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Background: Several reports have provided crucial evidence in animal models that epigenetic modifications, such as DNA methylation, may be involved in psychostimulant-induced stable changes at the cellular level in the brain. Epigenetic editors DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs) coordinate expression of gene networks, which then manifest as long-term behavioural changes. However, the extent to which aberrant DNA methylation is involved in the mechanisms of substance use disorder in humans is unclear. We previously demonstrated that cocaine modifies gene transcription, via DNA methylation, throughout the brain and in peripheral blood cells in mice., Results: We treated human peripheral blood mononuclear cells (PBMCs) from healthy male donors (n = 18) in vitro with psychostimulants (amphetamine, cocaine). After treatment, we assessed mRNA levels and enzymatic activities of TETs and DNMTs, conducted genome-wide DNA methylation assays and next-generation sequencing. We found that repeated exposure to psychostimulants decreased mRNA levels and enzymatic activity of TETs and 5-hydroxymethylation levels in PBMCs. These data were in line with observed hyper- and hypomethylation and mRNA expression of marker genes (IL-10, ATP2B4). Additionally, we evaluated whether the effects of cocaine on epigenetic editors (DNMTs and TETs) and cytokines interleukin-6 (IL-6) and IL-10 could be reversed by the DNMT inhibitor decitabine. Indeed, decitabine eliminated cocaine's effect on the activity of TETs and DNMTs and decreased cytokine levels, whereas cocaine increased IL-6 and decreased IL-10., Conclusions: Our data suggest that repeated psychostimulant exposure decreases TETs' enzymatic activity in PBMCs. Co-treatment with decitabine reversed TETs' levels and modulated immune response after repeated cocaine exposure. Further investigation is needed to clarify if TET could represent a putative biomarker of psychostimulant use and if DNMT inhibition could have therapeutic potential., (© 2022. The Author(s).)

Objective: To examine the genetic variability of Estonian Parkinson's disease (PD) patients using an ongoing epidemiological study in combination with a genetic analysis., Methods: This study was a community-based genetic screening study of 189 PD patients, and 158 age- and sex-matched controls screened for potential mutations in 9 PD genes using next-generation sequencing and multiplex ligation-dependent probe amplification method. Different clinimetric scales and questionnaires were used to examine PD patients and assess clinical characteristics and severity of the disease., Results: The overall frequency of pathogenic PD-causing variants was 1.1% (2/189), and any rare genetic variant was present in 21.2% (40/189) of the patients and in 8.2% (13/158) of the controls (P < .05). Variants of unknown significance accounted for 10.6% (20/189). Frequency of any GBA variant among PD patients was 10.1% (19/189) and in controls 3.8% (6/158). The frequency of any GBA variant in PD compared to controls was significantly higher (P = .035; OR 2.82; CI 95% 1.05-8.87). Burden of rare variants was not different between patients and controls. Also, a novel GBA pathogenic variant p.E10X was detected., Conclusion: Among different genetic variants identified in Estonian PD patients, GBA variants are the most common, while an overall pathogenic variant frequency was 1.1%., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Manganese-methcathinone encephalopathy (MME) is a rare parkinsonian syndrome described in drug addicts who have self-injected a home-made mixture containing methcathinone and manganese. We assessed 14 patients with MME and compared their results with 14 matched control subjects. The patients had a parkinsonian syndrome with symmetrical bradykinesia, dystonias, and postural, gait and speech impairment, with moderate restrictions in activities of daily living. Their cognitive status was assessed with the Russian version of the Wechsler Adult Intelligence Scale (WAIS) and with tests of attention (Trail Making Test, Bourdon-Wiersma Dot Cancellation Test), memory (Auditory Verbal Learning Test, Rey-Osterrieth Complex Figure), motor skills (Grooved Pegboard), visuospatial skills (Money Road Map Test, Benton Judgment of Line Orientation), and executive abilities (Verbal Fluency, 5-Point Test, Wisconsin Card Sorting Test). Only a few significant differences emerged. After controlling for multiple comparisons, the results in the WAIS Object Assembly subtest, the Grooved Pegboard test (dominant and nondominant hand) and the Verbal Fluency test remained significant., (Copyright © 2019. Published by Elsevier B.V.)

The substituted amphetamines have had a checkered medical history intertwined with a sensational cultural history. Mankind's insatiable fascination with speed has led to widespread misuse sometimes with disastrous neurological and psychiatric consequences that may cause a permanent harm but their potential to enhance cognition should not be dismissed or forgotten. Further, smarter research could perhaps still lead to an expanded beneficial role for stimulant use in modern society., (© 2015 Elsevier Inc. All rights reserved.)

Methcathinone abuse is a significant cause of parkinsonism among young patients in the Eastern European countries. The drug is synthesized from over-the-counter cold remedies containing ephedrine or pseudoephedrine. The final mixture contains a high concentration of manganese if potassium permanganate is used as the oxidant agent. Though manganese is an essential trace element and its homeostasis is well maintained, exposure to a high level of manganese is neurotoxic. The use of manganese-contaminated methcathinone may cause permanent neurological damage and severe disability. Drug users develop a distinctive extrapyramidal syndrome that resembles classic manganese intoxication. Methcathinone could have additive neurotoxic effect to the progression of parkinsonism. The most prevalent symptoms are symmetrical bradykinesia, dystonias, and early postural, gait, and speech impairment. After cessation of exposure, the syndrome is generally irreversible and can even progress., (© 2015 Elsevier Inc. All rights reserved.)

Methcathinone (ephedrone) is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese), or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We used microarrays to analyze whole-genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data were analyzed by Bayesian modeling and functional annotation. Of 28,869 genes on the microarrays, 326 showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative real-time PCR confirmed differential expression for the most of the genes selected for validation. Functional annotation and network analysis indicated activation of a gene network that included immunological disease, cellular movement, and cardiovascular disease functions (enrichment score 42). As HIV and HCV infections were confounding factors, we performed additional stratification of subjects. A similar functional activation of the "immunological disease" category was evident when we compared subjects according to injection status (past versus current users, balanced for HIV and HCV infection). However, this difference was not large therefore the major effect was related to the HIV status of the subjects. Mn-methcathinone abusers have blood RNA expression patterns that mostly reflect their HIV and HCV infections.

During recent years, a syndrome of hypokinesia, dysarthria, dystonia, and postural impairment, related to intravenous use of a "designer" psychostimulant derived from pseudoephedrine using potassium permanganate as the oxidant, has been observed in drug addicts in several countries in Eastern Europe with some cases also in Western countries. A levodopa unresponsive Parkinsonian syndrome occurs within a few months of abusing the homemade drug mixture containing ephedrone (methcathinone) and manganese. The development of this neurological syndrome has been attributed to toxic effects of manganese, but the role of the psychostimulant ephedrone is unclear. This paper describes the clinical syndrome, results of neuroimaging, and therapeutic attempts.