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Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson's disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin‐concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture‐induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit‐based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non‐motor PD symptoms. Peripheral acupuncture stimulation activates hypothalamic MCH neurons, leading to motor recovery and memory improvement in Parkinson's disease model mice. This study reveals distinct neural pathways from MCH neurons to the substantia nigra and hippocampus, elucidating the mechanisms of acupuncture‐induced recovery from dopaminergic neurodegeneration and hippocampal synaptic plasticity impairment, offering insights into therapeutic targets for PD.

Non-motor symptoms (NMSs) in Parkinson's disease (PD) are often overlooked and thus can impede clinical management and significantly reduce the patient's quality of life. The study aimed to determine the burden of NMS in the early stages of PD. A 1-year observational cross-sectional study was conducted at Mayo Hospital, Lahore, in 2019. The MDS-PD criteria were used to diagnose PD patients. The study included patients with Hoehn and Yahr (HY) stages 1-3. The frequency of NMSs was assessed using a non-motor symptom questionnaire (NMSQ), and the non-motor symptom scale (NMSS) score was derived using the NMSS. A total of 100 PD patients were enrolled in the study. Sixty-three (63%) were males and 37 (37%) were females. Their age ranged between 45 and 75 years with a mean ± SD of 57.46 ± 8.46. At least one NMS was reported by 84% of patients, with neuropsychiatric symptoms (68%) preponderant, followed by a change in taste and smell (64%). The mean NMSS score is 46.22 ± 22.098 (median 44) with a range from 0 to 88, with the trend being increasing score with the advancing stage. The use of the NMSQ and NMSS tools should be standard in clinical practice to identify the severity of the disease and commence appropriate care.

Background and purpose Deep brain stimulation (DBS) has emerged as a promising treatment for movement disorders. This prospective study aims to evaluate the effects of bilateral subthalamic nucleus DBS (STN‐DBS) on motor and non‐motor symptoms in patients with primary Meige syndrome. Methods Thirty patients who underwent bilateral STN‐DBS between April 2017 and June 2020 were included. Standardized and validated scales were utilized to assess the severity of dystonia, health‐related quality of life, sleep, cognitive function and mental status at baseline and at 1 year and 3 years after neurostimulation. Results The Burke−Fahn−Marsden Dystonia Rating Scale movement scores showed a mean improvement of 63.0% and 66.8% at 1 year and 3 years, respectively, after neurostimulation. Similarly, the Burke−Fahn−Marsden Dystonia Rating Scale disability scores improved by 60.8% and 63.3% at the same time points. Postoperative quality of life demonstrated a significant and sustained improvement throughout the follow‐up period. However, cognitive function, mental status, sleep quality and other neuropsychological functions did not change after 3 years of neurostimulation. Eight adverse events occurred in six patients, but no deaths or permanent sequelae were reported. Conclusions Bilateral STN‐DBS is a safe and effective alternative treatment for primary Meige syndrome, leading to improvements in motor function and quality of life. Nevertheless, it did not yield significant amelioration in cognitive, mental, sleep status and other neuropsychological functions after 3 years of neurostimulation.

In Parkinson's Disease (PD), deep brain stimulation of the subthalamic nucleus (STN‐DBS) reliably improves motor symptoms, and the circuits mediating these effects have largely been identified. However, non‐motor outcomes are more variable, and it remains unclear which specific brain circuits need to be modulated or avoided to improve them. Since numerous non‐motor symptoms potentially respond to DBS, it is challenging to independently identify the circuits mediating each one of them. Data compression algorithms such as principal component analysis (PCA) may provide a powerful alternative. This study aimed at providing a proof of concept for this approach by mapping changes along extensive score batteries to a few anatomical fiber bundles and, in turn, estimating changes in individual scores based on stimulation of these tracts. Retrospective data from 56 patients with PD and bilateral STN‐DBS was included. The patients had undergone comprehensive clinical assessments covering changes in appetitive behaviors, mood, anxiety, impulsivity, cognition, and empathy. PCA was implemented to identify the main dimensions of neuropsychiatric and neuropsychological outcomes. Using DBS fiber filtering, we identified the structural connections whose stimulation was associated with change along these dimensions. Then, estimates of individual symptom outcomes were derived based on the stimulation of these connections by inverting the PCA. Finally, changes along a specific non‐motor score were estimated in an independent validation dataset (N = 68) using the tract model. Four principal components were retained, which could be interpreted to reflect (i) general non‐motor improvement; (ii) improvement of mood and cognition and worsening of trait impulsivity; (iii) improvement of cognition; and (iv) improvement of empathy and worsening of impulsive‐compulsive behaviors. Each component was associated with the stimulation of spatially segregated fiber bundles connecting regions of the frontal cortex with the subthalamic nucleus. The extent of stimulation of these tracts was able to explain significant amounts of variance in outcomes for individual symptoms in the original cohort (circular analysis), as well as in the rank of depression outcomes in the independent validation cohort. Our approach represents an innovative concept for mapping changes along extensive score batteries to a few anatomical fiber bundles and could pave the way toward personalized deep brain stimulation. Delivering stimulation to the correct target is a challenge for deep brain stimulation. We propose a new approach that allows condensing a large battery of scores onto a few main dimensions, identifying the structural connections associated with each dimension, and estimating changes in individual scores based on their stimulation.

Background Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction (NMJ), driven by T cells, mediated by B cells, and dependent on autoantibodies. In addition to the typical motor symptoms of fluctuating weakness, the non‐motor symptoms are also prevalent among MG patients. This review aims to present the non‐motor symptoms of MG and their potential pathogenesis, hoping to contribute to personalized diagnosis and treatment. Methods This review elaborates the non‐motor symptoms of MG and systematically detail, for the first time, their potential pathogenic mechanisms, offering a new perspective for clinical evaluation. Results The non‐motor symptoms of MG include autonomic disorders (urinary, gastrointestinal, cardiovascular and ocular dysfunction), sensory disability (olfactory abnormalities, gustatory reduction and headaches), cognitive impairment, sleep disturbances, psychological problems (depression and anxiety), and TAMG‐associated specific syndromes. Due to their insidious onset and lack of awareness, these symptoms are often overlooked. We review the non‐motor symptoms of MG and first provide a systematic and detailed discussion on their potential mechanisms, including the influence of MG‐specific antibodies (cross‐reactivity of AChR‐Ab, expression of MuSK‐Ab, and striational antibodies at related functional sites), dysregulation of inflammatory factors and immune cells, collateral effects of motor symptoms, impacts of MG comorbidities, and paraneoplastic syndromes caused by thymoma. Conclusion Non‐motor symptoms are common in MG patients. Given a series of potential mechanisms probably involved exploring these non‐motor symptoms will not only enhance our understanding of MG but also aid in diagnosis and the development of precise, personalized treatments, ultimately improving the overall life quality of patients. We review the non‐motor symptoms of MG and their potential pathogenesis, hoping to contribute to personalized diagnosis and treatment.

Parkinson's disease (PD) is a common degenerative disease of the central nervous system that is characterized by movement disorders and non‐motor symptoms (NMSs). The associated NMSs primarily include neuropsychiatric symptoms, autonomic dysfunction, sleep‐wake disorders, pain, fatigue, and hyposmia. These NMSs can occur at any stage of PD, especially before the onset of motor symptoms, and may affect a patient's quality of life more than motor symptoms. Although PD is most commonly diagnosed in people over 65 years, some patients exhibit symptom onset before the age of 50, which is clinically known as early‐onset Parkinson's disease (EOPD). The high heterogeneity and incidence of EOPD‐associated NMSs can lead to the misdiagnosis of EOPD as other neurodegenerative diseases. In this review, we discuss the research progress related to NMSs in patients with EOPD, focusing on neuropsychiatric disorders, autonomic dysfunction, sleep disorders, and sensory impairment, and outline the association of NMSs with different genotypic alterations, with the aim of providing assistance in the clinical management of patients. This study reviews the research progress related to non‐motor symptoms (NMS) in patients with early onset Parkinson's disease (EOPD), including neuropsychiatric symptoms, autonomic dysfunction, sleep disorders, and sensory disorders and also summarizes the characteristics of NMS in the genetic form of Parkinson's disease (PD). Although motor symptoms are the key features of PD, NMS is receiving increasing attention. We believe that our study makes a significant contribution to the literature because this study shows that the NMSs of EOPD and late onset Parkinson's disease are significantly different, mainly in neuropsychiatric symptoms, autonomic function, sleep disturbances, and sensory disturbances. The wide variety and high incidence of NMS in EOPD are often overlooked, and the low rate of recognition and individual differences sometimes make it difficult to distinguish NMS from other neurodegenerative diseases. Further, we believe that this paper will be of interest to the readership of your journal because it emphasizes the importance of identifying and mastering the characteristics of each NMS in clinical practice for early diagnosis and intervention to improve patients' NMS and quality of life.

Introduction Apathy is one of the most common neuropsychiatric manifestations in Parkinson's disease (PD). Recent proposals consider apathy as a multidimensional construct, which can manifest in behavioral, cognitive, emotional, and/or social dimensions. Apathy also overlaps conceptually and clinically with other non‐motor comorbidities, particularly depression. Whether all of these dimensions are applicable to the apathetic syndrome experienced by people with PD is unclear. In the present study, we investigated the multidimensional pattern of apathy associated with PD, using the recently developed Apathy Motivation Index (AMI) which probes behavioral, emotional, and social apathy dimensions. We then examined the relationship between these dimensions and other features of PD commonly associated with apathy, including depression, anxiety, cognition, and motor state. Methods A total of 211 participants were identified from the New Zealand Brain Research Institute (NZBRI) longitudinal PD cohort. One hundred eight patients and 45 controls completed the AMI, administered as an online questionnaire, and additional assessments including neuropsychiatric, neuropsychological, and motor scores. The pattern of dimensional apathy in PD was assessed using a repeated‐measured analysis of variance, while simple linear regressions were performed to evaluate relationships between these dimensions and other variables. Results We found a significant interaction between group (PD versus control) and apathy subscale, driven mainly by higher levels of social and behavioral—but not emotional—apathy in those with PD. This result was strikingly similar to a previous study investigating social apathy in PD. Distinct patterns of dimensional apathy were associated with depression and anxiety, with social and behavioral apathy positively associated with depression, and emotional apathy negatively associated with anxiety. Conclusion This work provides further evidence for a distinct pattern of apathy in people with PD in which deficits manifest in some—but not all—dimensions of motivated behavior. It emphasizes the importance of considering apathy as a multidimensional construct in clinical and research settings. Apathy in Parkinson's disease manifests mainly along social and behavioural, rather than emotional dimensions. Increasing social and behavioural apathy is associated with more depressive symptomatology in this group. In contrast, the presence of emotional apathy is negatively associated with anxiety, demonstrating dissociable relationships between dimensions of apathy and other common non‐motor complications of PD.

Background Non‐motor symptoms (NMS) are integral to Parkinson's Disease (PD) and management remains a challenge. Safinamide is a novel molecule in relation to addressing NMS due to its multifocal mechanism of action with both dopaminergic and non‐dopaminergic properties. Objective To investigate the efficacy of safinamide on NMS and its burden in PD patients with motor fluctuations after 6 months of treatment. Methods This observational, multicenter, open‐label, pilot study assessed a wide range of NMS using the following rating scales, NMSS (non‐motor symptom scale), KPPS (King's PD pain scale), HADS (hospital anxiety and depression scale), PDQ‐8 (Parkinson's disease quality of life questionnaire), and PDSS‐2 (Parkinson's disease sleep scale), EuroQol‐5D 3 level version (EQ‐5D‐3L), CGI‐I (clinical global impression of improvement), and PGI‐C (patient global impression of change). Motor examination using UPDRS part III (Unified Parkinson's disease rating scale, motor examination), UPDRS IV (complications of therapy) and Hoehn and Yahr staging were also obtained. Results 27 patients were included in the analysis and were evaluated at baseline and ≥ 6 months after safinamide treatment. 26 patients had a daily maintenance dose of 100 mg and 1 patient a daily dose of 50 mg. Significant improvements in UPDRS IV, KPPS item 5 (region‐specific “off” dystonia), KPPS domain 3 (items 4–6, fluctuation related pain) and KPPS total score were observed after treatment with safinamide, while maintaining stable dopaminergic medication. No statistically significant differences were found in NMSS, HADS, PDSS‐2, EQ‐5D‐3L, and PDQ‐8 after treatment. Conclusions Our results suggest that safinamide may have a beneficial effect on pain, a key unmet need in fluctuating PD patients. In this observational prospective study we investigate the effects of safinamide on non‐motor symptoms in patients with fluctuating Parkinson's disease. Our main finding is a significant improvement in UPDRS IV and pain as measured by the KPPS.

To perform a linguistic translation using validated methodology of the Parkinson's Disease Non-motor Questionnaire (NMSQuest) in a Polish Parkinson's Disease (PD) population, and apply the Polish NMSQuest to a real-life PD population. Non-motor symptoms are one of the key drivers of quality of life in PD patients and occur from the prodromal stage to the end palliative stage. Clinical recognition is crucial to manage these symptoms, and the PD NMSQuest is a globally used patient-completed validated PD-specific tool which helps to flag 30 common NMS in the clinic. Cognitive pretesting and linguistic translation were performed in 35 consecutive Polish PD patients using the translational programme recommended by the Movement Disorders Society. The validated and translated Polish version was then used in 70 consecutive PD patients (including the 35 original patients who performed the pretest) from outpatient clinics (43 males and 27 females). The mean age of the patients was 67.45 years (range 40-81) with a mean duration of PD of 12.32 years (range 2-24) and a median Hoehn and Yahr (HY) score of 3. 70 patients (mean age 67.45; mean duration of PD 12.32 years range 2-24; median HY score 3) provided 100% endorsement of the usefulness and need for using Polish NMSQuest using a cognitive pretest questionnaire. A subsequent study of the utility of the Polish NMSQuest showed it to be reliable across a large range of PD patients from 40-81 years and HY stages 1-4, with a mean declared NMS per patient of 6 across all stages of PD. The Polish version of the NMSQuest is reliable, valid and endorsed by Polish PD patients. Subsequent clinical use shows this to be a useful self- declaration flagging tool for NMS which needs to be captured in clinical visits so that clinical care includes management of NMS in PD.

Some studies observed a benefit of Parkinson’s disease (PD) patients after treatment with safinamide in some non-motor symptoms (NMSs). The aim of this study was to analyze the effectiveness of safinamide on NMS burden in PD. SAFINONMOTOR (an open-label study of the effectiveness of safinamide on non-motor symptoms in Parkinson’s disease patients) is a prospective open-label single-arm study conducted in five centers from Spain. The primary efficacy outcome was the change from baseline (V1) to the end of the observational period (6 months) (V4) in the non-motor symptoms scale (NMSS) total score. Between May/2019 and February/2020 50 patients were included (age 68.5 ± 9.12 years; 58% females; 6.4 ± 5.1 years from diagnosis). At 6 months, 44 patients completed the follow-up (88%). The NMSS total score was reduced by 38.5% (from 97.5 ± 43.7 in V1 to 59.9 ± 35.5 in V4; p < 0.0001). By domains, improvement was observed in sleep/fatigue (−35.8%; p = 0.002), mood/apathy (−57.9%; p < 0.0001), attention/memory (−23.9%; p = 0.026), gastrointestinal symptoms (−33%; p = 0.010), urinary symptoms (−28.3%; p = 0.003), and pain/miscellaneous (−43%; p < 0.0001). Quality of life (QoL) also improved with a 29.4% reduction in the PDQ-39SI (from 30.1 ± 17.6 in V1 to 21.2 ± 13.5 in V4; p < 0.0001). A total of 21 adverse events in 16 patients (32%) were reported, 5 of which were severe (not related to safinamide). Dyskinesias and nausea were the most frequent (6%). Safinamide is well tolerated and improves NMS burden and QoL in PD patients with severe or very severe NMS burden at 6 months.