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Parkinson Disease: HELP
Articles from Georgetown University
Based on 78 articles published since 2010
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These are the 78 published articles about Parkinson Disease that originated from Georgetown University during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Minor hallucinations in Parkinson disease: A subtle symptom with major clinical implications. 2019

Lenka, Abhishek / Pagonabarraga, Javier / Pal, Pramod Kumar / Bejr-Kasem, Helena / Kulisvesky, Jaime. ·From the Department of Neurology (A.L.), Medstar Georgetown University Hospital, Washington, DC · Movement Disorders Unit, Neurology Department (J.P., H.B.-K., J.K.), Hospital de la Santa Creu i Sant Pau · Biomedical Research Institute (IIB-Sant Pau) (J.P., H.B.-K., J.K.), Sant Antoni Maria Claret · Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (J.P., J.K.), Barcelona, Spain · and Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS) (P.K.P.), Bangalore, India. ·Neurology · Pubmed #31289146.

ABSTRACT: OBJECTIVE: Psychosis is one of the most debilitating complications of Parkinson disease (PD). Although research on PD psychosis has been focused on the study of well-structured visual hallucinations (VH), currently accepted National Institute of Neurological Disorders and Stroke-National Institute of Mental Health diagnostic criteria emphasize minor hallucinations (MH) as the most common psychotic phenomena in PD. The objective of this review is to comprehensively describe the clinical and research advances on the understanding of MH and to provide future directions for obtaining further insights into their potential major implications for PD management and prognosis. METHODS: A PubMed search was done in November 2018 to identify articles on minor psychotic phenomena in PD. RESULTS: MH often precede the onset of well-structured VH and are associated with other nonmotor symptoms such as REM sleep behavior disorder and depression. The pattern of functional brain connectivity changes associated with MH involve visual-processing areas and attention control networks, which overlap with abnormalities described in patients with well-structured VH. The dysfunction of cortical networks in patients with MH may be an early indicator of a more widespread form of the disease. CONCLUSION: Although called "minor," MH may have major clinical and prognostic implications. Further research is needed to establish whether MH are associated with a higher risk of disabling psychotic complications, cognitive deterioration, or a more accelerated disease progression. Understanding the early neurobiological underpinnings of MH may provide the background for future studies to identify the progressive dysfunction of neural circuits leading to more severe forms of psychosis in PD.

2 Review Changing the treatment paradigm for Parkinson's disease psychosis with pimavanserin. 2019

Lyons, Kelly E / Pahwa, Rajesh / Hermanowicz, Neal / Davis, Thomas / Pagan, Fernando / Isaacson, Stuart. ·a Department of Neurology , University of Kansas Medical Center , Kansas City , KS , USA. · b Department of Neurology , University of California Irvine , Irvine , CA , USA. · c Department of Neurology , Vanderbilt University Medical Center , Nashville , TN , USA. · d Department of Neurology , Georgetown University Medical Center , Washington , DC , USA. · e Parkinson's Disease and Movement Disorders Center of Boca Raton , Boca Raton , FL , USA. ·Expert Rev Clin Pharmacol · Pubmed #31159608.

ABSTRACT:

3 Review Botulinum toxin for the treatment of tremor. 2019

Mittal, Shivam Om / Lenka, Abhishek / Jankovic, Joseph. ·Department of Neurology, Vikram Hospital, Bangalore, India. Electronic address: neurology.mittal@gmail.com. · Department of Neurology, MedStar Georgetown University Hospital, Washington, DC, USA. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA. ·Parkinsonism Relat Disord · Pubmed #30709779.

ABSTRACT: Tremor is a key clinical feature of several common neurological disorders. Adequate management of tremor has been an unmet need in clinical practice. Most of the anti-tremor medications have limited efficacy and are associated with undesirable adverse effects, especially in elderly patients. Several studies have reported good outcomes with the use of botulinum neurotoxin (BoNT) for the treatment of tremor. This article aims to systematically review these studies and to highlight the role of BoNT in the management of tremor. A PubMed search was performed in August 2018 to identify articles pertinent to this review. Majority of the studies that have assessed the efficacy of BoNT in tremor, enrolled patients with essential tremor (ET), Parkinson's disease (PD), and dystonic tremor. Results of these studies suggest clinically meaningful improvement in hand tremor in both ET and PD and vocal tremor in ET after BoNT therapy. Additionally, BoNT has been reported to be efficacious in alleviating head and palatal tremor, tremor in multiple sclerosis, and proximal positional tremor. It is apparent that BoNT injections tailored to the needs of individual patients yield better efficacy and lower adverse effects compared to fixed-muscle-fixed-dose approach. BoNT individualized approach adds to the armamentarium for patients who have medically refractory tremors or those who are unable to tolerate the anti-tremor medications. The studies are limited and mostly open-label; thus, randomized placebo-controlled studies are needed to prove the efficacy of BoNT in various tremor conditions.

4 Review Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities. 2018

Calabrese, Vittorio / Santoro, Aurelia / Trovato Salinaro, Angela / Modafferi, Sergio / Scuto, Maria / Albouchi, Ferdaous / Monti, Daniela / Giordano, James / Zappia, Mario / Franceschi, Claudio / Calabrese, Edward J. ·Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania. · IBREGENS, Nutraceuticals and Functional Food Biotechnologies Research Associated, University of Catania, Italy. · Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. · Department of Experimental, Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy. · Departments of Neurology and Biochemistry, and Neuroethics Studies Program, Georgetown University Medical Center, Washington, District of Columbia, USA. · Department of Medical Sciences, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy. · IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy. · Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts, USA. ·J Neurosci Res · Pubmed #30098077.

ABSTRACT: Age-related changes in the brain reflect a dynamic interaction of genetic, epigenetic, phenotypic, and environmental factors that can be temporally restricted or more longitudinally present throughout the lifespan. Fundamental to these mechanisms is the capacity for physiological adaptation through modulation of diverse molecular and biochemical signaling occurring from the intracellular to the network-systemic level throughout the brain. A number of agents that affect the onset and progression of Parkinson's disease (PD)-like effects in experimental models exhibit temporal features, and mechanisms of hormetic dose responses. These findings have particular significance since the hormetic dose response describes the amplitude and range of potential therapeutic effects, thereby affecting the design and conduct of studies of interventions against PD (and other neurodegenerative diseases), and may also be important to a broader consideration of hormetic processes in resilient adaptive responses that might afford protection against the onset and/or progression of PD and related disorders.

5 Review Voice Changes in the Elderly. 2018

Rapoport, Sarah K / Menier, Jayme / Grant, Nazaneen. ·Department of Otolaryngology-Head and Neck Surgery, Medstar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA. · Department of Physical Medicine and Rehabilitation, Medstar Georgetown University Hospital, 3800 Reservoir Road Northwest, Washington, DC 20007, USA. · Medstar Georgetown University Hospital, 1 Gorman Building, 3800 Reservoir Road Northwest, Washington, DC 20007, USA. Electronic address: nazaneen.grant@medstar.net. ·Otolaryngol Clin North Am · Pubmed #29887345.

ABSTRACT: The impact of aging is as inevitable in the larynx as on all biologic systems. The muscles of larynx have the potential to atrophy, the elastin fibers of lamina propria thin with age, and mucous production diminishes. As a result, vocal folds fail to approximate appropriately and the stress on once-robust vocal folds increases. These changes present as poor voice quality, vocal tension, tremor, and altered fundamental frequency. Rather than consider presbyphonia as an immutable diagnosis, we must see it as an opportunity to elevate our standard of care and set goals to work for therapeutic improvement of voice quality.

6 Review Toll-Like Receptor 2 Signaling and Current Approaches for Therapeutic Modulation in Synucleinopathies. 2018

Caplan, Ian F / Maguire-Zeiss, Kathleen A. ·Biology Department, Georgetown University, Washington, DC, United States. · Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United States. ·Front Pharmacol · Pubmed #29780321.

ABSTRACT: The innate immune response in the central nervous system (CNS) is implicated as both beneficial and detrimental to health. Integral to this process are microglia, the resident immune cells of the CNS. Microglia express a wide variety of pattern-recognition receptors, such as Toll-like receptors, that detect changes in the neural environment. The activation of microglia and the subsequent proinflammatory response has become increasingly relevant to synucleinopathies, including Parkinson's disease the second most prevalent neurodegenerative disease. Within these diseases there is evidence of the accumulation of endogenous α-synuclein that stimulates an inflammatory response from microglia via the Toll-like receptors. There have been recent developments in both new and old pharmacological agents designed to target microglia and curtail the inflammatory environment. This review will aim to delineate the process of microglia-mediated inflammation and new therapeutic avenues to manage the response.

7 Review The role of extended-release amantadine for the treatment of dyskinesia in Parkinson's disease patients. 2018

Elkurd, Mazen T / Bahroo, Laxman B / Pahwa, Rajesh. ·Department of Neurology, Medstar Georgetown University Hospital, Georgetown, Washington DC, USA. · Department of Neurology, University of Kansas Medical Center, KS, USA. ·Neurodegener Dis Manag · Pubmed #29564954.

ABSTRACT: Levodopa is the most efficacious treatment for Parkinson's disease (PD). Long-term treatment with levodopa is limited due to dyskinesia. Dyskinesia in PD can be socially and functionally disabling. Extended-release amantadine (amantadine ER) is the first approved medication for the treatment of dyskinesia. When it is given at bedtime, it reaches plasma concentration approximately twice the level achieved by amantadine immediate release. Amantadine ER reduces the severity and duration of dyskinesia during the day, reduces OFF time and increases ON time without troublesome dyskinesia. The most common side effects are hallucination, dizziness, orthostatic hypotension and pedal edema. This review discusses the safety and efficacy of amantadine ER in dyskinesia in PD patients.

8 Review Activating Autophagy as a Therapeutic Strategy for Parkinson's Disease. 2018

Fowler, Alan J / Moussa, Charbel E-H. ·Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Room 203-C, Building D, 4000 Reservoir Rd. NW, Washington, DC, USA. · Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Room 203-C, Building D, 4000 Reservoir Rd. NW, Washington, DC, USA. cem46@georgetown.edu. ·CNS Drugs · Pubmed #29492779.

ABSTRACT: Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease. Here, we review evidence from human, mouse, and cell culture studies to briefly explain these defects in autophagy in Parkinson's disease and the necessity for autophagy to be carefully and precisely tuned to maintain neuron survival. We summarize recent experimental agents for treating alpha-synuclein accumulation in α-synuclein Parkinson's disease and related synucleinopathies. Most of the efforts for developing experimental agents have focused on immunotherapeutic strategies, but we discuss why those efforts are misplaced. Finally, we emphasize why increasing autophagy flux for alpha-synuclein clearance is the most promising therapeutic strategy. Activating autophagy has been successful in preclinical models of Parkinson's disease and yields promising results in clinical trials.

9 Review Aging and Parkinson's Disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. 2018

Calabrese, Vittorio / Santoro, Aurelia / Monti, Daniela / Crupi, Rosalia / Di Paola, Rosanna / Latteri, Saverio / Cuzzocrea, Salvatore / Zappia, Mario / Giordano, James / Calabrese, Edward J / Franceschi, Claudio. ·Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, via Santa Sofia 97, 95123 Catania, Italy; IBREGENS, Nutraceuticals and Functional Food Biotechnologies Research Associated, University of Catania, Italy. Electronic address: calabres@unict.it. · Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via San Giacomo 12, 40126 Bologna, Italy; Interdepartmental Center "L. Galvani" (CIG), University of Bologna, Via San Giacomo 12, 40126 Bologna, Italy. · Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy. · Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy. · Department of General Surgery, Cannizzaro Hospital, University of Catania, Catania, Italy. · Department of Medical Sciences, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy. · Departments of Neurology and Biochemistry, and Neuroethics Studies Program, Georgetown University Medical Center, Washington, DC, USA. · Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, MA, USA. · IRCCS, Institute of Neurological Sciences of Bologna, Via Altura 3, 40139 Bologna, Italy. ·Free Radic Biol Med · Pubmed #29080843.

ABSTRACT: In order to better understand the pathogenesis of Parkinson's Disease (PD) it is important to consider possible contributory factors inherent to the aging process, as age-related changes in a number of physiological systems (perhaps incurred within particular environments) appear to influence the onset and progression of neurodegenerative disorders. Accordingly, we posit that a principal mechanism underlying PD is inflammaging, i.e. the chronic inflammatory process characterized by an imbalance of pro- and anti-inflammatory mechanisms which has been recognized as operative in several age-related, and notably neurodegenerative diseases. Recent conceptualization suggests that inflammaging is part of the complex adaptive mechanisms ("re-modeling") that are ongoing through the lifespan, and which function to prevent or mitigate endogenous processes of tissue disruption and degenerative change(s). The absence of an adequate anti-inflammatory response can fuel inflammaging, which propagates on both local (i.e.- from cell to cell) and systemic levels (e.g.- via exosomes and other molecules present in the blood). In general, this scenario is compatible with the hypothesis that inflammaging represents a hormetic or hormetic-like effect, in which low levels of inflammatory stress may prompt induction of anti-inflammatory mediators and mechanisms, while sustained pro-inflammatory stress incurs higher and more durable levels of inflammatory substances, which, in turn prompt a local-to-systemic effect and more diverse inflammatory response(s). Given this perspective, new treatments of PD may be envisioned that strategically are aimed at exerting hormetic effects to sustain anti-inflammatory responses, inclusive perhaps, of modulating the inflammatory influence of the gut microbiota.

10 Review The Emerging Role of Pimavanserin in the Management of Parkinson's Disease Psychosis. 2017

Hermanowicz, Neal / Alva, Gustavo / Pagan, Fernando / Espay, Alberto J / Patel, Amita / Madrid, Katya Cruz / Kremens, Daniel / Kenney, Jim / Arquette, Sheila / Tereso, Gary / Lopes, Maria / Farnum, Carolyn. ·1 Movement Disorders Program and Department of Neurology, University of California Irvine Health, Irvine, California. · 2 Chapman Global Medical Center, Orange, California; ATP Clinical Research, Costa Mesa, California; and University of California, Riverside, Orange, California. · 3 Department of Neurology; Movement Disorders Program; Georgetown University Hospital National Parkinsonism Foundation Center of Excellence; and Translational Neurotherapeutics Program, Georgetown University, Washington, DC. · 4 Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, Ohio. · 5 Institute for Psychiatric Education, Dayton Psychiatric Association, Dayton, Ohio. · 6 Academic Internal Medicine and Geriatrics, University of Illinois, and Jesse Brown Veterans' Center, Chicago, Illinois. · 7 Movement Disorders Program and Department of Neurology, Jefferson University, Philadelphia, Pennsylvania. · 8 Specialty and Pharmacy Contracts, Harvard Pilgrim Health Care, Quincy, Massachusetts. · 9 Pharmacy Services, Independent Health, Buffalo, New York. · 10 Health New England, Springfield, Massachusetts. · 11 Magellan Rx Management, Newport, Rhode Island. ·J Manag Care Spec Pharm · Pubmed #28636480.

ABSTRACT: A panel of experts drawn from neurology, psychiatry, geropsychiatry, geriatrics, and pharmacy representatives of 3 health plans convened in New York City on July 30, 2016, with the objective of sharing opinions, ideas, and information regarding the optimal management of Parkinson's disease psychosis (PDP). Three key points emerged from the discussion: (1) Because of the nature of Parkinson's disease and PDP, finding appropriate treatment can prove challenging; (2) emerging therapies may present an opportunity for effective disease management; and (3) moving forward, provider and patient education regarding PDP and available treatment options is essential for well-managed symptoms and better quality of life. The panel reviewed current practices and formulated recommendations on moving forward in the treatment of PDP. DISCLOSURES: This project and manuscript was funded by ACADIA Pharmaceuticals and developed by Magellan Rx Management. Lopes and Farnum are employees of Magellan Rx Management. Kremens has received consulting/speaker fees from Teva Pharmaceuticals, UCB, Sunovion, Impax, Lundbeck, ACADIA, USWorldMeds, Merz, Acorda, Kyowa, Neurocrine, and GE Healthcare. Pagan reports consulting/speaker fees from Teva Nanoscience, AbbVie, Impax, ACADIA, Medtronic, USWorldMeds, Merz, and Cynapsus and research and educational grants from USWorldMeds, Teva, and Medtronic. Patel has received consultant/speaker fees from ACADIA, Allergen, and Avanir. Alva reports research support from Accera, Allergan, Axovant, Eisai, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Suven, and Trans Tech and consultant/speaker fees from ACADIA, Alkermes, Allergan, Avanir, Janssen, Lundbeck, Merck, Nestle, Otsuka, Sunovion, Takeda, and Vanda. The other authors report no potential conflicts of interest, financial or otherwise.

11 Review Microbial Immuno-Communication in Neurodegenerative Diseases. 2017

Main, Bevan S / Minter, Myles R. ·Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center Washington, DC, USA. · Department of Neurobiology, University of ChicagoChicago, IL, USA; The Microbiome Center, University of ChicagoChicago, IL, USA. ·Front Neurosci · Pubmed #28386215.

ABSTRACT: Neuro-inflammation is a critical process by which the brain coordinates chemokine-regulated cellular recruitment, cytokine release, and cell-mediated removal of pathogenic material to protect against infection or brain injury. Dysregulation of this immune response is involved in multiple neurodegenerative disorders, however the precise contribution of neuro-inflammation to the exacerbation and progression of these diseases remains unclear. Evidence now suggests that commensal micro-organisms populating the host and their metabolites, collectively termed the microbiome, regulate innate immunity by influencing peripheral immune cell populations, and modulating microglial phenotype. Recent preclinical studies now demonstrate that perturbations in the host microbiome can induce alterations in pathological phenotypes associated with numerous neurodegenerative diseases. How perturbations in the host microbiome and subsequently altered peripheral immune status are communicated to the brain to influence neuro-inflammatory processes in these neurodegenerative disease settings is far from understood. This review provides insight into the regulation of neuro-inflammatory processes by the host microbiome in the context of neurodegenerative disease and highlights the potential importance of the blood-brain barrier and blood-cerebrospinal fluid-brain barrier, functioning as "immune barriers," to communicate host immune status to the brain. Understanding the mechanisms by which the commensal microbiome communicates with the brain to influence neuro-inflammatory processes will be critical in the development of microbially-targeted therapeutics in the potential treatment of neurodegenerative disorders.

12 Review ER stress and Parkinson's disease: Pathological inputs that converge into the secretory pathway. 2016

Mercado, Gabriela / Castillo, Valentina / Soto, Paulina / Sidhu, Anita. ·Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. Electronic address: mariamercado@med.uchile.cl. · Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. · Department of Biochemistry and Molecular and Cellular, Georgetown University, Washington D.C., USA. ·Brain Res · Pubmed #27103567.

ABSTRACT: The major clinical feature of Parkinson's disease (PD) is impairment in motor control as a result of extensive dopaminergic neuron loss in the substantia nigra pars compacta. The central pathological hallmark of PD is the formation of neuronal cytoplasmic inclusions of insoluble proteins called Lewy bodies, of which fibrillar aggregates of misfolded αSynuclein are the major components. Despite intense research on the pathogenic mechanism that trigger neuronal loss and disease progression, the neurogenesis of PD remains unknown. However, studies on genetics of PD have identified specific genes and proteins linked to this disease. Genetic mutations linked with different forms of familial PD have unveiled a closer relationship between pathology and impairments at different points in the secretory pathway. Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum and disruptions in protein clearance mechanisms result in activation of an adaptive stress pathway known as the unfolded protein response (UPR). UPR signaling is mediated by three stress sensors that induce independent and convergent signaling branches that help to maintain homeostasis, or eventually trigger cell death under chronic stress conditions. Signs of ER stress are observed in post-mortem tissue from sporadic human PD cases and in most animal models of the disease, implicating all three branches of this cellular response. However, the exact contribution of the UPR in the progression of PD or in dopaminergic neuron survival is not yet well understood. A large number of studies reveal a clear activation of the UPR in toxicological models resembling sporadic PD, where ATF6, XBP1 and CHOP have a functional role in controlling dopaminergic neuron survival in neurotoxin-based models of PD in vivo. Also pharmacological and gene therapy approaches aimed to target different points of this pathway have revealed an important functional role in PD pathogenesis. This article is part of a Special Issue entitled SI:ER stress.

13 Review Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease. 2015

Moussa, Charbel E-H. ·Department of Neurology, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, D.C., USA. ·Neurodegener Dis · Pubmed #26160424.

ABSTRACT: Parkin biology has emerged as an exciting area of pharmaceutical development for several human diseases, including cancer and neurodegeneration. Parkin's role is multifaceted in human health and disease and its function affecting major cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, is critical in the maintenance of cellular homeostasis. Loss of Parkin function due to aging, protein instability and gene mutations is manifest in a number of human diseases, contributing to the validation of this protein as a therapeutic target. Parkin activation to mobilize cellular quality control mechanisms and counteract dyshomeostasis is a highly desirable area for therapeutic development. The elucidation of Parkin's crystal structure and better understanding of possible posttranslational modifications (i.e. phosphorylation, ubiquitination, etc.) that regulate Parkin's enzymatic activity suggest that this protein is a therapeutic drug target in many human diseases. Here we review Parkin's role in health and disease and discuss the effects of self-ubiquitination and deubiquitination on Parkin activity. This review provides further evidence showing the longitudinal effects of Parkin deletion on mitochondrial function, oxidative stress and neurotransmitter balance in vivo using high-frequency (1)H/(13)C NMR spectroscopy.

14 Review A compensatory role for declarative memory in neurodevelopmental disorders. 2015

Ullman, Michael T / Pullman, Mariel Y. ·Brain and Language Laboratory, Department of Neuroscience, Georgetown University, Box 571464, Washington, DC 20057-1464, United States. Electronic address: michael@georgetown.edu. · Brain and Language Laboratory, Department of Neuroscience, Georgetown University, Box 571464, Washington, DC 20057-1464, United States. ·Neurosci Biobehav Rev · Pubmed #25597655.

ABSTRACT: Most research on neurodevelopmental disorders has focused on their abnormalities. However, what remains intact may also be important. Increasing evidence suggests that declarative memory, a critical learning and memory system in the brain, remains largely functional in a number of neurodevelopmental disorders. Because declarative memory remains functional in these disorders, and because it can learn and retain numerous types of information, functions, and tasks, this system should be able to play compensatory roles for multiple types of impairments across the disorders. Here, we examine this hypothesis for specific language impairment, dyslexia, autism spectrum disorder, Tourette syndrome, and obsessive-compulsive disorder. We lay out specific predictions for the hypothesis and review existing behavioral, electrophysiological, and neuroimaging evidence. Overall, the evidence suggests that declarative memory indeed plays compensatory roles for a range of impairments across all five disorders. Finally, we discuss diagnostic, therapeutic and other implications.

15 Review An update on the use of botulinum toxin therapy in Parkinson's disease. 2015

Mills, Reversa / Bahroo, Laxman / Pagan, Fernando. ·Movement Disorders Division, Department of Neurology, Georgetown University Hospital, 3900 Reservoir Rd, NW, 7 PHC, Washington, DC, 20007, USA, reversa.mills@gunet.georgetown.edu. ·Curr Neurol Neurosci Rep · Pubmed #25407133.

ABSTRACT: Botulinum toxin (BoNT) has gained widespread use in a variety of neurological conditions. Parkinson's disease is a complex neurodegenerative disorder manifested by motor and non-motor symptoms that can cause significant disability. BoNT has been used to effectively treat a variety of symptoms related to Parkinson's disease. This review will examine the current therapeutic indications of BoNT use in the following disorders related to Parkinson's disease: cervical dystonia, blepharospasm and lid apraxia, focal hand dystonia, foot dystonia, laryngeal dystonia, oromandibular dystonia, camptocormia, hand and jaw tremor, sialorrhea, hyperhidrosis, dysphagia, constipation, and overactive bladder.

16 Review Neuroprotective effects of angiotensin receptor blockers. 2015

Villapol, Sonia / Saavedra, Juan M. ·Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA; · Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, District of Columbia, USA. jms522@georgetown.edu. ·Am J Hypertens · Pubmed #25362113.

ABSTRACT: Angiotensin II receptor blockers (ARBs, collectively called sartans) are widely used compounds therapeutically effective in cardiovascular disorders, renal disease, the metabolic syndrome, and diabetes. It has been more recently recognized that ARBs are neuroprotective and have potential therapeutic use in many brain disorders. ARBs ameliorate inflammatory and apoptotic responses to glutamate, interleukin 1β and bacterial endotoxin in cultured neurons, astrocytes, microglial, and endothelial cerebrovascular cells. When administered systemically, ARBs enter the brain, protecting cerebral blood flow, maintaining blood brain barrier function and decreasing cerebral hemorrhage, excessive brain inflammation and neuronal injury in animal models of stroke, traumatic brain injury, Alzheimer's and Parkinson's disease and other brain conditions. Epidemiological analyses reported that ARBs reduced the progression of Alzheimer's disease, and clinical studies suggested amelioration of cognitive loss following stroke and aging. ARBs are pharmacologically heterogeneous; their effects are not only the result of Ang II type 1(AT1) receptor blockade but also of additional mechanisms selective for only some compounds of the class. These include peroxisome proliferator-activated receptor gamma activation and other still poorly defined mechanisms. However, the complete pharmacological spectrum and therapeutic efficacy of individual ARBs have never been systematically compared, and the neuroprotective efficacy of these compounds has not been rigorously determined in controlled clinical studies. The accumulation of pre-clinical evidence should promote further epidemiological and controlled clinical studies. Repurposing ARBs for the treatment of brain disorders, currently without effective therapy, may be of immediate and major translational value.

17 Review Immune responses in Parkinson's disease: interplay between central and peripheral immune systems. 2014

Su, Xiaomin / Federoff, Howard J. ·Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. · Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA ; Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. ·Biomed Res Int · Pubmed #24822191.

ABSTRACT: The etiology of Parkinson's disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Recent studies establish that central and peripheral inflammation occurs in the prodromal stage of the disease and sustains disease progression. Aging, heritable risk factors, or environmental exposures may contribute to the initiation of central or peripheral inflammation. One emerging hypothesis is that inflammation plays a critical role in PD neuropathology. Increasing evidence suggest that activation of the peripheral immune system exacerbates the discordant central inflammatory response and synergistically drives neurodegeneration. We provide an overview of current knowledge on the temporal profile of central and peripheral immune responses in PD and discuss the potential synergistic effects of the central and peripheral inflammation in disease development. The understanding of the nature of the chronic inflammation in disease progression and the possible risk factors that contribute to altered central and peripheral immune responses will offer mechanistic insights into PD etiology and pathology and benefit the development of effective tailored therapeutics for human PD.

18 Review Using viral-mediated gene delivery to model Parkinson's disease: do nonhuman primate investigations expand our understanding? 2014

Fiandaca, Massimo S / Federoff, Howard J. ·Department of Neurology, Georgetown University, Washington, D.C. 20007, USA; Department of Neuroscience, Georgetown University, Washington, D.C. 20007, USA. ·Exp Neurol · Pubmed #23524194.

ABSTRACT: In this review, we consider the use of nonhuman primate (NHP) models of Parkinson's disease (PD) produced using viral-mediated gene delivery and information they provide in comparison to other model systems in rodents and NHPs. To date, rodent and NHP PD models have found it difficult to fully recapitulate the human disorder and, therefore, provide little actual insight into disease progression. The viral-mediated gene delivery method for α-synuclein has been shown to produce a parkinsonian rodent and NHP. This novel viral-mediated gene transfer model in the NHP appears to provide a significant advance beyond neurotoxicant models, by more closely mimicking the more chronic time course of developed behavioral deterioration and neuropathology. Although we agree that the use of these novel methods inducing parkinsonian NHPs may provide relevant treatment insights, beyond those of more standard PD models, we remain cautious as to the preclinical models' ability to predict outcomes in human trials. In specific cases of certain novel medical therapeutics, therefore, we also consider the phase 0 clinical trial as offering an alternative to the currently non-predictive preclinical models, including those in the NHP.

19 Review Parallel mechanisms for direct and indirect membrane protein trafficking by synucleins. 2013

Oaks, Adam W / Sidhu, Anita. ·Laboratory of Molecular Neurochemistry; Department of Biochemistry and Molecular & Cellular Biology; Georgetown University Medical Center; Washington, DC USA. ·Commun Integr Biol · Pubmed #24563712.

ABSTRACT: More than 2 decades of work have yet to conclusively determine the physiological role of the synuclein proteins, even though these abundant brain constituents are participants in a broad array of cellular processes. Among proposed physiological roles is a functional interaction between the synuclein proteins and monoamine transporters contributing to transporter trafficking through direct protein-protein interactions. Recent work shows that an antagonistic effect of the synuclein proteins on the secretory functions of the endoplasmic reticulum and the Golgi apparatus appears to simultaneously influence trafficking of the dopamine transporter and other membrane proteins. Here, we highlight these new findings in view of the broader literature identifying the role of synucleins in protein trafficking and suggest emerging themes for ongoing and future work in the field of synuclein biology.

20 Review Network modeling to identify new mechanisms and therapeutic targets for Parkinson's disease. 2013

MacArthur, Linda / Ressom, Habtom / Shah, Salim / Federoff, Howard J. ·Georgetown University Medical Center, Washington, DC, USA. ·Expert Rev Neurother · Pubmed #23739005.

ABSTRACT: Biomolecules in subnetworks are the focus of a new strategy to develop drugs that halt complex diseases. In this article, the authors use genome-wide association study and linkage data derived from Parkinson's disease studies to illustrate how algorithms that use gene and protein interaction databases reveal subnetworks in biological systems that suggest mechanisms for disease progression. Network modeling may help develop testable hypotheses for neurodegenerative diseases and open up new avenues for therapeutic development.

21 Review Parkinson's disease. 2012

Mhyre, Timothy R / Boyd, James T / Hamill, Robert W / Maguire-Zeiss, Kathleen A. ·Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, NW NRB WP-24A, 20057, Washington, DC, USA, trm36@georgetown.edu. ·Subcell Biochem · Pubmed #23225012.

ABSTRACT: Parkinson's disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800's by James Parkinson as the 'Shaking Palsy'. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.

22 Review Improving outcomes through early diagnosis of Parkinson's disease. 2012

Pagan, Fernando L. ·Movement Disorders Program, Department of Neurology, Georgetown University Hospital, Washington, DC, USA. FPOGAN01@gunet.georgetown.edu ·Am J Manag Care · Pubmed #23039866.

ABSTRACT: Current diagnostic modalities in Parkinson's disease (PD) are limited by the fact that they identify PD by the presence of motor symptoms; by this point, over 60 percent of all dopamine neurons within specific regions of the basal ganglia may have been lost. Nonmotor symptoms manifest in PD long before motor symptoms, and the early presence of nonmotor symptoms offers an opportunity for early diagnosis and early treatment of PD, with consequent benefits to patient quality of life and potential treatment cost savings. Numerous different premotor symptoms have been identified; diminished olfactory function and REM behavioral sleep disorders (RBDs) may be particularly suitable for the purposes of early diagnosis. Olfactory testing, while in itself not specific for PD, has been shown to offer very high degrees of sensitivity and specificity in distinguishing PD from healthy controls and from other forms of parkinsonism, particularly when accompanied by other means of detection, such as sonography, motor symmetry evaluation, and magnetic resonance imaging (MRI)/diffusion tensor imaging. Biological biomarkers--including protein panels and autoantibody testing--have demonstrated excellent diagnostic capacity, and a recently identified 5-gene panel has been shown to have high specificity and sensitivity in distinguishing early PD from healthy controls and advanced PD. Increasingly sophisticated neuroimaging techniques are also proving capable of early PD detection and differentiation from other parkinsonian types. These recent developments in PD diagnosis underscore the necessity of rethinking what PD is and how, and when, it can be diagnosed.

23 Review Genomics and bioinformatics of Parkinson's disease. 2012

Scholz, Sonja W / Mhyre, Tim / Ressom, Habtom / Shah, Salim / Federoff, Howard J. ·Department of Neuroscience, Georgetown University, Washington, DC, USA. ·Cold Spring Harb Perspect Med · Pubmed #22762024.

ABSTRACT: Within the last two decades, genomics and bioinformatics have profoundly impacted our understanding of the molecular mechanisms of Parkinson's disease (PD). From the description of the first PD gene in 1997 until today, we have witnessed the emergence of new technologies that have revolutionized our concepts to identify genetic mechanisms implicated in human health and disease. Driven by the publication of the human genome sequence and followed by the description of detailed maps for common genetic variability, novel applications to rapidly scrutinize the entire genome in a systematic, cost-effective manner have become a reality. As a consequence, about 30 genetic loci have been unequivocally linked to the pathogenesis of PD highlighting essential molecular pathways underlying this common disorder. Herein we discuss how neurogenomics and bioinformatics are applied to dissect the nature of this complex disease with the overall aim of developing rational therapeutic interventions.

24 Review Misfolded α-synuclein and Toll-like receptors: therapeutic targets for Parkinson's disease. 2012

Béraud, Dawn / Maguire-Zeiss, Kathleen A. ·Department of Neurostience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA. ·Parkinsonism Relat Disord · Pubmed #22166424.

ABSTRACT: Parkinson's disease (PD) is typified by the loss of midbrain dopamine neurons, the presence of large proteinaceous α-synuclein-positive intracellular inclusions, oxidatively modified molecules and activated microglia. The etiology of sporadic PD is not fully understood but several lines of evidence suggest that genetic vulnerability and environmental toxicants converge to incite pathology--the multiple hit hypothesis. One gene linked to both familial and sporadic PD is SNCA, which encodes for the protein α-synuclein that has a propensity to misfold into toxic moieties. Here we show that α-synuclein directly activates microglia inciting the production of proinflammatory molecules and altering the expression of Toll-like receptors (TLRs). We discuss the role for α-synuclein-directed TLR expression changes in PD and the therapeutic potential of modifying this response.

25 Review Future directions for immune modulation in neurodegenerative disorders: focus on Parkinson's disease. 2010

Maguire-Zeiss, Kathleen A / Federoff, Howard J. ·Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA. ·J Neural Transm (Vienna) · Pubmed #20549523.

ABSTRACT: One common feature of neurodegenerative diseases is neuroinflammation. In the case of Parkinson's disease (PD), neuroinflammation appears early and persists throughout the disease course. The principal cellular mediator of brain inflammation is the resident microglia which share many features with related hematopoietically derived macrophages. Microglia can become activated by misfolded proteins including the PD relevant example, alpha-synuclein, a presynaptic protein. When activated, microglia release pro-inflammatory diffusible mediators that promote dysfunction and contribute to the death of the PD vulnerable dopaminergic neurons in the midbrain. Recently, the orphan nuclear receptor Nurr1, well known as a critical determinant in dopaminergic neuron maturation, has been ascribed two new properties. First, it promotes the production and release of the neuropeptide vasoactive intestinal peptide that functions both to stimulate dopaminergic neuron survival and inhibit neuroinflammation. Second, Nurr1 suppresses the expression and release of pro-inflammatory cytokines in glial cells. Herein, we discuss these new findings in context of strategies to attenuate neuroinflammation in PD.

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