The Botulinum NeuroToxin (BoNT) comprises several serotypes with distinct properties, mechanisms of action, sensitivity and duration of effect in different species. The serotype A (BoNT/A) is the ...prevalent neurotoxin applied in human's disease. In this paper we present an overview of the current knowledge regarding the duration of effect and the neuromuscular sprouting of different BoNT serotypes in humans. Then, we report the original results of a study in healthy subjects treated with BoNT/A, B, C and F using different neurophysiological techniques. Twelve healthy volunteers (7 men, 5 women) are treated with BoNT/A, B, C and F or placebo in Abductor digiti minimi (ADM) muscle of the hand. Before and after injections, an extensive neurophysiological study is performed with the CMAP amplitude variation, Multi-Motor Unit Action Potentials (MUAPs) analysis, the Turns/Amplitude ratio of interference pattern (IP) and determination of jitter and Fiber Density (FD) at single-fiber electromyography (SFEMG), at week 2 (w2), 4 (w4), 6 (w6) and 8 (w8). A maximal neuromuscular block is obtained at w2 for all the serotypes. Afterwards, the CMAP trend appear similar for BoNT/A, B, and C while, BoNT/F shows a faster recover. Multi-MUAPs analysis and IP detect mild changes at w2 for all serotypes, except for BoNT/F that shows a greater change since w4. SFEMG have minimal changes in FD while, Jitter increase at w2 with a slower decrease over the time for all BoNTs. In conclusion, BoNT/F has earlier sprouting and complete recovery at w8. Other serotypes present a slower and similar profile. The EMG appear useful to study the functional recovery in humans, and these results should provide new evidence for assessing different serotypes. These findings improve our knowledge regarding the methods to evaluate duration of effects and dose equivalents in different serotypes, that in the future could change the clinicians strategy for disease-tailored BoNT therapies.
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•Each BoNT serotype has distinct action in humans.•Duration of effect was measures by neurophysiological testing or clinical scales.•A review of clinical duration is reported.
Understanding the pathophysiology and genetic background of Parkinson’s disease (PD) increases the likelihood of developing effective disease-modifying therapeutic strategies. In particular, the ...discovery of genetic variants causing or increasing the risk for PD has contributed to refining the clinical, biological, and molecular classification of the disease and has offered new insights into sporadic forms. It is even more evident that specific genetic mutations can show different responses to pharmacological and device-aided therapies. To date, several agents acting on multiple PD-causing pathogenic pathways have been tested as disease-modifying strategies, with disappointing results. This may be caused by the recruitment of PD populations whose underlying molecular pathophysiology is heterogeneous. We believe that an effective model of personalized medicine must be prioritized in the near future. Here, we review the current therapeutic options under clinical and preclinical development for PD and discuss the key pending questions and challenges to face for successful clinical trials. Furthermore, we provide some insights into the role of genetics in guiding the decision-making process on symptomatic and device-aided therapies for PD in daily clinical practice.
•Alterations in weight and eating habits are frequent in Parkinson's disease.•An increase in body weight may also occur after deep brain stimulation.•Some non-motor symptoms may play a role in weight ...and eating abnormalities.•Further studies are warranted to confirm these interpretations.
Research on eating behaviours has extensively highlighted that cognitive systems interact with the metabolic system in driving food intake and in influencing body weight regulation. Parkinson's disease is a good model for studying these complex interactions since alterations in both body weight and cognitive domains have been frequently reported among these patients. Interestingly, even if different non-motor symptoms may characterize the course of the disease, their contribution to weight and food preference has been poorly investigated. This review describes body weight alterations and eating habits in patients with Parkinson's disease, including those who underwent deep brain stimulation surgery. In particular, the review considers the link between non-motor symptoms, affecting sensory perception, cognition, mood and motivation, and food intake and weight alterations. The take home message is twofold. First, we recommend a comprehensive approach in order to develop effective strategies in the management of patients' weight. Second, we also suggest that investigating this issue in patients with Parkinson's disease may provide some useful information about the mechanisms underlying food and weight regulation in healthy subjects.
Background
Huntington’s disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms ...still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients.
Methods
Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: “Deep brain stimulation,” “DBS,” and “HD,” “Huntington’s disease,” and “Huntington.” Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected.
Results
Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington’s Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%.
Conclusions
HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed.
Parkinson's disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal ...accumulation of abnormal α-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either α-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of α-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM).
We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant α-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce α-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.
Our results showed that a significant percentage of MSA and PD samples induced α-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.
Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for α-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages.
Introduction
Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying ...pathophysiologic mechanisms.
Objective
To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities.
Methods
Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted.
Results
A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors.
Conclusions
Our data support the evidence of a large overlap between FMD phenotypes.
Levodopa (L-DOPA) treatment, combined with the administration of dopa-decarboxylase inhibitors (DDCIs), is still the most effective symptomatic treatment of Parkinson's disease (PD). Although its ...efficacy in the early stage of the disease has been confirmed, its complex pharmacokinetics (PK) increases the variability of the intra-individual motor response, thus amplifying the risk of motor/non-motor fluctuations and dyskinesia. Moreover, it has been demonstrated that L-DOPA PK is strongly influenced by several clinical, therapeutic, and lifestyle variables (e.g., dietary proteins). L-DOPA therapeutic monitoring is therefore crucial to provide personalized therapy, hence improving drug efficacy and safety. To this aim, we have developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify L-DOPA, levodopa methyl ester (LDME), and the DDCI carbidopa in human plasma. The compounds were extracted by protein precipitation and samples were analyzed with a triple quadrupole mass spectrometer. The method showed good selectivity and specificity for all compounds. No carryover was observed, and dilution integrity was demonstrated. No matrix effect could be retrieved; intra-day and inter-day precision and accuracy values met the acceptance criteria. Reinjection reproducibility was assessed. The described method was successfully applied to a 45-year-old male patient to compare the pharmacokinetic behavior of an L-DOPA-based medical treatment involving commercially available
extracts and an LDME/carbidopa (100/25 mg) formulation.
Detection of the pathological and disease-associated alpha-synuclein (αSyn
) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson's disease ...(PD). We recently showed that αSyn
can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes.
OM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data.
The αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83-1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability.
Our study provides evidence that OM-αSyn
may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.
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