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The incidence and prevalence of Parkinson's disease (PD) is expected to raise dramatically over the next decades. Gender-related differences are not yet widely recognized, particularly regarding the response to dopaminergic medications. To analyse gender differences in the clinical effects of safinamide, compared to placebo, in Chinese PD patients of the pivotal XINDI trial. The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Patients were followed for 16 weeks receiving safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 items. A post-hoc analysis was performed to describe the efficacy of safinamide in both genders on motor symptoms, motor fluctuations and quality of life. 128 (42%) out of 305 patients enrolled were women and 177 (58%) men. Our additional analyses of the XINDI study have shown that safinamide, compared to placebo, was associated with improvements in motor symptoms, motor fluctuations and quality of life in both genders, with some differences in the response that did not reach statistical significance, possibly due to sample size limitation and post-hoc design of the study. The changes from baseline at week 16 were > 50% higher in the females compared to males for the total daily OFF time (− 1.149 h vs − 0.764 h in males), the total daily ON time (1.283 h vs 0.441 h in males), the UPDRS total score (− 8.300 points vs − 5.253 points in males) and the UPDRS part II score (− 2.574 points vs − 1.016 points in males). The changes from baseline at week 16 were higher in the females compared to males in the "ADL" domain (− 6.965 points vs − 5.772 points in males), the "Emotional well-being" domain (− 6.243 points vs − 4.203 in males), the "Stigma" domain (− 6.185 points vs − 4.913 points in males) and the "Bodily discomfort" domain (− 5.196 points vs 1.099 points in males), while were higher in males in the "Mobility" score (− 6.523 points vs − 4.961 points in females) and the "Communication" score (− 3.863 points vs − 1.564 points in females). Safinamide was shown to improve PD symptoms and quality of life in both male and female Chinese patients. Possible differences in the response between genders need to be further studied in larger and different ethnic populations. [ABSTRACT FROM AUTHOR]

Objectives Mild cognitive impairment ( MCI) is a common feature in Parkinson's disease ( PD). We performed an exploratory study to investigate dopaminergic nigrostriatal innervation and its cognitive correlates in early untreated PD patients with MCI as compared to cognitively intact patients. Patients and methods A consecutive series of 34- de-novo, drug-naïve patients with PD were enrolled. They underwent [123- I] FP- CIT SPECT and comprehensive neuropsychological battery. MCI was identified in 15 of 34 patients with PD. Results The two groups did not show any statistically significant difference in age, sex, disease duration, education, lateralization, and H& Y and Hospital Anxiety and Depression Scale scores. Logistic regression analysis showed that UPDRS- III was weakly associated with MCI ( P = 0.034). Partial correlation analysis controlling for UPDRS- III and age suggested that in PD patients with MCI reduced V3″ values in the more affected caudate were correlated with reduced performances in frontal assessment battery, Trail Making Test: part B minus Part A and copy task of the Rey- Osterrieth complex figure test. Reduced V3″ values in the more and less affected putamen were significantly related with reduced performance in frontal assessment battery and in copy task of Rey- Osterrieth complex figure test, respectively. No correlation was found between neuropsychological scores and DAT availability in PD patients without MCI. Conclusions Although preliminary, our results suggest that striatal dopamine depletion may contribute to some cognitive deficit in early never treated PD patients with MCI. [ABSTRACT FROM AUTHOR]

Background and purpose Cognitive impairment is common in Parkinson's disease ( PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 ( IGF-1) and cognitive functions in early, drug-naïve patients with PD. Methods Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2 years. Linear regression analysis was used to evaluate the relationships between neuropsychological scores and IGF-1. Repeated-measures anova was applied to assess changes in neuropsychological variables over time. Results At baseline, IGF-1 levels were related to phonological fluency. At follow-up, IGF-1 levels were associated with the Rey auditory verbal learning test (RAVLT) - immediate and delayed recall, Frontal Assessment Battery, verbal span and Benton judgement of the line orientation test. Patients with low IGF-1 levels at baseline showed a significantly faster decline of performances than patients with high IGF-1 levels on immediate and delayed recall of the RAVLT and interference task of the Stroop test. Conclusions Low serum IGF-1 levels are related to poor performance on executive tasks in early, drug-naïve patients with PD, and may predict poor performance on attention/executive and verbal memory tasks after a 2-year follow-up. [ABSTRACT FROM AUTHOR]

Background and purpose: The growth hormone (GH) and insulin-like growth factor (IGF) system may be involved in neurodegenerative processes, and some abnormalities have been reported in amyotrophic lateral sclerosis (ALS). Our aim was to investigate the GH–IGF axis in patients with ALS and evaluate correlations between this endocrine system and clinical features. Methods: Serum levels of GH, IGF-I, IGF-II, insulin, IGF-binding protein 1 (IGF-BP1), and IGF-binding protein 3 (IGF-BP3) were measured in 25 patients with ALS and 25 age-, gender-, and BMI-matched healthy controls. A GHRH plus arginine test was performed in patients and controls. Clinical status of patients was evaluated with the ALS Functional Rating Scale – Revised (ALSFRS-R) and upper motor neuron (UMN) score. Results:  GHRH plus arginine test showed GH deficiency (GHD) in 13 (52%) patients with ALS; severe GHD was found in 6 (24%) and partial GHD in 7 (28%) patients. IGF-I levels were significantly higher in patients with ALS than in healthy controls (182.9 ± 90.8 vs. 139.4 ± 58.1 ng/ml; P = 0.015). IGF-I levels were higher in patients with ALS with UMN score >10 than those with UMN score <10 (217.8 ± 100.8 vs. 155.5 ± 74.6 ng/ml, P = 0.05). IGF-II levels were significantly lower in patients with ALS than in healthy controls (720.9 ± 215 vs. 1001.9 ± 475.4 ng/ml; P = 0.03). Conclusions: The results demonstrate an impairment of the GH–IGFs system in ALS. The degenerative process in ALS might lead to a compensatory increase in IGF-I in an attempt to provide additional support to motor neurons or degenerating muscle fibers. The decrease in IGF-II levels may also be of pathological significance. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effects of prolonged physical therapy on disability in patients with Parkinson’s disease. The study was designed as an open long-term trial over 20 weeks. Twenty slightly to moderately affected parkinsonian patients were included (Hoehn & Yahr stages: 1.5–3). A comprehensive rehabilitation program was applied three times a week in all patients. Pharmacological treatment was kept stable. Evaluations were performed at baseline, at the end of treatment and after 3 months. Following physical rehabilitation, there was a significant improvement in UPDRS (ADL and motor sections) scores, Self-assessment Parkinson’s disease Disability Scale, Ten-Meter Walk test and Zung scale for depression. At 3-month follow-up clinical improvements were largely maintained. A sustained improvement of motor skills in PD patients can be achieved with a long-term comprehensive rehabilitation program. [ABSTRACT FROM AUTHOR]

Gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in people with Parkinson's Disease (PD). Probiotics and prebiotics are emerging as a potential therapeutic approach for PD patients. The aim of this paper was to assess the neurological and gastroenterological effects in PD patients with constipation after the administration of a synbiotic product, with a focus on behavioral and cognitive symptoms. We enrolled patients with stable PD who met diagnostic criteria for functional constipation and/or irritable bowel syndrome with constipation according to Rome IV Criteria. Patients received a synbiotic treatment (Enterolactis Duo, containing the probiotic strain Lacticaseibacillus paracasei DG and the prebiotic fiber inulin) for 12 weeks. A neurological and a gastroenterological evaluation were collected before and after the treatment. In addition, 16S rRNA gene profiling and short chain fatty acid quantification were performed to characterize the microbial ecosystem of fecal samples collected before (n = 22) and after (n = 9) the synbiotic administration. 30 patients were consecutively enrolled. After treatment, patients performed better in MDS-UPDRS part 1 (p = 0.000), SCOPA-AUT (p = 0.001), TAS-20 (p = 0.014), HAM-D (p = 0.026), DIFt (p = 0.003), PAS-A (p = 0.048). Gastroenterological evaluations showed improvements in PAC-SYM score (p < 0.001), number of complete bowel movement (p < 0.001) and BSFS (p < 0.001). After the synbiotic administration, we observed a significant increase in the abundance of the order Oscillospirales, as well as the Oscillospiraceae family and the species Faecalibacterium prausnitzii within this order in fecal samples. Synbiotic treatment demonstrates potential efficacy in ameliorating non-motor features in PD patients. [ABSTRACT FROM AUTHOR]

Clonidine has been proposed to differentiate multiple system atrophy (MSA) from idiopathic Parkinson's disease (IPD), as it does not increase growth hormone (GH) release in MSA. We studied GH release in response to clonidine in 7 IPD patients, 6 MSA patients, 4 patients affected by idiopathic late-onset cerebellar ataxia (ILOCA) and 8 healthy controls. In addition, we investigated the effects of GH releasing hormone plus arginine (GHRH-Arg) on GH release in the same patients. Both clonidine and GHRH-Arg raised serum GH levels in all groups examined. Clonidine failed to differentiate MSA from IPD and ILOCA. GHRH-Arg showed a lower increase of serum GH in MSA patients than in other groups, even if such difference was not statistically significant. We suggest that stimulation of GH release with GHRH-Arg rather than clonidine could differentiate MSA from IPD and ILOCA, but this hypothesis would need to be confirmed by further investigations. [ABSTRACT FROM AUTHOR]

We performed a clinical study to evaluate the unawareness of dyskinesias in patients affected by Parkinson's disease (PD) and Huntington's disease (HD). Thirteen PD patients with levodopa-induced dyskinesias and 9 HD patients were enrolled. Patients were asked to evaluate the presence of dyskinesias while performing specific motor tasks. The Abnormal Involuntary Movement Scale (AIMS) and Goetz dyskinesia rating scale were administered to determine the severity of dyskinesias. The Unified Parkinson's disease rating scale (UPDRS) and Unified Huntington's Disease Rating Scale (UHDRS) were used in PD and HD patients, respectively. In PD we found a significant negative relationship between unawareness score at standing and AIMS score and between unawareness score at hand pronation-supination and AIMS score for upper limbs. In HD we found a significant positive relationship between total unawareness score and UHDRS score and between total unawareness score and disease duration. In PD the unawareness seems to be inversely related with severity of dyskinesias, while in HD it is directly related to disease duration and severity. [ABSTRACT FROM AUTHOR]

Diagnosis of multiple system atrophy (MSA) may be improved by using multimodal imaging approaches. We investigated the use of T1-weighted/T2-weighted (T1w/T2w) images ratio combined with voxel-based morphometry to evaluate brain tissue integrity in MSA compared to Parkinson's disease (PD) and healthy controls (HC). Twenty-six patients with MSA, 43 patients with PD and 56 HC were enrolled. Whole brain voxel-based and local regional analyses were performed to evaluate gray and white matter (GM and WM) tissue integrity and mean regional values were used for patients classification using logistic regression. Increased mean regional values of T1w/T2w in bilateral putamen were detected in MSA-P compared to PD and HC. The combined use of regional GM and T1w/T2w values in the right and left putamen showed the highest accuracy in discriminating MSA-P from PD and good accuracy in discriminating MSA from PD and HC. A good accuracy was also found in discriminating MSA from PD and HC by either combining regional GM and T1w/T2w values in the cerebellum or regional WM and T1w/T2w in the cerebellum and brainstem. The T1w/T2w image ratio alone or combined with validated MRI parameters can be further considered as a potential candidate biomarker for differential diagnosis of MSA. [ABSTRACT FROM AUTHOR]

Background and purpose: Parkinson disease (PD) patients are classically classified according to two alternative motor subtyping methods: (i) tremor‐dominant versus postural instability and gait disorder; (ii) tremor‐dominant versus akinetic‐rigid. The degree of overlap between the two classification systems at diagnosis of PD and their temporal stability, as well as the correspondence between the two systems, were examined over a follow‐up period of 4 years. Methods: Newly diagnosed, untreated PD patients were classified as tremor‐dominant versus postural instability and gait disorder and tremor‐dominant versus akinetic‐rigid at baseline and after 2 and 4 years. Results: There was a poor overlap between the two classification systems at any time point and baseline subtype status could not predict 4‐year subtype membership. In fact, about half of our cohort shifted category during the first 2 years, regardless of the classification scheme adopted. A lower rate of shift was observed from 2‐ to 4‐year follow‐up. Conclusions: The two classical motor subtyping methods of PD poorly overlap, which implies that a patient can be categorized as tremor‐dominant in one classification system but not in the other. Moreover, their temporal instability undermines their prognostic value in the early stage of PD. [ABSTRACT FROM AUTHOR]

Background and purpose Very little is known about the progression of non-motor symptoms ( NMSs) in Parkinson's disease ( PD) and there are no longitudinal studies exploring this topic from the earliest stage, when patients receive the diagnosis. We here report on the progression of NMSs over 4 years from diagnosis in a cohort of de-novo, previously untreated, patients with PD. Methods Consecutive de-novo (disease duration < 2 years), untreated patients with PD were enrolled in this observational study. Evaluations were then scheduled every 2 years and included assessment of motor and non-motor features as well as of quality of life measures. Results Sixty-one patients were prospectively followed-up for 4 years from diagnosis. The majority of NMSs increased over time and significantly affected quality of life, whereas motor disability did not. There was no significant association between NMSs and dopaminergic therapy in terms of both drug class and total levodopa-equivalent daily dosage. Excessive daytime sleepiness was the only NMS correlating with therapy with dopamine agonists. Female patients were more likely to have worse quality of life. Conclusions Non-motor symptoms significantly increase over time, with a different progression rate for each one. NMSs significantly affect quality of life in PD and we here demonstrated that this was especially the case when patients were in their (motor) honeymoon period. Future trials should target non-dopaminergic networks and consider NMSs in their outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose Oxidative stress is a central pathogenic mechanism of Parkinson's disease ( PD), and the heme oxygenase ( HO) bilirubin pathway is one of the main mammalian antioxidative defences. Indeed, there is growing evidence of HO−bilirubin upregulation from early phases of PD. Our aim was to investigate bilirubin as a possible biomarker of PD diagnosis and progression. Methods A cross-sectional case−control study was performed to evaluate differences in bilirubin levels between newly diagnosed, drug-naïve PD subjects and controls. Afterwards, PD subjects were included in a 2-year longitudinal study to evaluate disease progression in relation to baseline bilirubin levels. Results Seventy-five de novo PD subjects were selected and matched with 75 controls by propensity score. Analysis of variance showed higher bilirubin levels in PD patients compared with controls ( P < 0.001). Linear regression analysis failed to show a relationship between bilirubin and Unified Parkinson's Disease Rating Scale ( UPDRS) part III ( P = 0.283) at baseline evaluation. At 2-year follow-up, indirect relationships between bilirubin levels and UPDRS part III ( P = 0.028) and between bilirubin levels and levodopa-equivalent daily dosage ( P = 0.012) were found. Conclusions Parkinson's disease subjects showed higher levels of bilirubin compared with controls. Bilirubin increase might be due to HO overexpression as a compensatory response to oxidative stress occurring from early stages of PD. [ABSTRACT FROM AUTHOR]

Background and purpose Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease ( PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy. Methods Sixty-two PD patients with a disease duration <2 years and without history of present or past therapy with pro-dopaminergic agents were included and underwent the Apathy Evaluation Scale ( S- AES), a clinical interview based on diagnostic criteria for apathy and a comprehensive neuropsychological battery to assess memory, frontal functions and visuospatial functions. Two years after the first assessment, all patients were re-evaluated on the S- AES, a clinical interview and neuropsychological tests. Results According to the cut-off value of the S- AES and diagnostic criteria for apathy, eight patients experienced apathy at both baseline and follow-up (A+A+), nine patients had apathy only at follow-up (A−A+), 37 patients never experienced apathy (A−A−) and eight patients showed apathy at the baseline only (A+A−). Cognitive performance significantly declined in all four groups. At both baseline and follow-up A+A+ performed worse than A−A− on visuospatial and frontal tests; A−A+ had lower scores than A−A− on the interference task of the Stroop test ( IT- ST). Regression analysis showed that poor performance on the IT- ST at baseline was the only independent predictor of onset of apathy at follow-up. Conclusions The results indicated a relationship between apathy and dysexecutive syndrome in early PD. Reduced scores on the IT- ST may predict development of apathy in PD patients. [ABSTRACT FROM AUTHOR]

Background and purpose Uric acid ( UA) has been studied extensively as a valuable biomarker of Parkinson's disease ( PD), but its relationship with non-motor symptoms ( NMS) in de novo PD has been poorly investigated. Our aim was to evaluate the usefulness of baseline serum UA as a marker of NMS progression in newly diagnosed PD. Methods Sixty-nine newly diagnosed PD patients were enrolled. At baseline, all patients completed the NMS questionnaire ( NMSQuest), and serum UA levels were measured. After 2 years, the NMSQuest was completed again and patients were categorized into four groups: NMS improvement (domain involvement at baseline but not at 2-year follow-up visit), NMS absence (domain not involved at baseline or 2-year follow-up visits), NMS presence (domain involvement both at baseline and 2-year follow-up visits) and NMS worsening (domain not involved at baseline but involved at 2-year follow-up). Results anova with post hoc Bonferroni correction showed that patients with NMS absence presented significantly higher UA values than patients with NMS presence with regard to the attention/memory ( P = 0.023), depression/anxiety ( P = 0.028) and cardiovascular domains ( P = 0.002), whilst no differences were found with regard to both the NMS improvement and worsening groups. In addition, multinomial regression analysis showed that the lowest tertile of NMS progression presented higher UA levels ( P = 0.023; odds ratio 0.488) compared with patients with greater NMS progression. Conclusions This is the first report of a relationship between serum UA and presence/progression of multiple NMS in de novo PD, providing additional evidence of the reliability of UA as a biomarker of PD and opening new insights on PD neuroprotection. [ABSTRACT FROM AUTHOR]