Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID) is an NIH-funded consortium dedicated to finding biomarkers involved in age-related thinking and memory problems. Alzheimer's disease and other dementias leave signatures on brain scans or in the blood called biomarkers. The MarkVCID study will measure a panel of candidate biomarkers in 1800 participants and watch them closely to see what they tell us about changes in brain function and risk of memory loss.

Age-related problems in thinking and memory represent some of the greatest risks to public health in the US and globally. Diseases that affect small blood vessels in the brain have been shown to be major contributors to these changes. However, research and patient care can be held back by limited biomarkers that identify who should be treated.

The MarkVCID Consortium includes 17 US medical centers, a Coordinating Center, an External Advisory Committee, and NIH leadership. Data and biospecimens collected as part of this research study will be stored in a research database and biorepositories, so that researchers can use this information to study brain function.

Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID) is an NIH-funded multisite consortium dedicated to developing promising predictive, diagnostic, target engagement and progression candidate biomarkers of small vessel disease in VCID. MarkVCID is a collaborative consortium of nine North American research sites (consisting of 17 institutions nationwide), a Coordinating Center, External Advisory Committee, and NIH leadership.

MGH serves as the Consortium's Coordinating Center and is comprised of an administrative and data core providing participating research sites with a common support infrastructure that facilitates cross-site collaborations, oversees development of standard operating procedures and data collection methods and manages consortium-wide data.

In phase two of the MarkVCID study, research sites are charged with enrolling and following ≥200 diverse human subjects with cognitive complaints and/or early symptomatic stages of cognitive impairment and dementia potentially associated with cerebrovascular small vessel disease. Sites will share data with the Coordinating Center which will be used for validation studies of chosen consortium biomarkers. Throughout the duration of the study, sites will utilize harmonized procedures and data collection methods to engage in multi-site biomarker validation. Both Cores comply with regulations for the protection of human research subjects (including Good Clinical Practices (GCP), 21 Code of Federal Regulations (CFR)) and with the International Conference on Harmonization (ICH) Regulations E2A and E6.

Inclusion Criteria:

• Age ≥ 60 and ≤ 90 years

• Diagnosis of normal cognition with at least one criterion for vascular risk*, subjective cognitive decline (preliminary diagnosis based on self-report question or eCog-12), mild cognitive impairment, or mild dementia based on standard research criteria

• Fluent in English or Spanish

• No contraindications to MRI including CVR

• No confounding neurologic, psychiatric, or medical disease

  *Participants with normal cognition must meet at least one criterion (diabetes, OR hypertension plus, OR MRI factors) for vascular risk prior to enrollment:

• Diabetes (at least one of the following):

  • Fasting (8-hour fast, usually overnight) blood sugar ≥126 mg/dL (≥7 mmol/L, or ≥1260 mg/L)
  • Random or Post-prandial blood sugar ≥200 mg/dL (≥11.11 mmol/L, or ≥2000 mg/L)
  • HbA1C ≥6.5% (or ≥47.5412 mmol/mol)
  • Treatment with an anti-diabetic medicine

• Hypertension plus (at least two of the following):

  • Use of anti-hypertensive medications for lowering blood pressure for ≥ 10 years
  • Current use of two or more anti-hypertensive medications for lowering blood pressure
  • One measured blood pressure in a research or clinical setting in the last 2 years with SBP ≥140 or DBP ≥90
  • A second measured blood pressure in a research or clinical setting on a different date in the last 2 years with SBP ≥140 or DBP ≥90
  • Evidence of likely HTN end-organ damage (e.g., LVH, albuminuria, eGFR<60, CHF)

• MRI factors (at least one of the following):

  • Peri-Ventricular Fazekas Extent Grade or Deep Fazekas Extent Grade ≥ 2
  • 1 or more microbleeds
  • 1 or more lacunar infarcts

Exclusion Criteria:

• Neurologic Disease: Based on the available data and investigator's impression, exclude those with confounding neurologic disease that would interfere with test performance or with biomarker analysis:

  • Frontotemporal lobar degeneration (FTLD)

  • Lewy body dementia (LBD)

  • Parkinson's disease

  • Multi system atrophy

  • Traumatic brain injury (TBI)-related cognitive impairment

  • TBI that interferes with MRI biomarker analyses (e.g., large volume traumatic lesion)

  • Non-small vessel strokes that interfere with test performance (e.g., post-stroke cognitive impairment or aphasia)

  • Non-small vessel strokes that interfere with MRI biomarker analysis (e.g., large volume strokes)

  • CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

  • Individuals known to be receiving, or planning to receive, anti-amyloid immunotherapy*

  • Other neurologic conditions that interfere with test performance or biomarker analysis

    • Individuals prescribed anti-amyloid immunotherapy after MarkVCID enrollment should be kept in the study.

• Medical and Psychiatric Conditions: Exclude those with medical and psychiatric conditions that would confound the course or interfere with test performance:

  • Schizophrenia or other active/severe psychotic disorders

  • Medical or psychiatric conditions likely to interfere with participation or retention (e.g., metastatic or malignant CNS cancer, active/severe depression or anxiety, HIV- Associated Neurocognitive Disorder)

  • Contraindications to MRI procedures, such as:

    • Claustrophobia
    • Cardiac pacemaker
    • Intracranial clips/metal implants

  • Contraindications to CVR:

    • COPD or other respiratory condition requiring oxygen therapy
    • Asthma or other respiratory condition requiring current use of medications such as inhalers

The study population will be selected from a variety of sources across the MarkVCID Consortium sites. These sources include, but are not limited to:

• MarkVCID1 or other research studies

• Alzheimer's Disease Research Center database

• Patient registries such as Volunteer for Health

• Community centers or organizations

• Clinics:

  • Primary care
  • Neurology
  • Stroke Center
  • Outpatient Diabetes
  • Memory & Aging

MarkVCID research openly shares both within and outside the MarkVCID Consortium to the greatest extent practical. As per the MarkVCID Consortium's Charter, MarkVCID investigators are granted broad access to MarkVCID data, samples, analytic tools, and other resources with relevant permissions in place. MarkVCID data and samples may also be shared with external collaborators in compliance with the Consortium's external data sharing policies outlined in the MarkVCID Data Use Agreement. The process for requesting data and biosamples is described below.

Internal

All MarkVCID research sites sign a Consortium Research Agreement governing the sharing of data and biosamples. Data entered in MarkVCID data systems by the research sites becomes available to all MarkVCID members, in accordance with the MarkVCID Data Sharing, Analysis, and Publications Policy and the MarkVCID Research Agreement.

External

If the request is approved by the MarkVCID Steering Committee, external users sign the DUA to gain access to the data. If biosamples are requested, external users will execute a Material Transfer Agreement (MTA) with the institution(s) providing samples. Biosamples typically ship within 3 months. Electronic data stored by the MarkVCID Consortium repository becomes available to the investigator about 3 weeks after project approval and signing of the DUA. Investigators requesting access to data and biosamples not held by the MarkVCID repository must contact relevant institution(s) and are subject to longer wait times.

A MarkVCID Project Proposal Form must be submitted for data and biosample requests. The form requires an overview, a description of requested data and/or biosamples, assays, experiments to be conducted, and publication plans. Data requests will be reviewed by the Sharing Subcommittee and biosample requests by the Fluid-Based Biomarkers Subcommittee. Reviews will be based on scientific rationale, overlap with already approved analyses, and, for biosample requests, the scientific priority of the study relative to the number of available biosamples. The Steering Committee will then review proposal recommendations and determine approval. Investigators with approved proposals will sign a DUA and receive applicable data via Globus encrypted transfer. Investigators with approved biosample requests will execute necessary MTAs and receive deidentified biosamples from holding sites.

Internal requests related to primary hypotheses of prespecified biomarker kits are exempt from the above.