Type-B monoamine oxidase inhibitors in neurological diseases: clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors, encompassing selegiline, rasagiline, and safinamide, are available to treat Parkinson's disease. These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease. There is also evidence supporting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease, such as mood deflection, cognitive impairment, sleep disturbances, and fatigue. Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors, particularly glial cell line-derived neurotrophic factor, which support dopaminergic neurons. Besides, safinamide may interfere with neurodegenerative mechanisms, counteracting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity. Due to the dual mechanism of action, the new generation of type-B monoamine oxidase inhibitors, including safinamide, is gaining interest in other neurological pathologies, and many supporting preclinical studies are now available. The potential fields of application concern epilepsy, Duchenne muscular dystrophy, multiple sclerosis, and above all, ischemic brain injury. The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline, rasagiline, and safinamide in Parkinson's disease and beyond, focusing on possible future therapeutic applications

Age at Onset Influences Progression of Motor and Non-Motor Symptoms during the Early Stage of Parkinson’s Disease: A Monocentric Retrospective Study

The interactions between the age at onset with other pathogenic mechanisms and the interplays between the disease progression and the aging processes in Parkinson’s disease (PD) remain undefined, particularly during the first years of illness. Here, we retrospectively investigated the clinical presentation and evolution of the motor and non-motor symptoms and treatment-related complications during the first 5 years of illness in subjects categorized according to age at onset. A total of 131 subjects were divided into “Early-Onset-PD” (EOPD; onset ≤49 years), “Middle-Onset-PD” (MOPD; onset 50–69 years) and “Late-Onset-PD” (LOPD; onset ≥70 years). The T0 visit was set at the time of the clinical diagnosis; the T1 visit was 5 years (±5 months) later. At T0, there were no significant differences in the motor features among the groups. At T1, the LOPD patients displayed a significantly higher frequency of gait disturbances and a higher frequency of postural instability. Moreover, at T1, the LOPD subjects reported a significantly higher frequency of non-motor symptoms; in particular, cardiovascular, cognitive and neuropsychiatric domains. The presented results showed a significantly different progression of motor and non-motor symptoms in the early course of PD according to the age at onset. These findings contribute to the definition of the role of age at onset on disease progression and may be useful for the pharmacological and non-pharmacological management of PD

Four Days Are Enough to Provide a Reliable Daily Step Count in Mild to Moderate Parkinson’s Disease through a Commercial Smartwatch

Daily steps could be a valuable indicator of real-world ambulation in Parkinson’s disease (PD). Nonetheless, no study to date has investigated the minimum number of days required to reliably estimate the average daily steps through commercial smartwatches in people with PD. Fifty-six patients were monitored through a commercial smartwatch for 5 consecutive days. The total daily steps for each day was recorded and the average daily steps was calculated as well as the working and weekend days average steps. The intraclass correlation coefficient (ICC) (3,k), standard error of measurement (SEM), Bland–Altman statistics, and minimum detectable change (MDC) were used to evaluate the reliability of the step count for every combination of 2–5 days. The threshold for acceptability was set at an ICC ≥ 0.8 with a lower bound of CI 95% ≥ 0.75 and a SAM < 10%. ANOVA and Mann–Whitney tests were used to compare steps across the days and between the working and weekend days, respectively. Four days were needed to achieve an acceptable reliability (ICC range: 0.84–0.90; SAM range: 7.8–9.4%). In addition, daily steps did not significantly differ across the days and between the working and weekend days. These findings could support the use of step count as a walking activity index and could be relevant to developing monitoring, preventive, and rehabilitation strategies for people with PD

Levodopa/carbidopa intestinal gel for pain related to levodopa-induced motor complications in Parkinson’s disease

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Age at Onset Influences Progression of Motor and Non-Motor Symptoms during the Early Stage of Parkinson’s Disease: A Monocentric Retrospective Study

The interactions between the age at onset with other pathogenic mechanisms and the interplays between the disease progression and the aging processes in Parkinson’s disease (PD) remain undefined, particularly during the first years of illness. Here, we retrospectively investigated the clinical presentation and evolution of the motor and non-motor symptoms and treatment-related complications during the first 5 years of illness in subjects categorized according to age at onset. A total of 131 subjects were divided into “Early-Onset-PD” (EOPD; onset ≤49 years), “Middle-Onset-PD” (MOPD; onset 50–69 years) and “Late-Onset-PD” (LOPD; onset ≥70 years). The T0 visit was set at the time of the clinical diagnosis; the T1 visit was 5 years (±5 months) later. At T0, there were no significant differences in the motor features among the groups. At T1, the LOPD patients displayed a significantly higher frequency of gait disturbances and a higher frequency of postural instability. Moreover, at T1, the LOPD subjects reported a significantly higher frequency of non-motor symptoms; in particular, cardiovascular, cognitive and neuropsychiatric domains. The presented results showed a significantly different progression of motor and non-motor symptoms in the early course of PD according to the age at onset. These findings contribute to the definition of the role of age at onset on disease progression and may be useful for the pharmacological and non-pharmacological management of PD

The impact of dysphagia in Parkinson's disease patients treated with levodopa/carbidopa intestinal gel

Background: Dysphagia is common in advanced phases of Parkinson disease (PD), and is a risk factor for aspiration pneumonia. Nonetheless, dysphagia has been poorly investigated in PD patients treated with levodopa-carbidopa intestinal gel (LCIG). We aimed to analyze the impact of dysphagia on mortality in LCIG treated patients and its relationship with other PD disability milestones. Methods: We retrospectively evaluated 95 consecutive PD patients treated with LCIG. Kaplan-Meier and log-rank test were used to compare mortality in patients with dysphagia from others. Cox regression was used to estimate the impact of dysphagia, age, disease duration, and Hoehn and Yahr (H&Y) on mortality in the entire cohort. Finally, univariate and multivariate regression analyses were used to estimate the association between dysphagia and age, disease duration, H&Y, hallucinations, and dementia. Results: A significantly higher mortality rate was observed in patients with dysphagia. In the Cox model, dysphagia was the only feature significantly associated with mortality (95%CI 2.780-20.609; p < 0.001). Univariate analyses showed a significant correlation between dysphagia and dementia (OR: 0.387; p:0.033), hallucinations (OR: 0.283; p:0.009), and H&Y score (OR: 2.680; p < 0.001); in the multivariate analysis, only the H&Y stage was associated with the presence of dysphagia (OR: 2.357; p:0.003). Conclusion: Dysphagia significantly increased the risk of death in our cohort of LCIG-treated patients, independently from other relevant features such as age, disease duration, dementia, and hallucinations. These findings support the management of this symptom as a priority in the advanced PD stages, even in people treated with LCIG

Prominent mitochondrial pathology in a case of refractory dermatomyositis: coincidence or concause?

Introduction: Mitochondrial alterations are a common finding in muscle biopsy of sporadic inclusion body myositis (s-IBM) and polymyositis with mitochondrial pathology (PM-Mito). Both disorders generally have poor treatment response. Nevertheless, mitochondrial myopathology has been rarely reported in dermatomyositis (DM) outside areas of perifascicular atrophy and a relationship with therapeutic outcome is not established. Methods: We report on clinical, immunological, radiological, and myopathological findings of a case of severe, treatment-refractory anti-Mi-2-positive DM. Results: A 77-year-old woman developed anti-Mi-2 DM with severe diffuse muscle weakness associated with abundant mitochondrial abnormalities at muscle biopsy, beside the typical features of inflammatory myopathy. The patient was poorly responsive to multiple-line therapies and finally anti-JAK (anti-Janus activated kinase) was administered, leading to partial clinical improvement. Discussion: Given the usual satisfactory treatment response and favorable outcome of anti-Mi-2 DM, we suppose that mitochondrial dysfunction on muscle biopsy could represent a marker of disease severity in DM, predicting a worse response to treatment and a poor clinical outcome. JAK-inhibitors could represent a good treatment option in refractory anti-Mi-2 DM with mitochondrial abnormalities