Is transcranial sonography useful to distinguish scans without evidence of dopaminergic deficit patients from Parkinson's disease?

BACKGROUND: Approximately 10% of patients clinically diagnosed with early Parkinson's disease (PD) subsequently have normal dopaminergic functional imaging. Transcranial sonography (TCS) has been shown to detect midbrain hyperechogenicity in approximately 90% of Parkinson's disease (PD) patients and 10% of the healthy population. The aim of this study was to investigate the prevalence of midbrain hyperechogenicity in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDD), in comparison to PD patients. METHODS: TCS was performed in 14 patients with SWEDD and 19 PD patients. RESULTS: There was a significantly increased area of echogenicity in the PD group (0.24 ± 0.06 cm(2) ), compared to the group of patients with SWEDD (0.13 ± 0.06 cm(2) ; P < 0.001). One (9.1%) of these patients, compared to 14 (82.5%) of the PD patients, was found to have hyperechogenicity (P < 0.001). CONCLUSIONS: We conclude that TCS is useful to distinguish PD patients from patients with suspected parkinsonism and SWEDD

Pain in Multiple System Atrophy a Systematic Review and Meta-Analysis

Background: Individuals with multiple system atrophy (MSA) often complain about pain, nonetheless this remains a poorly investigated non-motor feature of MSA. Objectives: Here, we aimed at assessing the prevalence, characteristics, and risk factors for pain in individuals with MSA. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, we systematically screened the PubMED, Cochrane, and Web of Science databases for papers published in English until September 30, 2022, combining the following keywords: “pain,” “multiple system atrophy,” “MSA,” “olivopontocerebellar atrophy,” “OPCA,” “striatonigral degeneration,” “SND,” “Shy Drager,” and “atypical parkinsonism.”. Results: The search identified 700 records. Sixteen studies provided information on pain prevalence in cohorts of MSA individuals and were included in a qualitative assessment based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Thirteen studies (11 cross-sectional, two longitudinal) scored ≥14 points on QUADAS assessment and were included in a quantitative analysis, pooling data from 1236 MSA individuals. The resulting pooled prevalence of pain in MSA was 67% (95% confidence intervals [CI] = 57%–75%), and significantly higher in individuals with MSA of parkinsonian rather than cerebellar type (76% [95% CI = 63%–87%] vs. 45% [95% CI = 33%–57%], P = 0.001). Pain assessment tools and collected information were highly heterogeneous across studies. Two studies reported pain treatment strategies and found that only every second person with MSA complaining about pain had received targeted treatment. Conclusions: We found that pain is a frequent, but still under-recognized and undertreated feature of MSA. Further research is needed to improve pain detection and treatment in MSA

Levodopa medication improves incidental sequence learning in Parkinson’s disease

Empirical evidence suggests that levodopa medication used to treat the motor symptoms of Parkinson’s disease (PD) may either improve, impair or not affect specific cognitive processes. This evidence led to the ‘dopamine overdose’ hypothesis that levodopa medication impairs performance on cognitive tasks if they recruit fronto-striatal circuits which are not yet dopamine-depleted in early PD and as a result the medication leads to an excess of dopamine. This hypothesis has been supported for various learning tasks including conditional associative learning, reversal learning, classification learning and intentional deterministic sequence learning, on all of which PD patients demonstrated significantly worse performance when tested on relative to off dopamine medication. Incidental sequence learning is impaired in PD, but how such learning is affected by dopaminergic therapy remains undetermined. The aim of the current study was to investigate the effect of dopaminergic medication on incidental sequence learning in PD. We used a probabilistic serial reaction time task (SRTT), a sequence learning paradigm considered to make the sequence less apparent and more likely to be learned incidentally rather than intentionally. We compared learning by the same group of PD patients (n = 15) on two separate occasions following oral administration of levodopa medication (on state) and after overnight withdrawal of medication (off state). Our results demonstrate for the first time that levodopa medication enhances incidental learning of a probabilistic sequence on the serial reaction time task in PD. However, neither group significantly differed from performance of a control group without a neurological disease, which indicates the importance of within group comparisons for identifying deficits. Levodopa medication enhanced incidental learning by patients with PD on a probabilistic sequence learning paradigm even though the patients were not aware of the existence of the sequence or their acquired knowledge. The results suggest a role in acquiring incidental motor sequence learning for dorsal striatal areas strongly affected by dopamine depletion in early PD.Mazda Beigi was supported by a 3+1 ESRC PhD studentship (R84003). Leonora Wilkinson was funded by a Career Development Fellowship from Parkinson’s UK

The Role of the Substantia Nigra Pars Compacta in Regulating Sleep Patterns in Rats

Background. As of late, dopaminergic neurotransmission has been recognized to be involved in the generation of sleep disturbances. Increasing evidence shows that sleep disturbances in Parkinson's disease (PD) patients are mostly related to the disease itself, rather than being a secondary phenomenon. Evidence contained in the literature lends support to the hypothesis that the dopaminergic nigrostriatal pathway is closely involved in the regulation of sleep patterns. Methodology/Principal Findings. To test this hypothesis we examined the electrophysiological activity along the sleep-wake cycle of rats submitted to a surgically induced lesion of the SNpc by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We demonstrated that a 50% lesion of the substantia nigra pars compacta (SNpc) suffices to produce disruptions of several parameters in the sleep-wake pattern of rats. A robust and constant decrease in the latency to the onset of slow wave sleep (SWS) was detected throughout the five days of recording in both light [F((22.16)) = 72.46, p<0.0001] and dark [F((22.16)) = 75.0, p<0.0001] periods. Also found was a pronounced increase in the percentage of sleep efficiency during the first four days of recording [F((21.15)) = 21.48, p<0.0001], in comparison to the sham group. Additionally, the reduction in the SNpc dopaminergic neurons provoked an ablation in the percentage of rapid eye movement sleep (REM) during three days of the sleep-wake recording period with a strong correlation (r = 0.91; p<0.0001) between the number of dopaminergic neurons lost and the percentage decrease of REM sleep on the first day of recording. On day 4, the percentage of REM sleep during the light and dark periods was increased, [F((22.16)) = 2.46, p<0.0007], a phenomenon consistent with REM rebound. Conclusions/Significance. We propose that dopaminergic neurons present in the SNpc possess a fundamental function in the regulation of sleep processes, particularly in promoting REM sleep.AFIPCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniv Fed Parana, Dept Farmacol, BR-80060000 Curitiba, Parana, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilFAPESP: 98/14.303-3Web of Scienc

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

Multiple system atrophy (MSA) is a progressive late onset neurodegenerative α-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of α-synuclein (αSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar αSYN and dysfunction of the ubiquitin–proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial αSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human αSYN expression and determined the presence of MSA-like neurodegeneration in this model as compared to wild-type mice. PSI induced open field motor disability in transgenic αSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic αSYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic αSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human αSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA

Motivational modulation of bradykinesia in Parkinson's disease off and on dopaminergic medication.

Motivational influence on bradykinesia in Parkinson's disease may be observed in situations of emotional and physical stress, a phenomenon known as paradoxical kinesis. However, little is known about motivational modulation of movement speed beyond these extreme circumstances. In particular, it is not known if motivational factors affect movement speed by improving movement preparation/initiation or execution (or both) and how this effect relates to the patients' medication state. In the present study, we tested if provision of motivational incentive through monetary reward would speed-up movement initiation and/or execution in Parkinson's disease patients and if this effect depended on dopaminergic medication. We studied the effect of monetary incentive on simple reaction time in 11 Parkinson's disease patients both "off" and "on" dopaminergic medication and in 11 healthy participants. The simple reaction time task was performed across unrewarded and rewarded blocks. The initiation time and movement time were quantified separately. Anticipation errors and long responses were also recorded. The prospect of reward improved initiation times in Parkinson's disease patients both "off" and "on" dopaminergic medication, to a similar extent as in healthy participants. However, for "off" medication, this improvement was associated with increased frequency of anticipation errors, which were eliminated by dopamine replacement. Dopamine replacement had an additional, albeit small effect, on reward-related improvement of movement execution. Motivational strategies are helpful in overcoming bradykinesia in Parkinson's disease. Motivational factors may have a greater effect on bradykinesia when patients are "on" medication, as dopamine appears to be required for overcoming speed-accuracy trade-off and for improvement of movement execution. Thus, medication status should be an important consideration in movement rehabilitation programmes for patients with Parkinson's disease

α-Synuclein Genetic Variants Predict Faster Motor Symptom Progression in Idiopathic Parkinson Disease

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson’s disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson’s patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson’s Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57–10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96–2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend  = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care

<p>Abstract</p> <p>Background</p> <p>Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common.</p> <p>Methods</p> <p>The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms.</p> <p>Results</p> <p>The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS.</p> <p>Conclusion</p> <p>The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.</p

α-Synuclein Expression Selectively Affects Tumorigenesis in Mice Modeling Parkinson's Disease

Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn- dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over- expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer