinfarcts are small, microscopic strokes that can occur in any region in the brain and the stroke creates a small amount of brain tissue that is hypoxic and, thus, dysfunctional. Microhemorrhages are small, microscopic bleeds in the brain and are thought to be the result of a small leak in the vessel wall of sufficient size to allow blood cells entry into the brain. Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid-beta in the walls of the blood vessels (typically arteries and arterioles, although sometimes capillaries can be involved). CAA is frequently seen in individuals with AD with varying severity, but can also occur without the concomitant AD pathology. Of course, in addition to microscopic changes, ischemic and hemorrhagic strokes affect significant volumes of brain tissue when they occur. Post-stroke dementia does fall under the VCID umbrella and is a significant entity that warrants more study since it is difficult to predict who will suffer post-stroke cognitive impairment and post-stroke dementia simply based on where their stroke occurred in the brain, or what treatment they received.

Clinically, VCID can be difficult to distinguish from individuals who may have cognitive impairment and dementia due to different substrates such as AD or LATE pathologies. There are thought to be several features that can be more significant in individuals with VCID than those with more progressive neurodegenerative conditions. First, VCID appears to impact executive functioning more than memory recall or verbal fluency. Executive function is the term given to the process our brain goes through to plan, set goals, and prioritize tasks. Attention can also be a part of our executive function. Second, depending on the vascular pathology of an individual, often times decline in functioning will be stepwise in individuals as opposed to a steady, more linear, decline. Finally, individuals with a history of hypertension, hypercholesterolemia, and type-2 diabetes, are at a greater risk of VCID than those individuals without such histories.

What is being studied at the Sanders-Brown Center on Aging related to VCID:

Several investigators have VCID-focused research projects:

• Christopher Norris, PhD, PI studies the function of the blood-vessels on a microscopic level in living mice to see how astrocytes surrounding the blood vessels interact and support normal vessel function, and how astrocytic calcium disruptions impact vascular function and subsequent learning and memory. The P01 AG078116 grant helps to support about 35 researchers across six different labs who are working on four main projects with a common theme: Strategies for Targeting Astrocyte Reactivity in Alzheimer’s Disease and Related Dementias (STAR-ADRD).

• Anika Hartz, PhD studies the blood-brain barrier, a specialized barrier that tightly regulates the entry and exit of many proteins and solutes to the brain. She has found that a specific transporter on the barrier is dysfunctional in models of Alzheimer’s disease and targets those pharmacologically.

The Sanders-Brown Center on Aging is also part of national VCID research studies:

• MarkVCID is a national consortium funded by National Institutes of Neurologic Disorders and Stroke (NINDS) that is tasked with the identification and validation of novel biomarkers for VCID. Biomarkers are being explored using MRI imaging, plasma, and cerebrospinal fluid. Led by Dr. Jicha, the UK-MarkVCID site has led the validation of several biomarkers for the consortium and collects and shares data with all the consortium sites.

• DiverseVCID: This is a multi-site study led by colleagues at UC-Davis that the Sanders-Brown Center on Aging is a part of that aims to understand what the causes and consequences of VCID are in a diverse population that is equally representative of Caucasian, Black, and Hispanic populations. The goal is to understand how vascular changes in late life cause brain injury that lead to cognitive decline.

(1R01HD064993) Co-PIs: Elizabeth Head, PhD and Frederick A. Schmitt, PhD
The study will identify new ways in which to detect Alzheimer's disease in adults with Down syndrome (DS) by monitoring changes in cognitive function, measuring brain changes by magnetic resonance imaging, and profiling patterns of proteins in the plasma. In parallel, autopsy studies of brain samples will help us to understand how non-invasive cognitive, imaging, and blood measures reflect the development of Alzheimer's disease in Down syndrome. Treatments for Alzheimer's disease in Down syndrome will be more effective if the disease is detected early and identifying biomarkers will greatly facilitate the development of therapeutics. Link to NIH abstract.