Alzheimer's - Dementia, Author Interviews, Genetic Research / 14.06.2023

MedicalResearch.com Interview with: Alexandra M Whiteley PhD Department of Biochemistry University of Colorado Boulder Boulder, Colorado MedicalResearch.com: What is the background for this study? Response: My laboratory was interested in understanding how UBQLN2 maintains cellular health. Ubiquilins facilitate protein degradation, but the precise proteins that they help to break down were not well understood. UBQLN2 is of particular interest because mutations in the UBQLN2 gene lead to a familial form of ALS. This project, which was published in eLife this year, stems from work that was published when I was a postdoctoral researcher at Harvard Medical School, where we found a link between UBQLN2 and the virus-like protein PEG10. Now at the University of Colorado, Boulder, my laboratory has focused on trying to understand this connection between the two proteins, and how PEG10 could contribute to ALS. (more…)
ALS, Alzheimer's - Dementia, Author Interviews, Biomarkers, JAMA, Multiple Sclerosis / 27.06.2019

MedicalResearch.com Interview with: Charlotte E. Teunissen, PhD Neurochemistry Laboratory, Department of Clinical Chemistry VU University Medical Centre, Neuroscience Campus Amsterdam Amsterdam, the Netherlands MedicalResearch.com: What is the background for this study? What are the main findings? Response: Several reports have shown increased in NfL in various neurological disorders, separately. We wanted to know how the levels are in these disorders relative to each other. Moreover, some reports showed absence of age effects in Multiple Sclerosis (MS) patients, which is normally present in controls. So, we thought that it would be good to study age effects in a large group of controls, and if these effects are absent in other diseases, similarly as in MS. (more…)
ALS, Author Interviews, Statins / 15.02.2019

MedicalResearch.com Interview with: Alastair J. Noyce MD, PhD Preventive Neurology Unit, Wolfson Institute of Preventive Medicine Queen Mary University of London, Department of Clinical and Movement Neurosciences, University College London, Institute of Neurology, London UK MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Amyotrophic lateral sclerosis (ALS) or motor neurone disease (MND) is a relentlessly progressive disorder that affects nerves which supply muscles. Over time the nerves die, leading to limb weakness, speech and swallowing problems, and ultimately breathing problems. Patients die on average 3-5 after diagnosis. There is no cure and the underlying disease processes are only understood in part. In this study, we adopted a large-scale approach to exploring causal risk factors for ALS. Causality is important because it implies that if one could modify or induce a change in a risk factor, one would observe a change in the risk of ALS. Observational studies struggle to prove causality definitely. Associations in observational studies can arise because: 1) the risk factor truly changes risk of ALS; or 2) something about ALS changes one’s exposure to the risk factor; or 3) the presence of another factor, which may or may not be known, can induce an association between a risk factor and ALS. Unless scenario 1 represents the truth, then changing the risk factor will not have any effect on risk of ALS. We used a proxy-based approach, known as Mendelian randomisation, to assess hundreds of possible risk factors for ALS for evidence of causality. What emerged from this was a very clear signal linking LDL cholesterol to risk of ALS. (more…)
ALS, Author Interviews, Pharmaceutical Companies / 27.09.2018

MedicalResearch.com Interview with: RetrotopeRobert J Molinari, Ph.D. President and CEO Retrotope, Inc.   MedicalResearch.com: What is the background for this study? How does RT001 differ from other treatments for neurodegenerative diseases?  Response: Lipid peroxidation in critical cell and mitochondrial membranes represents a common pathway of cell death in many neurodegenerative diseases, regardless of the initiating trigger of original damage, e.g. aberrant gene expression, misfolded proteins such as tau and amyloid, environmental insults, etc. This hypothesis was supported by work showing that stabilizing lipids (using virtually indistinguishable isotopic variants of the original dietary molecules) was able to mitigate disease-related cell dysfunction, and reverse disease in a variety of animal models, and more recently, in human patients enrolled in clinical trials. It has been known for decades that lipid peroxidation detritus of oxidized membrane fats are present in most all diseases of degeneration and aging, including Alzheimer’s disease, Parkinson’s disease, atherosclerosis, ALS, Huntington’s, and fatal inborn genetic errors resulting in neurodegenerative diseases (among others). The hypothesis that controlling such oxidation could provide therapeutic benefit was abandoned when numerous formal trials of classical antioxidants, e.g. Co-enzyme Q, Vitamin E, and others failed to provide meaningful benefit. We believed that the antioxidant mechanism used to attempt control of the membrane oxidation was flawed, but that the target itself was correct. Indeed, by using a new class of oral drugs that are lipids fortified against damage at the key susceptible bonds, we observed reduction in lipid peroxidation damage that halted, and even reversed neurodegenerative disease progression. Dosed in amounts and forms similar to omega 3 and 6 supplements, these drugs exhibited profound disease modification across a broad range of diseases in animal models, placebo controlled- and open label- human trials. (more…)
ALS, Author Interviews, Neurology / 21.08.2018

MedicalResearch.com Interview with: Pier Lorenzo Puri, M.D PhD Professor in the Development, Aging and Regeneration Program Sanford Burnham Prebys Medical Discovery Institute  MedicalResearch.com: What is the background for this study? What are the main findings? Response: My lab has been studying special repair cells called fibro-adipogenic progenitors (FAPs) and how these cells change in models of motor neuron diseases. These cells usually repair muscles after acute injury. But we are finding the FAPs change dramatically in disease settings. In this study we looked at these cells in models of spinal cord injury, ALS and spinal muscular atrophy, including muscle tissue from ALS patients. We found that FAPs change radically in several ways. Most importantly, the cells used a different signaling pathway, IL-6-STAT3, and when we blocked this signaling muscle atrophy and fibrosis halted. While further studies in humans are needed, this is a promising finding as FDA-approved medicines that block IL-6 and STAT3 are available.  (more…)
ALS, Alzheimer's - Dementia, Author Interviews, JAMA / 09.04.2018

MedicalResearch.com Interview with: Celeste Karch, PhD Assistant Professor of Psychiatry Molecular mechanisms underlying tauopathies Washington University School of Medicine St Louis MedicalResearch.com: What is the background for this study? What are the main findings? Response: Nearly half of all patients with amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder, develop cognitive problems that affect memory and thinking. Why a disease that primarily affects movement also disrupts thinking has been unclear. Our findings suggest that genetic connections between the two disorders may explain why they share some of the same features and suggest that some drugs developed to treat ALS also may work against frontotemporal dementia and vice versa. We used a statistical method in almost 125,000 individuals with ALS, frontotemporal dementia (FTD), progressive supranuclear palsy, corticobasal degeneration, Alzheimer’s disease and Parkinson’s disease to determine whether there are common genetic variants that increase risk for multiple neurodegenerative diseases. We found that common variants near the MAPT gene, which makes the tau protein, increases risk for ALS. MAPT has previously had been associated with diseases including frontotemporal dementia and Alzheimer’s disease. But the gene hadn’t been linked to ALS. We also identified variations in a second gene, BNIP1, which normally plays an important role in protecting against cell death, increased the risk of both ALS and frontotemporal dementia. ImportantlyBNIP1 mRNA levels were altered in people who had ALS and in patients with frontotemporal dementia, suggesting the BNIP1 may be a potential therapeutic target for both disorders. (more…)
Author Interviews, Columbia, JAMA, Neurology, Pulmonary Disease / 29.11.2017

MedicalResearch.com Interview with: Jinsy Andrews, MD, MS Director of Neuromuscular Clinical Trials Columbia University The Neurological Institute New York, NY 10032  MedicalResearch.com: What is the background for this study? Response: The importance of respiratory function in Amyotrophic Lateral Sclerosis (ALS) has long been recognized. Despite ALS being a clinical diagnosis with variable presentation and variable rates of disease progression, all patients experience respiratory symptoms and inevitably die typically from respiratory failure. At present there is no validated biomarker of disease progression or clinical staging system. Direct measure of respiratory function in ALS is important and can be measured using vital capacity. Although the forced maneuver (FVC) has been widely used in patients with ALS, it can underestimate the actual lung capacity by causing fatigue or inducing bronchospasm in patients with ALS. More recently, the slow maneuver (SVC) has been used since it can be obtained from patients with advancing disease which can potentially minimize missing data and may reduce any underestimation of actual lung capacity due to a forceful effort. However, the prognostic value of the decline in SVC is unclear in patients with ALS. (more…)
ALS, Author Interviews, Biomarkers, Neurology / 24.03.2017

MedicalResearch.com Interview with: Mary-Louise Rogers, PhD Senior Research Fellow, Lab Head, Motor Neurone Disease and Neurotrophic Research Laboratory, Department of Human Physiology, Centre for Neuroscience, Flinders University, School of Medicine, South Australia, Australia MedicalResearch.com: What is the background for this study? What are the main findings? Response: ALS is a fatal neurodegenerative disease in which motor neurons, cells that control muscle activity such as walking, talking and breathing, gradually die off, resulting in paralysis. There is no cure for ALS. In a groundbreaking study published in the journal Neurology, and led by Mary-Louise Rogers, Ph.D., senior research fellow at Flinders University, Australia, and Michael Benatar, M.D., Ph.D, University of Miami, Miller School of Medicine,  have identified concentrations of p75ECD, the extracellular domain on the common neurotrophin receptor p75, as the first biological fluid-based biomarker for ALS progression. . Neurotrophin receptor p75 is a growth factor receptor for neurotrophins whom promote the survival of nerve cells. Under normal circumstances, it is highly expressed on motor neurons during development but decreases after birth. Following nerve injury, however, the expression of p75 is increased and the extracellular domain of p75 is detectable in urine. Dr Rogers and her Doctoral student Stephanie Shepheard hypothesized and then showed, that p75ECD is excreted into the urine of SOD1 mice, the most commonly used animal model of ALS. These findings empowered further investigation of p75ECD, showing raised levels in the urine of patients with ALS and that it might have potential as an ALS biomarker. (more…)
ALS, Author Interviews, Genetic Research, JAMA / 15.02.2017

MedicalResearch.com Interview with: Prof. Dr. Christine Van Broeckhoven PhD DSc Professor in Molecular Biology and Genetics, University of Antwerp Science Director, VIB Center for Molecular Neurology Research Director, Laboratory for Neurogenetics, Institute Born-Bunge Senior Group Leader, Neurodegenerative Brain Diseases University of Antwerp and Dr. Sara Van Mossevelde, MD Center for Molecular Neurology, VIB Institute Born-Bunge, University of Antwerp Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp, Belgium MedicalResearch.com: What is the background for this study? What are the main findings? Response: Patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) and a C9orf72 repeat expansion present with highly variable onset ages of disease. In the Belgian patient cohort the onset ages ranged from 29 to 82 years of age. This high variability suggested the influence of modifying factors on disease expression. As in other repeat expansion diseases, repeat length is the prime candidate as genetic modifier. In a molecular study (Gijselinck et al., Molecular psychiatry 2016), we were able to provide evidence for an inverse correlation of repeat length with onset age in affected parent – affected children in a C0orf72 families. Also, the degree of methylation of the C9orf72 repeat correlated with repeat size. In this clinical study of affected parent – affected children pairs we provided additional evidence for the occurrence of disease anticipation in C9orf72 pedigrees by analyzing age at onset, disease duration and age at death in successive generations. Within 36 C9orf72 pedigrees with available age data of patients in two to four generations, we observed a significant decrease in age at onset across successive generation while no generational effect was seen on disease burden, disease duration or age at death. (more…)
ALS, Author Interviews, NEJM, Technology / 19.11.2016

MedicalResearch.com Interview with: Mariska Van Steensel PhD Nick F. Ramsey, Ph.D. Department of Neurology and Neurosurgery Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht, the Netherlands MedicalResearch.com: What is the background for this study? What are the main findings? Response: Patients who are severely paralyzed due to for example ALS or brain stem stroke are often unable to speak (also called ‘ Locked-in State'), and therefore need assistive devices, such as an eye tracker, for their communication. When these devices fail (e.g. due to environmental lighting or eye movement problems), people may indicate yes or no with eye blinks in response to closed questions. This leaves patients in a highly dependent position, since questions asked may or may not represent their actual wish or comment. In the current study, we used a technology called brain-computer interfacing (BCI), to allow a patient with late-stage amyotrophic lateral sclerosis (ALS) to control a communication device using her brain signals. The patient was implanted with subdural electrodes that covered the brain area that is normally responsible for hand movement. The electrodes were connected with wires, subcutaneously, to an amplifier/transmitter device that was placed subcutaneously under the clavicle. The patient was able to generate a signal equivalent to a mouse-click with this brain-computer interface by attempting to move her hand, and used it to make selections of letters or words on her communication device, with high accuracy and a speed of 2 letters per minute. She used the brain-computer interface system to communicate whenever she was outside, as her eye-tracker device does not function well in that situation. (more…)
ALS, Antioxidants, Author Interviews, Columbia, Inflammation, JAMA, Nutrition / 26.10.2016

MedicalResearch.com Interview with: Dr. Jeri Nieves PhD Director of bone density testing New York's Helen Hayes Hospital MedicalResearch.com: What is the background for this study? What are the main findings? Response: Amyotrophic lateral sclerosis (ALS) is a devastating severe neurodegenerative disorder that causes progressive muscle atrophy, paralyses, and eventual respiratory failure. Our objective was to evaluate the associations between nutrition and severity of ALS around the time of diagnosis. This was a cross-sectional analysis of data from a multicenter cohort of 302 patients with ALS. We assessed nutrient intake using a modified Block Food Frequency Questionnaire. The outcomes were respiratory function (measured using percentage forced vital capacity; FVC%) and functional performance measured by ALS Functional Rating Scale–Revised (ALSFRS-R), both considered important indicators of the severity of ALS. Results of the regression analysis were that higher intakes of antioxidants and carotenes from vegetable intake were associated with higher ALSFRS-R scores or better %FVC. We used a novel analysis to evaluate the diet as a whole and found that higher intakes of antioxidants, fiber from grains, vegetables, fruit, eggs, fish, and poultry were all associated with higher function in patients with ALS. However, milk and lunch meats were associated with lower measures of function. These consistent results from two different statistical analyses indicate that diet may help minimize the severity of ALS. Perhaps these findings point to the role of oxidative stress in ALS severity. In summary, increased consumption of antioxidant nutrients, foods high in carotenoids and fiber, vegetables and fruits, poultry and fish are associated with better function around the time of ALS diagnosis. (more…)
ALS, Alzheimer's - Dementia, Author Interviews, Nature / 07.05.2016

MedicalResearch.com Interview with: Ana Pereira, MD Instructor in Clinical Medicine Bruce McEwen's laboratory Rockefeller University  MedicalResearch.com: What is the background for this study? Dr. Pereira: The neurons most susceptible to dying in Alzheimer’s disease are the ones that use glutamate as a neurotransmitter (chemical messengers that enable neurotransmission). Glutamate is the major excitatory neurotransmitter in the brain and its regulation is critical for learning and memory. When glutamate is not located in the correct place and amount, it causes several deleterious effects to neurons that can ultimately lead to cell death. Importantly, the glutamate transporter EAAT2 is the dominant regulator of glutamate levels and it is highly depressed in Alzheimer’s disease. Furthermore, glutamatergic dysregulation is implicated in several pathological mechanisms in Alzheimer’s disease including the release and toxicities of the proteins implicated in Alzheimer’s disease: amyloid-beta (which form amyloid plaques) and tau (which form neurofibrillary tangles). Better regulation of glutamatergic neural circuits is critically important to effectively treat age-related cognitive decline and Alzheimer’s disease. (more…)
ALS, Author Interviews / 22.01.2016

More on Alzheimer's Disease on MedicalResearch.com MedicalResearch.com Interview with: Sandra Anne Banack Institute for Ethnomedicine Jackson Hole, WY Medical Research: What is the background for this study? What are the main findings? Response: Villagers from the island of Guam had 50-100x the incidence rates of ALS when compared with Western populations. Although the disease on Guam  was first identified as ALS it is now known as ALS/PDC because it can also have clinical features of Parkinson’s and Alzheimer's diseases. The pathological features of this disease include brain tangles and amyloid plaques that are also the diagnostic features of Alzheimer's disease.  We found that an environmental neurotoxin causes brain tangles and amyloid deposits in an animal model. This is the first time that brain tangles, known technically as neurofibrillary tangles, have been created in an animal model along with the amyloid deposits. The animal model can be used to screen potential drugs for Alzheimer's and potentially other neurodegenerative diseases quicker and at a fraction of the cost and risk of current methods using human subjects. In addition, we found that L-serine significantly reduced the formation of brain tangles exposed to this toxin. (more…)
ALS, Alzheimer's - Dementia, Author Interviews, JAMA, Multiple Sclerosis, Neurological Disorders, Stem Cells / 12.01.2016

MedicalResearch.com Interview with: Prof. Dimitrios Karussis M.D., Ph.D. Professor of Neurology Head, Multiple Sclerosis Center Hadassah BrainLabs Medical Research: What is the background for this study? What are the main findings? Prof. Karussis: BrainStorm Cell Therapeutics is developing innovative, autologous stem cell therapies for highly debilitating neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson’s Disease (PD).  Our technology, NurOwn™ is a first-of-its-kind approach that induces autologous bone marrow-derived Mesenchymal Stem Cells (MSCs) to secrete Neurotrophic Growth Factors (NTFs).  These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases. Data from the clinical trials described in the recent issue of the Journal of American Medicine – Neurology (JAMA Neurology), suggest that NurOwn can help patients with ALS.  The two trials featured in the article, a phase 1/2 and a phase 2a, studied the transplantation NurOwn cells in ALS patients.  These trials confirmed the excellent safety profile of NurOwn and suggest a clinically meaningful effect. The investigators used two well established clinical endpoints that measure disease activity in ALS, the Revised ALS Functional Rating Scale and Forced Vital Capacity, and were able demonstrate a slowing of disease activity in the period following treatment. (more…)
ALS, Author Interviews, Mayo Clinic, Science / 28.05.2015

Dr. Leonard Petrucelli Ph.D Mayo Clinic Jacksonville, FL 32224MedicalResearch.com Interview with: Dr. Leonard Petrucelli Ph.D Mayo Clinic Jacksonville, FL 32224 MedicalResearch: What is the background for this study? Dr. Petrucelli: According to the ALS Association, more than 30,000 Americans live with amyotrophic lateral sclerosis (ALS), a condition that destroys motor neuron cells that control essential muscle activity such as speaking, walking, breathing and swallowing. After Alzheimer’s disease, frontotemporal dementia (FTD) is the most common form of early onset dementia. It is characterized by changes in personality, behavior, and language due to loss of neurons in the brain’s frontal lobe. Once considered rare, frontotemporal dementia is now thought to account for up to 10 to 15 percent of all dementia cases, according to the Alzheimer’s Association. In 2011, Mayo investigator Rosa Rademakers, Ph.D., identified the most common genetic mutation known to cause ALS and FTD, namely a repeat expansion in the gene C9ORF72. The C9ORF72 repeat expansion leads to the generation of toxic RNA species that form abnormal foci, as well as inclusions of c9RAN proteins in affected cells in the central nervous system. Prior to this research study lead by Leonard Petrucelli, Chair of the Department of Neuroscience at the Mayo Clinic Florida, no animal model existed that fully recapitulated the known clinicopathological features of what is now collectively referred to as c9FTD/ALS. Without such an animal it has remained difficult to identify important mechanisms by which the repeat expansion leads to neurodegeneration and putative therapeutic targets that may mitigate disease in patients where currently there are no curative treatments. (more…)
ALS, Author Interviews, JAMA / 16.11.2014

MedicalResearch.com Interview with: Charles Tzu Chi Lee, PhD Associate Prof., Department of Public Health Kaohsiung Medical University, Kaohsiung, Taiwan Sanmin District, Kaohsiung City Taiwan Medical Research: What is the background for this study? What are the main findings? Dr. Lee: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease and most patients die within three to five years after symptoms appear. Studies have suggested angiotensin-converting enzyme inhibitors (ACEIs) may decrease the risk for developing neurodegenerative diseases. But there was still no human study discussing ACEIs use and ALS risk in literature. The study results indicate that when compared with patients who did not use ACEIs, the risk reduction was 17 percent (adjusted odds ratio of 0.83) for the group prescribed ACEIs lower than 449.5 cumulative defined daily dose (cDDD) and 57 percent (adjusted odds ratio 0.43) for the group prescribed ACEIs greater than 449.5 cDDD. (more…)
Author Interviews, JAMA, Neurological Disorders / 14.11.2014

MedicalResearch.com Interview with: Charles Tzu Chi Lee, PhD Associate Prof., Department of Public Health Kaohsiung Medical University, Kaohsiung, Taiwan Kaohsiung City 80708, Taiwan Medical Research: What is the background for this study? What are the main findings? Dr. Lee: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease and most patients die within three to five years after symptoms appear. Studies have suggested angiotensin-converting enzyme inhibitors (ACEIs) may decrease the risk for developing neurodegenerative diseases. But. there was still no human study discussing ACEIs use and ALS risk in literature. The study results indicate that when compared with patients who did not use ACEIs, the risk reduction was 17 percent (adjusted odds ratio of 0.83) for the group prescribed ACEIs lower than 449.5 cumulative defined daily dose (cDDD) and 57 percent (adjusted odds ratio 0.43) for the group prescribed angiotensin-converting enzyme inhibitors greater than 449.5 cDDD. (more…)
ALS, Author Interviews, JAMA, Radiology / 12.03.2014

Prof. Dr. Philip Van Damme, MD, PhD Neuromuscular Reference Center, Neurology Department, University Hospitals Leuven Vesalius Research Center, VIB, Leuven Leuven Institute of Neurodegenerative Disorders (LIND) KU Leuven, BelgiumMedicalResearch.com Interview with: Prof. Dr. Philip Van Damme, MD, PhD Neuromuscular Reference Center, Neurology Department, University Hospitals Leuven Vesalius Research Center, VIB, Leuven Leuven Institute of Neurodegenerative Disorders (LIND) KU Leuven, Belgium MedicalResearch.com: What are the main findings of the study? Prof: Van Damme: Earlier FDG-PET studies carried out in the 80’ties already pointed out that patients with ALS had decrease glucose uptake in the brain that is more extended than the motor cortex, at least at the group level. Of course, this imaging technique has been improved since then. We prospectively assessed the diagnostic and prognostic value of FDG-PET in patients that were referred to us because a diagnosis of ALS was suspected. The most important finding of our study probably is that FDG-PET shows perirolandic and variable frontotemporal hypometabolism in most patients with ALS at the first presentation in our clinic. It suggests that FDG-PET is a very sensitive marker of cerebral involvement in ALS, which has a high sensitivity at the single patient level. In addition our study revealed that the co-occurrence of extensive prefrontal or anterior temporal hypometabolism was present in about 10% of patients and had a negative effect on survival after disease onset. (more…)