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)

Parkinson’s Disease: Advanced Disease, Motor Complications, and Management

Several scales have been proposed to clinically evaluate the Motor Severity of Blepharospasm (BSP) but information about their measurement properties as a multicenter instrument is limited.

Measurement Properties of Clinical Scales Rating the Severity of Blepharospasm: A Multicenter Observational Study

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects fragile X (FMR1) gene premutation carriers in late life (an abnormally large allele that is not associated with clinical symptoms of Fragile X syndrome, but can expand into full mutation when transmitted to offspring). The prevalence in male carriers over 50 years is approximately 40%. In female carriers (approximately 1 in 260), the prevalence has not been as extensively studied, but may be as low as 8% over age 40. We present the case of a 65-year-old female with a 6-year history of bilateral hand tremor. The symptoms slowly progressed. Currently, she has tremor when holding a cup and has mild tremor when writing. She has no other issues with activities of daily living. She has no cognitive complaints, loss of dexterity or coordination, or other tremor localizations. In addition, she describes long-standing unsteadiness when walking. On physical examination, she has bilateral mild postural and moderate intention tremor of both arms. Mild tremor at rest in her left hand is also observed. Tone, power, and reflexes are normal. She has no limb ataxia, rigidity, or bradykinesia. During walking, she has mild reduced arm swing and her tandem gait is slightly unsteady. Her brain MRI shows mild atrophy, predominantly in the cerebellum, with no evidence of middle cerebellar peduncle (MCP) sign or corpus callosum splenium hyperintensity. Her father had arm tremor for many years. Her son has Fragile X syndrome. The patient has an FMR1 premutation (97 repeats), and her symptoms are compatible with FXTAS. Since the original description of FXTAS, there have been many reports and series describing phenotypic differences between males and females. In males, FXTAS is usually characterized by progressive tremor and gait ataxia. Other common features are parkinsonism, peripheral neuropathy, hypertension, autonomic dysfunction, anxiety, and depression. Cognitive decline is a highly prevalent and disabling symptom. Brain MRI usually shows atrophy of the cerebrum, cerebellar cortex, corpus callosum and pons, and white matter increased T2 signal intensity. The MCP sign (middle cerebellar peduncles hyperintense signal in T2) is observed in approximately 60% of the cases. In contrast, in females with FXTAS, tremor is rarely the initial presentation and is usually a later feature (prevalence of tremor range: 12%–75%) and ataxia is typically milder than in males. As in males, the neurophysiological characteristics of tremor in women with FXTAS have not been well studied. In addition, there are few detailed descriptions of the clinical features of tremor in FXTAS. Parkinsonism can be prominent as the disease progresses. Cognitive impairment is less commonly reported and leads to minor disability. Depression is a common feature (approximately 40%), and, interestingly, it was suggested that women with FXTAS show predisposition to psychogenic disorders. In female premutation carriers, primary ovarian dysfunction (20%), sensory loss (45%), chronic pain (26%), thyroid disorders (50%), and fibromyalgia are also common features. MRI studies showed MCP in only 13% of females. In our patient, the clinical presentation with a slowly progressive intention tremor and mild gait disturbance could potentially lead to the misdiagnosis of essential tremor. The early development of mild ataxia (rather than later onset that may be more common in essential tremor) was a clue to the diagnosis. In her case, the family history of Fragile X syndrome also clearly oriented the diagnosis; however, FXTAS should also be considered in the absence of a family history of mental retardation, autism, or learning disorders.

https://movementdisorders.onlinelibrary.wiley.com/doi/pdf/10.1002/mdc3.12129

Tremor‐Predominant Fragile X‐Associated Tremor/Ataxia Syndrome in a Female

Tourette’s syndrome (TS) is a complex neuropsychiatric disorder with a strong genetic component. There is a 60-fold higher risk of developing TS in children born to affected parents in comparison to the general population. Despite a strong heritability, there is scarce data on the susceptible genes and the underlying mutations. Although linkage analyses have found several candidate regions, there is little consensus seen across studies. Aggregated data from single-nucleotide polymorphism studies found TS as highly polygenic, with the majority of inherited risk distributed throughout the genome. To date, genome-wide significant loci could not be identified with certainty. Thus, disentangling the complex genetic architecture of TS has remained a major challenge. The discovery of copy number variations (CNVs) in structural genome analysis has led to increased understanding of the genetics of neuropsychiatric disorders. CNVs are small and large alterations to genomes, such as a gain or loss of coding sequence, which may overlap over several genes essential for biological pathways. Multiple rare CNVs (implying an underlying disease process) have been implicated in mental retardation, autism, and schizophrenia. These neuropsychiatric disorders are observed to share common biological pathways given that the genes contained in the rare CNVs share a common purpose of normal synaptic structure and neurotransmission. In this new large study of 6,527 unrelated individuals of European ancestry (2,434 TS cases and 4,093 ancestry-matched controls) published by Huang and colleagues, recurrent, rare CNVs were identified in two loci, in the NRXN1 (deletions) and CNTN6 (duplications), each conferring a significant substantial increase in the TS risk. They found that increased global CNV burden was mainly driven by large, rare, clinically relevant events. The current study findings are robust and promising given that previously exonic CNVs in the NRXN1 (presynaptic celladhesion molecule involved in synaptogenesis and synaptic transmission) did not survive genome-wide correction for multiple testing. The finding of duplications in the CNTN6 (encoding a cell-adhesion molecule involved in synaptogenesis and orientation of dendrites of pyramidal neurons) is also a novel association for TS. The current study was well characterized for obsessive compulsive disorder and attention deficit disorder, which are common comorbidities in TS. However, the full scope of phenotype associated with these rare CNVs is not clear and needs further characterization in future studies. Nevertheless, the study establishes a global enrichment in the burden of large, rare CNVs, a finding that will likely have significant impact on the future of TS genetics.

Susan H. Fox

Papers

Parkinson’s Disease: Advanced Disease, Motor Complications, and Management

Measurement Properties of Clinical Scales Rating the Severity of Blepharospasm: A Multicenter Observational Study

Tremor‐Predominant Fragile X‐Associated Tremor/Ataxia Syndrome in a Female

Complex genetics of Tourette's Syndrome: Piecing the puzzle.

The meaning of a “hippo” response on the Montreal Cognitive Assessment in Parkinson's disease