Abstract
An important aim in long‐term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the ...emergence of dyskinesias. One strategy is to enhance levodopa delivery to the brain by co‐administering it with inhibitors of peripheral dopa‐decarboxylase and catechol‐O‐methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed‐dose combinations as the branded formulation Stalevo
®
(Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials. Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual‐enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect. The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review. Some 300,000 patient‐years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non‐dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance.
Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and ...constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.
Introduction
Patients with idiopathic smell loss constitute an at-risk population for the development of Parkinson’s disease (PD). The study aimed to follow up a large number of patients with ...idiopathic smell and/or taste loss to define the incidence of PD in this population and, further, to assess characteristics of both olfactory and gustatory function and their possible association with PD development.
Methods
In this prospective case–control study, 833 patients diagnosed with an idiopathic smell disorder at our Smell and Taste Center during the last 15 years were contacted for a telephone interview. In 474 patients, a complete data set containing of demographic data, clinical information, retrospective smell and taste testing results, and telephone assessment was obtained.
Results
Out of 474 patients with idiopathic smell loss 45 (9.8%) had been diagnosed with PD, since they received the diagnosis of idiopathic smell and/or taste loss (mean 10.9 years after olfactory loss onset). Thus, with respect to the classification into olfactory/gustatory disorders, 28.6% of the patients with a combined olfactory and gustatory disorder developed PD, whereas in 9.9% of those with a pure olfactory disorder and in 3.8% of those with a pure gustatory disorder, PD was diagnosed. No association emerged between qualitative smell or taste loss and PD development.
Conclusion
This large patient cohort study extends the previous literature, indicating that risk stratification might be considerably improved by correct diagnostic allocation and emphasizes the need for an exhaustive olfactory and gustatory assessment in specialized centers.
Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants ...and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy.
We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16–65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre–post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702).
Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 95% CI 1·05–2·41, p<0·0001), 10 months (2·58 1·76–3·39, p<0·0001), and 14 months (3·12 2·06–4·19, p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 35% patients), back pain (38 22%), and nausea (19 11%). No serious adverse events were reported.
Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort.
None.
Parkinson's disease (PD) is a neurodegenerative disorder with both motor and non-motor symptoms. Despite the progressive nature of PD, early diagnosis, tracking the disease's natural history and ...measuring the drug response are factors that play a major role in determining the quality of life of the affected individual. Apart from the common motor symptoms, i.e., tremor at rest, rigidity and bradykinesia, studies suggest that PD is associated with disturbances in eating behavior and energy intake. Specifically, PD is associated with drug-induced impulsive eating disorders such as binge eating, appetite-related non-motor issues such as weight loss and/or gain as well as dysphagia-factors that correlate with difficulties in completing day-to-day eating-related tasks. In this work we introduce Plate-to-Mouth (PtM), an indicator that relates with the time spent for the hand operating the utensil to transfer a quantity of food from the plate into the mouth during the course of a meal. We propose a two-step approach towards the objective calculation of PtM. Initially, we use the 3D acceleration and orientation velocity signals from an off-the-shelf smartwatch to detect the bite moments and upwards wrist micromovements that occur during a meal session. Afterwards, we process the upwards hand micromovements that appear prior to every detected bite during the meal in order to estimate the bite's PtM duration. Finally, we use a density-based scheme to estimate the PtM durations distribution and form the in-meal eating behavior profile of the subject. In the results section, we provide validation for every step of the process independently, as well as showcase our findings using a total of three datasets, one collected in a controlled clinical setting using standardized meals (with a total of 28 meal sessions from 7 Healthy Controls (HC) and 21 PD patients) and two collected in-the-wild under free living conditions (37 meals from 4 HC/10 PD patients and 629 meals from 3 HC/3 PD patients, respectively). Experimental results reveal an Area Under the Curve (AUC) of 0.748 for the clinical dataset and 0.775/1.000 for the in-the-wild datasets towards the classification of in-meal eating behavior profiles to the PD or HC group. This is the first work that attempts to use wearable Inertial Measurement Unit (IMU) sensor data, collected both in clinical and in-the-wild settings, towards the extraction of an objective eating behavior indicator for PD.
Early diagnosis and timely treatment of Parkinson’s disease are essential factors to provide these patients with a longer period of a better quality of life. Olfactory loss is among the first ...non-motor symptoms of the disease; however, in light of the many causes of smell loss, it is a very unspecific biomarker and should only be used as part of a diagnostic test battery. In this study, we investigated the olfactory response in 71 subjects, consisting of Parkinson’s disease patients, hyposmic and anosmic patients of other causes, and normosmic individuals searching for sensitive, distinct biomarkers for which we used scalp event-related 64-channel electroencephalography and psychophysical tests. The analysis of the global field power indicated significant measurable differences between patients with Parkinson’s disease and otherwise olfactory dysfunctional and normosmic individuals. The localization of brain sources, in particular, provides evidence for differences in mainly late EEG-components suggesting a decline of central brain networks as a causal factor for olfactory loss in Parkinson’s disease. The findings indicate a different pattern of olfactory processing in patients with Parkinson’s disease compared to olfactory dysfunctions of other origin, which provide further insights into the mechanisms behind olfactory dysfunction in Parkinson’s.
Objective: Parkinson's Disease (PD) is a progressive neurodegenerative disorder, manifesting with subtle early signs, which, often hinder timely and early diagnosis and treatment. The development of ...accessible, technology-based methods for longitudinal PD symptoms tracking in daily living, offers the potential for transforming disease assessment and accelerating diagnosis. Methods: A privacy-aware method for classifying patients and healthy controls (HC), on the grounds of speech impairment present in PD, is proposed. Voice features from running speech signals were extracted from passively-captured recordings over voice calls. Language-aware training of multiple- and single-instance learning classifiers was employed to fuse and predict on voice features and demographic data from a multilingual cohort of 498 subjects (392/106 self-reported HC/PD patients). Results: By means of leave-one-subject-out cross-validation, the best-performing models yielded 0.69/0.68/0.63/0.83 area under the Receiver Operating Characteristic curve (AUC) for the binary classification of PD patient vs. HC in sub-cohorts of English/Greek/German/Portuguese-speaking subjects, respectively. Out-of sample testing of the best performing models was conducted in an additional dataset, generated by 63 clinically-assessed subjects (24/39 HC/early PD patients). Testing has resulted in 0.84/0.93/0.83 AUC for the English/Greek/German-speaking sub-cohorts, respectively. Conclusions: The proposed approach outperforms other methods proposed for language-aware PD detection considering the ecological validity of the voice data. Significance: This paper introduces for the first time a high-frequency, privacy-aware and unobtrusive PD screening tool based on analysis of voice samples captured during routine phone calls.
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