Author Interviews, Dermatology, Infections / 01.02.2019

MedicalResearch.com Interview with: [caption id="attachment_47172" align="alignleft" width="167"]Wenquan Zou, MD, PhD Associate Professor Departments of Pathology and Neurology Director of CJD Skin Project Associate Director National Prion Disease Pathology Surveillance Center Institute of Pathology Case Western Reserve University School of Medicine Cleveland, Ohio 44106 Dr. Wen Quan Zou[/caption] Wenquan Zou, MD, PhD Associate Professor Departments of Pathology and Neurology Director of CJD Skin Project Associate Director National Prion Disease Pathology Surveillance Center Institute of Pathology Case Western Reserve University School of Medicine Cleveland, Ohio 44106 MedicalResearch.com: What is the background for this study? Would you briefly explain the significance of prion-induced diseases and why they have been difficult to diagnosis? Response: Our previous study has demonstrated that infectious prions are detectable in the skin samples of patients with sporadic Creutzfeldt-Jakob disease (sCJD), the most common form of human prion disease, at the terminal stage by the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay and animal-based bioassay. The prion-induced diseases are significant because they are infectious diseases that can be transmitted inter-species and intra-species. For instance, mad cow disease, a prion disease in cattle, has been documented to transmit to humans. Currently, there are no cures for these fatal diseases. The definite diagnosis of prion diseases is difficult because it mainly depends on the availability of brain tissues obtained either by biopsy or autopsy for detection of prions. Brain biopsy is highly invasive and it is difficult to be accepted by patients and their families. Even for brain autopsy, it is not always feasible because of religious and cultural limitations in some regions or countries. 
Author Interviews / 23.01.2019

MedicalResearch.com Interview with: [caption id="attachment_47123" align="alignleft" width="184"]Dr-Byron Caughey Dr-Caughey[/caption] Byron Caughey, Ph.D.  Senior Investigator Chief, TSE/prion Biochemistry Section Laboratory of Persistent Viral Diseases NIH/NIAID Rocky Mountain Laboratories . Hamilton, MT 59840 USA MedicalResearch.com: What is the background for this study? Would you briefly explain the significance of prion-induced diseases and why they have been difficult to diagnosis?  Response: Although prion diseases such as Creutzfeldt-Jakob disease (CJD) are rarer than many other neurodegenerative diseases in humans, they are rapidly fatal, untreatable and transmissible. Therefore it is important to be able to diagnose prion diseases as early as possible, not only to accurately inform patients, families and caregivers, but also to reduce risks of transmission and  improve prospects for developing therapeutics. Toward these goals, we have shown that our RT-QuIC prion seed amplification assays are highly accurate for diagnosing sporadic CJD using patients’ spinal fluid and/or nasal brushings in the clinical phase of disease. However, these particular specimens may not always be available, and it remains unclear how early they become RT-QuIC-positive in infected individuals in the months or years prior to the onset of overt clinical signs. We also showed recently that skin samples obtained post-mortem from sCJD patients are RT-QuIC positive. In the current study, we determined how early prion seeds appear in the rodents infected with prions in order to gain clues as to whether analyses of skin biopsies might provide a means of early preclinical detection of prion infections in humans.
Author Interviews, Infections, NIH, Ophthalmology / 05.12.2018

MedicalResearch.com Interview with: Top, retina of a control patient. Bottom, retina from a patient with CJD. Arrowheads point to abnormal prions in the outer plexiform layer (opl), and the asterisk (*) marks more diffuse prions in the inner plexiform layer (ipl).Orrù et al., mBioByron Caughey, Ph.D. Senior Investigator Chief, TSE/prion Biochemistry Section Laboratory of Persistent Viral Diseases NIH/NIAID Rocky Mountain Laboratories Hamilton, MT 59840 USA  MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Corneal transplants have caused the transmission of Creutzfeldt-Jakob disease (CJD) in at least two cases, and pathological prion protein has been detected in the retinas of the eyes of sporadic CJD cases. To build on these previous indications of prions in eye tissue, we tested the distribution of prions in various components of eyes from 11 sCJD decedents. We applied a highly sensitive surrogate test for prions (RT-QuIC) that indicated that all of the sCJD cases had prions in multiple parts of their eye, including the cornea and sclera, which is the white outer surface of the eye. Retinas were usually contained the highest levels, in some cases approaching levels in the brain. Some other parts such as the cornea, lens and vitreous had much lower, but detectable, levels. 
Author Interviews, Cognitive Issues, Dermatology, Infections, Mental Health Research, Neurological Disorders, NIH / 23.11.2017

MedicalResearch.com Interview with: [caption id="attachment_38474" align="alignleft" width="400"]The brain of one patient who died from sporadic Creutzfeldt-Jacob disease (sCJD) appears nearly identical to the brain of a mouse inoculated with infectious prions taken from the skin of patients who died from sCJD. The brain of one patient who died from sporadic Creutzfeldt-Jacob disease (sCJD) appears nearly identical to the brain of a mouse inoculated with infectious prions taken from the skin of patients who died from sCJD.
Case Western Reserve University[/caption]   Byron Caughey, Ph.D. Senior Investigator Chief, TSE/prion Biochemistry Section Laboratory of Persistent Viral Diseases NIH/NIAID Rocky Mountain Laboratories Hamilton, MT      MedicalResearch.com: Would you briefly explain what is meant by Creutzfeldt-Jakob disease? Response: Creutzfeldt-Jakob disease (CJD) is an incurable—and ultimately fatal—transmissible, neurodegenerative disorder in the family of prion diseases. Prion diseases can be found in many mammalian species and are due to the conversion of normally harmless prion protein molecules into abnormally folded, aggregated and self-propagating clusters and filaments in the brain. The accumulation of these clusters has been associated with tissue damage that often leaves dying neurons and microscopic sponge-like holes in the brain. In the sporadic and genetic forms of CJD this pathogenic process appears to arise spontaneously in the patient. However, the transfer of the prion protein aggregates from a Creutzfeldt-Jakob disease patient into another human or experimental animal can initiate the pathogenic process in the recipient. These infectious forms of prion protein are called prions. Human prion diseases include fatal insomnia; kuru; Gerstmann-Straussler-Scheinker syndrome; and variant, familial and sporadic CJD. Sporadic CJD is the most common human prion disease, affecting about one in one million people annually worldwide. Other prion diseases include scrapie in sheep; chronic wasting disease in deer, elk and moose; and bovine spongiform encephalopathy (BSE), or mad cow disease, in cattle.
Author Interviews, Biomarkers, Infections, JAMA, Neurological Disorders / 12.12.2016

MedicalResearch.com Interview with: Zanusso Gianluigi M.D.Ph.D. Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona, Italy MedicalResearch.com: What is the background for this study? What are the main findings? Response: To determine RT-QuIC assay sensitivity and specificity in cerebrospinal fluid and olfactory mucosa in a large group of patients with a clinical diagnosis of probable, possible or suspect Creutzfeldt–Jakob disease (CJD) and controls. In these patients, RT-QuIC testing of CSF and olfactory mucosa provided a specificity and sensitivity of 100%. A softer swab for olfactory mucosa sampling provided the same sensitivity as using a brush .
Author Interviews, Infections, PLoS / 30.11.2016

MedicalResearch.com Interview with: Romolo Nonno, DVM, PhD Istituto Superiore di Sanità Dipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare Roma Italy MedicalResearch.com: What is the background for this study? What are the main findings? Response: Previous studies have suggested that prion populations are composed of a variety of conformational variants subjected to Darwinian evolution driven by selective regimes. However, the exact molecular mechanisms that make prions able to self-replicate and mutate are still poorly understood. A major technical advance in this field has been the discovery of techniques that allow to replicate prions in vitro, outside live organisms. One of these techniques, Protein Misfolding Cyclic Amplification (PMCA), allows to grow prion populations for a very high number of replications in a relatively short time period. Furthermore it is conceivable that the in vitro environment offers less constraint to prion replication than live animals or cells, due to the absence of active clearance and cell division, which are key players of conformers selection in ex vivo models. These features make PMCA an attractive tool to investigate prion replication, mutation and evolution. By using PMCA, we investigated the in vitro evolution of prion populations derived from natural scrapie. Unexpectedly, we found that the cloud of conformational variants which compose a natural scrapie isolate also includes “defective” variants which, once isolated, are unable to self-sustain in vivo. Importantly, we found that the defective prion mutant that we have isolated possesses unique biochemical properties in that its prion domain lacks the central region of prion protein, which is invariably present in known infectious mammalian prions.
Author Interviews, Infections, mBio, NEJM / 07.08.2014

Claudio Soto, PhD Professor of Neurology Director Mitchell Center for Alzheimer's disease and related Brain Disorders University of Texas Medical School at HoustonMedicalResearch.com Interview with: Claudio Soto, PhD Professor of Neurology Director Mitchell Center for Alzheimer's disease and related Brain Disorders University of Texas Medical School at Houston Medical Research: What are the main findings of the study? Dr. Soto: In this study we describe for the first time the highly sensitive detection of prions in human urine, specifically in samples from patients affected by the variant form of Creutzfeldt-Jakob disease (vCJD), which is the disease produced by infection with prions associated with bovine spongiform encephalopathy, also known as mad cow disease. For detection we used the protein misfolding cyclic amplification (PMCA) technique which amplifies the amount of abnormal prion protein in a cyclical manner conceptually analogous to the polymerize chain reaction. We detected prions in 13 of the 14 vCJD cases analyzed, and the only negative was a sample coming from a patient under treatment with a experimental drug injected directly into the brain. No false positive were observed in the more than 200 cases analyzed.  The concentration of abnormal prion protein in urine was estimated at 1x10^-16 g/ml, or 3x10^-21 moles/ml, which extrapolates to ~40-100 particles per ml of urine.