Wenquan Zou, MD, PhD, an expert in prion and degenerative neurological diseases, has received a two-year grant for developing diagnostic tools for Alzheimer’s disease, Parkinson’s disease, and other related brain-based degenerative disorders via an innovative skin test that uses ultrasensitive technology. The new test is much less invasive than evaluating brain tissue, which is the only approach for making a definitive diagnosis today.
Alzheimer’s is mainly associated with the accumulation of abnormal toxic amyloid β and tau proteins in the diseased brain. These “misfolded” proteins often hide in the brain and remain undetected as they destroy brain tissue—causing progressive memory loss, irreversible declines in thinking and speaking ability, severe mobility problems, and ultimately, death. Similarly, misfolded α-Syn proteins precipitate Parkinson’s disease, whose symptoms include tremors, loss of automatic movements, difficulty walking, and speech changes.
Changes in the brain associated with Alzheimer’s can begin more than 20 years before symptoms are detected, but the ultimate goal of Zou’s test is to pinpoint the abnormal proteins in skin samples of patients before symptoms appear. While there are currently no treatments for slowing or stopping the damage caused by the disease-causing proteins, many researchers think that treatments in the future will deliver the best results when administered early in the disease process, before symptoms and brain damage are detected. Routine skin testing of those at risk may prove effective in this regard.
“In addition to early diagnosis, pinpointing the misfolded proteins in more accessible specimens such as the skin can be used for effectively monitoring disease severity and evaluating the therapeutic value of new treatments for Alzheimer’s and other neurodegenerative diseases,” said Zou, who is an associate professor in the departments of Pathology and Neurology, and associate director of the National Prion Disease Pathology Surveillance Center, at Case Western Reserve University School of Medicine.
The grant will be the first full application of the recently developed RT-QuIC (real-time quaking-induced conversion) technology to the readily accessible skin specimens in order to diagnose Alzheimer’s. Previously he and his co-workers used the test to detect misfolded prion proteins in the skin of patients with Creutzfeldt-Jakob disease (CJD), which is sometimes described as the human version of mad cow disease. Prions are an abnormal form of a normally harmless protein found in the brain. They are responsible for an assortment of fatal neurodegenerative diseases called transmissible spongiform encephalopathies, including CJD in humans and mad cow disease and chronic wasting disease in animals. In that earlier work, RT-QuIC correctly detected abnormal prion proteins in the skin samples of each cadaver with CJD tested and in none of the non-CJD group, i.e., no “false positives.”
Under the new grant, Zou will work to confirm preliminary findings that he and his co-worker Dr. Zerui Wang have already achieved in collaboration with Drs. Bin Xu of Virginia Tech University and Thomas Beach of the Arizona Alzheimer’s Consortium. These initial, small-sample-size data revealed that the RT-QuIC test is able to detect misfolded tau proteins in autopsied skin and brain tissue samples of patients with Alzheimer’s disease.
The new test may offer several advantages over existing methods for diagnosing Alzheimer’s. For example, while brain imaging and cerebrospinal fluid analysis can detect some of the misfolded proteins, the two techniques are often ineffective in the early stages of the disease, expensive, and in the case of cerebrospinal fluid analysis, invasive. Moreover, while certain existing lab tests and immunofluorescence microscopy can detect misfolded tau and α-Syn proteins in the skin tissue of Alzheimer’s and Parkinson’s patients, these approaches have highly variable levels of sensitivity to the presence of the toxic proteins, making them generally unreliable and inconsistent as diagnostic tools.
In the new RT-QuIC test, researchers mix a small amount of skin sample with normal tau protein. The misfolded protein has the ability to convert the normal protein into the misfolded form by constantly shaking the mixtures. Once the normal protein is converted into the misfolded form, the particles bind together to form a larger aggregate that triggers a fluorescence probe to release fluorescence light monitored in a real-time scale by a researcher. In this way, the small amount of misfolded tau protein can be significantly amplified by integrating with the normal protein, and thus can be readily detected.
“Since skin biopsy is substantially less invasive than spinal tap and brain biopsy, and because RT-QuIC is highly sensitive and specific and therefore more accurate than other lab-based methods, it is conceivable that the test represents a promising tool for diagnosing, characterizing, and predicting Alzheimer’s disease as well as Parkinson’s and other neurodegenerative diseases,” said Zou.
Funding for the project is provided by the Alzheimer’s Association, Alzheimer’s Research UK, the Michael J. Fox Foundation for Parkinson’s Research, and the Weston Brain Institute. The grant award is for $149,729.00 over the course of two years (Grant ID: 18012).
To learn more about Case Western Reserve University School of Medicine, visit case.edu/medicine.
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Alzheimer's Assocation; Alzheimer’s Research UK; Michael J. Fox Foundation for Parkinson’s Research; Weston Brain Institute