Multiple Sclerosis: Rituximab Had Better Short and Medium Term Outcomes

MedicalResearch.com Interview with:
Fredrik Piehl MD PhD, prof. of Neurology

Neuroimmunology Unit. Dept Clinical Neuroscience
Neurology Dept.
Karolinska University Hospital (Solna)
Stockholm

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years we have seen a drastic increase in treatment options for relapsing-remitting multiple sclerosis (RRMS). However, it is difficult to deduce long term performance of different drugs based only on data from randomized controlled trials, since such trials are performed in selected patients without major co-morbidities and perhaps also enriched for those with a milder disease course. In addition, most trials only last for two years and lack relevant comparators. This lack of knowledge makes it difficult to predict if a drug will work or not for a given patient, in turn leading to frequent treatment switches but also different treatment practices across countries, regions or even between centers. This is also the case in Sweden, but with the additional aspect that some regions have opted to treat most newly diagnosed RRMS patients with rituximab (Rituxan/Mabthera), a drug not formally approved for RRMS, but with extensive safety data from other indications.

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Babies’ Brain Responses Predict Dyslexic Reading Skills in School

MedicalResearch.com Interview with:

Kaisa Lohvansuu, PhD
Postdoctoral Researcher
Jyväskylä Centre for Interdisciplinary Brain Research
Department of Psychology
University of Jyväskylä 

MedicalResearch.com: What is the background for this study?
Response: Developmental dyslexia, a specific reading disability, has a strong genetic basis: The risk of having developmental dyslexia at school age is eight times higher than usual if either of the parents has reading difficulty. It has been known that dyslexia and also family risk for dyslexia are strongly associated with a speech perception deficit, but the underlying mechanism of how the impaired speech processing leads to reading difficulties has been unclear.

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SVC As Marker of Respiratory Decline in Amyotrophic Lateral Sclerosis

MedicalResearch.com Interview with:

Jinsy Andrews, MD, MS Director of Neuromuscular Clinical Trials Columbia University The Neurological Institute New York, NY 10032 

Dr. Andrews

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.

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Parasitic Infection With Toxoplasmosis May Be Linked To Parkinson’s & Alzheimer’s Disease

MedicalResearch.com Interview with:

Under a magnification of 900X, this hematoxylin and eosin-stained (H&E) photomicrograph of a brain tissue specimen revealed a case of neurotoxoplasmosis in a patient who had also been diagnosed with multiple myeloma. Note the Toxoplasma gondii tissue cyst, within which bradyzoites could be seen developing. CDC Image

Rima McLeod, M.D., F.A.C.P, F.I.D.S.A
Professor of Ophthalmology and Visual Sciences,Pediatrics (Infectious Diseases), and The College,
Director, Toxoplasmosis Center,
Senior Fellow,Institute of Genomics, Genetics and Systems Biology, Member, Commitees on Immunology, and Molecular Medicine and Pathogenesis,
Member Global Health Center, Affiliate CHeSS;
Attending Physician, Chicago Medicine,
The University of Chicago

MedicalResearch.com: What is the background for this study?

* One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii.
* Approximately fifteen million of these have congenital toxoplasmosis.
* The parasite interconverts between slow-growing, encysted bradyzoites and rapid-growing tachyzoites.
* In mice, T. gondii creates a chronic intra-neuronal infection and an inflammatory process.
* Mice with acute and chronic infection have alterations in neurotransmitters, memory, seizures, and neurobehavior.
* Some epidemiologic-serologic studies show associations between seropositivity for T. gondii and human neurologic diseases, for example, Parkinson’s and Alzheimer’s diseases.
* Although neurobehavioral disease is associated with seropositivity, causality is unproven.
* Serologic studies of humans with diverse genetics are not optimal to detect strong associations or directionality.
* Epidemiologic associations also do not reveal parasite-modulated gene networks in human brain that could provide insights into how to cure and prevent resultant diseases.
* We need integrative approaches to examine relationships between brain parasitism and other brain diseases, to provide a foundation to identify key pathways and molecules for drug and vaccine design
* To address these problems, we considered two central questions: (i) If chronic brain parasitism associates with other neurologic diseases, what are they? And (ii) Which macromolecular networks are modulated by the parasite in human brain that lead to neuropathology which could underpin and facilitate design of treatments?
* We hypothesized that a systems approach integrating multiple levels of host parasite interactions might resolve these questions.
* To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain.  Continue reading

Granzyme B Probe Plus PET Scanning Helps Determine Response To Immunotherapy

MedicalResearch.com Interview with:

Ben Larimer, PhD research fellow in lab of Umar Mahmood, MD, PhD Massachusetts General Hospital Professor, Radiology, Harvard Medical School

Dr. Ben Larimer

Ben Larimer, PhD research fellow in lab of
Umar Mahmood, MD, PhD

Massachusetts General Hospital
Professor, Radiology, Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:
Although immunotherapies such as checkpoint inhibitors have revolutionized cancer treatment, unfortunately they only work in a minority of patients. This means that most people who are put on a checkpoint inhibitor will not benefit but still have the increased risk of side effects. They also lose time they could have spent on other therapies. The ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not greatly improves individual patient care and helps accelerate the development of new therapies.

The main purpose of our study was to find a way to separate immunotherapy responders from non-responders at the earliest time point possible, and develop an imaging probe that would allow us to distinguish this non-invasively.

Granzyme B is a protein that immune cells use to actually kill their target. They keep it locked up in special compartments until they get the right signal to kill, after which they release it along with another protein called perforin that allows it to go inside of tumor cells and kill them. We designed a probe that only binds to granzyme B after it is released from immune cells, so that we could directly measure immune cell killing. We then attached it to a radioactive atom that quickly decays, so we could use PET scanning to noninvasively image the entire body to see where immune cells were actively releasing tumor-killing granzyme B.

We took genetically identical mice and gave them identical cancer and then treated every mouse with checkpoint inhibitors, which we knew would result in roughly half of the mice responding, but we wouldn’t know which ones until their tumors began to shrink. A little over a week after giving therapy to the mice, and before any of the tumors started to shrink, we injected our imaging probe and performed PET scans. When we looked at the mice by PET imaging, they fell into two groups. One group had high PET uptake, meaning high levels of granzyme B in the tumors, the other group had low levels of PET signal in the tumors. When we then followed out the two groups, all of the mice with high granzyme B PET uptake ended up responding to the therapy and their tumors subsequently disappeared, whereas those with low uptake had their tumors continue to grow.

We were very excited about this and so we expanded our collaboration with co-authors Keith Flaherty and Genevieve Boland to get patient samples from patients who were on checkpoint inhibitor therapy to see if the same pattern held true in humans. When we looked at the human melanoma tumor samples we saw the same pattern, high secreted granzyme levels in responders and much lower levels in non-responders.

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Considering Circadian Rhythms May Aide in Diagnosis of Consciousness Disorders

MedicalResearch.com Interview with:

Copyright Anna-Lisa Bexten Dr. Christine Blume PhD Post-Doctoral Researcher University of Salzburg Centre for Cognitive Neuroscience (CCNS) Laboratory for Sleep, Cognition & Consciousness Research Salzburg

Dr. Christine Blume

Dr. Christine Blume PhD
Post-Doctoral Researcher
University of Salzburg
Centre for Cognitive Neuroscience (CCNS)
Laboratory for Sleep, Cognition & Consciousness Research
Salzburg

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We are governed by rhythmic processes. Many of these processes follow a circadian pattern, that is, they have a period length of approximately 24 hours and are under tight control of a biological master clock located in the suprachiasmatic nucleus of the hypothalamus. Given the circadian variation in global states like alertness, it is not surprising that consciousness also varies rhythmically in healthy individuals, it follows the sleep-wake cycle.

From a clinical perspective, misalignment of circadian rhythms, which occurs when the sleep-wake schedule is at odds with the light-dark cycle as in the case of night shifts, can cause considerable stress, have detrimental effects on the immune system and impair cognitive abilities. Despite the knowledge that entrained circadian rhythms are important for healthy body and brain functioning, very little is known about circadian rhythms in patients diagnosed with a disorder of consciousness (DOC) following severe brain injuries. We argue that studying circadian rhythms in DOC patients may be especially interesting and important for two reasons.

First, the presence or absence of circadian rhythms as well as anomalies in them could be informative about the state of the patient as well as their potential for recovery.

Second, this could provide information about time points that best capture remaining cognitive functions thereby minimising the risk of misdiagnoses.

Beyond this, examining circadian processes may also provide targets for therapeutic interventions such as light stimulation, which has proven successful in individuals with e.g. circadian sleep disorders. Interestingly, analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5-26.3h).

We found that especially scores on the arousal subscale of the Coma Recovery Scale-Revised (CRS-R) were closely linked to the integrity of circadian variations in body temperature.

Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in two out of eight patients.

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ALS: Urinary p75ECD as a Prognostic, Disease Progression, and Pharmacodynamic Biomarker

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

Dr. Rogers

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.

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Excessive Sleeping May Be Early Marker of Dementia

MedicalResearch.com Interview with:

Dr. Matthew P. Pase Sidney Sax NHMRC Fellow, Department of Neurology Boston University School of Medicine Investigator, Framingham Heart Study;  Senior Research Fellow, Swinburne University of Technology. Boston MA 02118

Dr. Matthew Pase

Dr. Matthew P. Pase
Sidney Sax NHMRC Fellow, Department of Neurology
Boston University School of Medicine

Investigator, Framingham Heart Study;
Senior Research Fellow, Swinburne University of Technology.
Boston MA 02118

MedicalResearch.com: What is the background for this study?

Response: Sleep disturbances are common in dementia. However, most studies have focused on patients who already have dementia and so it is unclear whether disturbed sleep is a symptom or a cause of dementia.

We studied 2,457 older participants enrolled in the Framingham Heart Study, a large group of adults sampled from the community in Framingham, Massachusetts. We asked participants to indicate how long they typically slept each night. Participants were then observed for the following 10-years to determine who developed dementia, including dementia due to Alzheimer’s disease. Over the 10 years, we observed 234 cases of dementia. Information on sleep duration was then examined with respect to the risk of developing dementia.
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Long Term Fampridine (AMPYRA) Improves Gait Function in Multiple Sclerosis

MedicalResearch.com Interview with:

Linard Filli, PhD Gait Research Lab Department of Neurology University Hospital Zurich Zürich

Dr. Linard Filli

Linard Filli, PhD
Gait Research Lab
Department of Neurology
University Hospital Zurich
Zürich

MedicalResearch.com: What is the background for this study?

Response: Gait dysfunction is common in patients with multiple sclerosis (MS) and is perceived as the most restricting of symptoms. Fampridine (4-aminopyridine, dalfampridine), a blocker of voltage-gated potassium channels, is currently the only approved medication for the symptomatic treatment of walking disorders in patients in both the early and late phases of  multiple sclerosis.

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Majority of Neurologists Report Symptoms of Burnout

MedicalResearch.com Interview with:

Neil A. Busis, M.D. University of Pittsburgh Physicians Department of Neurology Chief of Neurology, UPMC Shadyside Director of Community Neurology

Dr. Neil A. Busis

Neil A. Busis, M.D.
University of Pittsburgh Physicians
Department of Neurology
Chief of Neurology, UPMC Shadyside
Director of Community Neurology

MedicalResearch.com: What is the background for this study?

Response: Previous studies showed that neurologists have both one of the highest rates of burnout and the lowest rates of satisfaction with work-life balance, compared to other physicians.

The mission of the American Academy of Neurology (AAN) is to promote the highest quality patient-centered neurologic care and enhance member career satisfaction. This is why AAN President Dr. Terrence Cascino initiated this research, to better define the issue. Our findings can guide current and future programs to prevent and mitigate neurologist burnout, promote neurologist career satisfaction and well-being, and direct efforts to advocate on behalf of neurologists and their patients.

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Protein Loss in Urine Associated With Increased Risk of Dementia

MedicalResearch.com Interview with:

Kay Deckers, MSc PhD student School for Mental Health and Neuroscience Department of Psychiatry and Neuropsychology Maastricht University The Netherlands

Kay Deckers

Kay Deckers, MSc
PhD student
School for Mental Health and Neuroscience
Department of Psychiatry and Neuropsychology
Maastricht University
The Netherlands

MedicalResearch.com: What is the background for this study?

Response: In an earlier review (https://www.ncbi.nlm.nih.gov/pubmed/25504093), we found that renal dysfunction was one the new candidate risk factors of dementia and needed further investigation.

MedicalResearch.com: What are the main findings?

Response: Albuminuria is associated with an increased risk of developing cognitive impairment or dementia.

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Inclusion of Risk Biomarkers Improves Stroke Prediction

MedicalResearch.com Interview with:
Dr. Ashkan Shoamanesh MD FRCPC
Assistant Professor
Division of Neurology, Department of Medicine
McMaster University and
Dr. Jose Rafael Romero, MD
Associate Professor of Neurology
Boston University School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Framingham Heart Study is a population-based study of individuals residing in the community. Identifying people who are at risk for stroke can help us determine who would benefit most from existing or new therapies to prevent stroke. As inflammatory pathways are believed to contribute to vascular disease and stroke, we tested whether circulating biomarkers of inflammation and endothelial dysfunction could improve the predictive ability of the Framingham Stroke Risk Profile score, a model that contains classical vascular risk factors such as high blood pressure and diabetes.

Our main observation was that inclusion of 4 biomarkers (C-reactive protein, tumor necrosis factor receptor-2, total homocysteine, and vascular endothelial growth factor) in the Framingham Stroke Risk Profile improved its ability to predict a stroke (net reclassification improvement of 0.34 [0.12–0.57]).

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Calcium Supplements May Raise Risk of Dementia in Elderly Women with Cerebrovascular Disease

MedicalResearch.com Interview with:

Silke Kern, MD, PhD Neuropsychiatric Epidemiology Unit and Clinical Neurochemistry Laboratory Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy University of Gothenburg Gothenburg, Sweden

Dr. Silke Kern

Silke Kern, MD, PhD
Neuropsychiatric Epidemiology Unit and Clinical Neurochemistry Laboratory
Department of Psychiatry and Neurochemistry
Institute of Neuroscience and Physiology
Sahlgrenska Academy
University of Gothenburg
Gothenburg, Sweden

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Calcium has an important role in ischemic neuronal cell death and atherosclerosis. Several studies suggest that increased serum calcium increases the risk for vascular events and worsens the outcome after stroke. Widespread ischemic neuronal cell death and atherosclerosis might lead to dementia. We therefore examined if Calcium supplementation is associated with development of dementia. Our study is the first to show a relationship between Calcium supplementation and increased risk for dementia in older women. This risk is mainly confined to women with cerebrovascular disease (history of stroke or presence of white matter lesions).

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MRI Brain Scans Can Predict Disruption of Blood-Brain Barrier in Stroke Patients

MedicalResearch.com Interview with:

Dr. Richard Leigh MD Neuro Vascular Brain Imaging Unit National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda, MD

Dr. Richard Leigh

Dr. Richard Leigh MD
Neuro Vascular Brain Imaging Unit
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Bethesda, MD

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Patients who suffer an ischemic stroke have limited treatment options. One of the reasons for this is that our treatments can sometimes make the stroke worse by transforming the ischemic stroke into a hemorrhagic stroke. In our study we identified a new piece of information that we can extract from the patient’s MRI scan that informs us on the risk of having a hemorrhage.

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Mitoxantrone for Severe MS Linked To Increased Risk of Colon Cancer and Leukemia

MedicalResearch.com Interview with:

PD Dr. Mathias Buttmann Senior Consultant Neurologist and Head of the Multiple Sclerosis Outpatient Clinic University of Wuerzburg Wuerzburg, German

Dr. Mathias Buttmann

PD Dr. Mathias Buttmann
Senior Consultant Neurologist and Head of the Multiple Sclerosis Outpatient Clinic
University of Wuerzburg
Wuerzburg, Germany 

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Buttmann: The synthetic anthracenedione mitoxantrone is approved for disease-modifying treatment of patients with aggressive forms of relapsing or secondary progressive multiple sclerosis (MS). It has been known for years that this DNA-intercalating agent increases the risk of acute myeloid leukemia. We performed a retrospective cohort study to investigate whether mitoxantrone also increases the risk for other types of malignancies. We included all 677 mitoxantrone-treated  multiple sclerosis patients who were seen at our large German academic MS centre between 1994 and 2007 and collected follow-up information on the occurrence of malignancies, death and causes of death as of 2011. Follow-up was complete in 676 patients. The median age at mitoxantrone initiation was 41 years and the median follow-up duration was 8.7 years. We identified 37 patients with a malignancy after mitoxantrone initiation, among them 4 cases of acute myeloic leukemia and 7 cases of colorectal cancer.

Compared to the general population matched for sex, age and year of occurrence, we calculated an 1.5-fold increased incidence of any type of malignancy, a tenfold increased incidence of acute myeloic leukemia and a threefold increased incidence of colorectal cancer, while the incidence of other types of malignancies was not increased. Higher age at mitoxantrone initiation but neither higher cumulative mitoxantrone dose nor treatment with other immuosuppressive agents was identified as a malignancy risk factor. Fifty-five patients had died, among them 12 from a malignancy. Our study confirmed previous reports on an increased incidence of acute myeloic leukemia after mitoxantrone treatment and newly described an association between mitoxantrone therapy and an increased incidence of colorectal cancer.

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Olfactory Identification Predict Cognitive Impairment in Pediatric Onset Multiple Sclerosis

MedicalResearch.com Interview with:

Dr-Leigh-Elkins-Charvet.jpg

Dr. Leigh Elkins Charvet

Leigh Elkins Charvet, PhD
Director of MS Research
Multiple Sclerosis Comprehensive Care Center
Associate Professor of Neurology
NYU Langone Medical Center
New York, NY 10016

MedicalResearch.com: What is the background for this study?

Dr. Charvet One of the goals of our work is to identify cognitive impairment at the earliest point that it occurs in multiple sclerosis (MS), and ultimately to predict those who are at greatest risk.  Olfactory impairment is a feature of neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease and predicts cognitive decline.  Olfactory impairment has also been reported in adults with multiple sclerosis.  Our study, lead by Colleen Schwarz, measured olfactory identification and its link to cognitive performance in a subpopulation of those with earliest onset of MS—pediatric onset multiple sclerosis (POMS, referring to those with onset before the age of 18).

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Intellectual Activity May Delay Onset of Alzheimer’s Dementia

MedicalResearch.com Interview with:

Prashanthi Vemuri, PhD Mayo Clinic Rochester, Minnesota

Dr. Prashanthi Vemuri

Prashanthi Vemuri, PhD
Mayo Clinic
Rochester, Minnesota 

Medical Research: What is the background for this study? What are the main findings?

Dr. Vemuri: Lifetime Intellectual enrichment has been found to delay the symptoms of dementia but the impact on brain changes due to Alzheimer’s disease has been poorly understood. In this study we studied the impact of lifetime intellectual enrichment (education, occupation, and midlife cognitive activities) on the brain changes related to Alzheimer’s disease. We obtained serial imaging on 393 individuals from a population based sample. We found that in majority of the individuals, there were minimal effects of intellectual enrichment on brain changes due to Alzheimer’s disease. However in those with higher genetic risk of Alzheimer’s, lifetime intellectual enrichment had a protective effect on the brain.

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Can High-Dose Resveratrol Slow Dementia?

R. Scott Turner, MD, PhD Director of the Memory Disorders Program Georgetown University Medical CenterMedicalResearch.com Interview with:
R. Scott Turner, MD, PhD
Director of the Memory Disorders Program
Georgetown University Medical Center

Medical Research: What is the background for this study? What are the main findings?

Dr. Turner: The resveratrol trial originated from the extensive scientific literature demonstrating that caloric restriction (consuming only 2/3 usual calories) prevents or delays diseases of aging – including Alzheimer’s disease (AD) in laboratory animals. The molecular mechanism is thought to involve sirtuins – a group of genes/proteins that sense energy balance to regulate gene expression. Sirtuins are activated by caloric restriction (a mild stressor) to express genes that promote resilience of the organism. Resveratrol is a potent activator of sirtuins – thus bypassing the requirement for caloric restriction. On the opposite side of the coin – caloric excess, midlife obesity, and diabetes are strong risk factors for Alzheimer’s disease. And we have  long-known that resveratrol is found in red grapes, red wine, and other foods that promote general health.

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Chemotherapy and Radiation For Brain Cancer Lead To Brain Shrinkage

Jorg Dietrich, MBA MMSc MD PhD Director, Cancer & Neurotoxicity Clinic and Brain Repair Research Program Massachusetts General Hospital Cancer Center Assistant Professor of Neurology Harvard Medical SchoolMedicalResearch.com Interview with:
Jorg Dietrich, MBA MMSc MD PhD 
Director, Cancer & Neurotoxicity Clinic and Brain Repair Research Program
Massachusetts General Hospital Cancer Center
Assistant Professor of Neurology
Harvard Medical School

Medical Research: What is the background for this study? What are the main findings?

Dr. Dietrich: Understanding the adverse effects associated with cancer therapy is an important issue in oncology. Specifically, management of acute and delayed neurotoxicity of chemotherapy and radiation in brain cancer patients has been challenging. There is an unmet clinical need to better characterize the effects of standard cancer therapy on the normal brain and to identify patients at risk of developing neurotoxicity. In this regard, identifying novel biomarkers of neurotoxicity is essential to develop strategies to protect the brain and promote repair of treatment-induced damage.

In this study, we demonstrate that standard chemotherapy and radiation in patients treated for glioblastoma is associated with progressive brain volume loss and damage to gray matter – the area of the brain that contains most neurons.

A cohort of 14 patients underwent sequential magnetic resonance imaging studies prior to, during and following standard chemoradiation to characterize the pattern of structural changes that occur as a consequence of treatment.

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Type 2 Diabetes Linked to Decreased Brain Blood Flow and Cognitive Ability

Vera Novak, MD PhD Associate Professor of Neurology Dept. of Neurology, Stroke Division Director Syncope and Falls in the Elderly Laboratory Beth Israel Deaconess Medical Center Boston, MAMedicalResearch.com Interview with:
Vera Novak, MD PhD
Associate Professor of Neurology
Dept. of Neurology, Stroke Division
Director Syncope and Falls in the Elderly Laboratory
Beth Israel Deaconess Medical Center
Boston, MA

MedicalResearch: What is the background for this study?

Dr. Novak: Diabetes mellitus (DM) is a major contributor to morbidity and mortality.
Type 2 diabetes mellitus affects more than 44 million people in the U.S., and its numbers are growing rapidly, affecting up to 27% of older adults. Diabetes mellitus accelerates brain aging by about 5 years1, manifests as a widespread generalized atrophy2, and promotes earlier onset of vascular dementia and Alzheimer’s disease (AD).3,4 Diabetes mellitus -related atrophy manifests as worse cognitive function, memory, and gait, especially during a dual task, 5,6 and even a tight glycemic control did not improve cognitive function in participants of the large clinical trials 7.

MedicalResearch: What are the main findings?

Dr. Novak: Sixty-five participants (aged 66± 9.2 years) 35 with T2DM and 30 non-diabetic controls participated in this study. After 2 years of follow-up, participants with T2 Diabetes mellitus had diminished vascular reactivity in the brain (an ability to increase blood flow in responses to a task or metabolic demands) and performed worse on multiple cognitive tasks (in particular verbal learning and memory). In T2DM group, lower cerebral vasoreactivity correlated with worse performance on daily living activities. Specifically, the lower vasodilatation (ability to increase blood flow) was associated with worse mental functions. In addition, those with higher markers of inflammation had greater decline in vascular function in the brain.

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Hospital System Efficiently Uses MRI To Screen For Stroke and Shorten Treatment Window

Amie W. Hsia, MD Medical Director, Comprehensive Stroke Center MedStar Washington Hospital Center NIH Stroke Program at MWHC Associate Professor, Neurology Georgetown University Washington, DC 20010MedicalResearch.com Interview with:
Amie W. Hsia, MD
Medical Director, Comprehensive Stroke Center
MedStar Washington Hospital Center
NIH Stroke Program at MWHC
Associate Professor, Neurology
Georgetown University Washington, DC 20010

 

Medical Research: What is the background for this study? What are the main findings?

Dr. Hsia: Acute stroke is a common presenting problem in the emergency department. We know that “time is brain” and that for patients experiencing an ischemic or “blockage” type of stroke, the most common type, the sooner we can administer tPA, a clot-busting medication and the only FDA-approved medication to treat acute stroke, the better chance for a good outcome. Therefore, there is a goal national benchmark time of administering the drug to appropriate acute stroke patients within 60 minutes of their arrival to the emergency department. There are many steps that are necessary in the evaluation of an acute stroke patient in the emergency department before tPA can be given. This includes a brain scan to make sure a patient is not having the less common bleeding type of stroke. A CT or “CAT” scan is the typical type of brain scan that is performed in emergency departments across the country and the world to screen a patient before giving tPA. The primary purpose of the CT scan is to exclude bleeding; it is difficult to visualize an early stroke on CT. Though an MRI can give more complete information including showing the stroke as it is happening in these first few hours and though most hospitals have an MRI scanner, an MRI takes longer to perform and has not traditionally been used in an emergency setting.

At the two hospitals included in this study, MedStar Washington Hospital Center in D.C. and Suburban Hospital in Maryland, we are fortunate to serve as the sites for the NINDS intramural stroke clinical research program and use MRI routinely to screen acute stroke patients to learn more about stroke and develop new treatments for stroke. It is upon this foundation that we performed independent hospital-wide quality improvement initiatives engaging multidisciplinary committees with leadership from all the departments involved in the care of the acute stroke patient in that critical first 60 minutes. Inspired by our colleagues at Washington University in St. Louis led by Dr. Andria Ford who used similar methods in reducing treatment times with CT screening, we used lean manufacturing principles to streamline our processes that include MRI screening and dramatically reduced our treatment times from a baseline of 93 minutes down to 55 minutes while still maintaining safety. Through these efficiency improvements, we were able to achieve a 4-fold increase in the percentage of stroke patients treated with tPA within 60 minutes.
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Study Finds No Link Between Head Injuries and Parkinson’s Disease

MedicalResearch.com Interview with:
Line Kenborg, MSc, PhD

Survivorship Unit
Danish Cancer Society Research Center
Copenhagen

Medical Research: What is the background for this study? What are the main findings?

Response: The hypothesis that head injuries increase the risk for Parkinson disease has been examined in many studies during the past decades, but the findings have been highly inconsistent. We have previously examined the hypothesis in a study based on information on head injuries and Parkinson disease from the Danish National Hospital Registry. In this study, we found a positive association between a hospital contact for a head injury in middle or late adulthood and a diagnosis of Parkinson disease. The reported association, however, was almost entirely due to injuries that occurred during the months preceding the first hospital contact for Parkinson disease. Because we used information from registries, we lacked detailed diagnostic information to distinguish Parkinson disease from other types of parkinsonism, and we had no information on milder head injuries and head injuries in early life. So we wanted to study whether head injuries throughout life increased the risk for Parkinson disease in the largest interview-based case-control study to date including patients with a verified diagnosis of Parkinson disease. The main finding of our study is that we do not find any association between head injuries and Parkinson disease.

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Sleeping On Stomach May Increase Risk of Death in Epilepsy

James Tao, MD, Ph.D Assistant Professor Director, EEG Lab Department of Neurology, The University of Chicago, IL.MedicalResearch.com Interview with:
James Tao, MD, Ph.D
Assistant Professor Director, EEG Lab
Department of Neurology, The University of Chicago, IL.

Medical Research: What is the background for this study? What are the main findings?

Dr. Tao: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with chronic uncontrolled epilepsy. Patients often died in sleep, in bed, and unwitnessed. They were often found in prone position. These circumstances of SUDEP are remarkably similar to those of sudden infant death syndrome (SIDS). In our study, we found that 73% of 253 SUDEP patients were died in prone position. These findings suggest that sudden unexpected death in epilepsy may share the mechanisms similar to SIDS.

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Neurotic Symptoms In Midlife May Presage Alzheimer’s Dementia

Lena Johansson, PhD, MSc, RN Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry Sahlgrenska Academy at Gothenburg UniversityMedicalResearch.com Interview with:
Lena Johansson, PhD, MSc, RN
Institute of Neuroscience and Physiology
Department of Psychiatry and Neurochemistry
Sahlgrenska Academy at Gothenburg University


Medical Research: What are the main findings of the study?

Dr. Johansson: We found that a higher degree of neuroticism in midlife was associated with increased risk of Alzheimer’s disease over 38 years. On the 24 point scale, the risk increased with 4% per each step. Women who score high on the neuroticism scale were more likely to experience feelings such as anxiety, nervousness, worry, and irritability, and they were more moodiness and stress-prone.

The association between neuroticism and Alzheimer’s disease diminished after adjusting for longstanding perceived distress symptoms, which suggest that the associations was at least partly depended on long-standing distress symptoms.

When the two personality dimensions were combined, women with high neuroticism/low extraversion had a double risk of Alzheimer’s disease compared to those with low neuroticism/high extraversion.

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Memory Complaints May Presage Increased Risk Of Dementia

Richard J. Kryscio, PhD, Professor Sanders-Brown Center on Aging University of KentuckyMedicalResearch.com Interview with:
Richard J. Kryscio, PhD, Professor
Sanders-Brown Center on Aging
University of Kentucky

Medical Research: What are the main findings of the study?

Dr. Kryscio:  We followed 531 elderly over time assessing their cognition annually; of these 105 (about 20%) eventually were diagnosed with a serious cognitive impairment (either a mild cognitive impairment or a dementia) and 77% of the latter declared a subjective memory complaint prior to the diagnosis of the impairment.  In brief, declaration of a memory problem put a subject at three times the risk of a future impairment.
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Sleep Difficulties Linked To Shrinking Brain

Dr. Claire Sexton Ph.D. University of OxfordMedicalResearch.com Interview with:
Dr. Claire Sexton Ph.D.
University of Oxford

Medical Research: What are the main findings of the study?

Dr. Sexton: We found that sleep difficulties (which can include trouble falling asleep, waking up during the night, or waking up too early) were associated with an increased rate of decline in brain volumes over 3-5 years.

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Multiple Sclerosis: High Salt Intake Linked to More Relapses

MedicalResearch.com Interview with:
Dr. Mauricio Farez
Department of Neurology, Raúl Carrea Institute for Neurological Research
Buenos Aires, Argentina

Medical Research: What are the main findings of the study?

Dr. Farez: Our study shows that patients with Multiple Sclerosis (MS) with moderate to high sodium (salt) intake have also increased disease activity (more clinical relapses and more lesions on MRIs).

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Fluoroquinolones Linked To Increased Risk of Peripheral Neuropathy

Mahyar Etminan PharmD, MSc Scientist I Pharmaceutical Outcomes Programme (POPi) Faculty of Medicine | Assistant Professor, Department of Pediatrics The University of British Columbia | Child and Family Research Institute (CFRI) Vancouver, BC V5Z 4H4MedicalResearch.com Interview with:
Mahyar Etminan PharmD, MSc
Scientist I Pharmaceutical Outcomes Programme (POPi)
Faculty of Medicine | Assistant Professor, Department of Pediatrics
The University of British Columbia | Child and Family Research Institute (CFRI) Vancouver, BC

Medical Research: What are the main findings of the study?

Dr. Eiminan: Current users of Fluoroquinolones are at a twice their risk of developing peripheral neuropathy than non users.
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Recurrent Hypoglycemia Raises Stroke Risk in Kidney Disease Patients

MedicalResearch.com Interview with:
Prof. Chia-Huang Kao
From the Graduate Institute of Clinical Medical Science
Department of Radiation Oncology and Nuclear Medicine and PET Center
Graduate Institute of Clinical Medical Science
China Medical University Hospital, Taichung, Taiwan.

Medical Research: What are the main findings of the study?

Prof. Kao: Patients with chronic kidney disease (CKD) are at high risk for hypoglycemia; several factors are reported to contribute to hypoglycemia in these patients. However, most previous studies were limited by the relatively small number of patients with CKD included in the study by the exclusion of cases with CKD. In the present study, the incidence rate of hypoglycemia in patients with CKD was 4.5%, which is approximately twice the value noted in previous reports and multivariate analysis revealed a 2.53-fold increase in the risk of death for CKD patients with hypoglycemia after adjusting for related confounding factors including hypertension, hyperlipidemia, diabetes, and antidiabetic drugs.
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Parkinson Disease: Naltrexone May Be Useful For Impulse Control

Associate Professor of Psychiatry and Neurology Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA 19104-2676 Parkinson's Disease Research, Education and Clinical Center (PADRECC) Mental Illness Research, Education and Clinical Center (MIRECC) Philadelphia Veterans Affairs Medical CenterMedicalResearch.com Interview with:
Daniel Weintraub, M.D.
Associate Professor of Psychiatry and Neurology
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA 19104-2676
Parkinson’s Disease Research, Education and Clinical Center (PADRECC)
Mental Illness Research, Education and Clinical Center (MIRECC)
Philadelphia Veterans Affairs Medical Center

Medical Research: What are the main findings of the study?

Dr. Weintraub: That there is mixed evidence for the efficacy of naltrexone in the treatment of impulse control disorders in Parkinson’s disease, and the evidence is sufficient to support further study of this compound class for this indication.  In addition, the study demonstrates that it is possible to conduct a clinical trial in this area.
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Pre-Dementia Syndrome Characterized by Slow Gait, Cognitive Complaints

Joe Verghese, MBBS, MS Professor of Neurology and Medicine, Chief, Integrated Divisions of Cognitive & Motor Aging (Neurology) and Geriatrics (Medicine), Director, Resnick Gerontology Center, Murray D Gross Memorial Faculty Scholar in Gerontology, Albert Einstein College of Medicine Bronx, NY 10461MedicalResearch.com Interview with:
Joe Verghese, MBBS, MS
Professor of Neurology and Medicine,
Chief, Integrated Divisions of Cognitive & Motor Aging (Neurology) and Geriatrics (Medicine),  Director, Resnick Gerontology Center,
Murray D Gross Memorial Faculty Scholar in Gerontology,
Albert Einstein College of Medicine, Bronx, NY 10461

Medical Research: What are the main findings of the study?

Answer: Motoric Cognitive Risk Syndrome (MCR) is a newly described pre-dementia syndrome that is characterized by presence of slow gait and cognitive complaints in older adults without dementia or mobility disability. In this study, we report that the prevalence of Motoric Cognitive Risk Syndrome was 9.7% in 26,802 adults aged 60 and older from 22 cohort studies based in 17 countries. Presence of Motoric Cognitive Risk Syndrome was also associated with an almost two-fold risk of developing dementia.
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Stroke: Homocysteine Associated With Atherosclerosis of Cerebral Vessels

Sang-Beom Jeon, MD, PhD From the Department of Neurology Asan Medical Center University of Ulsan College of Medicine Seoul, Republic of Korea.MedicalResearch.com Interview with:
Sang-Beom Jeon, MD, PhD
From the Department of Neurology
Asan Medical Center
University of Ulsan College of Medicine
Seoul, Republic of Korea.

Medical Research: What are the main findings of the study?

Dr. Sang-Beom Jeon: In this MRI study of 825 stroke patients, we demonstrated that high plasma concentrations of homocysteine, also known as hyperhomocysteinemia, were associated with small-vessel disease (lacunar infarcts and leukoaraiosis) and large-vessel atherosclerosis of cerebral arteries.
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Epilepsy: Readmissions Increased By Refractory Seizures and Psychiatric Comorbidities

MedicalResearch.com Interview with:
Tracie A. Caller, MD , MPH
Neurophysiology Fellow
Dartmouth-Hitchcock Medical Center
1 Medical Center Dr., Lebanon NH 03756, USA

MedicalResearch: What are the main findings of the study?

Dr. Caller: We identified factors that appeared to increase the risk for a 30 day readmissions in the epilepsy population, which included refractory seizures but also coexistence of nonepileptic seizures and psychiatric comorbidities.
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Chronic Illness Increases Risk of Restless Legs Syndrome

MedicalResearch.com Interview with:
András Szentkirályi, MD, PhD
Research fellow:Westfälische Wilhelms-Universität Münster
Institut für Epidemiologie und Sozialmedizin
Germany, D-4814

MedicalResearch: What are the main findings of the study?

Dr. Szentkirályi : Based on two prospective, population-based cohort studies, we found that subjects having multiple chronic diseases are at an increased risk of suffering from restless legs syndrome (RLS). Moreover, increased multimorbidity was a significant predictor of developing new onset RLS. It is important to note that the observed relationship was not reduced when well-established causes of secondary restless legs syndrome (e.g. chronic renal disease) were excluded.
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Does Marijuana Increase Stroke Risk in Young Adults?

MedicalResearch.com Interview with:
Tara Dutta M.D.
Vascular Neurology Fellow
University of Maryland Medical Center

MedicalResearch: What are the main findings of the study?

Dr. Dutta: We analyzed data from the Stroke Prevention in Young Adults Study in order to evaluate for an association between self-reported marijuana use and ischemic stroke.   1,101 cases and 1,154 age, gender, and race-matched controls, aged 15-49 years old, were recruited from the greater Baltimore-Washington area between 1992 and 2008. Interviews were conducted to assess for various potential stroke risk factors, including illicit drug, alcohol, and tobacco use. Individuals reporting use of vasoactive illicit drugs, including cocaine and amphetamines, were excluded, yielding 751 cases and 813 controls. Logistic regression analysis was used to determine the association between marijuana use and ischemic stroke, adjusting for age, gender, race, current tobacco use, current alcohol use, hypertension, and diabetes.

We did not find a positive association between marijuana use and ischemic stroke risk in our population of young-onset stroke patients compared to matched controls, even after controlling for current tobacco and alcohol use, hypertension, and diabetes.   A statistically significant inverse relationship was observed between remote use (defined as any use over one year ago) and stroke risk (adjusted OR 0.77, CI 0.61-0.98, p = 0.03). We also looked to see whether recent use (in the past 30 days), and particularly recent heavy use, was associated with ischemic stroke risk as has been suggested in the medical literature. Though our data did not show this association, the number of patients reporting recent use in our study was very small­­­­­­­.

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MRI Findings as Surrogate Markers for Brain Microinfarcts

Kejal Kantarci, M.D. M.S. Professor of Radiology Division of Neuroradiology Mayo Clinic, Rochester, MN 55905 MedicalResearch.com Interview with:
Kejal Kantarci, M.D. M.S.
Professor of Radiology
Division of Neuroradiology
Mayo Clinic, Rochester, MN 55905

MedicalResearch: What are the main findings of the study?

Dr. Kantarci: Microinfarcts are one of the most common pathologies identified in the brains of older individuals and they impact cognition. However they are invisible lesions on MRI. We demonstrated that presence of microinfarcts in autopsied individuals are associated with the macroinfarcts identified on their MRI scans than they were alive. We also demonstrated that the presence of these invisible lesions are related to greater brain atrophy rates that are localized to watershed zones.
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Stroke: Prediction Tool Separates Risk For Ischemic vs Hemorrhagic Event

M. Arfan Ikram, MD, PhD Assistant professor in Neuroepidemiology Erasmus Medical Center Rotterdam, the NetherlandsMedicalResearch.com Interview with:
M. Arfan Ikram, MD, PhD
Assistant professor in Neuroepidemiology
Erasmus Medical Center
Rotterdam, the Netherlands


MedicalResearch.com: What are the main findings of this study?

Dr. Ikram: We show that the risk of stroke might be increased due to an increased risk of ischemic stroke or increased risk of hemorrhagic stroke. Because these subtypes of stroke require different -often opposite- clinical management, currently available prediction rules for any stroke are insufficient. We propose a novel prediction rule that provides separate risks for ischemic stroke and hemorrhagic stroke.
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Restless Legs Syndrome Linked to Decreased Physical Function

Xiang Gao, MD, PhD Assistant Professor in Medicine Harvard Medical School Associate Epidemiologist Brigham and Women's HospitalMedicalResearch.com Interview with:
Xiang Gao, MD, PhD
Assistant Professor in Medicine
Harvard Medical School
Associate Epidemiologist
Brigham and Women’s Hospital

MedicalResearch.com: What are the main findings of the study?

Dr. Gao: In this study including 12,556 men in the Health Professionals Follow-up Study, we found that the participants with Restless Legs Syndrome at baseline had significantly lower physical function (PF) score 6 years later than those without RLS, after adjusting for potential confounders. The magnitude of difference in physical function score for RLS symptoms ≥15 times/month vs no Restless Legs Syndrome was more than that of a 5-year increase of age or moderate amount of smoking. We also found that having daily daytime sleepiness and sleep duration ≥9 hours/day were associated with lower mean physical function value than not having these symptoms .
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How Does Cardiorespiratory Fitness Affect Cognitive Function in Middle Age?

David R. Jacobs Jr, PhD Divisions of Epidemiology School of Public Health University of Minnesota, MinneapolisMedicalResearch.com Interview with:
David R. Jacobs Jr, PhD
Divisions of Epidemiology
School of Public Health
University of Minnesota, Minneapolis


MedicalResearch.com: What are the main findings of this study?

Dr. Jacobs: Vigorous activity is what is well understood to improve cardiorespiratory fitness. People with high fitness are likely (based on this study) to

a) Lose fitness more slowly as they age and

b) To maintain sharper “thinking skills” into late middle age.

I think the message of this study is primarily for the people in the low to mid range of fitness in young adulthood.  Thus, of more importance to the general population, if the people with low to moderate fitness simply do things, be engaged in family, job, community, move around, they would  be able to do better on a treadmill test such as we used.  Because those who lost less fitness over average age 25 to average age 45 had higher thinking skills at age 50, people who start moving around are likely to reap the benefit of less loss of thinking skills by average age 50.

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Multiple Sclerosis: Monoclonal Antibody Tysabri Reduces Brain Inflammation

Jeppe Romme Christensen  MD PhD From the Danish Multiple Sclerosis Center Copenhagen University Hospital Hvidovre, Denmark.MedicalResearch.com Interview with:
Jeppe Romme Christensen  MD PhD
From the Danish Multiple Sclerosis Center
Copenhagen University Hospital Hvidovre, Denmark.

MedicalResearch.com: What are the main findings of the study?

Dr. Christensen: This study demonstrates that progressive multiple sclerosis (MS) patients have reduced inflammation and tissue damage in the brain after treatment with natalizumab. These findings highlight that progressive MS is an inflammatory disease and furthermore that peripheral circulating immune cells contribute to brain inflammation and tissue damage in progressive MS.

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Alcohol Use and Cognitive Impairment in Later Life

Osvaldo P. Almeida, MD, PhD, FRANZCP, FFPOA Professor & Winthrop Chair of Geriatric Psychiatry | School of Psychiatry & Clinical Neurosciences | University of Western Australia. Director of Research | Western Australian Centre for Health & Ageing | Centre for Medical Research | Western Australian Institute for Medical Research. Consultant | Department of Psychiatry | Royal Perth Hospital. Australia.MedicalResearch.com Interview with:
Osvaldo P. Almeida, MD, PhD, FRANZCP, FFPOA
Professor & Winthrop Chair of Geriatric Psychiatry | School of Psychiatry & Clinical Neurosciences | University of Western Australia.
Consultant | Department of Psychiatry | Royal Perth Hospital.

MedicalResearch.com: What are the main findings of this study?

Prof. Almeida: This study used the principles of Mendelian randomisation to clarify whether alcohol use is a direct cause of cognitive impairment in later life. The rationale behind this approach is that the genetic variation associated with lower risk of alcohol abuse or dependence should also be associated with lower risk of cognitive impairment if alcohol misuse is a direct cause cognitive impairment. We found no evidence for such an association.

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Huntington Disease Affects Driving Skill Even in Early Stages

Hannes Devos, PhD Assistant Professor Assistant Director Georgia Regents University Driving Simulator Lab Department of Physical Therapy College of Allied Health Sciences Georgia Regents University Augusta, GA 30912MedicalResearch.com Interview with:
Hannes Devos, PhD
Assistant Professor
Assistant Director Georgia Regents University Driving Simulator Lab Department of Physical Therapy
College of Allied Health Sciences
Georgia Regents University Augusta, GA 30912

MedicalResearch.com: What are the main findings of the study?

Dr. Devos: We compared on-road driving performance between 30 active drivers with Huntington disease and 30 age- and gender- matched control drivers. We found that Huntington disease affects all levels of driving skill due to motor and cognitive deficits and leads to unsafe driving, even in the early stages of the disease. Fourteen (47%) drivers with Huntington disease failed the road test compared with none of the controls.

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Diabetes Key Risk Factor for Cognitive Impairment in Late-Life

Rosebud O Roberts, M.B., Ch.B. Professor of Epidemiology Professor of Neurology Mayo ClinicMedicalResearch.com Interview with:
Rosebud O Roberts, M.B., Ch.B.
Professor of Epidemiology
Professor of Neurology
Mayo Clinic

 

MedicalResearch.com: What are the main findings of the study?

Dr. Roberts: The onset of type two diabetes in midlife (before age 65 years)  is associated with brain pathology (subcortical brain infarctions, reduced hippocampal volume, reduced whole brain volume) in late-life. Early onset of diabetes also increases the risk of developing mild cognitive impairment  which is an intermediate stage between normal cognitive aging and dementia. Our findings suggest that loss of brain volumes may be an intermediate stage or a link between diabetes and cognitive impairment.

We also found that diabetes onset in late-life (after age 65 years), is also associated with brain pathology (cortical infarctions, reduced whole brain volume).

Finally, onset of hypertension in midlife, but not late-life, is associated with brain pathology in late- life.

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