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Parkinson Disease: HELP
Articles from Michigan
Based on 329 articles published since 2008
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These are the 329 published articles about Parkinson Disease that originated from Michigan during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14
1 Editorial Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection. 2017

Labrie, Viviane / Brundin, Patrik. ·Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA. ·J Innate Immun · Pubmed #28866688.

ABSTRACT: Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood. We discuss a recent study reporting that viral infection induces alpha-synuclein expression in neurons of the gastrointestinal tract. Alpha-synuclein levels increased during norovirus infection in the duodenum of children. In an in vitro paradigm, monomeric and oligomeric alpha-synuclein acted as chemoattractants for neutrophils and monocytes, and promoted the maturation of dendritic cells. This suggests that alpha-synuclein facilitates immune responses to infection. We explore the possibility that intestinal infections, and associated inflammation, place individuals at increased risk of PD by increasing alpha-synuclein levels and promoting the formation of alpha-synuclein aggregates that propagate in a prion-like fashion via the vagal nerve to the brainstem.

2 Editorial What would Dr. James Parkinson think today? parcelling out the circuitry of levodopa-induced dyskinesias. 2017

Kordower, Jeffrey H. ·Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, 60612. · The Van Andel Research Institute, Grand Rapids Michigan, 49503. ·Mov Disord · Pubmed #28425143.

ABSTRACT: -- No abstract --

3 Editorial What would Dr. James Parkinson think today? II. Neuroimaging in Parkinson's disease. 2017

Albin, Roger L. ·Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. · Neurology Service & Geriatrics Research, Education, and Clinical Center, Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan, USA. · University of Michigan Morris K. Udall Center of Excellence for Parkinson's Disease Research, Ann Arbor, Michigan, USA. · University of Michigan Alzheimer Disease Center, Ann Arbor, Michigan, USA. ·Mov Disord · Pubmed #28218459.

ABSTRACT: -- No abstract --

4 Editorial Fetal grafts for Parkinson's disease: Decades in the making. 2016

Kordower, Jeffrey H / Olanow, C Warren. ·Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; Van Andel Institute, Grand Rapids, MI 49503; jkordowe@rush.edu. · Department of Neurology, Mt. Sinai School of Medicine, New York, NY 10029; Department of Neuroscience, Mt. Sinai School of Medicine, New York, NY 10029. ·Proc Natl Acad Sci U S A · Pubmed #27247420.

ABSTRACT: -- No abstract --

5 Editorial The pharmacodynamics of placebo: expectation effects of price as a proxy for efficacy. 2015

LeWitt, Peter A / Kim, Scott. ·From the Department of Neurology (P.A.L.), Parkinson's Disease and Movement Disorders Center, Henry Ford West Bloomfield Hospital · Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI · and Department of Bioethics (S.K.), National Institutes of Health, Bethesda, MD. ·Neurology · Pubmed #25632090.

ABSTRACT: -- No abstract --

6 Editorial How I examine my patient: the art of neurological examination for Parkinson's disease. 2014

Bloem, Bastiaan R / Brundin, Patrik. ·Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Department of Neurology, Nijmegen, The Netherlands. · Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA. ·J Parkinsons Dis · Pubmed #25281608.

ABSTRACT: -- No abstract --

7 Editorial Dopamine-dependent functional connectivity in Parkinson disease: a resting-state diagnosis? 2014

Bohnen, Nicolaas I / Martin, W R Wayne. ·From the Departments of Radiology and Neurology (N.I.B.), University of Michigan, and VA Ann Arbor Healthcare System, MI · and the Movement Disorders Program (W.R.W.M.), Division of Neurology, University of Alberta, Edmonton, Canada. ·Neurology · Pubmed #24920849.

ABSTRACT: -- No abstract --

8 Editorial Predicting the development of levodopa-induced dyskinesias: a presynaptic mechanism? 2014

Lewitt, Peter A / Mouradian, M Maral. ·From the Department of Neurology (P.A.L.), Henry Ford Hospital, Bloomfield · the Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI · and Center for Neurodegenerative and Neuroimmunologic Diseases (M.M.M.), Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ. ·Neurology · Pubmed #24719487.

ABSTRACT: After chronic levodopa use, many patients with Parkinson disease (PD) develop involuntary movements. Whether disabling or minor, levodopa-induced dyskinesia (LID) constitutes an undesirable outcome calling for better treatment strategies. Options for managing LID include delaying its onset by combining a dopaminergic agonist with levodopa from the start(1) or symptomatic control using amantadine. However, fundamental questions about LID remain: by what mechanisms does it develop, and why don't all patients go on to experience LID after sustained levodopa exposure?

9 Editorial Placebo: from belief to movement. 2014

Postuma, Ronald B / Albin, Roger L. ·From the Department of Neurology (R.B.P.), McGill University, Montreal General Hospital, Canada · Neurology Service & GRECC (R.L.A.), VAAAHS · Department of Neurology (R.L.A.), University of Michigan · and Michigan Alzheimer's Disease Center (R.L.A.), Ann Arbor. ·Neurology · Pubmed #24658928.

ABSTRACT: -- No abstract --

10 Editorial Feeling the need ... the need for speed (of processing training) in Parkinson disease. 2013

Chou, Kelvin L / Cronin-Golomb, Alice. ·From the Departments of Neurology and Neurosurgery (K.L.C.), University of Michigan, Ann Arbor · and the Department of Psychology (A.C.-G.), Boston University, MA. ·Neurology · Pubmed #24014502.

ABSTRACT: -- No abstract --

11 Review Triggers, Facilitators, and Aggravators: Redefining Parkinson's Disease Pathogenesis. 2019

Johnson, Michaela E / Stecher, Benjamin / Labrie, Viviane / Brundin, Lena / Brundin, Patrik. ·Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, MI 49503, USA; These authors contributed equally to this work. · Tomorrow Edition, Toronto, Canada; These authors contributed equally to this work. · Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, MI 49503, USA. · Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, MI 49503, USA. Electronic address: Patrik.Brundin@vai.org. ·Trends Neurosci · Pubmed #30342839.

ABSTRACT: We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective.

12 Review Molecular Imaging of the Cholinergic System in Parkinson's Disease. 2018

Bohnen, Nicolaas I / Kanel, Prabesh / Müller, Martijn L T M. ·Department of Radiology, University of Michigan, Ann Arbor, MI, United States; Department of Neurology, University of Michigan, Ann Arbor, MI, United States; Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI, United States; Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI, United States. Electronic address: nbohnen@umich.edu. · Department of Radiology, University of Michigan, Ann Arbor, MI, United States; Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI, United States. ·Int Rev Neurobiol · Pubmed #30314597.

ABSTRACT: One of the first identified neurotransmitters in the brain, acetylcholine, is an important modulator that drives changes in neuronal and glial activity. For more than two decades, the main focus of molecular imaging of the cholinergic system in Parkinson's disease (PD) has been on cognitive changes. Imaging studies have confirmed that degeneration of the cholinergic system is a major determinant of dementia in PD. Within the last decade, the focus is expanding to studying cholinergic correlates of mobility impairments, dyskinesias, olfaction, sleep, visual hallucinations and risk taking behavior in this disorder. These studies increasingly recognize that the regional topography of cholinergic brain areas associates with specific functions. In parallel with this trend, more recent molecular cholinergic imaging approaches are investigating cholinergic modulatory functions and contributions to large-scale brain network functions. A novel area of research is imaging cholinergic innervation functions of peripheral autonomic organs that may have the potential of future prodromal diagnosis of PD. Finally, emerging evidence of hypercholinergic activity in prodromal and symptomatic leucine-rich repeat kinase 2 PD may reflect neuronal cholinergic compensation versus a response to neuro-inflammation. Molecular imaging of the cholinergic system has led to many new insights in the etiology of dopamine non-responsive symptoms of PD (more "malignant" hypocholinergic disease phenotype) and is poised to guide and evaluate future cholinergic drug development in this disorder.

13 Review Nighttime Sleep and Daytime Sleepiness Improved With Pimavanserin During Treatment of Parkinson's Disease Psychosis. 2018

Patel, Neepa / LeWitt, Peter / Neikrug, Ariel B / Kesslak, Patrick / Coate, Bruce / Ancoli-Israel, Sonia. ·Parkinson's Disease and Movement Disorders Program, Henry Ford Hospital, West Bloomfield, MI. · Department of Psychiatry and Human Behavior, University of California Irvine, Irvine. · ACADIA Pharmaceuticals Inc, San Diego. · Departments of Psychiatry and Medicine, University of California, San Diego, La Jolla, CA. ·Clin Neuropharmacol · Pubmed #30303817.

ABSTRACT: INTRODUCTION: Impaired nocturnal sleep and excessive daytime sleepiness are common problems for patients with Parkinson's disease, and patients with Parkinson's disease with sleep dysfunction are 5 times more likely to experience psychotic symptoms. Pimavanserin, a 5-HT2A inverse agonist approved to treat Parkinson's disease psychosis, may improve sleep quality in patients with Parkinson's disease experiencing sleep disturbances. METHODS: Scales for Outcomes in Parkinson's Disease nighttime sleep (SCOPA-NS) and SCOPA-daytime sleepiness (DS) data obtained during 2 double-blind placebo-controlled studies of pimavanserin in persons with Parkinson's disease psychosis were evaluated. Data from the placebo and pimavanserin 34 mg groups in the 2 studies were pooled to provide further information on the effect of pimavanserin 34 mg on sleep. Additional analyses on the pooled study data were performed on participants with significantly impaired nighttime sleep and daytime sleepiness, defined as SCOPA-NS ≥7 and SCOPA-DS ≥5, respectively. RESULTS: In the pooled analysis, treatment effects, expressed as least squares mean reductions in SCOPA-NS at week 6, were -1.4 for pimavanserin 34 mg and -0.5 for placebo. At week 6, the decrease from baseline in SCOPA-DS for the pimavanserin 34 mg group was -1.7 and -1.2 for the placebo group (P = 0.108). When evaluating participants with impaired nighttime sleep and daytime sleepiness at baseline, the SCOPA-NS score change was -4.4 for the pimavanserin 34 mg group and -2.3 for the placebo group (P = 0.002), whereas the SCOPA-DS change was -2.9 and -1.9 for the pimavanserin 34 mg and placebo groups (P = 0.120), respectively. CONCLUSION: The data from the trials suggest that nighttime sleep improved with administration of pimavanserin, a novel 5-HT2A receptor inverse agonist/antagonist.

14 Review Prion-like propagation of pathology in Parkinson disease. 2018

Volpicelli-Daley, Laura / Brundin, Patrik. ·Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States. · Van Andel Research Institute, Center for Neurodegenerative Science, Grand Rapids, MI, United States. Electronic address: Patrik.Brundin@vai.org. ·Handb Clin Neurol · Pubmed #29887143.

ABSTRACT: Over 100 years ago, Lewy bodies and Lewy neurites were defined as a pathologic hallmark of Parkinson disease. Eighty years later, α-synuclein was found to be the primary component of these inclusions. Emerging evidence suggests that α-synuclein pathology propagates across interconnected networks throughout the nervous system in a prion-like manner. Pathologic α-synuclein seeds aggregation of native α-synuclein, resulting in the formation of insoluble inclusions. These seeds can propagate within the neuron and to interconnected neurons, resulting in the spread of pathology throughout the brain. Here, we discuss how the findings that α-synuclein pathology spreads throughout the nervous system has revolutionized our understanding about Parkinson disease pathogenesis and resulted in the development of novel therapeutic strategies to halt disease progression.

15 Review Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration. 2018

Quansah, Emmanuel / Peelaerts, Wouter / Langston, J William / Simon, David K / Colca, Jerry / Brundin, Patrik. ·Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, 333 Bostwick Ave, Michigan, 49503, USA. · KU Leuven, Laboratory for Gene Therapy and Neurobiology, 3000, Leuven, Belgium. · Stanford Udall Center, Department of Pathology, Stanford University, Palo Alto, CA, USA. · Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. · Metabolic Solutions Development Company, Kalamazoo, MI, 49007, USA. · Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, 333 Bostwick Ave, Michigan, 49503, USA. patrik.brundin@vai.org. ·Mol Neurodegener · Pubmed #29793507.

ABSTRACT: Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson's disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson's disease and recent research on rare inherited forms of Parkinson's disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria. Pharmacological inhibition of the MPC was recently found to be strongly neuroprotective in multiple neurotoxin-based and genetic models of neurodegeneration which are relevant to Parkinson's disease. In this review, we summarize the neuroprotective effects of MPC inhibition and discuss the potential putative underlying mechanisms. These mechanisms involve augmentation of autophagy via attenuation of the activity of the mammalian target of rapamycin (mTOR) in neurons, as well as the inhibition of neuroinflammation, which is at least partly mediated by direct inhibition of MPC in glia cells. We conclude that MPC is a novel and potentially powerful therapeutic target that warrants further study in attempts to slow Parkinson's disease progression.

16 Review ɑ-Synuclein strains and seeding in Parkinson's disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences. 2018

Peelaerts, W / Bousset, L / Baekelandt, V / Melki, R. ·Laboratory for Neurobiology and Gene Therapy, KU Leuven, 3000, Leuven, Belgium. · Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, 49503, USA. · Paris-Saclay Institute of Neuroscience, CNRS, 91190, Gif-sur-Yvette, France. · Laboratory for Neurobiology and Gene Therapy, KU Leuven, 3000, Leuven, Belgium. veerle.baekelandt@kuleuven.be. ·Cell Tissue Res · Pubmed #29704213.

ABSTRACT: Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion-like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, ɑ-synuclein (ɑSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of ɑSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on ɑSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis.

17 Review The concept of alpha-synuclein as a prion-like protein: ten years after. 2018

Steiner, Jennifer A / Quansah, Emmanuel / Brundin, Patrik. ·Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA. jennifer.steiner@vai.org. · Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA. ·Cell Tissue Res · Pubmed #29480459.

ABSTRACT: Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

18 Review Delta Opioid Pharmacology in Parkinson's Disease. 2018

Mabrouk, Omar S. ·Department of Chemistry, University of Michigan, 930 North University, Ann Arbor, MI, 48109, USA. omabrouk@umich.edu. · Department of Pharmacology, University of Michigan, 930 North University, Ann Arbor, MI, 48109, USA. omabrouk@umich.edu. ·Handb Exp Pharmacol · Pubmed #27718057.

ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disorder that compromises multiple neurochemical substrates including dopamine, norepinephrine, serotonin, acetylcholine, and glutamate systems. Loss of these transmitter systems initiates a cascade of neurological deficits beginning with motor function and ending with dementia. Current therapies primarily address the motor symptoms of the disease via dopamine replacement therapy. Exogenous dopamine replacement brings about additional challenges since after years of treatment it almost invariably gives rise to dyskinesia as a side effect. Therefore there is a clear unmet clinical need for improved PD therapeutics. Opioid receptors and their respective peptides are expressed throughout the basal ganglia and cortex where monoaminergic denervation strongly contributes to PD pathology. Delta opioid receptors are of particular interest because of their dense localization in basal ganglia and because activating this system is known to enhance locomotor activity under a variety of conditions. This chapter will outline much of the work that has demonstrated the effectiveness of delta opioid receptor activation in models of PD and its neuroprotective properties. It also discusses some of the challenges that must be addressed before moving delta opioid receptor agonists into a clinical setting.

19 Review Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease? 2017

Thirtamara-Rajamani, Keerthi / Li, Peipei / Escobar Galvis, Martha L / Labrie, Viviane / Brundin, Patrik / Brundin, Lena. ·Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA. ·J Parkinsons Dis · Pubmed #29103054.

ABSTRACT: Several large genome wide association studies have identified a locus in close proximity to the gene encoding the enzyme aminocarboxymuconate-semialdehyde-decarboxylase (ACMSD) to be associated with the risk for Parkinson's disease (PD), tentatively suggesting that this enzyme might influence PD pathogenesis. Further support for this comes from the recent identification of a disease-segregating stop codon mutation in ACMSD in a family with Parkinsonism, and a missense mutation in the ACMSD gene predicted to disrupt enzyme function in an individual with typical PD. ACMSD is part of the kynurenine pathway, responsible for the catalytic breakdown of tryptophan into NAD+, generating several neuroactive metabolites in the process. The enzyme is located at a key branch-point of the pathway, limiting the production of the neurotoxin quinolinic acid, which has excitotoxic and inflammatory properties. In this review, we discuss the genetic findings in light of the functions of ACMSD and its potential involvement in PD pathogenesis.

20 Review Prying into the Prion Hypothesis for Parkinson's Disease. 2017

Brundin, Patrik / Melki, Ronald. ·Van Andel Research Institute, Center for Neurodegenerative Science, Grand Rapids, Michigan 49503, and Patrik.Brundin@vai.org Ronald.Melki@cnrs.fr. · Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, 91190 Gif-sur-Yvette, France Patrik.Brundin@vai.org Ronald.Melki@cnrs.fr. ·J Neurosci · Pubmed #29021298.

ABSTRACT: In Parkinson's disease, intracellular α-synuclein inclusions form in neurons. We suggest that prion-like behavior of α-synuclein is a key component in Parkinson's disease pathogenesis. Although multiple molecular changes are involved in the triggering of the disease process, we propose that neuron-to-neuron transfer is a crucial event that is essential for Lewy pathology to spread from one brain region to another. In this review, we describe key findings in human postmortem brains, cultured cells, and animal models of disease that support the idea that α-synuclein can act as a prion. We consider potential triggers of the α-synuclein misfolding and why the aggregates escape cellular degradation under disease conditions. We also discuss whether different strains of α-synuclein fibrils can underlie differences in cellular and regional distribution of aggregates in different synucleinopathies. Our conclusion is that α-synuclein probably acts as a prion in human diseases, and a deeper understanding of this step in the pathogenesis of Parkinson's disease can facilitate the development of disease-modifying therapies in the future.

21 Review Therapeutic approaches to target alpha-synuclein pathology. 2017

Brundin, Patrik / Dave, Kuldip D / Kordower, Jeffrey H. ·Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: Patrik.Brundin@vai.org. · The Michael J Fox Foundation, New York, NY 10017, USA. · Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. ·Exp Neurol · Pubmed #28987463.

ABSTRACT: Starting two decades ago with the discoveries of genetic links between alpha-synuclein and Parkinson's disease risk and the identification of aggregated alpha-synuclein as the main protein constituent of Lewy pathology, alpha-synuclein has emerged as the major therapeutic target in Parkinson's disease and related synucleinopathies. Following the suggestion that alpha-synuclein pathology gradually spreads through the nervous system following a stereotypic pattern and the discovery that aggregated forms of alpha-synuclein can propagate pathology from one cell to another, and thereby probably aggravate existing deficits as well as generate additional symptoms, the idea that alpha-synuclein is a viable therapeutic target gained further support. In this review we describe current challenges and possibilities with alpha-synuclein as a therapeutic target. We briefly highlight gaps in the knowledge of the role of alpha-synuclein in disease, and propose that a deeper understanding of the pathobiology of alpha-synuclein can lead to improved therapeutic strategies. We describe several treatment approaches that are currently being tested in advanced animal experiments or already are in clinical trials. We have divided them into approaches that reduce alpha-synuclein production; inhibit alpha-synuclein aggregation inside cells; promote its degradation either inside or outside cells; and reduce its uptake by neighbouring cells following release from already affected neurons. Finally, we briefly discuss challenges related to the clinical testing of alpha-synuclein therapies, for example difficulties in monitoring target engagement and the need for relatively large trials of long duration. We conclude that alpha-synuclein remains one of the most compelling therapeutic targets for Parkinson's disease, and related synucleinopathies, and that the multitude of approaches being tested provides hope for the future.

22 Review Molecular Imaging and Updated Diagnostic Criteria in Lewy Body Dementias. 2017

Bohnen, Nicolaas I / Müller, Martijn L T M / Frey, Kirk A. ·Departments of Radiology and Neurology, University of Michigan, and Neurology service and GRECC, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA. nbohnen@umich.edu. · Departments of Radiology and Neurology, University of Michigan, and Neurology service and GRECC, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA. · Functional Neuroimaging, Cognitive and Mobility Laboratory, Domino's Farms, University of Michigan, Lobby B, Suite 1000, Level I; 24 Frank Lloyd Wright Drive, Box 362, Ann Arbor, MI, 48105-9755, USA. · Department of Radiology, Division of Nuclear Medicine, 1500 East Medical Center Drive, Room B1-G505 UH, Ann Arbor, MI, 48109-5028, USA. ·Curr Neurol Neurosci Rep · Pubmed #28808912.

ABSTRACT: PURPOSE OF REVIEW: The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB). RECENT FINDINGS: There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies. PDD patients have lower cortical β-amyloid deposition than DLB. Preliminary tau PET studies suggest a gradient of increasing tau binding from cognitively normal PD (absent to lowest) to cognitively impaired PD (low) to DLB (intermediate) to Alzheimer disease (AD; highest). However, tau binding in DLB, including the medial temporal lobe, is substantially lower than in AD. Alzheimer-type proteinopathies appear to be more common in DLB compared to PDD with relative but no absolute differences. Given the spectrum of overlapping pathologies, future α-synuclein ligands are expected to have the best potential to distinguish the LBD from pure AD.

23 Review α-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease. 2017

Singh, Sushil K / Dutta, Aloke / Modi, Gyan. ·Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India. · Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA. ·Future Med Chem · Pubmed #28632413.

ABSTRACT: Parkinson's disease (PD) is a multifactorial progressive neurological disorder. Pathological hallmarks of PD are characterized by the presence of α-synuclein (αSyn) aggregates known as Lewy bodies. αSyn aggregation is one of the leading causes for the neuronal dysfunction and death in PD. It is also associated with neurotransmitter and calcium release. Current therapies of PD are limited to only symptomatic relief without addressing the underlying pathogenic factors of the disease process such as aggregation of αSyn. Consequently, the progression of the disease continues with the current therapies. Therefore, the modulation of αSyn aggregation is an emerging approach as a novel therapeutic target to treat PD. There are two major aspects that might be targeted therapeutically: first, protein is prone to aggregation, therefore, anti-aggregative or compounds that can break the pre-existing aggregates should be helpful. Second, there are number of molecular events that may be targeted to combat the disease.

24 Review Aging and Parkinson's disease: Different sides of the same coin? 2017

Collier, Timothy J / Kanaan, Nicholas M / Kordower, Jeffrey H. ·Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, USA. · Mercy Health Hauenstein Neuroscience Center, Grand Rapids, Michigan, USA. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA. ·Mov Disord · Pubmed #28520211.

ABSTRACT: Despite abundant epidemiological evidence in support of aging as the primary risk factor for PD, biological correlates of a connection have been elusive. In this article, we address the following question: does aging represent biology accurately characterized as pre-PD? We present evidence from our work on midbrain dopamine neurons of aging nonhuman primates that demonstrates that markers of known correlates of dopamine neuron degeneration in PD, including impaired proteasome/lysosome function, oxidative/nitrative damage, and inflammation, all increase with advancing age and are exaggerated in the ventral tier substantia nigra dopamine neurons most vulnerable to degeneration in PD. Our findings support the view that aging-related changes in the dopamine system approach the biological threshold for parkinsonism, actively producing a vulnerable pre-parkinsonian state. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

25 Review Shaking Up the Debate: Ensuring the Ethical Use of DBS Intervention Criteria for Mid-Stage Parkinson's Patients. 2017

Eijkholt, Marleen / Cabrera, Laura Y / Ramirez-Zamora, Adolfo / Pilitsis, Julie G. ·Center for Ethics & Humanities in the Life Sciences, Michigan State University, Grand Rapids, MI, USA. · Center for Ethics & Humanities in the Life Sciences, Michigan State University, East Lansing, MI, USA. · Department of Neurology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA. · Department of Neuroscience and Experimental Therapeutics, Albany Medical Center, Albany, NY, USA. ·Neuromodulation · Pubmed #28497554.

ABSTRACT: OBJECTIVES: Deep brain stimulation (DBS) is a well-established treatment for the management of severe motor fluctuations in advanced Parkinson's disease (PD). Until recently, device regulation, medical, and insurance practices limited DBS to patients with advanced stages of PD. In February 2016 this changed, however, when the US Food and Drug Administration (FDA) granted formal approval for the use of brain stimulator in mid-stage PD patients. In this article, we examine whether DBS in mid-stage PD can be ethically justified beyond the FDA approval. MATERIALS AND METHODS: We scrutinize the current risk-benefit profile, the costs-benefit profile, and the capacity for informed consent requirement, to ask if use of subthalamic nucleus (STN) in mid-stage DBS is ethically appropriate. RESULTS: We propose that mid-stage DBS decisions could be appropriate under a shared decision-making model, which embraces a broad quality of life perspective. CONCLUSION: Although it might be too premature to know how the FDA decision will affect medical and insurance practices, we conclude by arguing that revisions to persisting guidelines seems justified both on scientific and ethical grounds.

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