Duke, UNC to collaborate in fight against Alzheimer’s disease

The Duke University and the University of North Carolina Alzheimer’s Disease Research Collaborative (Duke/UNC ADRC) brings together leading researchers in Alzheimer’s disease and related dementias across two major research institutions.

Together, the Duke/UNC ADRC aims to catalyze and support research, innovations in clinical care and academic work force development (with North Carolina Central University, East Carolina University and UNC Pembroke as partner institutions) in this field. Its ultimate purpose is to reduce the burden of Alzheimer’s disease and related dementias regionally and nationally. The outstanding scientific environment at both institutions enables novel research to identify effective methods of prevention and/or early intervention, and to reduce racial and urban/rural disparities associated with dementia. Read more about it here.

DCNN faculty involved in core areas of the Duke/UNC ADRC include Carol Colton, PhD, Shih-Hsiu “Jerry” Wang, MD, PhD, Michael Lutz, PhD, and Neurology Department Chair Richard O’Brien, MD, PhD.

Duke Neurology Research Round Up, January 2021

NIH EEGThe final month of 2020 saw fifteen new publications written or co-written by members of the Duke Department of Neurology. Sneha Mantri, MD, MS, was a lead author of a new study examining factors contributing to burnout and moral injury among health-care workers at Duke. Our Neuromuscular Disease faculty wrote multiple studies advancing our understanding of myasthenia gravis, including how the COVID-19 pandemic is affecting people with this condition. Other articles answered questions about stroke, Parkinson’s, and other diseases. Read short summaries of each of these publications, and find links to the original articles below.

Translational Brain Sciences

  • Tatiana Segura, PhD, was the senior author of a new review article examining the role macrophages play in the body’s inflammatory and self-repairing processes, as well as how to engineer biomaterials that steer macrophages for tissue regeneration. Read that article in Frontiers in Bioengineering and Biotechnology.
  • While the APOE4 gene appears to increase Alzheimer’s disease risk by increasing neuroinflammation, the specific neuroinflammatory pathways involved are unclear. A team including Michael Lutz, PhD, analyzed targeted proteomic data from samples of cerebrospinal fluid using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. Read what they found in the Journal of Alzheimer’s Disease.

Parkinson’s Disease and Movement Disorders

  • Burt Scott, MD, PhD, contributed to a new study that examined changes in the retina and choroid of eyes in individuals with Parkinson’s disease. The cross-sectional study found that individuals with Parkinson’s had significant differences in vessel and perfusion density, showing potential for a non-invasive biomarker for this condition. Read the full study in JAMA Ophthalmology.

General and Community Neurology

  • Sneha Mantri, MD, MS, was the first author of a Journal of Nervous and Mental Disease study that examined moral injury symptoms among health-care professionals at Duke. Nearly 1 in 4 (23.9%) of professionals had symptoms causing moderate or greater impairment. Burnout, recent medical errors, and lower religiosity were associated with greater moral injury. Read the full article here.

Multiple Sclerosis and Neuroimmunology

  • The COVID-19 pandemic has added new complexity to care for many chronic diseases, including multiple sclerosis. One model to quickly and effectively share information for this condition is Project ECHO, a videoconference-based education and case consultation program offered to providers caring for patients with MS. Mark Skeen, MD, was part of a team reporting on this project. Read that article in Multiple Sclerosis and Related Disorders.

Neuromuscular Disease

  • A new study offers important evidence about the use of non-invasive ventilation for ALS patients in hospice care. Senior author Rick Bedlack, MD, PhD, and colleagues performed a retrospective cross-sectional study of patients, finding those who continued on non-invasive ventilation had a similar length of stay without incurring overwhelming financial or administrative costs. Read that article in the American Journal of Hospice and Palliative Care.
  • A new study answers important questions about the immune profiles associated with autoimmune seronegative myasthenia gravis (SN MG). Senior authors Jeffrey Guptill, MD, MHS, John Yi, PhD (Department of Surgery), and colleagues performed high‐dimensional flow cytometry on blood samples from SN MG patients, healthy controls, and acetylcholine receptor antibody MG patients. The team found reduced plasmablast frequencies were strongly associated with a SN MG diagnosis, making them a potential diagnostic biomarker in the future. Shruti Raja, MD, Lisa Hobson-Webb, MD, Karissa Gable, MD, Vern Juel, MD, and Natalia Gonzalez, MD, contributed to the Muscle and Nerve article, which is available here.
  • Patients with myasthenia gravis may be particularly vulnerable during the COVID-19 pandemic from risks of worsening disease, potential adverse effects of COVID-19, and a limited ability to fight off infection related to immunosuppressive treatments. Lead authors Yingkai Li, MD, PhD, and Jeffrey Guptill, MD, MPH, and colleagues in our Neuromuscular Division (Douglas Emmett, the DCRI’s Marjan Cobbaert, MPH, Donald Sanders, MD, Vern Juel, MD, Lisa Hobson-Webb, MD, Janice Massey, MD, Karissa Gable, MD, Shruti Raja, MD, and Natalia Gonzalez, MD) conducted a survey of nearly 2,000 patients at Duke to better understand how patients are experiencing the COVID‐19 pandemic, including where they receive relevant information, how it has affected medical care, and what measures they use to protect themselves. Read what they found in Muscle and Nerve.

Memory Disorders

  • A new case report case report highlights the importance of assessing clinical trajectory in patients with rapidly progressing dementia. Lead authors Andy Liu, MD, and Elijah Lackey, MD, as well as Jodi Hawes, MD, wrote the case report for Case Reports in Neurological Medicine. Read it here.
  • Sarah Cook, PhD, was a co-author of a recent article in Neuropsychology that used comprehensive neuropsychological criteria to identify patients with mild cognitive impairment (MCI) in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study. The team found that NP criteria identified a proportion of MCI and reversion rate within ACTIVE that is consistent with prior studies involving community-dwelling samples. Read more about the study here.
  • Brenda Plassman, PhD, was the senior author of a new study examining cognitive decline in relation to hearing loss, vision loss, or the loss of both senses. Their analysis of nearly 300 older individuals found a significant association between hearing loss, dual sensory loss and faster cognitive decline. Read that study in the Journal of the American Geriatric Society.

Neurocritical Care

  • The shortage of available donor lungs remains an impediment to life-saving organ donation for those with end-stage pulmonary disease. Cherylee Chang, MD, wrote an editorial discussing the significance of this problem, factors limiting the availability of lungs for donation, and risks and benefits of deepening the pool of potential donors. Read that article in Critical Care Medicine. 

Stroke

  • Wayneho Kam, MD, and Nada El-Husseini, MD, wrote a new chapter in the ASPC Manual of Preventive Cardiology. The chapter, “Prevention of Ischemic Stroke,” provides the latest evidence-based practice guidelines on the primary prevention of ischemic stroke, focusing on nine vascular risk factors and their conferred stroke risk. Read that chapter here.
  • A new study by senior author Ying Xian, MD, PhD, Daniel Laskowitz, MD, MHS, and colleagues examined how changes in informed consent policies affected door-to-needle times in stroke patients receiving thrombolytic therapy with tissue plasminogen activator (tPA). Their analysis of nearly 1,000 patients found that changing policy to require verbal rather than written consent reduced door to needle times by 5.6 minutes on average. Read the full study in the Journal of Stroke and Cerebrovascular Disease.
  • Xian also contributed to a new study examining the American Heart Association’s Target: Stroke quality initiative, which disseminated feasible strategies to shorten door-to-needle times for thrombolytic therapy. Xian and colleagues at the DCRI analyzed date from nearly 1500 Get with the Guidelines-Stroke hospitals, finding that door-to-needle times decreased from 80 to 68 minutes on average. Read that study here.

Duke Neurology Research Round Up, November 2020

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Neuron image courtesy NIH

Members of the Duke Neurology Department contributed to 14 new peer-reviewed studies this October, advancing our understanding of or ability to treat Parkinson’s disease, Alzheimer’s, stroke, and other conditions. Laurie Sanders, PhD, and Claudia Gonzalez Hunt, PhD, advanced our understanding of the links between mitochondrial DNA damage and Parkinson’s disease, providing a potential avenue for future therapies. Andy Liu, MD, contributed to a study that compared how changes in the structure of the eye differ between patients with Alzheimer’s, mild cognitive impairment, and healthy individuals. Tatiana Segura, PhD, was the senior author of a study discussing how the injection of hydrogel biomaterial scaffolds to the brain after stroke may improve brain plasticity and endogenous repair. And Andrew Spector, MD, discussed the founding, mission, and future plans of the Society of Black Neurologists in a short article in Lancet Neurology.

Read more about those articles, and find links to the original research, below.

General Neurology

  • The Society of Black Neurologists (SBN) was founded almost two years ago to foster discussion, mentorship, and camaraderie among Black neurologists.Since then it has grown to more than 200 members worldwide and has organized in-person events and webinars. First author Andrew Spector, MD, and colleagues discuss the SBN and its goals for the future in the latest issue of Lancet Neurology. Read that article here.

Memory Disorders

 

Epilepsy, Clinical Neurophysiology, and Sleep

  • A new article in the Journal of Clinical Neurophysiology answers questions about double train transcranial electrical stimulation (dt-TES) for motor-evoked potentials (MEP). Senior author Aatif Husain, MD, first author Emily Kale, and Michael Lutz determined that MEP amplitudes benefited the most from asymmetric dt-TES with 2 + 7 pulses. Read that article here.

Neurocritical Care

  • Neurocritical care fellow Vyas Viswanathan MD, contributed to a retrospective review of 152 patients with inflammation due to cerebral amyloid angiopathy. The team found evidence that corticosteroid-treatment leads to clinical and radiological short-term improvement for the condition. Read that study in the Journal of Neuroimmunology.
  • A new case study offers insights and understanding of the potential for spinal cord stimulation as a possible treatment for paraplegia. A team including Saurabh Sinha, MD, Dana Lott, DPT, and Emily Kale discuss the case of an individual with chronic complete L1 paraplegia and chronic pain who received spinal cord stimulation implantation, noting his progress over the next year and a half. Read the full study in Spinal Cord Series and Cases.

Translational Brain Sciences

  • New strategies are urgently needed to treat neurological deficits caused by stroke. Senior author Tatiana Segura, PhD, and colleagues discuss how the injection of hydrogel biomaterial scaffolds to the brain after stroke may improve brain plasticity and endogenous repair in a video article for the Journal of Visualized Experiments. View that article here.
  • The arrival of effective treatments for Alzheimer’s disease would have profound implications for the way we diagnose, study, triage, and allocate resources to patients with the condition. Ornit Chiba-Falek, PhD, was the senior author of a study that discusses what those treatments might mean for caregivers, clinicians, researchers, and the healthcare system at large. Read that discussion in Life Sciences, Society and Policy.
  • Mitochondrial DNA damage may be a sensitive measure of altered kinase activity in patients with Parkinson’s disease, according to a new article by lead authors Laurie Sanders, PhD, Claudia Gonzalez-Hunt, PhD, Catherine Toste, and colleagues. By providing an extended profile of LRRK2 kinase modulation, this finding may provide a biomarker-guided entry into clinical trials for Parkinson’s. Read that Scientific Reports article here.
  • A new article by lead author Alexandra Badea, PhD, and colleagues combined MRI and micro CT studies in an animal model of microcephaly. Their study shows that lack of the GIT1 protein results in skull shape abnormalities, that are associated with brain atrophy, white matter, and cortical layer deficiencies. The team used clustering of volume covariance adjacency matrices to identify vulnerable brain region networks that change in a concerted fashion. Read that article in Magnetic Resonance Imaging.

Stroke and Vascular Neurology

  • A new review article discusses carotid webs, a common mechanism for stroke, particularly for younger patients without vascular risk factors. First author Brian Mac Grory, MD, and colleagues discuss the origins, visualization strategies, and management of this condition, which appears in the Journal of Neurology, Neurosurgery, and Psychiatry.
  • Mac Grory also contributed to a new Neurology article examining impact of delirium on withdrawal of life-sustaining treatment after intracerebral hemorrhage. The single-center cohort study found that delirium was associated with withdrawal of treatment after intracerebral hemorrhage regardless of when it occurs. Read that article here.
  • A team including Ying Xian, MD, PhD, investigated whether the Centers for Medicare and Medicaid’s elimination of trial admissions and the initiation of documentation requirements limited inpatient rehabilitation facility access while increasing skilled nursing facility (SNF) utilization compared to home discharge (HD) in ischemic stroke (IS) patients. Read that article here.

Neuromuscular Disease

  • Lisa Hobson-Webb, MD, was part of a group that developed and tested a 12-week respiratory muscle training program to address progressive respiratory muscle weakness in late-onset Pompe disease (LOPD). Read the results of their sham-controlled clinical trial in Neuromuscular Disorders.
  • In the latest issue of Muscle and Nerve, a team including Don Sanders, MD, used Extrapolated‐Reference‐Values‐Procedure (E‐Ref) to compare data with the recently‐published reference‐value for concentric electrode jitter. The team found the E-Ref jitter cut-off value results were not significantly different from the reported reference values. Read that story here.

Duke Neurology Research Round Up, October 2020

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Image courtesy NIH

This September, members of the Duke Neurology Department contributed to 26 new studies, advancing our knowledge of neuroscience at the subcellular, national, and global levels. Ornit Chiba-Falek, PhD, and Laurie Sanders, PhD, lead studies that answered questions about the genetic origins of Parkinson’s disease and its connection to some forms of breast cancer. Meanwhile, Ying Xian, MD, PhD, and Shreyansh Shah, MD, and colleagues at the Duke Clinical Research Institute examined data from more than 250,000 stroke patients to examine how treatments of stroke differ depending on whether that stroke occurs inside or outside of a hospital. And Deborah Koltai, PhD, was an author and editor of 11 articles in a special issue of Epilepsy and Behavior providing a comprehensive analysis of the cultural, medical, and economic factors affecting epilepsy care in Uganda. Read more about these studies and more, and find links to the original articles, in the paragraphs below.

Neurocritical Care

  • To date, there remains a lack of high-quality data on how to best define, document, and respond to brain death/death by neurologic criteria (BD/DNC). As part of the World Brain Death Project, an international panel of experts including Cherylee Chang, MD, worked together to analyze literature on this subject and provided minimum clinical criteria to determine BD/DNC. Read that article in JAMA.
  • A new article in the latest issue of Neurocritical Care examined the neuroprotective potential of argon inhalation in traumatic brain injury in vivo in a group of mice. Daniel Laskowitz, MD, MHS, Haichen Wang, MD, and Viviana Cantillana contributed to the study, which is available here. Read more.

General and Community Neurology

  • Andrew Spector, MD, co-wrote a letter to the editors of The Journal of Allergy and Clinical Immunology: In Practice discussing opportunities to enhance the AAAAI Physician Burnout Survey. Read that letter here.

Epilepsy, Sleep and Neurophysiology

  • Status epilepticus remains a neurologic emergency with high morbidity and mortality, and there are many unanswered questions about optimal early treatment. Vishal Mandge, MD, and Aatif Husain, MD, wrote a review article in the Journal of Clinical Neurophysiology that describes important drug trials that have shaped our understanding of the treatment of status epilepticus and proposes clinical trial methodology considerations for all stages of the condition. Read that article here.
  • Epilepsy is the most common serious chronic neurological disease in the world. Treating this condition in developing countries requires considering a host of concerns, including local cultures and belief systems about epilepsy, lack of access to medicine, patterns of health care use, and resources available in local hospitals. Deborah Koltai, PhD, was the guest editor of a recent issue of Epilepsy and Behavior that examine how culture, resources, and disease intersect with epilepsy care in Uganda. The 11 articles in this issue include discussions of opportunities and future directions from studying the cultural context of epilepsy care, how stakeholders and healthcare providers view barriers to care, and a systematized literature review of stigma interventions for epilepsy.  Read those articles and more here.
  • Non-invasive  positive  pressure  ventilation  (NPPV)  is  a  technique  used  to  deliver  mechanical ventilation  to  patients  with  respiratory  failure  through  a  noninvasive  interface  such  as  nasal mask, facemask, or nasal plugs. In the latest issue of Chest,  Andrew Spector, MD, and former sleep fellow  Shravana  Deepthi  Gudivada  MD, discuss how they qualify  inpatients  with  acute on  chronic  hypercapnic respiratory  failure  for  home  NPPV at  the  time  of discharge. Read their article here.

Memory Disorders

  • Brenda Plassman, PhD, was the co-author of a Neurology article that examined interactions between sex, race, and risk of dementia diagnosis after traumatic brain injury among older veterans. Their analysis of a large, nationwide cohort found an increased risk for all races with the highest risk of dementia following TBI for white veterans. Read that article here. 
  • A new study in the Journal of Alzheimer’s Disease, helped answer questions about how aerobic exercise and a healthy diet improve neurocognition. A team including James Burke, MD, PhD, and Kathleen Welsh Bohmer, PhD, examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants in a trial of older adults with cognitive impairment randomized to receive a healthy diet, exercise, both, or a control condition. They found several metabolic biomarkers associated with increases in executive function. Read that study here.

Neurodegeneration and Neurotherapeutics

  • Genetic studies have identified variants in the LRRK2 gene as important components of the pathobiology of Parkinson’s disease. The Duke Center for Neurobiology and Neurotherapeutics’ Andrew West, PhD, was the senior author of a new article discussing the biomarker regulatory process for Parkinson’s disease, emerging LRRK2 biomarker candidates, assays, underlying biomarker biology, and clinical integration. Read that article in Frontiers in Neuroscience.

Translational Brain Sciences

  • Alpha-synuclein SNCA appears to play a role in the origins of Parkinson’s disease (PD); however, the normal function of this protein and the pathway that mediates its pathogenic effect has yet to be discovered. Ornit Chiba-Falek, PhD, was the senior author of a new study investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations, A53T and SNCA-triplication, and their corresponding corrected lines by genome- and epigenome-editing. Read that article in Human Molecular Genetics. 
  • Simon Davis, PhD, was the lead author of a new Cerebral Cortex study that used functional magnetic resonance imaging (fMRI) and representational similarity analysis to examine how visual and semantic representations predicted subsequent memory for single item encoding. Read that study here.
  • The TRPV-4 ion channel helps regulate the blood-brain barrier, making it a potential therapeutic target for efforts to reduce neuroinflammation associated with dysfunction of the blood-brain barrier. A team including Wolfgang Liedtke, MD, PhD, investigated the role the ion channel plays in permeability of the blood-brain barrier during periods of neuroinflammation. Read what they found in Frontiers in Cell and Developmental Biology.
  • Diseases of the central nervous system have historically been among the most difficult to treat using conventional pharmacological approaches. Viral-mediated gene transfer represents an attractive alternative for the delivery of therapeutic cargo to the nervous system. Ornit Chiba-Falek, PhD, contributed to a review article discussing the potential of this technique for new strategies for treating neurodegenerative disease. Read that article in Frontiers in Molecular Neuroscience.
  • A new study in the American Journal of Pathology found that the mutation that causes the most common type of familial Parkinson’s disease also appears to directly increase the risk for breast cancer. Senior author Laurie Sanders, PhD, postdoctoral associate Claudia Gonzalez -Hunt, PhD, and colleagues found that somatic LRRK2 mutations, the most common cause of familial Parkinson’s disease occur frequently in breast cancer. The high mutation burden seen in this subset of tumors suggest that LRRK2 mutations may herald benefit from immune checkpoint inhibition. Read that study here.

Parkinson’s and Movement Disorders

  • The FDA approved the use of levodopa oral dry powder inhalation for Parkinson’s patients whose current carbidopa/levodopa dose is wearing off prematurely. But this treatments not recommended for patients with chronic respiratory diseases, such as asthma and/or chronic obstructive lung disease (COPD). A team including Jeffrey Cooney, MD, discuss the existing evidence and recommendations for this subset of patients. Read that discussion in Parkinsonism & Related Disorders.
  • Resident Amanda Currie, MD, contributed to a new pilot study that examined subthalamic nucleus (STN) deep brain stimulation on outcomes for patients with Parkinson’s disease. The Neurology article found that STN DBS reduced the odds of requiring polypharmacy and reduced the likelihood of tremor at five years. Read that article here.

Stroke

  • Even though many acute ischemic strokes occur while patients are hospitalized, there are limited data on the rates of intravenous thrombolysis or endovascular therapy for patients who experience a stroke while in a hospital. Ying Xian, MD, PhD, and Shreyansh Shah, MD contributed to a JAMA Neurology study that compared data from more than 250,000 patients who underwent reperfusion therapy for stroke either in or out of a hospital. Among other findings, they found that in-hospital stroke onset was associated with reperfusion therapy, longer delays to reperfusion, and worse functional outcomes. Read that article here.

Duke Neurology Research Round Up, June 2020

NIH EEGNew research from the Duke Neurology Department advanced our understanding of neurological diseases and patient care at the basic science, translational, and clinical levels. Among other topics, our faculty, trainees, and staff found evidence for virtual reality’s potential in neurorehabilitation, tested a wearable device that can help better identify seizures, and reviewed how our understanding of the hippocampus has evolved over the past generation. Read the short paragraphs below to learn more about these and other topics, and find links to the original journal articles themselves.

Translational Brain Sciences

  • Late‐onset Alzheimer’s disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiologies. Lead authors Ornit Chiba-Falek, PhD, and Michael Lutz, PhD, and colleagues performed genetic pleiotropy analysis using LOAD and PTSD genome‐wide association study  datasets from white and African‐American populations, followed by functional‐genomic analyses. They found common genetic signatures for LOAD and PTSD and suggested immune response as a common pathway for these diseases. Read that study in Alzheimer’s & Dementia here.
  • Over the past four decades, memory researchers have greatly expanded our understanding of the hippocampus, the horse-shaped region deep in the human brain. Simon Davis, PhD, was the senior author of a new study in the Proceedings of the National Academy of Sciences that summarizes and discusses these findings, including evidence that the hippocampus is involved in implicit and working memory as well as episodic memory, and a developing hypothesis that the hippocampus’ main purpose is to associate different kinds of information. Read that study here.
  • A new Heliyon study by senior author Al La Spada, MD, PhD, found that over-expression of normal Senataxin (SETX) protein, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. Read that study here.

 

Multiple Sclerosis and Neuroimmunology

  • Twitter is a tool that offers enormous potential for providers and people living with multiple sclerosis to quickly share data, best practices, tips, and other information. In a letter to the editors of Multiple Sclerosis Journal, Suma Shah, MD, discusses this potential, both as it relates to the ongoing COVID-19 pandemic and in general. Read that letter here.

Stroke and Neurocritical Care

  • A new Stroke study co-authored by Michael “Luke” James, MD, evaluated both MRI markers and APOE genotype predicted recurrence of intracerebral hemorrhage. They then developed a preliminary classification system to use this data to stratify patients’ likelihood of recurrence into low, medium or high risk. Read that study here.
  • A new randomized controlled trial co-authored by Wuwei “Wayne” Feng, MD, examined the benefits of cathodal transcranial direct current stimulation (c-tDCS)  in reducing motor impairment and improving upper limb function and quality of life in stroke patients. Forty stroke patients were assigned to either c-tDCS with virtual reality (VR) or, as a control group, VR alone. While both groups saw improvement, improvements in the experimental group were significantly higher. Read the article in the Journal of Neuroengineering and Rehabilitation.
  • James also contributed to a Neurocritical Care study that examined whether reductions in systolic blood pressure after intracerebral hemorrhage affected patient outcomes. Their results suggest that for early SBP reduction to have an effective therapeutic effect, both target levels and optimum SBP reduction goals vis-à-vis hematoma volume should be considered. Read that study here.

Clinical Neurophysiology

  • Aatif Husain, MD, was the senior author of a new study in the Journal of Clinical Neurophysiology that offers a potential pathway to better differentiate between epileptic seizures and psychogenic nonepileptic seizures: a surface electromyography device patients can wear on their arms. Their analysis of 17 patients experiencing 34 events found that the wearable device offers potential for differentiation both by automated and expert review. Read that article here.

Memory Disorders

  • A new systematic review protocol outlined by senior author Brenda Plassman, PhD, aims to identify risk and protective factors of dementia among adults with post-traumatic stress disorder. Read more in the British Medical Journal Open.

Stroke and Neurocritical Care

  • A new JAMA article co-written by Ying Xian, MD, PhD, found that longer door-to-needle times were associated with higher all-cause mortality and higher likelihood of all-cause readmission among patients with acute ischemic stroke treated with intravenous tissue plasminogen activator. Read this retrospective cohort study of more than 60,000 patients here.
  • Xian also contributed to a systematic review and network meta-analysis that compared and ranked all available treatment interventions for depressive disorders in children and adolescents. Their analysis found that fluoxetine (alone or with cognitive and behavioral therapy) appeared in general to be the best choice for acute treatment of moderate-to-severe depressive disorder in children and adolescents. The authors cautioned however, that the effects of these interventions varied between individuals, so decision should be made on a case-by-case basis. Read that study here.
  • Senior author Jeffrey Guptill, MD, MHS, as well as Daniel Laskowitz, MD, MHS, Shruti Raja, MD, and colleagues, contributed to the first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics of MW189, a novel central nervous system-penetrant small-molecule drug with potential to help patients with intracerebral hemorrhage or traumatic brain injury. Read about that trial in Clinical Pharmacology in Drug Development.
  • Autoimmune encephalitis (AE) is a group of disorders causing synaptic receptor dysfunction with a broad range of neurological symptoms that has been historically difficult to differentiate clinically. In the latest issue of Neurotherapeutics senior authors Brad Kolls, MD, PhD, and graduating Neurocritical Care Fellow Alok Saghal, MD, as well as Yasmin O’Keefe, MD, review the epidemiology, clinical features and treatments, and basic science tools and techniques relevant to a subtype of this condition, NMDA receptor mediated autoimmune encephalitis (NMDAr-AE). Read that article here. 

Other topics

  • Thomas Farrer, PhD is a co-author of a new workbook, Essentials of the California Verbal Learning Test: CVLT-C, CVLT-2, & CVLT3. This book covers the administration, scoring, and interpretation of those three tests. It also includes a discussion of the strengths and weaknesses of the assessment, a review of the CVLT’s performance in clinical populations, and illustrative case reports. Read more about the book here.NIH EEG

Faculty Spotlight: Matthew Scaglione, PhD

As a graduate student, Matthew Scaglione, PhD, became interested in how the body made and destroyed proteins–and how these processes could go wrong in neurodegenerative disease. Now, as an assistant professor at Duke, his research straddles the intersections between neurology, molecular genetics, and microbiology to better understand how we might be able to develop treatments for these conditions. For this week’s spotlight interview, we talk to Scaglione about about how a cellular slime mold may help us develop treatments for Huntington’s disease, how the COVID-19 epidemic has changed his work and home life, and brewing beer and raising a family and a group of pullets when he’s not at Duke.

What were your pre-COVID-19 responsibilities within Duke and the Neurology Department?
I am an Assistant Professor who runs a research laboratory that focuses on understanding the underlying causes of neurodegenerative diseases. The laboratory largely focuses on understanding how protein quality control pathways recognize and handle misfolded proteins that accumulate in these diseases. I have the pleasure of working with graduate students, senior scientists, and research technicians on a daily basis. I have a secondary appointment in Neurology and have really enjoyed all of the great journal clubs, data updates, and talks that occur in the department.

How has the COVID-19 epidemic changed that work? What does a typical workday look like for you nowadays?
The epidemic has definitely changed my work schedule. I am working with my students to write up a couple manuscripts and reviews, all being coordinated with Zoom meetings a few times a week. We still have our weekly update meetings, journal clubs, and lab meetings via Zoom as well. The biggest change has been that I get to also be a tutor for a 2nd and 5th grader. It makes getting work done more challenging but has been rewarding as well.

Your primary appointment is with the Department of Molecular Genetics and Microbiology. How do this discipline and neurology complement each other in your research?
Our lab investigates an amoeba that we and others have found to be resistant to certain types of protein aggregation. Having appointments in both Molecular Genetics and Microbiology (MGM) and Neurology is the perfect mix for our laboratory. Our lab uses genetic approaches in this microbe to learn about potential ways to combat neurodegenerative diseases, so interacting with other labs that are interested in molecular genetics, microbiology, and neurology is the ideal fit for my group!

How did you get interested in this field? What do you think is the most exciting development in the field of neurodegeneration in the past 10 years (or the most exciting development we’ll see in the next decade?

I became really interested in how proteins were made and destroyed as a graduate student. While I was finishing up graduate school, I started reading about how proteins form clumps in most neurodegenerative disease and how this protein clumping may be the underlying cause of these diseases. This coupled with the lack of effective therapeutics for neurodegenerative disease piqued my interest.

I think one of the biggest developments in the past ten years has been the development of RNAi and antisense technologies. These technologies allows for suppression of the expression of the toxic proteins that cause neurodegenerative diseases. This has great potential to treat a variety of neurodegenerative diseases and these therapies are already in clinical trials. I also think this potential therapeutic highlights the need for continued investment in basic science. The whole idea for these therapies comes from basic science research done in the worm.

What is the focus of your current research? How will the results of this research help us better understand or treat neurodegenerative diseases?
Our lab is really interested in the model organism Dictyostelium discoideum (dicty), more commonly known as a cellular slime mold or the social ameoba. This organism has been studied for over 70 years because it has the unusual ability to switch from being a single cellular organism to being multicellular. Our lab is interested in dicty because they naturally contain long stretches of the same amino acid. In some diseases like Huntington’s disease these long strings of the same amino acid trigger protein clumping and neurodegeneration. We have found that unlike other organisms dicty are resistant to this protein clumping phenomenon. Our hope is that we can fully understand all the ways that dicty resist protein clumping then transform our findings into novel therapeutics.

How has the COVID-19 epidemic affected your life outside of Duke? What’s one positive strategy or resource you’ve found that helps you cope?
The epidemic has definitely changed my work schedule. I am working with my students to write up a couple manuscripts and reviews, all being coordinated with Zoom meetings a few times a week. We still have our weekly update meetings, journal clubs, and lab meetings via Zoom as well. The biggest change has been that I also am a tutor for a 2nd and 5th grader. It makes getting work done more challenging but has been rewarding as well.

What other passions or hobbies do you have outside of work?
Outside of work I love spending time with my family, gardening, cooking, brewing beer, and raising chickens.

M Scaglione

Scaglione and family enjoy the fruits of their efforts after designing themed costumes.

Duke Neurology Research Round Up, April 2020

NIH nerveWhat do a genetic analysis of the intersecting pathways between Alzheimer’s disease and depression, a national prize-winning essay examining the ethics of unionization for physicians, and a systematic review of the literature surrounding a new potential form of therapy for stroke recovery have in common? They’re all subjects of peer-reviewed journal articles written or co-written by members of the Neurology Department published this March.

In our latest “Research Round Up” installment we review each of the 11 articles members of our Department contributed to and provide links to the original studies themselves.

Ethics

  • Unionization poses many ethical issues for physicians, with the most important being how to collectively bargain without putting their patients at risk. Resident Danielle Howard, MD, wrote an essay outlining these dilemmas, how they impact vulnerable populations such as residents, and ways that unionization can cause no harm, or even benefit, to patients. This essay was the grand prize winner in  the American Medical Association’s Art of Medicine contest. Read it in the AMA’s Journal of Ethics here.

Stroke

  • Senior author Wuwei “Wayne” Feng, MD, MS, Carmen Graffagnino, MD, Shreyansh Shah, MD, and colleagues conducted a systematic review of the literature surrounding S-Nitrosoglutathione (GSNO), a nitric oxide donor that may offer neuroprotective and neuro-recovery effects. Their analysis of 6 animal and 4 human studies found GSNO provided significant benefits in both preclinical and clinical studies, indicating that this molecule offers potential as a new form of therapy. Read the full article in Experimental Neurology here.
  • Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications but conflicting reports on outcome after stroke. Senior author Michael “Luke” James, MD, Shreyansh Shah, MD, and colleagues evaluated whether pre–intracerebralhemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome in a large, multi-ethnic case-control cohort. They found that pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcomes after ICH. Read the full article in Stroke.
  • Stroke published a letter to the editor by resident Martin Weiss, MD, Shreyansh Shah, MD, and Wuwei “Wayne” Feng, MD wrote a letter discussing a recent article about calculating the hematoma volume of spontaneous intracerebral hemorrhage. Read that article here.

Translational Brain Sciences

  • Patients who have late-onset Alzheimer’s disease (LOAD) are more likely to have depression, and depressed patients are also more likely to develop LOAD, suggesting either a shared cause or intersecting pathways between the conditions. Lead authors Michael Lutz, PhD, and Ornit Chiba-Falek, PhD, as well as Julio Barrera, and Daniel Sprague, examined the overlapping genetic signatures underpinning the common phenotypic manifestations and inter-relationship between these two conditions. Read what they found in Translational Psychiatry.
  • Senior author Alexandra Badea, PhD, Richard O’Brien, MD, PhD, and colleagues wrote an article in Frontiers in Physics that  provides guidelines for new protocols in mouse models of neurological conditions. Read their evaluations of diffusion imaging protocols with various spatial and angular resolutions here.
  • A team including Al La Spada, MD, PhD, analyzed the progression of a mouse model of Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, from both physiological and histological perspectives. Their analysis uncovered new information about alteration in muscle function in the condition and suggested routes for new muscle-targeted therapies. Read their article in Disease Models and Mechanisms.
  • Audrey Dickey, PhD, contributed to a new Journal of Neuroscience article found that inhibition of the dynamin-related protein 1 (Drp1) is neuroprotective. The article also identified Bβ2, a neuron-specific Drp1 activator, which may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke. Read that article here.

Neurocritical Care

  • Elevated systolic blood pressure after successful revascularization via endovascular therapy is a known predictor of poor outcome. However, the optimal SBP goal following EVT is still unknown. Christa Swisher, MD, Shreynash Shah, MD, Ovais Inamullah, MD, and Shareena Rahman, MD, were part of an international multicenter study that compared functional and safety outcomes between different systolic blood pressure goals after EVT with successful revascularization. They found correlations for improved outcomes with lower blood pressure in three designated intervals. Read the full study in Annals of Neurology.

Neuromuscular Disease

  • Familial, but not sporadic, forms of amoytrophic lateral sclerosis are associated with a structural variant within the sequestosome 1 gene, according to a new case-control study in Neurology Genetics written by Rick Bedlack, MD, PhD, and colleagues. Read that article here.

Sleep Disorders

  • In the latest issue of Neuromuscular Disorders, senior author Andrew Spector, MD, and former sleep fellow Raj Bhui, MD, present a case in which a patient with late-onset Pompe disease was able to discontinue positive airway pressure therapy for his obstructive sleep apnea after treatment with enzyme replacement therapy for his Pompe disease. It is likely that an improvement in muscle tone from the enzyme replacement therapy was sufficient to eliminate his obstructive sleep apnea. Read that article here.

Neuro-Oncology

Student Spotlight: Alexa Putka

PutkaThis week’s “Spotlight” interview shines on Alexa Putka, an undergraduate researcher in the lab of Audrey Dickey, PhD. Putka talks to us about the passion, puzzle-solving, and collaboration that motivate her work to help better understand and reduce the effects of Huntington’s and other neurodegenerative diseases. She also talks about how her recent research fellowship from the Huntington’s Disease Society of America, and enjoying reading, axe-throwing, and time with family when she’s not at Duke.

 

What are your current responsibilities within the Dickey lab? What does a typical day for you look like?
My current responsibilities vary depending on what experiments we are conducting, which means that my “typical day” is also highly fluid. However, while I am actively working on an experiment, I am highly focused on generating quality data. For example, my recent experiments involve live-cell imaging in neurons using fluorescent calcium indicators to understand the role of mitochondria in buffering calcium to mediate excitotoxicity in Huntington’s Disease (HD).

This project involved extensive research into how to use such calcium indicators, which translated to trial and error on my part in determining how to use these proteins for my experiment. I find this search for the most effective method to study a particular intracellular process to be one of the most exciting parts of my day-to-day research, as I have the opportunity to delve into the literature, further understand the conceptual basis for my experiment, and then compare what other researchers have done to fill in the gaps for my methodology. After generating data, I am able to learn about how to analyze it, fitting these pieces into the larger picture of the intracellular signaling pathways affected by HD.

What do you enjoy the most about your time in the Dickey lab?
My favorite part of research with Dr. Dickey is the pursuit of a solution—I enjoy the search for the pieces of the puzzle that fit together to uncover connections in intracellular pathways, which provide ever-growing strategies to ameliorate the effects of neurodegenerative diseases. I also enjoy working with Dr. Dickey and our other lab members. I find that everyone brings a different perspective to each problem, and the constant collaboration and support provides additional motivation for our research.

What’s the hardest part of your research?
Setbacks are one of the hardest parts about research. Oftentimes, results of an experiment are not what I would expect, and it can be difficult to discern exactly what went wrong. However, when I look at the situation from a different perspective, I view these setbacks as a challenge, a way to test my skills of scientific inquiry, and an opportunity to learn something new. When this occurs, I work with Dr. Dickey and the rest of our lab to understand what happened, and this collaboration provides me with renewed hope that we can find a way around the problem and learn how to use the setback to our advantage. These problems usually help us better understand the protein we are studying, as factors we hadn’t previously considered become important for future experiments.

What plans do you have for what you’d like to do after graduation? If you could have any job in the world, what would it be?
Next fall, I plan to apply to Neurobiology PhD programs. I am very interested in continuing to pursue work with neurodegenerative diseases and intracellular signaling pathways that contribute to disease, but ultimately, I hope graduate school will broaden my understanding of other biomedical science fields and current research.

After graduate school, I’m not completely sure what I want to do, but I hope to pursue research in an academic setting because I have a passion for working with students to introduce them to topics that excite me, and I hope to foster my love for science in future students.

You recently received a fellowship from the Huntington’s Disease Society of America to study a research topic related to Huntington’s. What research question are you examining, and how will those results help us better understand or treat Huntington’s?
I am very grateful for the HDSA in supporting my research with Dr. Dickey. My work aims to explore the cellular mechanisms of excitotoxicity in HD. Excitotoxicity occurs when unrestrained glutamatergic signaling, increased intracellular calcium levels, and disrupted BDNF trafficking cause mitochondrial failure and cell death. Preliminary results from our lab indicate that a nuclear transcription factor called PPAR-delta (PPARd) can act as a neuro-therapeutic agent and protect cells against excitotoxicity.

Since excitotoxicity has multiple components, we sought to determine the precise mechanism of PPARd. While these experiments are ongoing, they implicate PPARd in functioning through the excitotoxicity pathway to ameliorate HD pathologies, which means that this pathway can serve as the target of therapeutic agents. The hope is that we can use this research to develop drugs to alleviate the symptoms of patients suffering from HD.

What passions or hobbies do you have outside of Duke?

While I am a very busy student outside of my time in the lab, I greatly enjoy reading nonfiction books, working with incoming Duke students through a program that welcomes them to campus in the summer, and spending time with my friends and family. As an eccentric side note, I also went axe-throwing recently (bars featuring axe throwing seem to be a new trend), which was extremely fun and surprisingly not too difficult. Maybe that will become my new hobby!

Putka Chicago

Putka enjoys a visit to Chicago (above), as well as amateur axe-throwing, below.

Putka ax

Do you have a (non-headshot) photo of yourself that you can share?

Duke Neurology Research Round Up, January 2020

NIH EEGMembers of the Duke Department of Neurology contributed to nine studies in peer-reviewed journals published in December 2019. In the fields of neurodegeneration and neuromuscular disease, our faculty found potential new avenues for therapies for spinocerebellar ataxia type 7 (SCA7) and myasthenia gravis. Other studies by our faculty and housestaff answered important questions about how reductions in blood pressure affect outcomes for thrombectomy, outcomes for deep brain stimulation for patients with Parkinson’s, and other areas. Read summaries about each of these articles, and find links to the original studies below.

Neurodegeneration and Neurotherapeutics

  • New research sheds light on the origins of SCA7 and demonstrates effective new therapeutic pathways for SCA7 and the more than 40 other types of spinocerebellar ataxia. The study, which appears in Neuron, implicates metabolic dysregulation leading to altered calcium homeostasis in neurons as the underlying cause of cerebellar ataxias. Read it here.
  • La Spada also contributed to a new statement from the American College of Medical Genetics and Genomics that examined whether there was sufficient evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients. Read that full statement in Genetics in Medicine.

Stroke

  • Christa Swisher, MD, Shareena Rahman, MD, and Ovais Inamullah, MD, were part of a multicenter retrospective study that examined the associations between reductions in systolic blood pressure and mechanical thrombectomy. The analysis of nearly 1,400 patients found that reductions in systolic blood pressure were inversely associated with poor outcomes but not safety outcomes. Read the full article in the Journal of Neurointerventional Surgery.

Neuroimmunology

  • Existing normative flow cytometry data have several limitations, such as small sample sizes, incompletely described study populations, variable methodology, and limited depth for defining lymphocyte subpopulations. Jeffrey Guptill, MD, MHS, was the senior author of a study that provides resources to better compare and extract data for subjects across gender, race, and age group. Read that study in PLoS One.

Neuromuscular Disease

  • Therapies that target Th17 cells could be a fruitful avenue for helping patients with myasthenia gravis, according to a new study by senior author Jeff Guptill, MD, MHS, Karissa Gable, MD, Vern Juel, MD, Janice Massey, MD, Shruti Raja, MD, Lisa Hobson-Webb, MD, and Melissa Russo. The team found that  the transcription factor RoRy, reduced the frequency of Th17 cells without affecting other T helper subsets. Read that article in Experimental Neurology.

General Neuroscience

  • Miguel Nicolelis, MD, PhD, was the senior author an analysis in Scientific Reports that examined the pitfalls and shortcomings of rotational dynamics, a proposed type of neuronal processing that exists in organisms from leeches to primates. Read that article here.

Movement Disorders

  • Sneha Mantri, MD, MS, contributed to a nationwide analysis of readmission and post-operative outcomes for Parkinson’s patients who have had deep brain stimulation surgery. Their analysis of more than 6,000 patients found favorable short-term hospitalization rates after DBS as well as persistent socioeconomic disparities in DBS. Read the full study in Parkinsonism and Related Disorders here.

Memory Disorders

  • Andy Liu, MD, was the first author of a JAMA Neurology study that answers important questions about the neuropsychiatric symptoms associated with tuberous sclerosis. Their case control study found that adults with tuberous sclerosis had similar cognitive and behavioral difficulties, as well as similar cerebrospinal fluid biomarkers, than patients with frontotemporal dementia. Read that study here. 

Sleep Disorders

  • Transvenous phrenic nerve stimulation (PNS) shows promise as a treatment for central sleep apnea, according to a study in the Journal of Clinical Sleep Medicine. Andrew Spector, MD, and colleagues examined nearly 200 patients who had received transvenous PNS, finding that it significantly improved CAS severity, sleep quality, ventricular function and quality of life, regardless of whether patients had heart failure. Read their full study here.

Profiles in Brain Sciences: Andrew West, PhD

Even as our understanding of how factors like genetics, metabolomics, and the environment contribute to Parkinson’s disease has rapidly advanced over the past 20 years, there are still no disease-modifying therapies for Parkinson’s or almost any other neurodegenerative disease. The Duke Center for Neurodegeneration and Neurotherapeutics’ Andrew West, PhD, is working to change that. For our first “Profiles in Brain Sciences” interview of 2020, West talks to us about his multidisciplinary in this area and why he’s hopeful that we’ll see treatments for at least some forms of the condition over the next few years. He also talks about how targeting different therapies toward specific populations with Parkinson’s is more likely to be effective than a unified “magic bullet” approach.

How are you and your lab working to better understand Parkinson’s disease? What projects in this area are you working on at the moment?
We work to translate discoveries made in human genetic studies into meaningful therapies that slow or halt the progression of Parkinson’s disease. We work with a combination of model systems and biospecimens from the clinic to help guide our understanding of how Parkinson’s disease changes over time, how it varies from person to person, and who might best benefit from precision therapeutic approaches. Our recent efforts focus on understanding and translating therapies directed towards the most common genetic causes of Parkinson’s disease, mutations in a gene called LRRK2 (we pronounce it LARK-two). We are developing model systems surrounding LRRK2 which has effects both in inflammation pathways and in neurons susceptible to disease, evaluating new therapies in these models that will go into clinical trial, and biomarkers to help guide clinical efforts.

How will this research lead to better treatments or quality of life for patients living with these conditions?
There is yet no known therapy that slows or halts the progression of Parkinson’s disease. Any advance towards our goal of disease modification will be groundbreaking for the millions affected by Parkinson’s disease and related disorders. In many ways, we think Parkinson’s disease is less complex than other neurological conditions, so we expect development of therapies to combat Parkinson’s disease may help serve as a template to pursue therapies for other complex diseases.

In addition to the Duke Center for Neurodegeneration and Neurotherapeutics, your work also spans the Departments of Neurobiology and Pharmacology & Cancer Biology. How do each of these fields inform and contribute to your work?
Engaging complex disease requires complex approaches, and a multi-disciplinary approach helps address bottlenecks and gaps that otherwise would slow down or inhibit progress. We keep a close watch on what is happening in cancer biology, both in understanding the complexities of heterogeneous disease in diverse clinical populations and the dangers of over-simplification of model systems in guiding experimental direction. One of the dramatic positive lessons we are trying to import in Parkinson’s disease is the successful utilization of biomarkers in patient stratifies in cancer that can be the difference between a failed or successful clinical trial. Likewise, we try to use the best pharmacological agents and approaches we can, with the expertise here in the Department helping us optimize experiments. The neurobiology happening here at Duke in Parkinson’s disease focuses on the neuronal systems affected and outcomes that provide insight into both health and disease.

What do you see as the biggest change in how we understand Parkinson’s and neurodegeneration since you earned your doctorate?
We understand Parkinson’s as a disorder that ultimately affects most of the brain, with a diversity of possible disease origins from the gut to the olfactory system. The genes linked to heritable aspects of late-onset (typical) Parkinson’s disease appear to be coalescing around dysfunction of the endolysosomal system which can be complicated to probe and understand in model systems and can change with age in different cell types. Certainly the evidence is now overwhelming that the ‘beating heart’ of Parkinson’s disease, for most patients, appears to revolve around changes of a protein called alpha-synuclein, with LRRK2 and other genes like GBAI modifying how alpha-synuclein interacts in disease. Our models have improved as well as general scientific rigor around testing hypotheses, so we think the conditions are right for the first wave of disease-modifying therapies to be found in the next few years.

What important or exciting change(s) in this field do you see coming over the next decade?
I think the next ten years will herald the arrival of therapies that are developed initially for genetically-defined segments of Parkinson’s disease that will spill over into typical late-onset Parkinson’s disease guided by precision biomarker approaches. It is clear, at least to me, there will be no one magic pill or bullet that will help everyone with disease. Treatments, effective initially in tightly defined disease populations, will need to be combined into temporally defined in disease with patients biochemically categorized to predict therapeutic benefit in diverse populations of disease. Complex diseases require complex therapies, and right now Parkinson’s disease is a blank slate. I believe this will change soon.

What passions or hobbies do you have outside of the Department?
Inspired by shows on HGTV, DIY channel and the like, I am known to gut kitchens, bathrooms, and other rooms down to their studs and build them back up again. I enjoy learning about the latest developments in plumbing, electrical, and other systems that I can work with. I am probably most relaxed browsing the aisles of big-box hardware stores on the weekend. Perhaps it is nice to see the immediate fruits of projects that are vastly less complex and time consuming than those we do in the lab! I am very fortunate to have a loving (and patient) family with two girls in elementary school and my wife who is involved with clinical genetics. Since moving to Duke, we have acquired a small herd of fainting goats that provide entertainment, and I have ambitions for sheep and chickens soon!

Andrew West

Above, Andrew and Kristen West enjoy the Grand Canyon, while below, Georgia West grabs her father’s glasses.

A West glasses grabbing