When I speak of research, I am not talking about dedicated molecular biological investigation in a so-called wet laboratory, or crunching big numbers in front of computer screens to identify risk ...factors. By paying attention to what Burroughs had to say, I explored the magic of apomorphine6 and the dreamachine (a stroboscopic flicker device that produces visual stimuli) as a method for investigating visual hallucination.7 An article in The New Statesman8 and passages in Junkie9 helped me to understand the dopamine dysregulation syndrome better than anything I read in the academic literature.10 When our findings were greeted with scepticism, I remembered what Burroughs had said about the harm created by vanity: doctors are, by and large, drastically limited in their outlook. ...new drugs with astronomically high price tags or biosimilar formulations with no evident superiority over existing cheaper medicines pour onto the market and are sold for large profits.
Obituary for Dr. John C. Steele (1934–2022) Morris, Huw R.; Lees, Andrew J.
Movement disorders,
January 2023, 2023-Jan, 2023-01-00, 20230101, Letnik:
38, Številka:
1
Journal Article
Summary Background Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa ...compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations. Methods We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30–83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14–15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov , NCT01568073. Findings Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was −56·0 min (SE 13·4; 95% CI −82·3 to −29·7) for placebo, −96·3 min (13·4; −122·6 to −70·0) for entacapone, −91·3 min (13·5; −117·7 to −64·8) for opicapone 5 mg, −85·9 min (13·7; −112·8 to −59·1) for opicapone 25 mg, and −116·8 min (14·0; −144·2 to −89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline −60·8 min, 95% CI −97·2 to −24·4; p=0·0015) and non-inferior to entacapone (−26·2 min, −63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group. Interpretation The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit. Funding BIAL.
Multiple system atrophy (MSA) is a progressive neurodegenerative disease presenting clinically with parkinsonian, cerebellar, and autonomic features. α‐Synuclein (αsyn), encoded by the gene SNCA, is ...the main constituent of glial cytoplasmic inclusion (GCI) found in oligodendrocytes in MSA, but the methods of its accumulation have not been established. The aim of this study is to investigate alterations in regional and cellular SNCA mRNA expression in MSA as a possible substrate for GCI formation. Quantitative reverse transcription polymerase chain reaction (qPCR) was performed on postmortem brain samples from 15 MSA, 5 IPD, and 5 control cases to investigate regional expression in the frontal and occipital regions, dorsal putamen, pontine base, and cerebellum. For cellular expression analysis, neurons and oligodendrocytes were isolated by laser‐capture microdissection from five MSA and five control cases. SNCA mRNA expression was not significantly different between the MSA, IPD and control cases in all regions (multilevel model, P = 0.14). After adjusting for group effect, the highest expression was found in the occipital cortex while the lowest was in the putamen (multilevel model, P < 0.0001). At the cellular level, MSA oligodendrocytes expressed more SNCA than control oligodendrocytes and expression in MSA neurons was slightly lower than that in controls, however, these results did not reach statistical significance. We have demonstrated regional variations in SNCA expression, which is higher in cortical than subcortical regions. This study is the first to demonstrate SNCA mRNA expression by oligodendrocytes in human postmortem tissue using qPCR and, although not statistically significant, could suggest that this may be increased in MSA compared to controls. GLIA 2014;62:964–970
Main points
The methods of accumulation of a‐synuclein in glial cytoplasmic inclusion (GCI) found in oligodendrocytes in MSA have not been established. This study raises the possibility of altered cellular SNCA mRNA expression in MSA as a possible substrate for GCI formation.
Can stress trigger Parkinson's disease? Djamshidian, Atbin; Lees, Andrew J
Journal of neurology, neurosurgery and psychiatry,
08/2014, Letnik:
85, Številka:
8
Journal Article
Recenzirano
Odprti dostop
In this manuscript we summarize the role of chronic stress as a potential trigger factor for Parkinson's disease. Underlying mechanisms and stress-induced changes to the neuronal networks have been ...highlighted. Examples of stress induced reversible symptoms that resemble parkinsonism in humans and in animal models raise the question whether emotional stress can cause striatal degeneration in susceptible patients. A Pubmed literature review searching for the terms 'Stress', 'Distress and Parkinson's disease', 'Emotional Distress and Parkinson's disease', 'Stress and Parkinson's disease', 'Prodromal Parkinson's disease', 'Non motor symptoms and Parkinson's disease', 'Paradoxical kinesia', 'Psychogenic parkinsonism', 'Functional somatic syndromes', 'Chronic fatigue syndrome', 'Irritable bowel syndrome', 'Fibromyalgia', 'Dopamine and fibromyalgia', 'Dopamine and chronic fatigue syndrome' and 'Dopamine and irritable bowel syndrome' was carried out until April 2013. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this viewpoint.
These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms ...have multiple pathologies; (2) neither pathology type nor distribution correlate with disease severity or progression in Parkinson's disease; (3) aggregated α-synuclein in the form of Lewy bodies is not a space-occupying lesion but the insoluble fraction of its precursor, soluble monomeric α-synuclein; (4) pathology spread is passive, occurring by irreversible nucleation, not active replication; and (5) low cerebrospinal fluid α-synuclein levels predict brain atrophy and clinical disease progression. The transformation of α-synuclein into Lewy pathology may occur as a response to biological, toxic, or infectious stressors whose persistence perpetuates the nucleation process, depleting normal α-synuclein and eventually leading to Parkinson's symptoms from neuronal death. We propose testing the loss-of-function synucleinopenia hypothesis by evaluating the clinical and neurodegenerative rescue effect of replenishing the levels of monomeric α-synuclein.
•Lewy pathology is made of what once were normal α-synuclein monomers.•Once transformed into pathology, any function α-synuclein had is lost.•Pathology does not drive symptoms or cause degeneration; loss of α-synuclein does.•The synucleinopenia hypothesis is testable and falsifiable by evaluating the effect of increasing soluble α-synuclein levels.
Objective
A small group of Parkinson's disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and ...Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome DDS). We aimed to evaluate levodopa‐induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients.
Methods
We used a two‐scan positron emission tomography protocol to calculate the percentage change in 11C‐raclopride binding potential from a baseline withdrawal (off drug) state to the binding potential after an oral dose of levodopa. We related the subjective effects of levodopa to the effects on endogenous dopamine release of a pharmacological challenge with levodopa in eight control PD patients and eight patients with DDS.
Results
PD patients with DDS exhibited enhanced levodopa‐induced ventral striatal dopamine release compared with levodopa‐treated patients with PD not compulsively taking dopaminergic drugs. The sensitized ventral striatal dopamine neurotransmission produced by levodopa in these individuals correlated with self‐reported compulsive drug “wanting” but not “liking” and was related to heightened psychomotor activation (punding).
Interpretation
This provides evidence that links sensitization of ventral striatal circuitry in humans to compulsive drug use. Ann Neurol 2006
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