Small RNAs in plasma extracellular vesicles define biomarkers of premanifest changes in Huntington's disease.

Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV-sRNAs are downregulated early in mutation carriers and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF-Glu-CTC, tRF-Gly-GCC, miR-451a, miR-21-5p, miR-26a-5p, miR-27a-3p and let7a-5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR-21-5p was significantly decreased over time in a longitudinal study; and miR-21-5p and miR-26a-5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV-sRNAs define an early biosignature in mutation carriers with specific species highlighting the progression and cognitive changes occurring at the premanifest stage.

Cognitive phenotyping of GBA1-Parkinson's disease: A study on deep brain stimulation outcomes.

BACKGROUND: Heterozygous variants in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson's Disease (PD). GBA1-PD patients exhibit earlier disease onset, severe motor impairment, and heightened cognitive decline. Deep Brain Stimulation (DBS) offers motor improvement for PD patients, but its cognitive effects, particularly in GBA1-PD, are debated. METHODS: This study involved 96 PD patients who underwent subthalamic nucleus DBS at Hospital de la Santa Creu i Sant Pau between 2004 and 2023. Clinical and neuropsychological assessments were conducted pre- and post-surgery, focusing on Mattis Dementia Rating Scale (MDRS) and Frontal Systems Behavior Scale (FrSBe). Patients were categorized into GBA1-PD and non-GBA1-PD groups, with non-GBA1-PD further divided into cognitive fast-progressors and slow-progressors. RESULTS: GBA1 variants were present in 13.5 % of patients. GBA1-PD patients showed greater cognitive decline over time, particularly in attention, conceptualization, and memory, compared to non-GBA1-PD. Non-GBA1-PD fast-progressors exhibited significant cognitive deterioration in initiation and conceptualization within the first year post-DBS. Motor outcomes improved similarly across all groups, but slow-progressors showed a greater reduction in Levodopa Equivalent Daily Dose (LEDD). CONCLUSIONS: GBA1-PD patients experience more rapid cognitive decline, particularly in posterior-cortical and fronto-striatal functions. Additionally, a subset of non-GBA1-PD patients shows significant early cognitive decline post-DBS, especially in executive functions. Baseline MDRS scores do not predict cognitive outcomes, highlighting the need for further research to refine prognostic tools. Despite cognitive challenges, GBA1-PD patients benefit from DBS in terms of motor outcomes, underscoring the importance of individualized assessments for DBS suitability, regardless of genetic status.

Effects of Safinamide on Motor and Non-Motor Symptoms in Patients with Parkinson's Disease and Motor Fluctuations.

INTRODUCTION: Parkinson's disease (PD) involves the progressive loss of dopaminergic neurons, leading to motor and non-motor symptoms that significantly impact patients' quality of life. Safinamide modulates dopaminergic and glutamatergic systems, offering a promising treatment approach. METHODS: This meta-analysis evaluated the efficacy of safinamide as an add-on therapy to levodopa for PD patients with motor fluctuations. Following PRISMA guidelines, literature searches were conducted in PubMed and Embase (2014-2022). Inclusion criteria were studies on adult PD patients receiving safinamide with levodopa. Outcomes included on-time without troublesome dyskinesia, off-time, UPDRS Part III motor scores, UPDRS Part II activities of daily living scores, PDQ-39 emotional well-being, and GRID-HAMD scores. RESULTS: Among thirteen eligible studies, safinamide significantly improved on-time without troublesome dyskinesia at 100 mg/day (mean difference (MD): -0.90; 95% CI -1.12 to -0.67; P<0.00001) and 50 mg/day (MD: -0.77; 95% CI -1.21 to -0.34; P=0.0005) compared to placebo. It also reduced off-time (100 mg/day: MD: -0.94; 95% CI -1.19 to -0.70; P<0.00001; 50 mg/day: MD: -0.72; 95% CI -1.03 to -0.41; P<0.00001) and improved UPDRS-III motor scores (100 mg/day: MD: -3.01; 95% CI -4.15 to -1.86; P<0.00001; 50 mg/day: MD: -2.93; 95% CI -5.14 to -0.71; P=0.001). Mood improvements were noted in PDQ-39 emotional well-being scores (MD: -5.22; 95% CI -6.90 to -3.54) and GRID-HAMD scores (MD: -0.60; 95% CI -0.95 to -0.25; P=0.0009). Safinamide also positively affected pain (RR: 1.10; 95% CI 1.03 to 1.18). CONCLUSION: Compared to placebo, safinamide significantly benefits motor and non-motor symptoms in PD patients, but further research is necessary to fully explore its therapeutic potential.

Impact of Stimulation Frequency on Verbal Fluency Following Bilateral Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

OBJECTIVE: The effects of stimulation frequency on verbal fluency (VF) following subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) are not well understood. The present study examines the impact stimulation frequency has on VF following bilateral STN-DBS in PD. METHODS: Prospective study of 38 consecutive patients with PD with low frequency STN-DBS (LFS) (n = 10) and high frequency STN-DBS (HFS) (n = 14), and a non-operated PD control group consisting of patients with fluctuating response to dopaminergic medication (n = 14) homogeneous in age, education, disease duration, and global cognitive function. Patients were evaluated on VF tasks (letter, semantic, action verbs, alternating). A one-way analysis of variance (ANOVA) was conducted to assess distinctions between groups. Pre- and post-surgical comparisons of fluencies were performed for operated groups. A mixed ANOVA was applied to the data to evaluate the interaction between treatment (HFS vs. LFS) and time (pre- vs. post-surgery). Strategy use (clustering and switching) was evaluated. RESULTS: Semantic and letter fluency performance revealed significant differences between HFS and LFS groups. Pre- and post-surgical comparisons revealed HFS negatively affected letter, semantic, and action fluencies, but LFS had no effect on VF. No interaction effect or main effect of treatment was found. Main effect of time was significant for semantic and action fluencies indicating a decrease in postoperative fluency performance. Patients with LFS produced larger average cluster sizes than patients with HFS. CONCLUSION: LFS may be less detrimental to VF, but these findings suggest that VF decline following STN-DBS is not caused by stimulation frequency alone.

Prediction of Cognitive Heterogeneity in Parkinson's Disease: A 4-Year Longitudinal Study Using Clinical, Neuroimaging, Biological and Electrophysiological Biomarkers.

OBJECTIVE: Cognitive impairment in Parkinson's disease (PD) can show a very heterogeneous trajectory among patients. Here, we explored the mechanisms involved in the expression and prediction of different cognitive phenotypes over 4 years. METHODS: In 2 independent cohorts (total n = 475), we performed a cluster analysis to identify trajectories of cognitive progression. Baseline and longitudinal level II neuropsychological assessments were conducted, and baseline structural magnetic resonance imaging, resting electroencephalogram and neurofilament light chain plasma quantification were carried out. Linear mixed-effects models were used to study longitudinal changes. Risk of mild cognitive impairment and dementia were estimated using multivariable hazard regression. Spectral power density from the electroencephalogram at baseline and source localization were computed. RESULTS: Two cognitive trajectories were identified. Cluster 1 presented stability (PD-Stable) over time, whereas cluster 2 showed progressive cognitive decline (PD-Progressors). The PD-Progressors group showed an increased risk for evolving to PD mild cognitive impairment (HR 2.09; 95% CI 1.11-3.95) and a marked risk for dementia (HR 4.87; 95% CI 1.34-17.76), associated with progressive worsening in posterior-cortical-dependent cognitive processes. Both clusters showed equivalent clinical and sociodemographic characteristics, structural magnetic resonance imaging, and neurofilament light chain levels at baseline. Conversely, the PD-Progressors group showed a fronto-temporo-occipital and parietal slow-wave power density increase, that was in turn related to worsening at 2 and 4 years of follow-up in different cognitive measures. INTERPRETATION: In the absence of differences in baseline cognitive function and typical markers of neurodegeneration, the further development of an aggressive cognitive decline in PD is associated with increased slow-wave power density and with a different profile of worsening in several posterior-cortical-dependent tasks. ANN NEUROL 2024.

Skin Tau Quantification as a Novel Biomarker in Huntington's Disease.

BACKGROUND: Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease. OBJECTIVE: This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes. METHODS: In this cross-sectional study, we measured skin tau levels using enzyme-linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel-based morphometry approach. RESULTS: Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG-Age-Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease-related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters. CONCLUSIONS: This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society.

Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies.

Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson's disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain.

Crossed-reflex in antiphospholipid chorea.

Chorea is a hyperkinetic movement disorder associated with various underlyingconditions, including autoimmune diseases such as antiphospholipid syndrome (APS). APS can manifest with a wide range of neurological symptoms, including chorea. We present a case of a 77-year-old man with subacute generalized chorea secondary to primary APS. Notably, the patient exhibited a left patellar crossed-reflex, a phenomenon rarely documented in chorea cases, the pathophysiology of which has not yet been elucidated. In summary, this case challenges the traditional demographics of antiphospholipid syndrome (APS) by suggesting a potential link between APS and late-age patients. It emphasizes the importance of considering APS in late-onset chorea cases.

Levodopa-Induced Dyskinesias are Frequent and Impact Quality of Life in Parkinson's Disease: A 5-Year Follow-Up Study.

BACKGROUND: Levodopa-induced dyskinesias (LID) are frequent in Parkinson's disease (PD). OBJECTIVE: To analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients' quality of life (QoL). PATIENTS AND METHODS: PD patients from the 5-year follow-up COPPADIS cohort were included. LID were defined as a non-zero score in the item "Time spent with dyskinesia" of the Unified Parkinson's Disease Rating Scale-part IV (UPDRS-IV). The UPDRS-IV was applied at baseline (V0) and annually for 5 years. The 39-item Parkinson's disease Questionnaire Summary Index (PQ-39SI) was used to asses QoL. RESULTS: The frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5-year follow-up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (ß = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (ß = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ-39SI. CONCLUSION: LID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL.

Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Cognitive disorders in advanced Parkinson's disease: challenges in the diagnosis of delirium.

Parkinson's disease (PD) is a neurodegenerative condition that is frequently associated with cognitive disorders. These can arise directly from the primary disease, or be triggered by external factors in susceptible individuals due to PD or other predisposing factors. The cognitive disorders encompass PD-associated cognitive impairment (PD-CI), delirium, PD treatment-associated cognitive side effects, cognitive non-motor fluctuations, and PD-associated psychosis. Accurate diagnosis of delirium is crucial because it often stems from an underlying disease that may be severe and require specific treatment. However, overlapping molecular mechanisms are thought to be involved in both delirium and PD, leading to similar clinical symptoms. Additionally, there is a bidirectional interaction between delirium and PD-CI, resulting in frequent concurrent processes that further complicate diagnosis. No reliable biomarker is currently available for delirium, and the diagnosis is primarily based on clinical criteria. However, the screening tools validated for diagnosing delirium in the general population have not been specifically validated for PD. Our review addresses the current challenges in the diagnosis of these cognitive disorders and highlights existing gaps within this field.

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

Cognitive phenotype and neurodegeneration associated with Tau in Huntington's disease.

OBJECTIVE: The clinical phenotype of Huntington's disease (HD) can be very heterogeneous between patients, even when they share equivalent CAG repeat length, age, or disease burden. This heterogeneity is especially evident in terms of the cognitive profile and related brain changes. To shed light on the mechanisms participating in this heterogeneity, the present study delves into the association between Tau pathology and more severe cognitive phenotypes and brain damage in HD. METHODS: We used a comprehensive neuropsychological examination to characterize the cognitive phenotype of a sample of 30 participants with early-to-middle HD for which we also obtained 3 T structural magnetic resonance image (MRI) and cerebrospinal fluid (CSF). We quantified CSF levels of neurofilament light chain (NfL), total Tau (tTau), and phosphorylated Tau-231 (pTau-231). Thanks to the cognitive characterization carried out, we subsequently explored the relationship between different levels of biomarkers, the cognitive phenotype, and brain integrity. RESULTS: The results confirmed that more severe forms of cognitive deterioration in HD extend beyond executive dysfunction and affect processes with clear posterior-cortical dependence. This phenotype was in turn associated with higher CSF levels of tTau and pTau-231 and to a more pronounced pattern of posterior-cortical atrophy in specific brain regions closely linked to the cognitive processes affected by Tau. INTERPRETATION: Our findings reinforce the association between Tau pathology, cognition, and neurodegeneration in HD, emphasizing the need to explore the role of Tau in the cognitive heterogeneity of the disease.

Parkinson disease psychosis: from phenomenology to neurobiological mechanisms.

Parkinson disease (PD) psychosis (PDP) is a spectrum of illusions, hallucinations and delusions that are associated with PD throughout its disease course. Psychotic phenomena can manifest from the earliest stages of PD and might follow a continuum from minor hallucinations to structured hallucinations and delusions. Initially, PDP was considered to be a complication associated with dopaminergic drug use. However, subsequent research has provided evidence that PDP arises from the progression of brain alterations caused by PD itself, coupled with the use of dopaminergic drugs. The combined dysfunction of attentional control systems, sensory processing, limbic structures, the default mode network and thalamocortical connections provides a conceptual framework to explain how new incoming stimuli are incorrectly categorized, and how aberrant hierarchical predictive processing can produce false percepts that intrude into the stream of consciousness. The past decade has seen the publication of new data on the phenomenology and neurobiological basis of PDP from the initial stages of the disease, as well as the neurotransmitter systems involved in PDP initiation and progression. In this Review, we discuss the latest clinical, neuroimaging and neurochemical evidence that could aid early identification of psychotic phenomena in PD and inform the discovery of new therapeutic targets and strategies.

Predicting Disability in Progressive Supranuclear Palsy Using Bedside Frontal-Lobe Signs.

BACKGROUND: Frontal lobe signs in progressive supranuclear palsy (PSP) are prevalent and occur early in the disease. Although they are recognized in clinical practice, studies are needed to systematically investigate them for an in-depth understanding of the neurological substrate and their potential prognostic implications in the disease. OBJECTIVES: To study the predictive role of frontal lobe signs in PSP, as well as to describe their neuropsychological and anatomical correlations. METHODS: Nine recognized signs of frontal lobe dysfunction were assessed in 61 patients with PSP. Those signs able to predict PSP Rating Scale (PSPRS) score at baseline were selected, a survival analysis was performed and associations with neuropsychological tests and cortical thickness parameters in brain MRI were studied. RESULTS: Grasping, anosognosia and orobuccal apraxia predicted the PSPRS score independently of age, gender, clinical subtype and disease duration. The occurrence of groping in the first 4 years could be a predictor of survival. Grasping and anosognosia were associated with frontal cognitive dysfunction, whereas orobuccal apraxia and groping were related to a more widespread cognitive impairment, involving temporal-parietal areas. Presence of groping showed an extensive cortical atrophy, with predominant prefrontal, temporal and superior parietal cortical thinning. CONCLUSIONS: Grasping, groping, anosognosia and orobuccal apraxia are easily evaluable bedside clinical signs that reflect distinct stages of disease progression. Grasping, anosognosia and orobuccal apraxia predict disease disability in patients with PSP, and early onset groping could be a survival predictor.

Facial emotion recognition deficits are associated with hypomimia and related brain correlates in Parkinson's disease.

Hypomimia is a frequent manifestation in Parkinson's disease (PD) that can affect interpersonal relationships and quality of life. Recent studies have suggested that hypomimia is not only related to motor dysfunction but also to impairment in emotional processing networks. Therefore, we hypothesized that the severity of hypomimia could be associated with performance on a task aimed at assessing facial emotion recognition. In this study, we explored the association between hypomimia, recognition of facial expressions of basic emotions using the Ekman 60 Faces Test (EF), and brain correlates of both hypomimia and performance on the EF. A total of 94 subjects underwent clinical assessments (neurological and neuropsychological examinations), and 56 of them participated in the neuroimaging study. We found significant correlation between hypomimia, EF Disgust (r = -0.242, p = 0.022) and EF Happiness (r = -0.264, p = 0.012); an independent reduction in Cortical Thickness (Cth) in the postcentral gyrus, insula, middle and superior temporal gyri, supramarginal gyrus, banks of the superior temporal sulcus, bilateral fusiform gyri, entorhinal cortex, parahippocampal gyrus, inferior and superior parietal cortex, and right cuneus and precuneus; and multiple correlations between negative emotions such as EF Disgust or EF Anger and a reduced Cth in fronto-temporo-parietal regions. In conclusion, these results suggest that the association between hypomimia and emotion recognition deficits in individuals with PD might be mediated by shared circuits, supporting the concept that hypomimia is not only the result of the dysfunction of motor circuits, but also of higher cognitive functions.

Validation of the Italian version of the Parkinson's Disease- Cognitive Functional Rating Scale.

A key distinguishing factor between mild cognitive impairment (MCI) and dementia in Parkinson's disease (PD) lies in the notable decrease in functioning due to cognitive impairment. The Parkinson's Disease-Cognitive Functional Rating Scale (PD-CRFS) was developed to assess functional limitations caused by cognitive impairment, while reducing the influence of motor impairment. The aim of this multicenter study was to (i) validate the Italian version of the PD-CFRS in PD, (ii) determine optimal cut-off scores for detecting MCI and dementia in PD, (iii) compare its performances with the most established functional assessment tool (IADL). Six hundred and sixty nine PD participants were recruited from 4 Italian Movement Disorders centers (Venice, Milan, Gravedona, and Salerno). They underwent Level-II cognitive evaluation, which resulted in 282 PD-NC, 310 PD-MCI, and 77 PDD. The PD-CFRS's psychometric and clinimetric properties, applicability, and responsiveness were analyzed. The PD-CFRS showed high acceptability. Floor and ceiling effects were acceptable. It also displayed strong internal consistency (Cronbach's α = 0.738), and test-retest reliability (ICC = .854). The PD-CFRS demonstrated higher coefficient of variation to detect dysfunction in PD-MCI patients in comparison to the IADL scale (PD-CFRS 96% vs IADL 22.5%). Convergent validity with the IADL was r = - 0.638 and - 0.527 in males and females, respectively. PD-CFRS total score negatively correlated with global cognition (MoCA corrected score r = - 0.61; p < 0.001). A cut-off score > 6.5 identified PDD with a sensitivity of 90% and specificity of 88% (AUC = .959). A cut-off value of > 1 detected PD-MCI with a sensitivity of 68% and specificity of 69% (AUC = .695). The Italian version of the PD-CFRS demonstrated to be an easy, valid and reliable tool that properly captures functional impairment due to cognitive decline in PD. It also proved to be particularly effective in the advanced stages of PD, and would be a useful support for the diagnosis of PD-MCI and PDD.

The Effects of Safinamide in Chinese and Non-Chinese Patients with Parkinson's Disease.

INTRODUCTION: Ethnicity differences are an important determinant in the clinical manifestation of Parkinson's disease (PD), but they are not yet widely recognized, particularly regarding the response to dopaminergic medications. The aim of this paper is to analyze the efficacy and safety of safinamide in Chinese patients with PD in the pivotal studies SETTLE and XINDI compared to the non-Chinese population of the SETTLE trial. METHODS: SETTLE (NCT00627640) and XINDI (NCT03881371) were phase III, randomized, double-blind, placebo-controlled, multicenter trials. Patients received 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. Safety was evaluated through the frequency of adverse events. Data from 440 non-Chinese and 109 Chinese patients in the SETTLE study, and 305 Chinese patients in the XINDI trial were considered for this post hoc analysis. RESULTS: Significant positive results were seen in favor of safinamide in all populations for the primary and secondary endpoints, with no differences in terms of magnitude. No "treatment by ethnicity" interaction was detected for any parameters, confirming the homogeneity of treatment effects between different populations. The safety and tolerability of safinamide in Chinese patients were similar to those in the other ethnic groups, without unexpected adverse reactions. CONCLUSIONS: Safinamide was shown to improve PD symptoms and quality of life in different ethnic populations, without any treatment by race interaction. Further studies are warranted to investigate potential differences in a real-life situation. TRIAL REGISTRATION NUMBER: SETTLE (NCT00627640) and XINDI (NCT03881371).

Baseline Large-Scale Network Dynamics Associated with Disease Progression in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a genetically determined disease with motor, cognitive, and neuropsychiatric disorders. However, the links between clinical progression and disruptions to dynamics in motor and cognitive large-scale networks are not well established. OBJECTIVE: To investigate changes in dynamic and static large-scale networks using an established tool of disease progression in Huntington's disease, the composite Unified Huntington's Disease Rating Scale (cUHDRS). METHODS: Sixty-four mutation carriers were included. Static and dynamic baseline functional connectivity as well as topological features were correlated to 2-year follow-up clinical assessments using the cUHDRS. RESULTS: Decline in cUHDRS scores was associated with higher connectivity between frontal default-mode and motor networks, whereas higher connectivity in posterior, mainly visuospatial regions was associated with a smaller decline in cUHDRS scores. CONCLUSIONS: Structural disruptions in HD were evident both in posterior parietal/occipital and frontal motor regions, with reciprocal increases in functional connectivity. However, although higher visuospatial network connectivity was tied to a smaller cUHDRS decline, increased motor and frontal default-mode connections were linked to a larger cUHDRS decreases. Therefore, divergent functional compensation mechanisms might be at play in the clinical evolution of HD.

Staging Parkinson's disease according to the MNCD classification correlates with caregiver burden.

BACKGROUND AND OBJECTIVE: Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients' quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status. PATIENTS AND METHODS: Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4-5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers. CONCLUSION: Staging PD according to the MNCD classification is correlated with caregivers' strain and burden.