Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

Dynamic Stability, Symmetry, and Smoothness of Gait in People with Neurological Health Conditions.

Neurological disorders such as stroke, Parkinson's disease (PD), and severe traumatic brain injury (sTBI) are leading global causes of disability and mortality. This study aimed to assess the ability to walk of patients with sTBI, stroke, and PD, identifying the differences in dynamic postural stability, symmetry, and smoothness during various dynamic motor tasks. Sixty people with neurological disorders and 20 healthy participants were recruited. Inertial measurement unit (IMU) sensors were employed to measure spatiotemporal parameters and gait quality indices during different motor tasks. The Mini-BESTest, Berg Balance Scale, and Dynamic Gait Index Scoring were also used to evaluate balance and gait. People with stroke exhibited the most compromised biomechanical patterns, with lower walking speed, increased stride duration, and decreased stride frequency. They also showed higher upper body instability and greater variability in gait stability indices, as well as less gait symmetry and smoothness. PD and sTBI patients displayed significantly different temporal parameters and differences in stability parameters only at the pelvis level and in the smoothness index during both linear and curved paths. This study provides a biomechanical characterization of dynamic stability, symmetry, and smoothness in people with stroke, sTBI, and PD using an IMU-based ecological assessment.

Mood disturbances in newly diagnosed Parkinson's Disease patients reflect intrathecal inflammation.

In Parkinson's disease (PD), neuroinflammation may be involved in the pathogenesis of mood disorders, contributing to the clinical heterogeneity of the disease. The cerebrospinal fluid (CSF) levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, IL-9, IL-12, IL-17, interferon (IFN)γ, macrophage inflammatory protein 1-alpha (MIP-1a), MIP-1b, granulocyte colony stimulating factor (GCSF), eotaxin, tumor necrosis factor (TNF), and monocyte chemoattractant protein 1 (MCP-1), were assessed in 45 newly diagnosed and untreated PD patients and in 44 control patients. Spearman's correlations were used to explore possible associations between CSF cytokines and clinical variables including mood. Benjamini-Hochberg (B-H) correction for multiple comparisons was applied. Linear regression was used to test significant associations correcting for other clinical variables. In PD patients, higher CSF concentrations of the inflammatory molecules IL-6, IL-9, IFNγ, and GCSF were found (all B-H corrected p < 0.02). Significant associations were found between BDI-II and the levels of IL-6 (Beta = 0.438; 95%CI 1.313-5.889; p = 0.003) and IL-8 (Beta = 0.471; 95%CI 0.185-0.743; p = 0.002). Positive associations were also observed between STAI-Y state and both IL-6 (Beta = 0.452; 95%CI 1.649-7.366; p = 0.003), and IL-12 (Beta = 0.417; 95%CI 2.238-13.379; p = 0.007), and between STAI-Y trait and IL-2 (Beta = 0.354; 95%CI 1.923-14.796; p = 0.012), IL-6 (Beta = 0.362; 95%CI 0.990-6.734; p = 0.01), IL-8 (Beta = 0.341; 95%CI 0.076-0.796; p = 0.019), IL-12 (Beta = 0.328; 95%CI 0.975-12.135; p = 0.023), and IL-17 (Beta = 0.334; 95CI 0.315-4.455; p = 0.025). An inflammatory CSF milieu may be associated with depression and anxiety in the early phases of PD, supporting a role of neuroinflammation in the pathogenesis of mood disturbances.

A novel manual therapy approach for managing acute interscapular pain following median sternotomy for open cardiac surgery: A clinical comparative analysis.

INTRODUCTION: Acute interscapular pain is a frequent postoperative complication observed in patients who have undergone median sternotomy. This study aimed to assess a novel approach to manual therapy utilizing the Regional Interdependence (RI) concept for managing interscapular pain in post-sternotomy patients. MATERIALS AND METHODS: In an observational study, a cohort of 60 consecutively admitted patients undergoing median sternotomy was enrolled. Data collection involved standardized clinical evaluations conducted at specific time points: prior to manual treatment (T0), following five manual treatments (T5), and at post-treatment days 10 (T10) and 30 (T30). The Experimental Group (EG) received manual treatment based on the RI concept, performed in a seated position to accommodate individual clinical conditions and surgical wound considerations. The Control Group (CG) received simulated treatment involving identical exercises to the EG but lacking the physiological or biomechanical stimulation. RESULTS: Among the initial 60 patients, 36 met the inclusion criteria, while 24 were excluded due to one or more exclusion criteria. Treatment outcomes revealed a statistically significant improvement in the EG compared to the CG, not only in terms of pain reduction but also in functional recovery and consequent disability reduction. DISCUSSION: The RI concept emerges as a potentially valuable therapeutic approach for addressing interscapular dysfunction, particularly in highly complex post-sternotomy patients. This study highlights the clinical relevance of the RI concept in the management of interscapular pain and highlights its potential utility in improving patient outcomes in the challenging context of sternotomy surgery.

Compassionate mind training for people with Parkinson's disease: A pilot study and predictors of response.

INTRODUCTION: People with Parkinson's disease (PD) often present with disabling neuropsychiatric symptoms. Compassionate mind training (CMT) is a psychological approach effective in reducing stress and promoting psychological well-being. Heart rate variability (HRV), a measure reflecting sympathovagal balance, has been associated with psychological well-being and a compassionate attitude. AIM: To assess the feasibility and effectiveness of CMT in enhancing the quality of life and psychological well-being in PD patients. Additionally, we evaluated HRV as a physiomarker for assessing the CMT outcomes. METHODS: Twenty-four PD patients participated in the study. A 6-week online CMT intervention was delivered on a weekly basis. At baseline and post-intervention patients completed questionnaires assessing depression, anxiety and quality of life. In a subsample of 11 patients, HRV was measured at baseline and post-intervention in three conditions: at rest, during stress and after 3 min of deep breathing. RESULTS: The attendance rate was 94.3%. Quality of life and perceived stigma improved post-intervention as compared with baseline (p = 0.02 and p = 0.03 for PD Questionnaire-39 total score and Stigma subscore, respectively). After CMT, patients presented better physiological regulation to stress, as measured by higher HRV as compared with baseline (p = 0.005). Notably, patients who were more resilient to stress at baseline (less decrease in HRV during stress) experienced a more substantial reduction in anxiety and depression following CMT. CONCLUSIONS: CMT is feasible and can improve quality of life and stigma in PD patients. HRV emerges as a promising physiomarker for predicting and measuring the outcomes of psychological interventions in PD.

Advanced Parkinson's disease treatment patterns in Italy: an observational study interim analysis.

BACKGROUND: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. PATIENTS AND METHODS: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. RESULTS: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). CONCLUSION: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.

Patients with Parkinson's disease (PD) often exhibit fluctuations in their response to oral levodopa; however, real-world studies on the management of these fluctuations are lacking. This planned interim analysis of the real-world, multicentre, observational PD Fluctuations treatment Pathway (PD-FPA) study found that adequate levodopa dosing and adjunctive medications can stabilize Italian patients with advanced PD and improve their quality of life.

Effects of dopaminergic treatment on inhibitory control differ across Hoehn and Yahr stages of Parkinson's disease.

Motor inhibitory control, a core component of cognitive control, is impaired in Parkinson's disease, dramatically impacting patients' abilities to implement goal-oriented adaptive strategies. A progressive loss of the midbrain's dopamine neurons characterizes Parkinson's disease and causes motor features responsive to dopaminergic treatments. Although such treatments restore motor symptoms, their impact on response inhibition is controversial. Most studies failed to show any effect of dopaminergic medicaments, although three studies found that these drugs selectively improved inhibitory control in early-stage patients. Importantly, all previous studies assessed only one domain of motor inhibition, i.e. reactive inhibition (the ability to react to a stop signal). The other domain, i.e. proactive inhibition (the ability to modulate reactive inhibition pre-emptively according to the current context), was utterly neglected. To re-examine this issue, we recruited cognitively unimpaired Parkinson's patients under dopaminergic treatment in the early (Hoehn and Yahr, 1-1.5, n = 20), intermediate (Hoehn and Yahr 2, n = 20), and moderate/advanced (Hoehn and Yahr, 2.5-3, n = 20) stages of the disease. Using a cross-sectional study design, we compared their performance on a simple reaction-time task and a stop-signal task randomly performed twice on dopaminergic medication (ON) and after medication withdrawal (OFF). Normative data were collected on 30 healthy controls. Results suggest that medication effects are stage-dependent. In Hoehn and Yahr 1-1.5 patients, drugs selectively impair reactive inhibition, leaving proactive inhibition unaffected. In the ON state, Hoehn and Yahr two patients experienced impaired proactive inhibition, whereas reactive inhibition is no longer affected, as it deteriorates even during the OFF state. By contrast, Hoehn and Yahr 2.5-3 patients exhibited less efficient reactive and proactive inhibition in the OFF state, and medication slightly improved proactive inhibition. This evidence aligns with the dopamine overdose hypothesis, indicating that drug administration may overdose intact dopamine circuitry in the earliest stages, impairing associated cognitive functions. In later stages, the progressive degeneration of dopaminergic neurons prevents the overdose and can exert some beneficial effects. Thus, our findings suggest that inhibitory control assessment might help tailor pharmacological therapy across the disease stage to enhance Parkinson's disease patients' quality of life by minimizing the hampering of inhibitory control and maximizing the reduction of motor symptoms.

Elderly Onset of Functional Motor Disorders: Clinical Correlates from the Italian Registry.

BACKGROUND: Functional motor disorders (FMD) are a frequent neurological condition affecting patients with movement disorders. Commonly described in younger adults, their manifestation can be also associated to an elderly onset. OBJECTIVE: To assess the prevalence and describe the clinical manifestations of FMD with elderly and younger onset and their relationship with demographical and clinical variables. METHODS: We recruited patients with a "clinically definite" diagnosis of FMD from the Italian Registry of FMD. Patients underwent extensive clinical assessments. For elderly onset, we set a chronological cut-off at 65 years or older according to WHO definition. Multivariate regression models were implemented to estimate adjusted odds ratio of elderly FMD onset related to clinical characteristics. RESULTS: Among the 410 patients, 34 (8.2%) experienced elderly-onset FMD, with a mean age at onset of 70.9 years. The most common phenotype was tremor (47.1%), followed by gait disorders, weakness, and dystonia (29.4%, 23.5%, 14.7%, respectively). Eleven elderly patients had a combined phenomenology: 9 exhibited two phenotypes, 2 had three phenotypes. Weakness was isolated in 3/8 patients and combined with another phenotype in 5/8, manifesting as paraplegia (n = 4); upper limb diplegia (n = 2), hemiparesis/hemiplegia (n = 1), and tetraparesis/tetraplegia (n= 1). Non-motor and other functional neurological disorders occurred more frequently in the younger group (89.1%) than the elderly (73.5%). Neurological and non-neurological comorbidities were more prevalent in the elderly group (82.4%) as opposed to the younger (32.7%). In a multivariate regression analysis, elderly-onset FMD was significantly associated with neurological comorbidities, including parkinsonism (OR 6.73) and cerebrovascular diseases (OR 5.48). CONCLUSIONS: These results highlight the importance of achieving an accurate diagnosis of FMD in the elderly, as it is crucial for effectively managing FMD symptoms and addressing neurological comorbidities.