Neurology Research at UMass Medical School

 

 BoscoLabAtScopeA

 “Working in the UMMS Neurology Dept is a great experience due to the wide variety of research and clinical interests represented within the department.  This offers numerous and eclectic viewpoints on questions that a researcher might not have envisioned. This strengthens the scientific atmosphere of the entire department and university. “

 The Neurology Department at the University of Massachusetts Medical School has renewed its commitment to expand and invigorate research in Neurology throughout central Massachusetts and New England. The recruitment of Dr. Robert H. Brown in 2008 as Chair of Neurology has brought an expansion in faculty and facilities devoted to improving the level of the Neurosciences. Examples of this research can be seen in the UMass Medical School, the Lazare Research Building and the adjacent facilities at Research Park.

RESEARCH INTERESTS

Daryl A. Bosco, PhD   [Faculty Page]
Elucidating the factors involved in sporadic ALS

Microscope ImageOne focus of my lab is to elucidate the molecular mechanism(s) underlying sporadic forms of neurodegenerative diseases, with an emphasis on amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. Approximately 10% of ALS cases are inherited through Mendelian genetics, whereas the vast majority (~90%) of cases are classified as sporadic ALS (sALS). The factors involved in sALS have yet to be identified; the challenge being that sporadic forms of neurodegenerative diseases are multifactorial, involving a complex interplay between genetics and environment. Our goal is to develop relevant models to identify genetic and environmental factors involved in sporadic ALS (sALS) pathogenesis.
Investigating protein mis-function associated with neurodegenerative disease
Mutations in the gene encoding Cu, Zn-superoxide dismutase (SOD1) are known to cause inherited, or familial, forms of ALS (fALS). We are currently investigating the hypothesis that post-translational modifications to the wild type SOD1 protein cause it to adapt a conformation similar to the mutant SOD1 proteins, and that this process is involved in some sporadic forms of the disease. For example, oxidation of SOD1 WT (SODox) causes this protein to mimic the fALS-associated mutants. The effect of SODox compared to mutant SOD is being studied in the context of various biological assays, including axonal transport and programmed cell death. In addition, we are employing biophysical methods to i. structurally characterize SODox, and ii. identify small molecules that can stabilize oxidized SOD1.

 Recent Articles: Daryl A. Bosco

Localized thermodynamic coupling between hydrogen bonding and microenvironment polarity substantially stabilizes proteins.
Nat Struct Mol Biol. 2009 Jul;16(7):684-90 

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Science. 2009 Feb 27;323(5918):1205-8.

 

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David Drachman, MD, Principal Investigator; Joan Swearer, PhD; Mitchell Albert, PhD; YanPing Sun, PhD  [Faculty Page]
Alzheimer’s Disease Endothelial Facilitation Study

The etiology of late-onset sporadic Alzheimer’s Disease (LOSAD)- a gradual-onset, progressive dementia - remains unknown. Its cerebral pathology is defined by neuritic plaques containing fragmented neuritic particles and b -amyloid (Ab ), and by neurofibrillary tangles (NFT). It is becoming evident that LOSAD may not be related to A? formation; and clinical trials to reduce Ab formation have been ineffective. Our current study derives from extensive evidence that LOSAD is associated with vascular risk factors; and that microvascular endothelium is abnormal in AD cortical tissue. Microvascular endothelium is critical in: 1) conveying blood and nutrients to the brain; and 2) providing trophic factors that maintain the integrity of the 100 billion brain neurons. We will study the effect of 4 drugs that improve the function of cerebral endothelial cells: 3 drugs that facilitate endothelial nitric oxide synthase (eNOS), and 1 drug that decreases endothelin-1. Simvastatin, l-Arginine and tetrahydrobiopterin (BH4) will be given sequentially and cumulatively, followed by Bosentan. These drugs will be given to controls, and to patients with early AD. Efficacy will depend on the brain function; as a surrogate marker, we will measure change in blood flow to the brain, using advanced fMRI Arterial Spin labeling (ASL) measurements.

Recent Articles:

Memory and the brain: beyond intracranial phrenology.
Curr Neurol Neurosci Rep. 2008 Jul;8(4):269-73

Nature or nurture: education and the trajectory of declining brain function with age and Alzheimer disease.
Neurology. 2008 May 6;70(19 Pt 2):1725-7

 

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Marc Fisher, MD  [Faculty Page]

Our lab has focused on using diffusion/perfusion MRI to evaluate the evolution of the ischemic penumbra for many years. We use arterial spin labeling perfusion MRI and absolute ADC values on diffusion MRI to determine the location and extent of the ischemic penumbra in rat stroke models and to evaluate the effects of therapies on its evolution. We have demonstrated that high flow normobaric oxygen can extend penumbral survival and in an embolic stroke model extend the time window for the successful use of i.v. tpa. We have also evaluated the effects of neuroprotective drugs on penumbral survival and histologically confirmed tissue salvage. We also perform functional MRI and have used this technique to evaluate the relationship between the ischemic penumbra and preservation of functional activity. We anticipate future studies that will evaluate combination therapies of neuroprotection and thrombolysis regarding effects on in-vivo and histologically assessed tissue salvage and preservation of brain function assessed by fMRI. 

Recent Articles:

Granulocyte-colony stimulating factor delays PWI/DWI mismatch evolution and reduces final infarct volume in permanent-suture and embolic focal cerebral ischemia models in the rat.
Stroke. 2009 Sep;40(9):3102-6. Epub 2009 Jul 30.

Use of telemedicine to increase thrombolysis and advance care in acute ischemic stroke.
Cerebrovasc Dis. 2009;27 Suppl 4:9-14. Epub 2009 Jun 18. Review.

Cardiac workup of ischemic stroke: can we improve our diagnostic yield?
Stroke. 2009 Aug;40(8):2893-8. Epub 2009 May 28.

 

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Fen-Biao Gao, PhD [Faculty Page]

Our lab uses a combination of molecular, cellular, genetic, and behavioral approaches to further dissect the pathogenic mechanisms of frontotemporal dementia with a focus on mutant CHMP2B, progranulin and C9ORF72. We will identify common underlying pathways as potential targets for therapeutic interventions. To this end, multiple experimental systems will be utilized, including Drosophila, mouse models, and patient-specific induced pluripotent stem (iPS) cells. Another major research interest in our laboratory is the mciroRNA pathway. The roles of specific microRNAs in neuronal development and neurodegeneration will be investigated in detail.

 

Recent Articles:

Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.
Nature Medicine   2014 Dec;20(12):1444-51.

Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation.
Mol Cell. 2013 Oct 24;52(2):264-71.

Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons.
Acta Neuropathol. 2013 Sep;126(3):385-99. 

 


Edward Ginns, MD, PhD   [Faculty Page]

Dr. Ginns’ research uses molecular approaches to gain insight into the pathogenesis of human developmental disorders, especially those causing brain dysfunction. In the Lysosomal Storage Disorders Program his interests focus on a "bench-to-bedside" approach, using Gaucher disease as a prototypic disorder to provide a better understanding of how the molecular pathology impacts the clinical course in patients and transgenic Gaucher mice, and for the development of novel therapeutic strategies, including gene therapy. For the more complex disorders, his laboratory and collaborators conduct linkage, candidate gene, mutation and genomic association studies in humans and animal models to identify susceptibility genes for human diseases, including bipolar affective disorder and obscessive compulsive disorder (OCD). Within the UMMS/UMMMC Molecular Diagnostics Laboratory, Dr. Ginns and his collaborators explore ways to provide more rapid, personalized and cost effective molecular clinical tests using state-of-the art technologies. 

Recent Articles:

Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia.Biol Psychiatry. 2009 Jun 15;65(12):1006-14. Epub 2009 Jan 1.

 

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Lawrence J. Hayward, MD, PhD   [Faculty Page]

Blue-Gloved HandThe Hayward lab seeks to understand the mechanisms by which specific gene mutations cause brain and spinal cord motor neurons to die in amyotrophic lateral sclerosis (ALS). These insights may help us to develop effective therapies for the more common sporadic forms of ALS and related motor neuron diseases. In one project, we have employed biochemical and biophysical approaches to characterize mutant Cu/Zn superoxide dismutase (SOD1) proteins that injure motor neurons in familial ALS. We showed that SOD1 mutants exhibit impaired metal binding or stability and are prone to pathological misfolding that may promote adverse interactions with other cellular proteins or membranes. In another project, the lab is characterizing animal models based on newly identified ALS-related genes so that we can develop novel systems to screen for modulators of motor neuron health and disease progression. We are expressing ALS genes in zebrafish models, which allow rapid experimental manipulation and visualization to test specific hypotheses at the molecular and cellular level in vivo.

 

Recent Articles:

Metal deficiency increases aberrant hydrophobicity of mutant superoxide dismutases that cause amyotrophic lateral sclerosis.
J Biol Chem. 2009 Aug 3.

A common property of amyotrophic lateral sclerosis-associated variants: Destabilization of the Cu/Zn superoxide dismutase electrostatic loop.
J Biol Chem. 2009 Jul 27

Sensitive and specific identification of wild type and variant proteins from 8 to 669 kDa using top-down mass spectrometry.
Mol Cell Proteomics. 2009 Apr;8(4):846-56

 

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Carolina Ionete, MD PhD [Faculty Page]

Clinical research in Multiple Sclerosis and other immune mediated CNS diseases
My research is devoted to understanding the nervous system immune mediated diseases. Specific areas of interest are the interplay between psychiatric disorder and multiple sclerosis (MS), the clinical trials using new agents in treatment of MS, the biomarkers of MS disease activity and the biomarkers of HIV associated neurocognitive disorders.

 

Recent Articles:

Byatt N, Rothschild AJ, Riskind P, Ionete C, Hunt AT. Relationships between multiple sclerosis and depression. J Neuropsychiatry Clin Neurosci. 2011; 23(2):198-200.

 

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John Landers, PhD   [Faculty Page]

Genetics of Familial and Sporadic ALS
Amyotrophic lateral sclerosis (ALS) is a uniformly lethal, age-dependent neurodegenerative disorder with a typical survival of 2 to 5 years. Our laboratory is focused on using high-throughput genomic technologies to identify the genes involved in the development of sporadic and familial ALS. Most recently, our lab has utilized high-density SNP arrays to analyze over 300,000 DNA polymorphisms within ~4,000 subjects to test for their association to sporadic ALS. Through our efforts, we have identified KIFAP3, a kinesin II complex member responsible for fast anterograde axonal transport, as a modifier of survival in sporadic ALS. Homozygotes for the favorable allele located in the promoter region of KIFAP3 display a survival advantage of 14.0 months, a substantial increment (~30%) in this disease. Currently, our efforts are focused on understanding how KIFAP3 influences survival and how we can use this information to aid in the development of strategies to extend the lifespan of ALS patients. 

Recent Articles:

 Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.
Nat Genet. 2009 Oct;41(10):1083-7. Epub 2009 Sep 6.

DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS.
Neurosci Lett. 2009 Sep 29;463(1):64-9. Epub 2009 Jul 9.

Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis.
Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9004-9. Epub 2009 May 18.

 

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Majaz Moonis, MD   [Faculty Page]

My research focuses on several interrelated areas that affect stroke and dementia outcomes. More specifically I am interested in the following areas: Outcome research related to specific interventions affecting the vascular endothelium in stroke and Alzheimer’s disease; health care disparities relating to race, age and gender in stroke and dementia; optimal management and effects on primary and secondary stroke prevention; genetic markers in cryptogenic stroke to aid in sub-classification and management; clinical trials in acute stroke and stroke prevention; data mining in sleep related disorders; and stroke.

Recent Articles:

 Use of telemedicine to increase thrombolysis and advance care in acute ischemic stroke.
Cerebrovasc Dis. 2009;27 Suppl 4:9-14. Epub 2009 Jun 18. Review.

Long-term statin therapy and CSF cholesterol levels: implications for Alzheimer's disease.
Dement Geriatr Cogn Disord. 2009;27(6):519-24. Epub 2009 May 29.

Intraarterial thrombolysis within the first three hours after acute ischemic stroke in selected patients.
Stroke. 2009 Jul;40(7):2611-2. Epub 2009 May 14.

 

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Susanne Muehlschlegel, MD, MPH [Faculty Page]

Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study
Dantrolene in the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage

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Jaishree Narayanan, MD   [Faculty Page]

1) Modification of anti-epileptic medication binding to P-glycoprotein
Computational modeling of P-GP, molecular dynamics and study of binding mechanisms to anti-epileptic medications as well as inhibition techniques
2) Frequency flow analysis of EEG to detect and suppress seizures
Frequency flow analysis of EEG for seizure prediction and design of a suppression sequence
3) Effect of treatment of PLEDS on patient outcome
Study the risk-benefits of treating patients with non-anoxic PLEDS on their EEG
4) Efficacy of verapamil in medically refractory epilepsy
Determine if low dose verapamil, a P-glycoprotein inhibitor can improve seizure control in patients with medically refractory epilepsy
5) Treatment of patients with post-hypothermia PEDS
Study the risk-benefits of aggressively treating patients with PEDS on their EEG, after hypothermia for cardiac arrest
6) A randomized clinical trial for treatment of refractory status epilepticus.
Determine if Propofol or pentobarbital is better for treatment of refractory status epilepticus.

Recent Articles:

 Latency to first spike in the EEG of epilepsy patients.
Seizure. 2008 Jan;17(1):34-41. Epub 2007 Jul 26.

 

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Peter Novak, MD   [Faculty Page]

1) Autonomic neuropathy in Parkinson’s disease and multiple system atrophy and dysautonomia in general. We are exploring a variety of approaches to the dynamic analysis of the autonomic nervous system and cerebral blood flow in dysautonomia. Another research interest includes evaluation of dermal innervation in autonomic neuropathy using markers of neurodegeneration. We also designed a single-center open label pilot study to evaluate the effect of IVIg in multiple system atrophy. The study is ongoing. 2) Mechanisms of deep brain stimulation (DBS) in Parkinson disease. The purpose of this project is to clarify how the deep brain stimulation of the subthalamic nucleus (STN) interacts with underlying neuronal activity and how these changes affect the function of basal ganglia. This project utilizes computer modeling, and direct recordings of the neuronal activity during DBS to clarify the proposed mechanisms of DBS - inhibition, excitation or modulation of the STH activity.

Recent Articles:

 Effect of deep brain stimulation of the subthalamic nucleus upon the contralateral subthalamic nucleus in Parkinson disease.
Neurosci Lett. 2009 Sep 29;463(1):12-6. Epub 2009 Jul 16.

Isolation of the brain-related factor of the error between intended and achieved position of deep brain stimulation electrodes implanted into the subthalamic nucleus for the treatment of Parkinson's disease.
Neurosurgery. 2009 May;64(5 Suppl 2):374-82; discussion 382-4.

White matter hyperintensities and dynamics of postural control.
Magn Reson Imaging. 2009 Jul;27(6):752-9. Epub 2009 Feb 28.

 

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David Paydarfar, MD   [Faculty Page]

My research is devoted to understanding the neural control of autonomic functions. Specific areas of interest are the genesis of respiratory rhythm, the coordination of breathing and swallowing, and the maintenance of circulation during upright posture. The major goal is to understand how normal control mechanisms break down and lead to certain common disease states: central apnea, neurogenic aspiration, and neurally mediated syncope.

Recent Articles:

 Developmental aspects of the upper airway: report from an NHLBI Workshop, March 5-6, 2009.
Proc Am Thorac Soc. 2009 Sep 15;6(6):513-20.

Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation.
J Appl Physiol. 2009 Jul 16.

Respiratory failure induced by acute organophosphate poisoning in rats: effects of vagotomy.
Gaspari RJ, Paydarfar D.

 

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Daniel A. Pollen, MD   [Faculty Page]

I am currently engaged in two lines of research. First, with respect to clinical research, I am continuing work as to how lipophilic versus hydrophilic statins affect cerebrospinal fluid markers for Alzheimer’s disease and brain cholesterol metabolism both in pre-symptomatic subjects with known PS1 mutations and in asymptomatic subjects who are either heterozygous or homozygous for the apolipoprotein E?4 allele. Second, I am continuing my very basic research on the neural correlates of primary visual perception and how such correlated neuronal activity might engender perceptual experience. I am continuing to work on my new hypothesis entitled “The anchored loop hypothesis: an ecological approach to the emergence of primary visual perception.” My recent publications in both fields can be easily accessed by looking up my name in PubMed.

Recent Articles:

 Long-term statin therapy and CSF cholesterol levels: implications for Alzheimer's disease.
Dement Geriatr Cogn Disord. 2009;27(6):519-24. Epub 2009 May 29.

Fundamental requirements for primary visual perception.
Cereb Cortex. 2008 Sep;18(9):1991-8. Epub 2007 Dec 17. Review.

 

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Paula D. Ravin, MD   [Faculty Page]

The Movement Disorder division of Neurology is currently concluding a research study of "Disabling dyskinesias in Parkinson's disease with motor fluctuations" and another of "Psychosis in Parkinson's disease." We have ongoing enrollment for "Droxydopa for orthostatic hypotension in Parkinsonian disorders" and "IvIg therapy for Multi-System Atrophy syndrome." We hope to initiate a trial soon for a new botulinum toxin in cervical dystonia and are collaborating with Neurosurgery on several studies of DBS programming parameters and olfaction, mood and affect recognition, and cognition.

Recent Articles:

 Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme.
J Clin Oncol. 2008 Dec 1;26(34):5610-7. Epub 2008 Nov 3.

 

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Peter Riskind, MD, PhD   [Faculty Page]

Dr. Riskind directs the UMMHC Multiple Sclerosis Center, a regional treatment, teaching and clinical research site for individuals with multiple sclerosis and other inflammatory CNS disorders. He is a site principal investigator for many multicenter trials of new drugs for Multiple Sclerosis and is conducting a number of investigator-initiated studies concerning factors that my affect the risk or severity of MS. In addition, the MS group is assessing optimal outcome measures in MS patients.

Recent Articles:

 

 

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William J. Schwartz, MD   [Faculty Page]

This laboratory studies behavioral state in mammals, and how behavior is regulated by the environment and adapts to it. We have focused on the circadian “clock,” an endogenous 24-hr timekeeping mechanism that regulates physiological, endocrinological, and behavioral rhythmicity. We have been attracted to this system because it is a powerful model for investigating the cellular and molecular mechanisms that underlie environmental regulation of behavioral state. Our work has primarily focused on the suprachiasmatic nucleus (SCN) of the hypothalamus, the “master” circadian pacemaker, a tissue composed of multiple autonomous single-cell circadian oscillators. We have been using molecular tools to show that some well-known circadian behaviors emerge at the tissue level, in the interactions between SCN neurons rather than in the expression of “clock genes” within neurons. Current projects are aimed at (a) defining the mechanisms by which social interactions may impact circadian behaviors and the functioning of clock cells and circuits, and (b) elucidating the possible role of circadian dysrhythmias - e.g., in thermoregulation and energy metabolism - in the pathophysiology of neurodegenerative diseases, especially using transgenic mouse models of motor neuron disease. 

Recent Articles:

 Circadian rhythms:  how does a reindeer tell time?
Curr Biol. 2010; 20: R280-R282.

A role for the habenula in the regulation of hamster locomotor activity cycles
Eur J Neurosci. 2011; 34:478-488.

Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays.
Proc Natl Acad Sci USA. 2011 108:17219-17224.

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Miguel Sena-Esteves, PhD   [Faculty Page]

 The Sena-Esteves laboratory is investigating gene therapy approaches for the treatment of neurodegenerative lysosomal storage diseases such as GM1-gangliosidosis and GM2-gangliosidoses (Tay-Sachs and Sandhoff diseases). We have devised new ways to deliver therapeutic levels of the missing enzymes to the entire brain by injection of adeno-associated virus (AAV) vectors into specific structures in the CNS. Based on the exceptional results that we have obtained in animal models, we are initiating pre-clinical studies that will culminate in a human clinical trial for Tay-Sachs disease. Similar work is planned for GM1-gangliosidosis.
Also we are working on developing new AAV vectors capable of crossing the blood brain barrier for effective gene delivery to the brain after intravascular infusion. We have introduced a new paradigm for brain tumor gene therapy based on the genetic modification of normal brain to create an environment, which is non-permissive to tumor growth. We have demonstrated the effectiveness of this approach for preventing the formation and precluding growth of brain tumors using xenograft models in nude mice. Also we are initiating studies directed at understanding the contribution of different genes to the migratory behavior of GBM cells and strategies to counteract it. Finally we are investigating new gene therapy approaches for Ataxia Telangiectasia.

Recent Articles:

 Directed evolution of adeno-associated virus for glioma cell transduction.
J Neurooncol. 2009 Jul 19.

Gaussia Luciferase Variant for High-Throughput Functional Screening Applications.
Anal Chem. 2009 Jul 14.

Mutant sodium channel for tumor therapy.
Mol Ther. 2009 May;17(5):810-9. Epub 2009 Mar 3.

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