Journal of Neural Transmission最新文献

The demographic development and the advance of intensified yet time and personnel-intensive therapeutic options constitute increasing challenges for the care of people with advanced Parkinson's disease (PD). Often, the multitude of motor and non-motor symptoms cannot be adequately addressed in an ambulatory setting The concept of a Parkinson's day clinic has been put forward to meet the requirements for these patients who not necessarily require the full medical support of an inpatient treatment and was included into the Parkinson's guidelines of the German Neurological Society as a novel and promising medical care model. While the guidelines put forward some recommendations as to which patients are most likely to benefit from treatment in a Parkinson's day clinic, it has not yet been decided which infrastructural, operational, personnel and qualitative requirements such a setting should provide. Here we provide recommendations on the basis of an expert consensus as to which patients will particularly benefit from treatment in a Parkinson´s day clinic and which services such a day clinic should address in order to provide successful therapy. Furthermore we suggest a standard operating procedure (SOP) and we give examples of patients who are suitable for treatment in a Parkinson´s day clinic.

Traditional advanced therapies in Parkinson's disease (PD) with motor fluctuations and dyskinesias like continuous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG), levodopa-carbidopa entacapone intestinal gel (LECIG), or deep brain stimulation (DBS) have played a central role in managing therapy-related complications. Recently, continuous subcutaneous foslevodopa/foscarbidopa infusion (CSFLI) has emerged as a novel therapeutic option. This manuscript provides insights from one year of real-world experience with CSFLI, addressing critical questions that clinicians face when selecting the most appropriate therapy for advanced PD. Our discussion centers on key considerations for patient selection, exploring which individuals may benefit more from CSFLI compared to other device-aided therapies. We highlight CSFLI's advantages in flexibility and ease of use but also consider limitations, particularly its side effects, such as skin-related issues. Recommendations are presented on how to prevent and manage these adverse effects to maximize patient compliance and therapeutic success. Additionally, the paper examines strategies for optimizing concurrent oral medications when combined with CSFLI, providing guidance on balancing pump infusion with necessary adjunctive oral treatments.

While multiple sclerosis (MS) is associated with various movement disorders, in particular tremor and ataxia, its combination with parkinsonism is rare and co-occurrence of MS and Parkinson disease (PD) has been reported in only few definite cases. Theories about this co-occurrence range from coincidental to causal, but the true prevalence, basic features and causal relations between the two entities have not been systemically evaluated. Although there are cases of causal relationship between parkinsonism and MS related to demyelinating lesions affecting the dopaminergic nigrostriatal pathway, in a limited number of cases, PD (some gene-mediated) and MS may coexist as two separate diseases in the same patients. The prevalence of MS in LRRK2 PD, while rare, supports an important role for immune function in both disorders, while the role of PD-related PINK is still open. Furthermore, several common genes such as BACE2, CD69, CLC, CPA3 and DEFAs may play important roles in MS and PD, while MS and PD share iron accumulation in substantia nigra, which may be due to protein-protein interaction networks related to metal homeostasis. In view of the various pathogenic possibilities, the causal relationship of concurring MS and PD deserves critical consideration.

Botulinum toxin type A (BoNT) has emerged as a potential alternative to conventional therapies to many debilitating chronic diseases characterised by inflammatory states. However, the biological rationale remains ambiguous. Our review aimed to systematically assessed which biochemical biomarkers have been reported in clinical research to evaluate BoNT analgesic and mood-lifting effects in head and neck chronic conditions related to inflammation. We searched databases and registries between inception and September 29, 2023. Of the nine included studies, there were concerns about risk of bias for six studies. The leading biomarker with five studies was the calcitonin gene-related peptide (CGRP), followed by serotonin with two studies. Oxidative stress biomarkers were only reported in one study. Several important players in inflammatory processes and different immune cell classes have been evaluated in four studies. There was only one trial measuring changes in beta Tubulin and SNAP-25, and another study evaluating cutaneous neuropeptide substance-P. After BoNT, a significant effect was reported in six studies, including decrease in plasma levels of CGRP in chronic migraine and trigeminal neuralgia; serotonin decrease when collected from human tears in refractory intractable dry eye disease and increase in peripheral blood platelets in painful cervical dystonia associated to depression and anxiety; decrease in plasma concentration of markers of oxidative damage to proteins and increase in biomarkers for antioxidant power; decrease in expression of gene sets involved in inflammatory pathways and immune cells classes in the periosteum and metalloproteinase-9 molecule in the tears. BoNT seems to affect some biomarkers present in chronic inflammatory conditions. However, the certainty evidence found was very low to moderate. This study is registered on PROSPERO (CRD42023432131).

Botulinum toxin (BT) therapy is the therapy of choice for most forms of dystonia. We want to describe its costs, if all dystonia patients in Germany would have access to optimal BT therapy. For this, we combined the latest data on epidemiology of dystonia and dosing of BT therapy for dystonia. Missing data were generated for this study. Based on official German pharmacy sales prices, optimal treatment for all dystonia patients in Germany with a population of 84.1 million would generate annual drug costs of €155.5 million (cervical dystonia 89.3, tardive dystonia 22.1, generalised dystonia 17.9, blepharospasm 9.3, segmental dystonia 5.9, writer's cramp 5.3, arm dystonia 3.2, oromandibular dystonia 2.3, musician's dystonia 0.3, spasmodic dysphonia 0.1) This is €1.85 annually per capita or 0.3% of the total 2021 drug budget and 42% of the 2021 Parkinson drug budget of German public insurance companies. Actual costs for the health care system are considerably lower, as there are various discounts to consider. Further reductions would be possible. BT therapy's individual costs are high. Its costs for the health care system, however, are marginal. Comparing projected and actual costs, would allow estimating availability and quality of BT therapy of dystonia in Germany.

While interstitial cystitis along with bladder pain syndrome (IC/BPS) is still poorly treated, published clinical evidence suggests that onabotulinumtoxinA (natural botulinum neurotoxin type A (BoNT/A)) intradetrusor injections is efficient in IC/BPS. However, as bladder instillation could be a safer and more convenient administration route, we aimed to investigate the effect of BoNT/A needle-free administration in an IC/BPS rodent model. Cyclophosphamide (CYP) was used to induce IC/BPS in rats. The resulting symptoms mimicked the main key features of human non-ulcerative IC/BPS. AbobotulinumtoxinA (aboBoNT-A) or reference compounds used in the clinic were delivered as a single intravesical administration into the bladder via the urethra. Visceral allodynia and hyperalgesia were assessed at the abdominal level with von Frey filaments before and after bladder pain induction. The levels of BoNT/A-cleaved SNAP25 (c-SNAP25), total SNAP25 (SNAP25^N-ter), beta-3 tubulin and CGRP in bladders were also quantified using immunohistochemistry (IHC), as well as the histopathological lesions. AboBoNT-A was well tolerated up to 30 U/rat. Allodynia and hyperalgesia were significantly decreased after aboBoNT-A dosing, with higher efficacy compared to references. c-SNAP25 IHC levels were low and similar in the detrusor for the 3 aboBoNT-A groups. Neither CYP or aboBoNT-A induced any change in the amount of SNAP25, beta-3 tubulin or CGRP. Some CYP-induced histopathological lesions showed a trend in improvement under aboBoNT-A. AboBoNT-A displayed analgesic properties that could translate into better therapies for visceral pain. Interestingly, intravesical (needle-free) administration seems like a promising and reproducible route for botulinum toxin therapy in patients with IC/BPS.

The crucial role of steroid hormones in health and diseases merits their high-throughput, accurate and affordable measurements in biological specimens. Despite advances in analytical methods, sensing and quantifying steroid hormones remains challenging. Immunoassays offer excellent sensitivity but are inherently labour-intensive, costly, and prone to false positives. Mass spectrometry (MS) has been increasingly utilised, with the main hurdle being the isobaric tendencies of similar analytes, which complicates their separation and accurate quantification. This study compares ultrahigh-performance supercritical fluid chromatography separation (UHPSFC) and ultra-high-performance liquid chromatography (UHPLC) for MS detection. It optimises the column chemistry, temperature, and pressure to provide an operational protocol for the resolution and quantification of analytes. It presents the systematic characterisation of UHPSFC-MS performance by investigating spiked blood samples using Solid-Phase Extraction (SPE) and describes the matrix effects associated with MS measurements. Although both separation methods showed adequate resolution, specificity, and retention time, UHPSFC-MS was superior for five out of seven columns tested. With added high-throughput capacities, UHPSFC-MS, thus, offers an optimal solution for the analysis of steroid hormones for research, medical chemistry, and clinical diagnostics.

Botulinum neurotoxins (BoNT) are established biopharmaceuticals for neuromuscular and secretory conditions based on their ability to block neurotransmitter release from neurons by proteolyzing specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Recently, a mutant catalytic domain of serotype E (LC/E) exhibiting 16 mutations was reported to cleave the phosphatase and tensin homolog (PTEN). This molecule represents an attractive new target in neurons as several reports support PTEN knockdown as a strategy to stimulate axonal regeneration after injury. Though this LC/E mutant was shown to cleave PTEN in primary neurons through lentivirus-based expression, its expression and functionality as mutated full-length BoNT/E have not been studied. Hence, we assembled the 16 mutations stepwise in a bacterial expression plasmid for LC/E and purified several multiple mutants of LC/E. Biochemical characterization showed that the 16-fold mutant did not exhibit a detectable activity toward SNAP-25 up to 10 µM final concentration while it displayed an EC₅₀ of approximately 200 nM for PTEN, exceeding 1000-fold that for LC/E-wt on the native substrate SNAP-25. Unexpectedly, expression of the full length 16-fold mutated BoNT/E did not provide soluble protein, possibly due to an interference of the interaction between LC and the translocation domain. Reversion of individual mutations revealed the E159L and S162Q substitutions, critical for redirecting LC/E activity toward PTEN, as main culprits for the solubility issue. To overcome this problem, we applied a methodology proved successful years ago, harnessing a proteolytically inactive variant of BoNT type D (BoNT/Di) as neurospecific delivery system for cargo proteins. The fusion protein LCE-16x-BoNT/Di could be produced in sufficient yields. Activity tests using rat cerebellar granule neurons showed BoNT/E-like activity for LC/E-wt-BoNT/Di, but no PTEN-directed activity for LC/E-16x-BoNT/Di.

Botulinum toxin is considered first-line treatment for focal hand dystonia in musicians. Mild, temporary weakness is a common accompaniment of effective injection. We present a unique case of delayed-onset, severe, prolonged weakness and atrophy in a patient with musician's dystonia, successfully treated with botulinum toxin for over 10 years, following injection of his usual muscles at his well-established dose. This pianist received botulinum toxin treatment for more than 10 years, with a stable response. Six weeks after an injection, he developed progressive severe weakness and atrophy of the affected forearm involving both injected and uninjected muscles. Weakness and atrophy took over one year without further injections to resolve. The clinical course and laboratory testing were not suggestive of brachial neuritis, plexopathy, or neuralgic amyotrophy. The literature contains rare case reports of severe weakness and atrophy after botulinum toxin injection, sometimes with delayed onset and sometimes affecting distant muscles. Frequently presenting with pain, such cases often have evidence of plexopathy or neuralgic amyotrophy which were absent in our patient. Clinicians should be aware of this rare potential severe adverse event associated with botulinum toxin.

Levodopa remains central to Parkinson's disease (PD) treatment, but long-term use can cause motor complications, highlighting the need for additional therapies. Mucuna pruriens (MP), a natural source of levodopa, shows potential in managing these complications. Further research is needed to compare its pharmacokinetics (PK) and clinical outcomes with traditional levodopa formulations. This randomised, single-blind, crossover trial compared the PK, clinical outcomes, and safety of MP powder against levodopa/benserazide dispersible tablets (Levodopa DT) in PD patients with motor complications. Twelve participants were recruited to receive either 30 g of MP powder or two 100/25 levodopa DT in separate sessions with a two-week washout between sessions. Key PK parameters (AUC, Cmax, Tmax, and t_½) were measured. Clinical assessments used standard rating scales and adverse events were recorded. Data from 11 participants were analysed after one withdrawal. MP powder demonstrated significantly higher overall drug exposure, with a geometric mean AUC_0-∞ of 12,424.81 compared to 7981.69 ng·h/mL for levodopa DT. The geometric mean ratio was 155.67% (90% CI 134.59-180.04), exceeding the bioequivalence acceptance range of 80-125%. However, the two treatments exhibited similar Tmax and t₁/₂ values, indicating comparable rates of absorption and elimination. Clinically, MP provided a longer ON state without dyskinesia-232.2 min versus 161.8 min for levodopa DT (p = 0.01). Mild and transient adverse events, such as nausea and dizziness, were more frequently associated with MP. MP offers superior drug exposure and extends the ON state without increasing dyskinesia, positioning it as a promising alternative to synthetic levodopa for managing motor symptoms. These findings support MP's potential role in alleviating motor complications in PD treatment.