March 9, 2022/Neurosciences/Research

A Closer Look at the Cleveland Clinic Brain Study

How the new longitudinal investigation could become the Framingham Heart Study of brain health


Early this year, Cleveland Clinic’s Neurological Institute launched a first-of-kind longitudinal investigation called the Cleveland Clinic Brain Study. The study will collect data from thousands of neurologically healthy adults over a 20-year period with the aim of identifying biomarkers and targets for preventing and curing neurodegenerative disorders and other neurologic diseases.


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Eligible participants — adults with no known neurologic disease who are 50 or older (or 20 or older with a first-degree relative with multiple sclerosis) — will undergo regular assessments designed to detect biomarkers and causes of neurologic disorders before symptoms begin. Assessments will include structural (neuroimaging, retina imaging), cognitive (neuropsychological exams) and neurophysiologic (EEGs, sleep studies) components as well as blood and stool testing to evaluate potential systemic and microbiome indicators of neurologic risk.

The effort is analogous to what the famed Framingham Heart Study set out to do in the late 1940s, only with a focus on neurologic disease instead of cardiovascular disease and with access to a full complement of 2020s-era medical technology.

While an earlier post reported on details of the Cleveland Clinic Brain Study design, Consult QD caught up with two of the study’s co-principal investigators — functional neurosurgeon Andre Machado, MD, PhD, Chair of Cleveland Clinic’s Neurological Institute, and epileptologist Imad Najm, MD, Director of Cleveland Clinic’s Charles Shor Epilepsy Center — for a bit more context on the rationale behind the investigation. Highlights are presented in edited form below.

Q: Can you describe the essence of the Cleveland Clinic Brain Study?

Dr. Machado: This is the first study of this scale, depth and detail to explore the underpinnings of neurological disease before it manifests. The interest here is to study a very, very large cohort of normal individuals (without neurological disease) and follow them up as they age. We know that while most will age healthy, some unfortunately will age into neurological disease. Our objective is to understand the silent phase of disease — what is happening to the brain, to the body and to overall health in the years that precede the first manifestation. That silent phase will be the most valuable time in which to try new interventions directed at new disease targets.

Q: What drove development of this study?

Dr. Najm: The risk of being affected by a neurological disorder increases exponentially with age, reaching a peak annual incidence of approximately 15% in healthy individuals aged 75 and older. Neurologists are all too aware that the diagnosis of neurological disorders during the later stages of life is made after symptoms are reported and/or clinical signs are first seen — and sometimes even later. At that point, there have been changes at the molecular and cellular levels that preceded the clinical signs and symptoms, and neurologists must try to address the disorder at a stage when it is very difficult to stop, let alone trying to prevent it. This is why we saw a clear need for an in-depth characterization of the brain and multiple body systems at various levels before the disease starts — during the silent phase that Dr. Machado mentioned — with a primary goal of identifying the fingerprints of disease before it happens.


Q: Can you speak about the study population and what it’s like to do a study exclusively with people free of neurologic disease?

Dr. Machado: The fact that the study is, by definition, investigating people without neurological disease is somewhat counterintuitive to the public, but our early study participants really understand and believe in the concept behind this. One question we hear is why our age threshold of 50 is lowered to 20 for just one group of people — those with a first-degree relative with multiple sclerosis. We want to be clear that we are looking at all neurological diseases, not just multiple sclerosis. Because symptoms of multiple sclerosis typically begin before age 50, we wanted to be sure we would not be missing the silent period for this disease in those who may be at higher risk due to family history, so we decided to enroll these individuals at a younger age.

Another point worth noting is that this study needs to be representative of America in order to be successful. The more inclusive we can be across both women and men and across races and ethnicities, the more informative the findings will be to help develop new treatments down the line. We intend to take advantage of the global organization that Cleveland Clinic is, starting with Ohio and then quickly expanding to Florida and then internationally. Also, it’s important to know that study participants do not need to be patients of Cleveland Clinic.

Q: Which disciplines are involved in conducting the study?

Dr. Najm: We have multiple departments, centers and specialists involved. First we have various neurology subspecialists, including specialists in Alzheimer’s disease, movement disorders, stroke, epilepsy and multiple sclerosis. Then outside the neurological subspecialties, we are working with psychiatrists, psychologists, neuropsychologists, neuroradiologists, ophthalmologists, cardiologists and geneticists with bioinformatics expertise.

Q: What expectations do you have about the study’s findings?

Dr. Machado: This study is unusual in that we do not have a predefined hypothesis. We have some thoughts on what we think we will learn, but we fully expect to learn things that none of us are anticipating now. We also expect that people outside our field may find ways to analyze these data that we are not aware of today, especially since the study duration of 20 years or more means that this will be continued by the next generation of researchers.

Dr. Najm: It’s helpful to think in terms of what we hope to learn in the short term versus the long term. In the short term, I think we should be able to identify surrogate biomarkers in the silent phase of disease to predict the onset of various neurological problems. Because of the degree of hypercharacterization that our study participants are undergoing, these surrogate biomarkers could be blood biomarkers, such as inflammatory biomarkers, or they could involve the structure of the brain, as revealed by MRI, or they could be at the neurophysiological level or the neuropsychological or cognitive levels. We suspect that in the short term there may be some surrogate biomarkers — in contrast to causative biomarkers — in the silent phase to tell us that a given person is at risk of developing a disease such as dementia, Parkinson’s, stroke, multiple sclerosis or epilepsy, among others.


The mid- to long-term part of the study is when we expect the most exciting findings will come. This will be the phase of identifying actionable biomarkers, targets for treatment. This phase will include the design of medications or biological interventions to target the identified causative biomarkers.

Additionally, we hope to identify pathways of disease — genetic or molecular pathways that are causative for a type of Alzheimer’s, for example, or implicated in the silent phase of epilepsy development. We may then be able to target these pathways by repurposing already existing medications for treatment of at-risk individuals. This would be consistent with the long-term goal of this study, which is to find a cure for these neurological disorders.

Q: Any final thoughts on the study?

Dr. Machado: At a fundamental level, this study is about the next generation. Today we benefit from great advancements of medicine that were developed by our predecessors, our ancestors. They dedicated their time, effort and resources for us to have better health. I think this is an opportunity for us, given the technological advancements that we now have, to do the same and provide better neurological outcomes for our next generations. This is not only for ourselves and our patients, but it is for our children and grandchildren, as the results may take some time to become clear and transform practice.

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