Publications by authors named "Patrik Brundin"

225 Publications

Drug Repurposing for Parkinson's Disease: The International Linked Clinical Trials experience.

Front Neurosci 2021 19;15:653377. Epub 2021 Mar 19.

Parkinson's Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, United States.

The international Linked Clinical Trials (iLCT) program for Parkinson's to date represents one of the most comprehensive drug repurposing programs focused on one disease. Since initial planning in 2010, it has rapidly grown - giving rise to seven completed, and 15 ongoing, clinical trials of 16 agents each aimed at delivering disease modification in Parkinson's disease (PD). In this review, we will provide an overview of the history, structure, process, and progress of the program. We will also present some examples of agents that have been selected and prioritized by the program and subsequently evaluated in clinical trials. Our goal with this review is to provide a template that can be considered across other therapeutic areas.
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http://dx.doi.org/10.3389/fnins.2021.653377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017145PMC
March 2021

Viviane Labrie in Memoriam: Recollections of a Star Who Left Us Far Too Early.

Mov Disord 2021 Apr 25;36(4):800-802. Epub 2021 Mar 25.

Department of Neurodegenerative Science, Parkinson's Disease Center, Van Andel Institute, Grand Rapids, Michigan, USA.

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http://dx.doi.org/10.1002/mds.28598DOI Listing
April 2021

An extended release GLP-1 analogue increases α-synuclein accumulation in a mouse model of prodromal Parkinson's disease.

Exp Neurol 2021 Mar 13;341:113693. Epub 2021 Mar 13.

Parkinson's Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA. Electronic address:

The repurposing of drugs developed to treat type 2 diabetes for the treatment of Parkinson's disease (PD) was encouraged by the beneficial effect exerted by the glucagon-like peptide 1 (GLP-1) analogue exenatide in a phase 2 clinical trial. The effects of GLP-1 analogues have been investigated extensively using rodent toxin models of PD. However, many of the toxin-based models used lack robust α-synuclein (α-syn) pathology, akin to the Lewy bodies and neurites seen in PD. One prior study has reported a protective effect of a GLP-1 analogue on midbrain dopamine neurons following injection of α-syn preformed fibrils (PFF) into the striatum. Here, we used olfactory bulb injections of PFF as a model of prodromal PD and monitored the effect of a long-acting GLP-1 analogue on the propagation of α-syn pathology in the olfactory system. Thirteen weeks after PFF injection, mice treated with long-acting the GLP-1 analogue had a significant increase in pathological α-syn in brain regions connected to the olfactory bulb, accompanied by signs of microglia activation. Our results suggest that the nature of the neuronal insult and intrinsic properties of the targeted neuronal population markedly influence the effect of GLP-1 analogues.
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http://dx.doi.org/10.1016/j.expneurol.2021.113693DOI Listing
March 2021

Decreased Risk of Parkinson's Disease After Rheumatoid Arthritis Diagnosis: A Nested Case-Control Study with Matched Cases and Controls.

J Parkinsons Dis 2021 ;11(2):821-832

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.

Background: Rheumatoid arthritis (RA) and the genetic risk landscape of autoimmune disorders and Parkinson's disease (PD) overlap. Additionally, anti-inflammatory medications used to treat RA might influence PD risk.

Objective: To use a population-based approach to determine if there is an association between pre-occurring rheumatoid arthritis (RA) and later-life risk of PD.

Methods: The study population was 3.6 million residents of Sweden, who were alive during part or all of the follow-up period; 1997-2016. We obtained diagnoses from the national patient registry and identified 30,032 PD patients, 8,256 of whom each was matched to ten controls based on birth year, sex, birth location, and time of follow-up. We determined the risk reduction for PD in individuals previously diagnosed with RA. We also determined if the time (in relation to the index year) of the RA diagnosis influenced PD risk and repeated the analysis in a sex-stratified setting.

Results: Individuals with a previous diagnosis of RA had a decreased risk of later developing PD by 30-50% compared to individuals without an RA diagnosis. This relationship was strongest in our conservative analysis, where the first PD diagnosis occurred close to the earliest PD symptoms (odds ratio 0.47 (CI 95% 0.28-0.75, p = 0.0006); with the greatest risk reduction in females (odds ratio 0.40 (CI 95% 0,19-0.76, p = 0.002).

Discussion: Our findings provide evidence that individuals diagnosed with RA have a significantly lower risk of developing PD than the general population. Our data should be considered when developing or repurposing therapies aimed at modifying the course of PD.
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http://dx.doi.org/10.3233/JPD-202418DOI Listing
January 2021

Using Technology to Reshape Clinical Care and Research in Parkinson's disease.

J Parkinsons Dis 2021 Feb 16. Epub 2021 Feb 16.

Radboud University Nijmegen Medical Center; Donders Institute for Brain, Cognition and Behavior; department of neurology.

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http://dx.doi.org/10.3233/JPD-219002DOI Listing
February 2021

T Cells Limit Accumulation of Aggregate Pathology Following Intrastriatal Injection of α-Synuclein Fibrils.

J Parkinsons Dis 2021 ;11(2):585-603

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.

Background: α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of α-synucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease.ObjectiveTo study the role of the adaptive immune system with respect to α-syn pathology.

Methods: We injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology, proteinase K-resistant α-syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naïve T and B cells into PFF-injected immunocompromised mice.

Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated α-syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice.

Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental α-synucleinopathy.
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http://dx.doi.org/10.3233/JPD-202351DOI Listing
January 2021

COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel?

J Parkinsons Dis 2021 ;11(1):3-8

Yerkes National Primate Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

Several COVID-19 vaccines have recently been approved for emergency use according to governmental immunization programs. The arrival of these vaccines has created hope for people with Parkinson's disease (PD), as this can help to mitigate their risk of becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can lead to serious, life-threatening disease, at least among those with more advanced PD. However, both persons with PD and physicians looking after these individuals have expressed concerns about the vaccine's efficacy and safety in the specific context of PD and its symptomatic treatment. Here, we discuss our perspective on these concerns, based on our interpretation of the literature plus the unfolding experience with widespread vaccination in the population at large. Because the benefits and risks of COVID-19 vaccines do not appear to be different than in the general population, we recommend COVID-19 vaccination with approved vaccines to persons with PD, unless there is a specific contraindication. Some caution seems warranted in very frail and terminally ill elderly persons with PD living in long-term care facilities.
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http://dx.doi.org/10.3233/JPD-212573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990445PMC
February 2021

The Dawning of a Brighter Future: Celebrating 10 Years of Journal of Parkinson's Disease.

J Parkinsons Dis 2021 ;11(1):1-2

Center for Parkinson's Disease, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.

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http://dx.doi.org/10.3233/JPD-219001DOI Listing
January 2021

Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson's Disease.

Metabolites 2021 Jan 4;11(1). Epub 2021 Jan 4.

Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA.

The gut microbiome can impact brain health and is altered in Parkinson's disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls ( = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix ( = 15 PD, 12 C) and ileum ( = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.
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http://dx.doi.org/10.3390/metabo11010029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823437PMC
January 2021

Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial.

JAMA Neurol 2021 Mar;78(3):312-320

Steven's Institute of Technology, Marlboro, New Jersey.

Importance: There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD).

Objectives: To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers.

Design, Setting, And Participants: This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure).

Interventions: Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation.

Main Outcomes And Measures: The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers.

Results: At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF.

Conclusions And Relevance: While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD.

Trial Registration: ClinicalTrials.gov Identifier: NCT03205488.
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http://dx.doi.org/10.1001/jamaneurol.2020.4725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737147PMC
March 2021

Is COVID-19 a Perfect Storm for Parkinson's Disease?

Trends Neurosci 2020 12 21;43(12):931-933. Epub 2020 Oct 21.

Division of Medicine, Neurology and Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Three recent case reports (by Méndez-Guerrero et al.,Cohen et al., and Faber et al.) describe the development of acute parkinsonism following coronavirus disease 2019 (COVID-19). We discuss possible underlying cellular and molecular mechanisms, and whether COVID-19 might be associated with elevated long-term risk of Parkinson's disease (PD).
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http://dx.doi.org/10.1016/j.tins.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577682PMC
December 2020

Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants - Let's get even more personal.

Transl Neurodegener 2020 10 16;9(1):39. Epub 2020 Oct 16.

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA.

Parkinson's disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove "precise" or "personalized" enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.
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http://dx.doi.org/10.1186/s40035-020-00218-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565766PMC
October 2020

Mitomycin-C treatment during differentiation of induced pluripotent stem cell-derived dopamine neurons reduces proliferation without compromising survival or function in vivo.

Stem Cells Transl Med 2021 Feb 30;10(2):278-290. Epub 2020 Sep 30.

Department of Neurological Sciences, Rush University, Chicago, Illinois, USA.

Nongenetic methodologies to reduce undesirable proliferation would be valuable when generating dopamine neurons from stem cells for transplantation in Parkinson's disease (PD). To this end, we modified an established method for controlled differentiation of human induced pluripotent stem cells (iPSCs) into midbrain dopamine neurons using two distinct methods: omission of FGF8 or the in-process use of the DNA cross-linker mitomycin-C (MMC). We transplanted the cells to athymic rats with unilateral 6-hydroxydopamine lesions and monitored long-term survival and function of the grafts. Transplants of cells manufactured using MMC had low proliferation while still permitting robust survival and function comparable to that seen with transplanted dopamine neurons derived using genetic drug selection. Conversely, cells manufactured without FGF8 survived transplantation but exhibited poor in vivo function. Our results suggest that MMC can be used to reduce the number of proliferative cells in stem cell-derived postmitotic neuron preparations for use in PD cell therapy.
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http://dx.doi.org/10.1002/sctm.20-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848297PMC
February 2021

Perturbation of in vivo Neural Activity Following α-Synuclein Seeding in the Olfactory Bulb.

J Parkinsons Dis 2020 ;10(4):1411-1427

Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA.

Background: Parkinson's disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded α-Synuclein (α-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of α-Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. α-Syn fibrils injected into the OB of mice cause progressive propagation of α-Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits.

Objective: We hypothesized that accumulation of pathogenic α-Syn in the OB impairs neural activity in the olfactory system.

Methods: To address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed α-Syn fibrils in the OB.

Results: We detected α-Syn pathology in both the OB and PCX. We also observed that α-Syn fibril injections influenced odor-evoked activity in the OB. In particular, α-Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of α-Syn pathology.

Conclusion: Together, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.
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http://dx.doi.org/10.3233/JPD-202241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018612PMC
January 2020

Alterations in odor hedonics in the 5XFAD Alzheimer's disease mouse model and the influence of sex.

Behav Neurosci 2020 Oct 6;134(5):407-416. Epub 2020 Aug 6.

Department of Pharmacology and Therapeutics, University of Florida.

Olfactory impairments, including deficits in odor detection, discrimination, recognition, and changes in odor hedonics, are reported in the early stages of Alzheimer's disease (AD). Rodent models of AD display deficits in odor learning, detection, and discrimination-recapitulating the clinical condition. However, the impact of familial AD genetic mutations on odor hedonics is unknown. We tested 2-, 4-, and 6-month-old 5XFAD (Tg6799) mice in the 5-port odor multiple-choice task designed to assay a variety of odor-guided behaviors, including odor preferences/hedonics. We found that 5XFAD mice investigated odors longer than controls, an effect that was driven by 6-month-old mice. Interestingly, this effect was carried by females in the 5XFAD group, who investigated odors longer than age-matched males. Upon examining behavior directed toward individual odors to test for aberrant odor preferences, we uncovered that 5XFAD females at several ages displayed heightened preferences toward some of the odors, indicating aberrant hedonics. We observed no impairments in the ability to engage in the task in 5XFAD mice. Taken together, 5XFAD mice, particularly 5XFAD females, displayed prolonged odor investigation behavior and enhanced preferences to certain odors. The data provide insight into hedonic alterations that may occur in AD mouse models and how these are influenced by biological sex. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018610PMC
October 2020

Parkinson's Disease: We Care!

J Parkinsons Dis 2020 ;10(s1):S1-S3

Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.

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http://dx.doi.org/10.3233/JPD-209003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592664PMC
January 2020

Moving Forward in Times of Crisis.

J Parkinsons Dis 2020 ;10(3):747-748

Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.

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http://dx.doi.org/10.3233/JPD-209001DOI Listing
August 2020

Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson's Disease.

Mov Disord 2020 11 25;35(11):2028-2037. Epub 2020 Jul 25.

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, USA.

Background: The objective of this study was to determine whether neurotoxic kynurenine metabolites, induced by inflammation, in plasma and cerebrospinal fluid (CSF) are associated with symptom severity and nigral pathology in Parkinson's disease (PD).

Methods: Clinical and MRI data were obtained from 97 PD and 89 controls. We used ultra-performance liquid chromatography to quantify kynurenine metabolites and high-sensitivity multiplex assays to quantify inflammation in plasma and CSF. We evaluated group-wise differences as well as associations between the biomarkers, motor and nonmotor symptoms, and nigral R2* (MRI metric reflecting iron content).

Results: PD subjects had >100% higher 3-hydroxykynurenine and 14% lower 3-hydroxyanthranilic acid in plasma. The 3-HK in plasma was closely associated with both symptom severity and disease duration. PD subjects also had 23% lower kynurenic acid in the CSF. Higher CSF levels of the excitotoxin quinolinic acid were associated with more severe symptoms, whereas lower levels of the neuroprotective kynurenic acid were linked to olfactory deficits. An elevated quinolinic acid/picolinic acid ratio in the CSF correlated with higher R2* values in the substantia nigra in the entire cohort. Plasma C-reactive protein and serum amyloid alpha were associated with signs of increased kynurenine pathway activity in the CSF of PD patients, but not in controls.

Conclusions: In PD, the kynurenine pathway metabolite levels are altered in both the periphery and the central nervous system, and these changes are associated with symptom severity. Replication studies are warranted in other cohorts, and these can also explore if kynurenine metabolites might be PD biomarkers and/or are involved in PD pathogenesis. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754343PMC
November 2020

Deficits in olfactory sensitivity in a mouse model of Parkinson's disease revealed by plethysmography of odor-evoked sniffing.

Sci Rep 2020 06 8;10(1):9242. Epub 2020 Jun 8.

Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.

Hyposmia is evident in over 90% of Parkinson's disease (PD) patients. A characteristic of PD is intraneuronal deposits composed in part of α-synuclein fibrils. Based on the analysis of post-mortem PD patients, Braak and colleagues suggested that early in the disease α-synuclein pathology is present in the dorsal motor nucleus of the vagus, as well as the olfactory bulb and anterior olfactory nucleus, and then later affects other interconnected brain regions. Here, we bilaterally injected α-synuclein preformed fibrils into the olfactory bulbs of wild type male and female mice. Six months after injection, the anterior olfactory nucleus and piriform cortex displayed a high α-synuclein pathology load. We evaluated olfactory perceptual function by monitoring odor-evoked sniffing behavior in a plethysmograph at one-, three- and six-months after injection. No overt impairments in the ability to engage in sniffing were evident in any group, suggesting preservation of the ability to coordinate respiration. At all-time points, females injected with fibrils exhibited reduced odor detection sensitivity, which was observed with the semi-automated plethysmography apparatus, but not a buried pellet test. In future studies, this sensitive methodology for assessing olfactory detection deficits could be used to define how α-synuclein pathology affects other aspects of olfactory perception and to clarify the neuropathological underpinnings of these deficits.
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http://dx.doi.org/10.1038/s41598-020-66201-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280205PMC
June 2020

GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop.

J Parkinsons Dis 2020 ;10(3):875-891

The Edmond J Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
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http://dx.doi.org/10.3233/JPD-202004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458523PMC
January 2020

Impact of the COVID-19 Pandemic on Parkinson's Disease and Movement Disorders.

Mov Disord Clin Pract 2020 May 16;7(4):357-360. Epub 2020 Apr 16.

Paracelsus-Elena Klinik, Kassel, Department of Neurosurgery University Medical Center Goettingen Goettingen Germany.

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http://dx.doi.org/10.1002/mdc3.12953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197322PMC
May 2020

Impact of the COVID-19 Pandemic on Parkinson's Disease and Movement Disorders.

Mov Disord 2020 05 16;35(5):711-715. Epub 2020 Apr 16.

Paracelsus-Elena Klinik, Kassel, Department of Neurosurgery, University Medical Center, Goettingen, Goettingen, Germany.

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http://dx.doi.org/10.1002/mds.28067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996401PMC
May 2020

Novel approaches to counter protein aggregation pathology in Parkinson's disease.

Prog Brain Res 2020 30;252:451-492. Epub 2019 Nov 30.

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, United States. Electronic address:

The primary neuropathological characteristics of the Parkinsonian brain are the loss of nigral dopamine neurons and the aggregation of alpha synuclein protein. Efforts to development potentially disease-modifying treatments have largely focused on correcting these aspects of the condition. In the last decade treatments targeting protein aggregation have entered the clinical pipeline. In this chapter we provide an overview of ongoing clinical trial programs for different therapies attempting to reduce protein aggregation pathology in Parkinson's disease. We will also briefly consider various novel approaches being proposed-and being developed preclinically-to inhibit/reduce aggregated protein pathology in Parkinson's.
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http://dx.doi.org/10.1016/bs.pbr.2019.10.007DOI Listing
January 2021

Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?

Neurology 2020 03 26;94(11):481-494. Epub 2020 Feb 26.

From the Department of Neurology (A.J.E.), James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, OH; Edmond J. Safra Program in Parkinson's Disease (L.V.K.), Krembil Research Institute, Toronto Western Hospital, Ontario, Canada; Department of Neurology and Neurosurgery (Z.G.-O.), Montreal Neurological Institute, and Department of Human Genetics (Z.G.-O.), McGill University, Montreal, Quebec, Canada; Department of Clinical Neurosciences (C.H.W.-G.), John van Geest Centre for Brain Repair, University of Cambridge, UK; Division of Medical Oncology and Hematology (P.L.B.), Princess Margaret Cancer Centre, University Health Network, and Department of Medicine (P.L.B.), University of Toronto, Ontario, Canada; Departments of Medicine (S.M.R.), Pediatrics (S.M.R.), Cell Developmental and Integrative Biology (S.M.R.), and Neurology (D.G.S.), University of Alabama at Birmingham; Department of Clinical and Experimental Medicine (F.M.), University of Messina, Italy; Institute of Molecular and Clinical Sciences (F.M.), St George's University of London, UK; Edmond J. Safra Program in Parkinson's Disease (A.F., A.P.S., A.E.L.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto; Krembil Research Institute (A.F., A.P.S., A.E.L.); Tomorrow Edition (B.S.), Toronto, Ontario, Canada; Consultorio y Laboratorio de Neurogenética (M.A.K.), Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA; Programa de Medicina de Precision y Genomica Clinica (M.A.K.), Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Buenos Aires, Argentina; Clinical Genomics Program (M.J.F.), Norman Fixel Institute for Neurological Diseases, McKnight Brain Institute, University of Florida Clinical and Translational Science Institute, Gainesville; Clinical Trials Statistical & Data Management Center (C.S.C.), University of Iowa College of Public Health, Iowa City; Department of Neurology (M.A.S.), Massachusetts General Hospital, Boston; Michael J. Fox Foundation for Parkinson's Research (T.S.), New York City, NY; Department of Neurology (R.B.P.), Montreal General Hospital, Quebec; Research Imaging Centre (A.P.S.), Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada; Laboratory of Neurogenetics (A.B.S.), National Institute on Aging, NIH, Bethesda, MD; Department of Clinical Neurosciences (R.A.B.), John van Geest Centre for Brain Repair, WT-MRC Cambridge Stem Cell Institute, University of Cambridge, UK; Clinical Trials Coordination Center (K.K.), University of Rochester Medical Center, NY; Department of Neurology and Neuroscience (C.W.O.), Mount Sinai School of Medicine, New York, NY; Clintrex LLC (C.W.O.), Sarasota, FL; Division of Neurosurgery (A.L.), Krembil Neuroscience Institute, Toronto Western Hospital, Ontario, Canada; Department of Neurological Sciences (J.H.K.), Rush University Medical Center, Chicago, IL; Coeruleus Clinical Sciences (J.M.C.), Woodbridge, CT; and Center for Neurodegenerative Science (P.B.), Van Andel Institute, Grand Rapids, MI.

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.
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http://dx.doi.org/10.1212/WNL.0000000000009107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220234PMC
March 2020

Editorial: Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases.

Front Mol Neurosci 2019 17;12:312. Epub 2020 Jan 17.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Gottingen, Göttingen, Germany.

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http://dx.doi.org/10.3389/fnmol.2019.00312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978792PMC
January 2020

Does Developmental Variability in the Number of Midbrain Dopamine Neurons Affect Individual Risk for Sporadic Parkinson's Disease?

J Parkinsons Dis 2020 ;10(2):405-411

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.

Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder that is coupled to both widespread protein aggregation and to loss of substantia nigra dopamine (DA) neurons, resulting in a wide variety of motor and non-motor signs and symptoms. Recent findings suggest that the PD process is triggered several years before there is sufficient degeneration of DA neurons to cause onset of overt motor symptoms. According to this concept, the number of DA neurons present in the substantia nigra at birth could influence the time from the molecular triggering event until the clinical diagnosis with lower number of neurons at birth increasing the risk to develop the disease. Conversely, the risk for diagnosis would be reduced if the number of DA neurons is high at birth. In this commentary, we discuss the genetic and epigenetic factors that might influence the number of nigral DA neurons that each individual is born with and how these may be linked to PD risk.
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http://dx.doi.org/10.3233/JPD-191877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242832PMC
January 2020

The Future of Parkinson Care and Research is Here.

J Parkinsons Dis 2020 ;10(1):1-3

Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.

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http://dx.doi.org/10.3233/JPD-199006DOI Listing
April 2021

α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb.

Acta Neuropathol Commun 2019 12 30;7(1):221. Epub 2019 Dec 30.

Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Avenue N.E, Grand Rapids, MI, 49503, USA.

Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates.In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.
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http://dx.doi.org/10.1186/s40478-019-0859-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937797PMC
December 2019

Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology.

Clin Geriatr Med 2020 02 24;36(1):1-12. Epub 2019 Aug 24.

Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503-2518, USA.

Parkinson disease is a complex, age-related, neurodegenerative disease associated with dopamine deficiency and both motor and nonmotor deficits. Many environmental and genetic factors influence Parkinson disease risk, with different factors predominating in different patients. These factors converge on specific pathways, including mitochondrial dysfunction, oxidative stress, protein aggregation, impaired autophagy, and neuroinflammation. Ultimately, treatment of Parkinson disease may focus on targeted therapies for pathophysiologically defined subtypes of Parkinson disease patients.
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http://dx.doi.org/10.1016/j.cger.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905381PMC
February 2020

Endogenous alpha-synuclein monomers, oligomers and resulting pathology: let's talk about the lipids in the room.

NPJ Parkinsons Dis 2019 12;5:23. Epub 2019 Nov 12.

1Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612 USA.

Alpha-synuclein is an intrinsically disordered, highly dynamic protein that pathogenically aggregates into inclusion structures called Lewy bodies, in several neurogenerative diseases termed synucleinopathies. Despite its importance for understanding disease, the oligomerization status of alpha-synuclein in healthy cells remains unclear. Alpha-synuclein may exist predominantly as either a monomer or a variety of oligomers of different molecular weights. There is solid evidence to support both theories. Detection of apparent endogenous oligomers are intimately dependent on vesicle and lipid interactions. Here we consider the possibility that apparent endogenous alpha-synuclein oligomers are in fact conformations of membrane-bound alpha-synuclein and not a bona fide stable soluble species. This perspective posits that the formation of any alpha-synuclein oligomers within the cell is likely toxic and interconversion between monomer and oligomer is tightly controlled. This differs from the hypothesis that there is a continuum of endogenous non-toxic oligomers and they convert, through unclear mechanisms, to toxic oligomers. The distinction is important, because it clarifies the biological origin of synucleinopathy. We suggest that a monomer-only, lipid-centric view of endogenous alpha-synuclein aggregation can explain how alpha-synuclein pathology is triggered, and that the interactions between alpha-synuclein and lipids can represent a target for therapeutic intervention. This discussion is well-timed due to recent studies that show lipids are a significant component of Lewy pathology.
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http://dx.doi.org/10.1038/s41531-019-0095-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851126PMC
November 2019