This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

/pdf/mds-clinical-diagnostic-criteria-for-parkinson-s-disease-74dzuucoq6.pdf

MDS clinical diagnostic criteria for Parkinson's disease

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities.

/pdf/the-molecular-logic-of-endocannabinoid-signalling-4bguoe2w8n.pdf

The molecular logic of endocannabinoid signalling

Objective
To present the International Parkinson and Movement Disorder Society (MDS) Clinical Diagnostic Criteria for Parkinson9s disease.
Background
Although several diagnostic criteria for Parkinson9s disease have been proposed, none have been officially adopted by an official Parkinson society. Moreover, the commonest-used criteria, the UK brain bank, were created more than 25 years ago. In recognition of the lack of standard criteria, the MDS initiated a task force to design new diagnostic criteria for clinical Parkinson9s disease.
Methods/Results
The MDS-PD Criteria are intended for use in clinical research, but may also be used to guide clinical diagnosis. The benchmark is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise. Although motor abnormalities remain central, there is increasing recognition of non-motor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the MDS-PD Criteria retain motor parkinsonism as the core disease feature, defined as bradykinesia plus rest tremor and/or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies upon three categories of diagnostic features; absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of PD diagnosis). Two levels of certainty are delineated: Clinically-established PD (maximizing specificity at the expense of reduced sensitivity), and Probable PD (which balances sensitivity and specificity).
Conclusion
The MDS criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, criteria will need continuous revision to accommodate these advances. Disclosure: Dr. Postuma has received personal compensation for activities with Roche Diagnostics Corporation and Biotie Therapies. Dr. Berg has received research support from Michael J. Fox Foundation, the Bundesministerium fur Bildung und Forschung (BMBF), the German Parkinson Association and Novartis GmbH.

MDS Clinical Diagnostic Criteria for Parkinson's Disease (S19.001)

University Department of Clinical Neurosciences, IoN, London, UK; University of Toronto, Toronto Western Hospital, Toronto, ON, Canada; University of South Florida, Tampa, FL, USA; Baylor College of Medicine, Houston, TX, USA; Sant Pau Hospital, Autonomous University of Barcelona and Ciberned, Barcelona, Spain; Kansas University Medical Center, Kansas, KS, USA; Medical University of Innsbruck, Austria; Merck Serono S.A., Geneva, Switzerland; EMD Serono, Rockland, MA, USA 378

SETTLE study design: A 24-week, double-blind, placebo-controlled study of the efficacy and safety of safinamide as add-on therapy to levodopa in patients with Parkinson's diseases Add-On Therapy to Levodopa in Patients with Parkinson's disease

BACKGROUND: Current Health Canada instructions for use of the dopamine agonists (DA), pramipexole and ropinirole, state that Parkinson's disease (PD) patients should be told not to drive. The objective was to assess neurologists' actual clinical practice concerning driving advice they give to PD patients starting a DA. METHODS: An online survey was created consisting of 4 items regarding demographics, 5 regarding PD and driving, and 9 regarding DA use and driving. The survey was distributed to 563 neurologists. RESULTS: In total 96 neurologists (17.9%) responded. 4.4% tell patients with PD not to drive, solely because they are taking a DA. Respondents assess the patient's tendency for excessive daytime sleepiness and sleep attacks after starting a DA more frequently than after starting other dopaminergic drugs (p Language: en

/pdf/clinical-practice-regarding-dopamine-agonist-use-and-driving-4xlmey52hx.pdf

Clinical practice regarding dopamine-agonist use and driving in Parkinson's disease.

This two volume publication is a comprehensive overview on animal models, with particular emphasis on methodologies and assessment of behavior/neurological function. The topics cover the majority o...

Animal Models of Movement Disorders: Volume II

Long-term treatment of Parkinson's disease with the dopamine precursor 3,4-dihydroxyphenylalanine (l-DOPA) is compromised by the development of motor complications, including involuntary movements termed dyskinesia. The neural mechanisms underlying l-DOPA-induced dyskinesia (LID) involve altered activity of GABAergic striatal output pathways resulting, directly and indirectly, in underactivity of the output regions of the basal ganglia. These GABAergic striatal efferents employ, as co-neurotransmitters, a variety of opioids produced from the large molecular weight opioid precursors pre-proenkephalin-A and -B (PPE-A and PPE-B).

Effects of Opioid Antagonists on l-DOPA-Induced Dyskinesia in Parkinson's Disease

The exact etiology for Parkinson’s disease (PD) continues to remain complex and elusive. Several lines of etiologies have been investigated including gene mutations, exposure to environmental toxins, mitochondrial dysfunction, and increased oxidative stress to the neurons. There continues to be mounting evidence to support an immune dysregulation and an aberrant inflammatory process contributing to pathogenesis. Recent studies have shown that, despite the dogma that peripheral immune cells do not cross the blood– brain barrier, in fact, there is infiltration of peripheral immune cells into the central nervous system, and autoreactive T cells are directed against α-synuclein as plausible associations of significant neurodegeneration. However, most data have emerged from animal models with no clear understanding on the exact pathogenic role of lymphocytes and how they contribute to progression of human PD. Furthermore, it is unclear whether the immune attack in PD is led by the innate immune cells or the reactive immune cells. In this study by Sommer and colleagues, peripheral blood T cells are co-cultured with autologous fibroblasts. The fibroblasts are reprogrammed into human induced pluripotent stem cells, which then further differentiate into midbrain neurons. The investigators find the midbrain neurons to succumb to death if co-cultured with T cells that are drawn from PD patients, whereas they survive when the source for T cells is age-matched controls. Neuronal death is noted to accelerate when co-cultured with IL17-producing CD4 + T (Th17) lymphocytes, whereas these neurons are rescued from dying when IL17 receptor is blocked or when human anti-IL17 antibody (Secukinumab) is applied to the culture. The effects of IL17 are PD specific, demonstrating a substantially increased gene dysregulation upon exposure to IL17 in the midbrain neurons of PD patients when compared with the healthy controls. The IL17 expression for the lymphocytes is also not affected by the addition of primary astrocytes. The validation of the findings of Sommer and colleagues will require further testing in a PD model that in vivo captures the complexity of pathogenesis. Future studies will need to focus on antigen specificity for Th17 cells because the current study does not implicate α-synuclein as the primary antigen and the role of microglia are also important to investigate. Although the study findings suggest that Secukinumab (a drug approved by the Food and Drug Administration for the treatment of psoriasis) may have a potential neuroprotective role in PD, many further tests will be necessary prior to a successful clinical application. Nevertheless, a direct evidence for immune attack led by Th17 lymphocytes in PD is no doubt exciting and indisputably pushes the envelope.

/pdf/th17-lymphocyte-spearheads-the-immune-attack-in-parkinson-s-ux0nzlwurk.pdf

Susan H. Fox

Papers

SETTLE study design: A 24-week, double-blind, placebo-controlled study of the efficacy and safety of safinamide as add-on therapy to levodopa in patients with Parkinson's diseases Add-On Therapy to Levodopa in Patients with Parkinson's disease

Clinical practice regarding dopamine-agonist use and driving in Parkinson's disease.

Animal Models of Movement Disorders: Volume II

Effects of Opioid Antagonists on l-DOPA-Induced Dyskinesia in Parkinson's Disease

Th17 lymphocyte spearheads the immune attack in Parkinson's disease: New evidence for neuronal death.