New NIH grant to support innovative skin testing approach for diagnosing Parkinson's disease

Wenquan Zou, MD, PhD, an expert in degenerative neurological diseases, along with his collaborators Shu G. Chen, PhD also from the Case Western Reserve University School of Medicine, Jiyan Ma, MD, PhD, from Van Andel Institute in Grand Rapids, Michigan, and Thomas Beach, MD, PhD, from Banner Sun Health Research Institute, Sun City, Arizona, have received a five-year, $3.6 million grant from the National Institutes of Health for diagnosing Parkinson's disease (PD) via an innovative skin testing approach. Also part of the team is Steven Gunzler, MD, a neurologist at the University Hospitals Cleveland Medical Center and the School of Medicine.

The methodology uses highly sensitive technology to detect the presence in the skin of "misfolded" alpha-synuclein (α-Syn) proteins that are the cause of nerve cell dysfunction and death in PD.

Skin testing offers several advantages over existing diagnostic tools:

• It is much less invasive than the current most effective method in living patients: analyzing the cerebrospinal fluid--the liquid surrounding the brain and spinal cord--both spinal tap and skin biopsy test for the presence of misfolded α-Syn protein, an essential protein found in the human brain, but obtaining CSF requires a needle insertion into the spinal column while a skin biopsy is done with a small hollow punch inserted less than one inch into the skin of the neck or legs.
• Brain imaging and certain blood tests can also be currently used to help diagnose PD, but they are not fully accurate or sensitive.
• Physical changes associated with PD (including tremors, difficulty walking and speech problems) are debilitating. As the α-Syn proteins begin accumulating 10-20 years before these symptoms appear, the testing could help identify people long before symptoms appear.

"Ascertaining the presence, volume, and dispersion of the misfolded α-Syn proteins in more accessible specimens such as the skin can also be used for monitoring the progression of the disease and evaluating the effectiveness of new treatments," said Zou, 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 School of Medicine.

The movement difficulties in PD are linked to the loss of dopamine-producing brain cells, but the α-Syn proteins eventually spreads from cell to cell throughout the brain often leading to immobility and even dementia.

In earlier studies, researchers used antibodies tagged with colored or fluorescent compounds to visualize α-Syn in skin under the microscope. But the accuracy of these methods varied from lab to lab and were not positive in all people with PD.

In their preliminary study, Zou, Zerui Wang, a research fellow from the Zou lab, and Chen have found that an ultrasensitive test known as real-time quaking-induced conversion (RT-QuIC) detected misfolded forms of α-Syn in autopsied skin tissues of PD patients with very high specificity and sensitivity. The samples were then sent to the Ma lab for examination with another test, protein misfolding cyclic amplification (PMCA), by which Katelyn Becker observed that skin α-Syn was detectable by PMCA too in PD patients but not in non-Parkinson's controls-again confirming accuracy and sensitivity. The new research will expand on their earlier efforts by studying a significantly larger number of patients.

We hypothesize that RT-QuIC and PMCA are highly sensitive and robust platforms to establish skin α-Syn as a biomarker (indicator) for post-mortem and pre-mortem diagnoses of PD, and the method might be extended to other neurodegenerative diseases as well.

Wenquan Zou from Case Western Reserve School of Medicine

The new research will be carried out in conjunction with a recent grant Zou received from a consortium of funders including the Alzheimer's Association, Michael J. Fox Foundation for Parkinson's Research, and the Weston Brain Institute to use RT-QuIC to help diagnose Alzheimer's disease, which is primarily associated with the accumulation of abnormal, mis-folded toxic amyloid β and tau proteins in the diseased brain-also via skin testing.

Previously, in a study generating major international media attention, Zou and colleagues used the RT-QuIC test to detect mis-folded prion proteins in the skin of patients with Creutzfeldt-Jakob disease, which is sometimes described as the human version of mad cow disease. Prions, an abnormal form of a normally harmless protein found in the brain, are responsible for several fatal neurodegenerative diseases in humans and animals.

"We are hopeful that our findings will pave the way for painless, accurate, and early detection of a series of devastating neurogenerative diseases that are sure to escalate in number as the aging of the population continues and individuals live longer with chronic diseases," said Zou.