Synbiotic supplementation may globally improve non-motor symptoms in patients with stable Parkinson's disease: results from an open label single-arm study.

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.

Magnetic resonance T1w/T2w ratio and voxel-based morphometry in multiple system atrophy.

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.

Attachment styles, identification of feelings and psychiatric symptoms in functional neurological disorders.

OBJECTIVE: The contribution of psychological and psychiatric symptoms in the development of Functional Neurological Disorders (FND) is unclear. We therefore aimed to investigate the role of different attachment styles (AS) and their relationship with psychiatric symptoms in FND patients as compared with both subjects with neurological disorders (ND) and healthy controls (HC); and the possible differences between patients with functional movement disorders (FMD) and with functional seizures. METHODS: In this case-control study, forty-six patients with FND were compared to 34 with ND and 30 HC, by means of an extensive battery to investigate the presence of alexithymia, depression, anxiety, dissociation and to explore their AS using the Revised Experiences in Close Relationships instrument (ECR-R). RESULTS: Patients with FND had higher depression and alexithymia as well as an avoidant pattern on the ECR-R than patients with ND. In the FND group, ECR-R avoidance was an independent predictor of psychiatric symptoms and, altogether, ECR-R avoidance, the somatic-affective component of depression and difficulty identifying feelings were independent predictors of FND. Gender, anxiety and difficulty identifying feelings predicted the presence of functional seizures. CONCLUSION: The avoidant AS may be an important psychological factor influencing the presence of mood disorders and alexithymia. Their co-occurence might drive maladaptive responses underlying the presence of FND. Although we demonstrated a large overlap between FND phenotypes, patients with functional seizures might have higher alexithymia, which in turn could explain a defensive response less anchored to body reactions and physical symptoms.

The PRIAMO study: active sexual life is associated with better motor and non-motor outcomes in men with early Parkinson's disease.

BACKGROUND AND PURPOSE: Data suggest a relationship between sexual dysfunction, mainly erectile dysfunction in men, and worse disease progression in Parkinson's disease (PD). There is scant evidence on the correlates of sexual activity in PD patients. By involving a subgroup of 355 patients from the PRIAMO (Parkinson Disease Non Motor Symptoms) study, the present 24-month longitudinal prospective analysis aims to demonstrate that the presence of active sexual life is associated with disease progression in early PD. METHODS AND RESULTS: Multivariable mixed-effect logistic regression models showed that gastrointestinal symptoms [odds ratio 0.56, 95% confidence interval (CI) 0.39-0.82, P = 0.003] and apathy (odds ratio 0.42, 95% CI 0.29-0.63, P < 0.001) were less likely to be associated with sexual activity in men. Analysis also demonstrated that sexual activity in men was associated with lower motor disability (coefficient -2.881, 95% CI -4.732 to -1.030, P = 0.002), better quality of life (coefficient -24.196, 95% CI -44.884 to -3.508, P = 0.022; coefficient 0.083, 95% CI 0.023-0.143, P = 0.006) and lower depression scores (coefficient -1.245, 95% CI -2.104 to -0.387, P = 0.004). No association was shown in women. CONCLUSIONS: This is the first prospective longitudinal study involving a large cohort of PD patients suggesting that sexual activity is associated with lower motor and non-motor disability as well as with better quality of life in men. These findings should prompt movement disorders specialists to periodically inquiry about their patients' sexual life.

Comparing postural instability and gait disorder and akinetic-rigid subtyping of Parkinson disease and their stability over time.

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.

Spread of dystonia in patients with idiopathic adult-onset laryngeal dystonia.

BACKGROUND AND PURPOSE: Adult-onset laryngeal dystonia (LD) can be isolated or can be associated with dystonia in other body parts. Combined forms can be segmental at the onset or can result from dystonia spread to or from the larynx. The aim of this study was to identify the main clinical and demographic features of adult-onset idiopathic LD in an Italian population with special focus on dystonia spread. METHODS: Data were obtained from the Italian Dystonia Registry (IDR) produced by 37 Italian institutions. Clinical and demographic data of 71 patients with idiopathic adult-onset LD were extracted from a pool of 1131 subjects included in the IDR. RESULTS: Fifty of 71 patients presented a laryngeal focal onset; the remaining subjects had onset in other body regions and later laryngeal spread. The two groups did not show significant differences of demographic features. 32% of patients with laryngeal onset reported spread to contiguous body regions afterwards and in most cases (12 of 16 subjects) dystonia started to spread within 1 year from the onset. LD patients who remained focal and those who had dystonia spread did not show other differences. CONCLUSIONS: Data from IDR show that dystonic patients with focal laryngeal onset will present spread in almost one-third of cases. Spread from the larynx occurs early and is directed to contiguous body regions showing similarities with clinical progression of blepharospasm. This study gives a new accurate description of LD phenomenology that may contribute to improving the comprehension of dystonia pathophysiology.

Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients.

INTRODUCTION: Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. METHODS: 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn-Tolosa-Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). RESULTS: Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. CONCLUSIONS: Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.

Non-invasive brain stimulation for dystonia: therapeutic implications.

Dystonia is characterized by excessive muscle contractions giving rise to abnormal posture and involuntary twisting movements. Although dystonia syndromes are a heterogeneous group of disorders, certain pathophysiological mechanisms have been consistently identified across different forms. These pathophysiological mechanisms have subsequently been exploited for the development of non-invasive brain stimulation (NIBS) techniques able to modulate neural activity in one or more nodes of the putative network that is altered in dystonia, and the therapeutic role of NIBS has hence been suggested. Here all studies that applied such techniques as a therapeutic intervention in any forms of dystonia, including the few works performed in children, are reviewed and emerging concepts and pitfalls of NIBS are discussed.

The PRIAMO study: urinary dysfunction as a marker of disease progression in early Parkinson's disease.

BACKGROUND AND PURPOSE: New venues are currently being explored to predict disease progression in Parkinson's disease (PD), such as non-motor subtypes and models merging motor and non-motor symptoms (NMS). By involving a subgroup of 585 patients from the PRIAMO (Parkinson Disease Non-motor Symptoms) study, the present 24-month longitudinal prospective analysis aimed to demonstrate that urinary dysfunction is an early marker of higher motor and non-motor burden as well as lower health-related quality of life. METHODS AND RESULTS: Multivariable mixed-effect logistic regression models controlling for demographic and clinical variables showed that the following NMS domains were associated with urinary dysfunction: gastrointestinal [odds ratio (OR) 2.57, 95% confidence interval (CI) 1.67-3.97, P < 0.001], cardiovascular (OR 2.22, 95% CI 1.18-4.17, P = 0.013), skin (OR 1.81, 95% CI 1.06-3.08, P = 0.029), sleep (OR 2.06, 95% CI 1.34-3.16, P = 0.001), pain (OR 1.85, 95% CI 1.21-2.83, P = 0.004), fatigue (OR 2.40, 95% CI 1.56-3.68, P < 0.001), apathy (OR 2.79, 95% CI 1.72-4.52, P < 0.001) and respiratory (OR 1.82, 95% CI 1.02-3.23, P = 0.039). Analysis also demonstrated that urinary dysfunction was associated with higher motor disability (coefficient 1.73, 95% CI 0.68-2.78, P = 0.001) and lower health-related quality of life (coefficient -0.05, 95% CI -0.08 to -0.02, P < 0.001, and coefficient -3.49, 95% CI -5.21 to -1.77, P < 0.001) but not with more severe cognitive disability (coefficient -0.34, 95% CI -0.92 to 0.24, P = 0.251). CONCLUSIONS: This is the first prospective longitudinal study involving a large cohort of PD patients demonstrating the relevance of urinary dysfunction as an early marker of higher motor and non-motor disability as well as lower health-related quality of life. These findings support a role for urinary dysfunction as an early marker of more severe disease progression.

Event related desynchronisation predicts functional propriospinal myoclonus.

OBJECTIVE: Recent diagnostic criteria for functional movement disorders have proposed a "laboratory supported" level of diagnostic certainty where the clinical diagnosis is supported by a positive test. For functional myoclonus the Bereitschaftspotential (BP) is generally accepted as a positive laboratory test. We hypothesised that a different EEG measure, event-related desynchronisation (ERD), might be more effective. METHODS: We analysed 20 patients with functional propriospinal myoclonus (fPSM) and 9 controls with organic myoclonus and performed back-averaging for BPs plus time-frequency decomposition to assess ERD and calculated sensitivity and specificity for both techniques. RESULTS: The BP was present in only 25% of patients with fPSM while the majority showed a significant ERD (mean 38 Hz; sensitivity 65%). ERD was significant at the group level (p < 0.001), but not the BP (p > 0.05). Both BP and ERD were absent in our control group. CONCLUSION: ERD in high-beta may be a useful new test for positive diagnosis of functional myoclonus.

Impaired eye blink classical conditioning distinguishes dystonic patients with and without tremor.

INTRODUCTION: Tremor is frequently associated with dystonia, but its pathophysiology is still unclear. Dysfunctions of cerebellar circuits are known to play a role in the pathophysiology of action-induced tremors, and cerebellar impairment has frequently been associated to dystonia. However, a link between dystonic tremor and cerebellar abnormalities has not been demonstrated so far. METHODS: Twenty-five patients with idiopathic isolated cervical dystonia, with and without tremor, were enrolled. We studied the excitability of inhibitory circuits in the brainstem by measuring the R2 blink reflex recovery cycle (BRC) and implicit learning mediated by the cerebellum by means of eyeblink classical conditioning (EBCC). Results were compared with those obtained in a group of age-matched healthy subjects (HS). RESULTS: Statistical analysis did not disclose any significant clinical differences among dystonic patients with and without tremor. Patients with dystonia (regardless of the presence of tremor) showed decreased inhibition of R2 blink reflex by conditioning pulses compared with HS. Patients with dystonic tremor showed a decreased number of conditioned responses in the EBCC paradigm compared to HS and dystonic patients without tremor. CONCLUSION: The present data show that cerebellar impairment segregates with the presence of tremor in patients with dystonia, suggesting that the cerebellum might have a role in the occurrence of dystonic tremor.

The non-motor side of the honeymoon period of Parkinson's disease and its relationship with quality of life: a 4-year longitudinal study.

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.

The role of cerebellum in patients with late onset cervical/segmental dystonia?--evidence from the clinic.

BACKGROUND: There is evidence from animal studies, post-mortem pathology, functional imaging and neurophysiological studies to suggest that the cerebellum may be involved in the pathophysiology of dystonia. We sought to explore further the association of clinical and radiological abnormalities of the cerebellum in patients with dystonia. METHODS: We retrospectively reviewed patients from our movement disorders research database, with predominant cervical dystonia who have been seen within last 6 months and had available routine magnetic resonance imaging (MRI). The clinical details including presence of cerebellar signs, imaging findings and results of investigations were recorded on a proforma. The results were analysed using percentages and means with standard deviation. RESULTS: Out of 188 patients included 26 had evidence of cerebellar abnormality on neuroimaging. 17 patients showed cerebellar atrophy and 10 of these had cerebellar signs on examination. These patients were tested negative for common inherited ataxias. 9 patients had cerebellar lesions on MRI, reported as low grade tumour (n = 2), cerebellar infarct (n = 3), cyst (n = 2), white matter hyperintensity (n = 1) and ectopia (n = 1) out of these 4 had cerebellar signs. CONCLUSION: The findings from our study suggest that there may be overt clinical or radiological cerebellar involvement in 14% of cases with cervical/segmental dystonia. However, larger prospective studies are needed in this context.

Increased bilirubin levels in de novo Parkinson's disease.

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.

Cognitive performances and DAT imaging in early Parkinson's disease with mild cognitive impairment: a preliminary study.

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.

Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study.

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.

Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson's disease.

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.