In June 2019, I wrote a column with Dr. Stephen Liggett outlining the objectives of basic research and faculty recruitment strategy at the USF Health Byrd Alzheimer’s Center from a basic/translational science perspective. However, faculty recruitment is only one of multiple building blocks needed to build a world-class Alzheimer’s disease (AD) research program. Here then are some thoughts on the next key steps toward achieving this goal — a plan that goes beyond faculty recruitments, bridges the basic and clinical research divide, and takes us closer to establishing a National Institutes of Health-funded Alzheimer’s Disease Research Center (ADRC) at the Byrd.
Tackling The Problem Of Dementias
Three main missions of the Byrd Alzheimer’s Center, Division of Basic Research are 1. Identifying the root causes of dementia, 2. Devising promising strategies for therapeutic intervention, and 3. Early detection of dementia. According to the NIH, Alzheimer’s disease and related dementias (ADRDs) include frontotemporal dementia (FTD), Lewy body dementia (LBD), vascular dementia (VD), and mixed etiology dementias (MED). Truthfully, though, most AD cases involving patients older than age 65 are mixed dementias comprising AD-type pathology (amyloid and tau) together with combinations of vascular, Lewy body, and/or TDP-43 pathologies. LBDs, primarily characterized by a-synuclein deposits, include both dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), since some late-stage Parkinson’s disease (PD) patients also develop dementia. Differentiating between DLB and PDD, or between Alzheimer’s and DLB, can be challenging. In addition, 10-20% of patients with FTD later develop ALS symptoms; likewise, some ALS patients develop FTD-type dementia. Therefore, it is not surprising that ALS and FTD share multiple common genetic causes and the protein TDP-43 as a common pathological hallmark.
The fog of confusion about what constitutes a specific dementia leads to three general implications. First, at best, our present understanding of the causes and progression of dementias is hazy. Second, we know multiple processes drive dementia, and the interactions between these processes are likely synergistic, suggesting that no single “magic bullet” will fully combat dementia. Third, molecular processes driving ADRDs very often include those driving PD and ALS.
Early Detection and Establishing an Integrated Biospecimen Bank
One holy grail of ADRD biomarker research is to develop inexpensive, reliable, and noninvasive pathobiological signatures that can accurately predict the progression of preclinical stages to mild cognitive impairment to full-blown dementias, whatever their type, and demonstrate clear separation from non-demented controls, ALS, and PD. This biomarker information can be used as surrogates for prognosis and effectiveness during clinical trials, eventually facilitating a more personalized approach to therapies.
The Byrd, and its associated clinics and departments, is the epicenter of ADRD research at USF. We have recruited five new NIH-funded investigators in the past two years. This success bodes well for the next phase of expansion and integration. The new recruits, core capabilities, and asset map of Byrd basic research are outlined here.
Presently, USF researchers do not systematically take full advantage of the tremendous opportunities of phenotyping and the potential for genetic and biomarker research within the Byrd and the Departments of Neurology, Neurosurgery, and Psychiatry and Behavioral Sciences (i.e. the Neuroscience Institute). Of note, USF’s NIH-funded studies Preventing Alzheimer’s With Cognitive Training (PACT) and Keys to Staying Sharp provide excellent sources of community-based data of individuals with both mild cognitive impairment and no dementia. My lab recently began using this cohort in a pilot biomarker study in collaboration with Dr. Jerri Edwards.
The buildup of proteinopathy (i.e., amyloid, tau, TDP-43, a-synuclein) begins 10 to 20 years before clinical symptoms. Some brain proteinopathy is reflected in the periphery and can be detected in blood and skin tissues with sensitive methods. A recent study showed that brain-derived exosome biomarkers in blood plasma are now as diagnostically effective as the same biomarkers in cerebrospinal fluid for MCI and AD. Another highly promising method of early disease detection is through a simple and quantitative plate reader assay (RT-QuIC) from skin biopsy samples. Here, minute amounts of misfolded proteins (i.e., tau, a-synuclein, PrPSC, etc.) are amplified up to a billion-fold with matching recombinant proteins by virtue of prion-like seeding properties of all proteinopathies. I have seen some highly encouraging assay results and believe that this relatively noninvasive, simple method could transform the biomarker landscape.
One of the key steps for us will be establishing a more integrated and centralized patient biospecimen bank, one that systematically collects blood (and other fluids such as CSF), skin biopsy samples, and eventually brain together with detailed clinical information. In fact, a biospecimen bank/biomarker core is also one of the requirements of an NIH-funded ADRC.
Elevating University Research with A Cell Reprogramming Core
The integrated biospecimen bank would help us establish a cell reprogramming core to handle both induced pluripotent stem cells (iPSCs) and patient-derived primary fibroblasts. Both iPSCs and fibroblasts can be reprogrammed into different cell types, including neurons, glia, and endothelial cells. This new core capability would not only serve the Byrd but all of USF (which has no cell reprogramming core), elevating the quality and disease relevance of research university-wide.
Building Out The Byrd Laboratories
The Byrd currently houses 10 ADRD labs with three cores, and has remaining wet lab space for two to three additional labs once the Heart Institute moves downtown. To facilitate new faculty recruitments and the biospecimen bank/cell reprogramming core, we need to get back on track to build out the 4th and 6th floors of the Byrd, originally planned in 2019 with preliminary blueprints. This buildout would add approximately 5,200 square feet of space to house three to four additional labs, including the biospecimen bank and cell reprogramming core.
Establishing An NIH-Funded ADRC
The NIH currently funds 32 ADRCs in the U.S. While 12% of the country’s dementia patients live in Florida, only two ADRCs serve Florida – the Mayo Clinic (Jacksonville) and the University of Florida (Gainesville). Florida seniors, especially those in the Tampa bay area, are overwhelmingly underserved. We have an opportunity to change this by establishing an ADRC at the Byrd. The NIH requires seven cores for ADRC funding: 1. Administrative, 2. Clinical, 3. Data Management & Statistical , 4. Neuropathology, 5. Outreach, recruitment, & engagement, 6. Biomarker, and 7. Education. The Byrd clinic has a large patient base and excellent clinical operation with five out of seven core capabilities today. With the proper investment of resources, we have the opportunity to establish an ADRC at USF. Such resources will likely come from multiple sources, including the Neuroscience Institute, the Byrd Alzheimer’s Center, various departments, and the Office of Research.
David E. Kang, PhD
Director, Division of Basic Research, Byrd Alzheimer’s Center
Fleming Endowed Chair in Alzheimer’s Disease
Professor, Department of Molecular Medicine
USF Health Morsani College of Medicine
