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Subtle gait and cognitive dysfunction are common in Parkinson's disease (PD), even before most evident clinical manifestations. Such alterations can be assumed as hypothetical phenotypical and prognostic/progression markers. To compare spatiotemporal gait parameters in PD patients with three cognitive status: cognitively intact (PD-noCI), with subjective cognitive impairment (PD-SCI) and with mild cognitive impairment (PD-MCI) in order to detect subclinical gait differences. One hundred PD patients were consecutively enrolled and divided in three groups based on both the first item od MDS-UPDRS part I and an extensive neuropsychological evaluation: 41 PD-noCI, 15 PD-SCI and 44 PD-MCI. They were evaluated with gait analysis acquired in three different conditions (normal gait, motor and cognitive dual task). Spatiotemporal variables were extracted. A univariate statistical analysis (parametric ANOVA test or non-parametric Kruskal-Wallis test, as appropriate) with post-hoc analysis was carried out in order to evaluate the significant differences among the groups. In normal gait task, the three groups showed several differences, all due to the comparison between PD-MCI and PD-noCI, as disclosed by post-hoc analysis. In dual task conditions, mostly in the cognitive dual task, the three groups showed increased gait alterations that, at post-hoc analysis, mirrored the magnitude of cognitive dysfunction (PD-noCI < PD-SCI < PD-MCI). Peculiar prodromal gait patterns-especially those highlighted by cognitive dual task-could be considered possible markers to objectify self-reported symptoms-based construct, like SCI, and to early intercept subjects with different clinical evolutions and prognoses, even representing an innovative clustering/phenotyping tool for PD subtypes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical standards: All people recruited for the study gave their informed consent prior to their inclusion. All acts were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments., (© 2025. The Author(s).)

Parkinson's disease (PD) is characterized by a slow, short-stepping, shuffling gait pattern caused by a combination of motor control limitations due to a reduction in dopaminergic neurons. Gait disorders are indicators of global health, cognitive status, and risk of falls and increase with disease progression. Therefore, the use of quantitative information on the gait mechanisms of PD patients is a promising approach, particularly for monitoring gait disorders and potentially informing therapeutic interventions, though it is not yet a well-established tool for early diagnosis or direct assessment of disease progression. Over the years, many studies have investigated the spatiotemporal parameters that are altered in the PD gait pattern, while kinematic and kinetic gait parameters are more limited. A scoping review was performed according to the PRISMA guidelines. The Scopus and PubMed databases were searched between 1999 and 2023. A total of 29 articles were included that reported gait changes in PD patients under different gait conditions: single free walking, sequential motor task, and dual task. The main findings of our review highlighted the use of optoelectronic systems for recording kinematic parameters and force plates for measuring kinetic parameters, due to their high accuracy. Most gait analyses in PD patients have been conducted at self-selected walking speeds to capture natural movement, although studies have also examined gait under various conditions. The results of our review indicated that PD patients experience alterations in the range of motion of the hip, knee, and ankle joints, as well as a reduction in the power generated/absorbed and the extensor/flexor moments. These findings suggest that the PD gait pattern may be more effectively understood using kinematic and kinetic parameters.

Parkinson's disease (PD) is the second most common movement disorder in the world. It is characterized by motor and non-motor symptoms that have a profound impact on the independence and quality of life of people affected by the disease, which increases caregivers' burdens. The use of the quantitative gait data of people with PD and deep learning (DL) approaches based on gait are emerging as increasingly promising methods to support and aid clinical decision making, with the aim of providing a quantitative and objective diagnosis, as well as an additional tool for disease monitoring. This will allow for the early detection of the disease, assessment of progression, and implementation of therapeutic interventions. In this paper, the authors provide a systematic review of emerging DL techniques recently proposed for the analysis of PD by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Scopus, PubMed, and Web of Science databases were searched across an interval of six years (between 2018, when the first article was published, and 2023). A total of 25 articles were included in this review, which reports studies on the movement analysis of PD patients using both wearable and non-wearable sensors. Additionally, these studies employed DL networks for classification, diagnosis, and monitoring purposes. The authors demonstrate that there is a wide employment in the field of PD of convolutional neural networks for analyzing signals from wearable sensors and pose estimation networks for motion analysis from videos. In addition, the authors discuss current difficulties and highlight future solutions for PD monitoring and disease progression.

Introduction: Impulse control disorders (ICDs) frequently occur in Parkinson's disease (PD), and an early identification is essential to prevent severe psychosocial consequences. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) has been developed to evaluate the severity of ICDs along with a range of impulsive-compulsive behaviors (ICBs) in PD; however, its Italian version has not yet been validated., Methods: One hundred consecutive outpatients with PD were administered an Italian version of the QUIP-RS and a brief neuropsychological assessment to evaluate global cognitive status and scales to measure depression, apathy and impulsive disorders. We evaluated the internal consistency, convergent and divergent validity, and factorial structure of QUIP-RS. We also explored the possible association between QUIP-RS scores and clinical factors and dopaminergic medication., Results: Subsyndromal ICDs manifestations were observed in 54% of the patients, and one in four (22%) reported two or more ICDs or related behaviors. The QUIP-RS demonstrated good internal consistency (Cronbach's alpha = 0.806) and construct validity, and its factorial structure reflected different ICDs and ICBs domains. No association emerged between QUIP-RS scores and the clinical aspects of PD and dopaminergic medication., Conclusion: We provided, for the first time, an Italian translation of the QUIP-RS and demonstrated its feasibility in clinical and research settings. Severity of ICDs was independent of clinical factors and dopaminergic medication, underlining the need to adopt a broader perspective on their etiopathology in PD., (© 2024. The Author(s).)

Background: Progressive supranuclear palsy (PSP) is a rare 4R-tauopathy. Transcranial direct current stimulation (tDCS) may improve specific symptoms., Objectives: This randomized, double-blinded, sham-controlled trial aimed at verifying the short-, mid-, and long-term effect of multiple sessions of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) cortex in PSP., Methods: Twenty-five patients were randomly assigned to active or sham stimulation (2 mA for 20 minute) for 5 days/week for 2 weeks. Participants underwent assessments at baseline, after the 2-week stimulation protocol, then after 45 days and 3 months from baseline. Primary outcomes were verbal and semantic fluency. The efficacy was verified with analysis of covariance., Results: We failed to detect a significant effect of active stimulation on primary outcomes. Stimulation was associated to worsening of specific behavioral complaints., Conclusions: A 2-week protocol of anodal left DLPFC tDCS is not effective in PSP. Specific challenges in running symptomatic clinical trials with classic design are highlighted. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Background: Social cognition is impaired in Parkinson's disease (PD). Whether social cognitive impairment (iSC) is a by-product of the underlying cognitive deficits in PD or a process independent of cognitive status is unknown. To this end, the present study was designed to investigate the weight of specific cognitive deficits in social cognition, considering different mild cognitive impairment subtypes of PD (PD-MCI)., Methods: Fifty-eight PD patients underwent a neuropsychological battery assessing executive functions, memory, language, and visuospatial domains, together with social cognitive tests focused on theory of mind (ToM). Patients were divided into subgroups according to their clinical cognitive status: amnestic PD-MCI (PD-aMCI, n = 18), non-amnestic PD-MCI (PD-naMCI, n = 16), and cognitively unimpaired (PD-CU, n = 24). Composite scores for cognitive and social domains were computed to perform mediation analyses., Results: Memory and language impairments mediated the effect of executive functioning in social cognitive deficits in PD patients. Dividing by MCI subgroups, iSC occurred more frequently in PD-aMCI (77.8%) than in PD-naMCI (18.8%) and PD-CU (8.3%). Moreover, PD-aMCI performed worse than PD-CU in all social cognitive measures, whereas PD-naMCI performed worse than PD-CU in only one subtype of the affective and cognitive ToM tests., Conclusions: Our findings suggest that ToM impairment in PD can be explained by memory dysfunction that mediates executive control. ToM downsides in the amnesic forms of PD-MCI may suggest that subtle changes in social cognition could partly explain future transitions into dementia. Hence, the evaluation of social cognition in PD is critical to characterize a possible behavioral marker of cognitive decline., (© 2023. The Author(s).)

Objectives: The Caregiver's Inventory Neuropsychological Diagnosis Dementia (CINDD) is an easy tool designed to quantify cognitive, behavioural and functional deficits of patients with cognitive impairment. Aim of the present study was to analyse the psychometric properties of the CINDD in Mild Cognitive Impairment (MCI) and Dementia (D)., Design, Setting and Participants: The CINDD, composed by 9 sub-domains, was administered to fifty-six caregivers of patients with different types of dementia (D) and 44 caregivers of patients with MCI. All patients underwent an extensive neuropsychological assessment, the Neuropsychiatric Inventory (NPI) and functional autonomy scales. The reliability, convergent construct validity and possible cut-off of CINND were measured by Cronbach's alpha (α), Pearson's correlation and ROC analysis, respectively., Results: The D and MCI patients differed only for age (p=0.006). The internal consistency of CINDD was high (α= 0.969). The α-value for each CINDD domain was considered acceptable, except the mood domain (α=0.209). The CINDD total score correlated with cognitive screening tests; each domain of the CINDD correlated with the corresponding score from either tests or NPI (p<0.05), except for visuo-spatial perception skills and apathy. A screening cut-off equal to 59, can be used discriminate D from MCI (Sensitivity=0.70, Specificity=0.57)., Conclusion: The CINDD is a feasible, accurate and reliable tool for the assessment of cognitive and behavioural difficulties in patients with different degree of cognitive impairment. It may be used to quantify and monitor caregiver-reported ecological data in both clinical and research settings., (© 2024. The Author(s).)

Mild cognitive impairment (MCI) and gait deficits are commonly associated with Parkinson's disease (PD). Early detection of MCI associated with Parkinson's disease (PD-MCI) and its biomarkers is critical to managing disability in PD patients, reducing caregiver burden and healthcare costs. Gait is considered a surrogate marker for cognitive decline in PD. However, gait kinematic and kinetic features in PD-MCI patients remain unknown. This study was designed to explore the difference in gait kinematics and kinetics during single-task and dual-task walking between PD patients with and without MCI. Kinematic and kinetic data of 90 PD patients were collected using 3D motion capture system. Differences in gait kinematic and kinetic gait features between groups were identified by using: first, univariate statistical analysis and then a supervised machine learning analysis. The findings of this study showed that the presence of MCI in PD patients is coupled with kinematic and kinetic deviations of gait cycle which may eventually identify two different phenotypes of the disease. Indeed, as shown by the demographical and clinical comparison between the two groups, PD-MCI patients were older and more impaired. Moreover, PD-MCI kinematic results showed that cognitive dysfunction coexists with more severe axial symptoms and an increase postural flexion. A lack of physiological distal-to-proximal shift in joint kinetics was evidenced in the PD phenotype associated with cognitive impairments.

The use of wearable sensors for calculating gait parameters has become increasingly popular as an alternative to optoelectronic systems, currently recognized as the gold standard. The objective of the study was to evaluate the agreement between the wearable Opal system and the optoelectronic BTS SMART DX system for assessing spatiotemporal gait parameters. Fifteen subjects with progressive supranuclear palsy walked at their self-selected speed on a straight path, and six spatiotemporal parameters were compared between the two measurement systems. The agreement was carried out through paired data test, Passing Bablok regression, and Bland-Altman Analysis. The results showed a perfect agreement for speed, a very close agreement for cadence and cycle duration, while, in the other cases, Opal system either under- or over-estimated the measurement of the BTS system. Some suggestions about these misalignments are proposed in the paper, considering that Opal system is widely used in the clinical context.

The exact pathophysiology of cognitive impairment in multiple system atrophy (MSA) is unclear. In our longitudinal study, we aimed to analyze (I) the relationships between cognitive functions and some subcortical structures, such as putamen and cerebellum assessed by voxel-based morphometry (VBM) and T1-weighted/T2-weighted (T1w/T2w) ratio, and (II) the neuroimaging predictors of the progression of cognitive deficits. Twenty-six patients with MSA underwent a comprehensive neuropsychological battery, motor examination, and brain MRI at baseline (T 0 ) and 1-year follow-up (T 1 ). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T 1 , we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (β =  - 9.45, p = .02) and T1w/T2w value in the left putamen (β = 230.64, p = .01) were significant predictors of global cognitive status at T 0 , explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (β = 2188.70, p = .02) significantly predicted cognitive worsening at T 1 , explaining 64% of the variance. Our results suggest a role for the putamen and cerebellum in the cognitive changes of MSA, probably due to their connections with the cortex. The putaminal T1w/T2w ratio may deserve further studies as a marker of cognitive impairment in MSA., (© 2022. The Author(s).)

Background: This study aimed at: (1) assessing, in an Italian cohort of non-demented Parkinson's disease (PD) patients, the construct validity of the Montreal Cognitive Assessment (MoCA) against both first- and second-level cognitive measures; (2) delivering an exhaustive and updated evaluation of its diagnostic properties., Methods: A retrospective cohort of N = 237 non-demented PD patients having been administered the MoCA was addressed, of whom N = 169 further underwent the Mini-Mental State Examination (MMSE) and N = 68 the Parkinson's Disease Cognitive Rating Scale (PD-CRS). A subsample (N = 60) also underwent a second-level cognitive battery encompassing measures of attention/executive functioning, language, memory, praxis and visuo-spatial abilities. Construct validity was assessed against both the PD-CRS and the second-level cognitive battery. Diagnostics were tested via receiver-operating characteristics analyses against a below-cut-off MMSE score., Results: The MoCA was associated with both PD-CRS scores (p < .001) and the vast majority of second-level cognitive measures (ps < .003). Both raw and adjusted MoCA scores proved to be highly accurate to the aim of identifying patients with MMSE-confirmed cognitive dysfunctions. A MoCA score adjusted for age and education according to the most recent normative dataset and < 19.015 is herewith suggested as indexing cognitive impairment in this population (AUC = .92; sensitivity = .92; specificity = .80)., Discussion: The Italian MoCA is a valid and diagnostically sound screener for global cognitive inefficiency in non-demented PD patients. Further studies are nevertheless needed that confirm its diagnostic values against a measure other than the MMSE., (© 2023. The Author(s).)

Gender is an important factor influencing epidemiological and clinical features of Parkinson's disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman's correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment., (© 2023. The Author(s).)

Altered self-awareness or anosognosia may impact patients' everyday life by interfering with their safe and independent functioning. Symptom awareness has been linked to executive dysfunctions caused by damage to frontal regions. Apathy is a frequent neuropsychiatric manifestation of Parkinson's disease (PD) and is considered a consequence of altered functioning of cortico-subcortical circuitries connecting the prefrontal cortex (PFC) with the basal ganglia. Thus, apathetic PD patients may be not be fully aware of their condition due to shared neuropathophysiological mechanisms. The present study aimed to explore the awareness of apathy in PD patients by comparing the self-reported evaluations with their caregivers' ratings. Moreover, we explored the clinical predictors of possible discrepancies and their consequences on patients' self-reported evaluation of quality of life (QoL). We found a fair agreement between patients' self-reports and caregivers' ratings on apathy scores, with patients reporting less severe apathetic symptoms, especially those related to executive and auto-activation processing, compared to their caregivers' reports. Executive functioning was found to mediate the relationship between disease stage and awareness of the apathetic state. Awareness of executive apathy impacted patients' self-reported QoL. Therefore, PD patients might be unaware of their apathetic symptoms, especially those with worse executive functioning, which plays a key role in metacognitive processes such as self-monitoring and error detection. Anosognosia for apathy in PD patients may affect their QoL perception and leads to misleading self-report evaluations that delay diagnosis and treatment.

Introduction: Depression is one of the most disabling neuropsychiatric manifestations of Parkinson's disease (PD) and requires proper screening and diagnosis because it affects the overall prognosis and quality of life of patients. This study aimed to assess the psychometric and diagnostic properties of the Beck Depression Inventory-II (BDI-II) in an Italian PD cohort., Materials and Methods: Fifty consecutive outpatients with PD underwent the Italian version of the BDI-II and other questionnaires to evaluate anxiety and apathetic symptoms. Patients' caregivers completed the depression/dysphoria domain of the Neuropsychiatric Inventory (NPI-D). We evaluated the internal consistency, convergent and divergent validity, and factorial structure of BDI-II. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were computed using ROC analyses, and an optimal cutoff was defined using the Youden index., Results: The BDI-II proved to be internally consistent (Cronbach's α = 0.840) and substantially met the bi-factorial structure. Regarding construct validity, the BDI-II was substantially related to anxiety measures, but not to apathy. With the combination of the NPI-D and anxiety score used as the gold standard, the BDI-II overall showed good accuracy (AUC = 0.859) with adequate sensitivity (75%) and specificity (87%). The optimal cutoff point was defined at 14.50., Conclusions: We provide evidence of the psychometric and diagnostic properties of the Italian version of the BDI-II as a screening tool for depression in patients with PD. The BDI-II was found to be reliable and valid for the measurement of depression in patients with PD; therefore, it is available for use in clinical research and practice., (© 2023. The Author(s).)

Background: This study aimed at assessing the cross-sectional and longitudinal clinimetrics and feasibility of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease (PD) patients., Methods: N = 109 PD patients underwent the FAB and the Montreal Cognitive Assessment (MoCA). A subsample of patients further underwent a thorough motor, functional and behavioral evaluation (the last including measures of anxiety, depression and apathy). A further subsample was administered a second-level cognitive battery tapping on attention, executive functioning, language, memory, praxis and visuo-spatial abilities. The following properties of the FAB were tested: (1) concurrent validity and diagnostics against the MoCA; (2) convergent validity against the second-level cognitive battery; (4) association with motor, functional and behavioral measures; (5) capability to discriminate patients from healthy controls (HCs; N = 96); (6) assessing its test-retest reliability, susceptibility to practice effects and predictive validity against the MoCA, as well as deriving reliable change indices (RCIs) for it, at a ≈ 6-month interval, within a subsample of patients (N = 33)., Results: The FAB predicted MoCA scores at both T0 and T1, converged with the vast majority of second-level cognitive measures and was associated with functional independence and apathy. It accurately identified cognitive impairment (i.e., a below-cut-off MoCA score) in patients, also discriminating patients from HCs. The FAB was reliable at retest and free of practice effects; RCIs were derived according to a standardized regression-based approach., Discussion: The FAB is a clinimetrically sound and feasible screener for detecting dysexecutive-based cognitive impairment in non-demented PD patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Introduction: Progressive supranuclear palsy (PSP) is an atypical parkinsonism characterized by prominent gait and postural impairment. The PSP rating scale (PSPrs) is a clinician-administered tool to evaluate disease severity and progression. More recently, digital technologies have been used to investigate gait parameters. Therefore, object of this study was to implement a protocol using wearable sensors evaluating disease severity and progression in PSP., Methods: Patients were evaluated with the PSPrs as well as with three wearable sensors located on the feet and lumbar area. Spearman coefficient was used to assess the relationship between PSPrs and quantitative measurements. Furthermore, sensor parameters were included in a multiple linear regression model to assess their ability in predicting the PSPrs total score and sub-scores. Finally, differences between baseline and three-month follow-up were calculated for PSPrs and each quantitative variable. The significance level in all analyses was set at ≤ 0.05., Results: Fifty-eight evaluations from thirty-five patients were analyzed. Quantitative measurements showed multiple significant correlations with the PSPrs scores (r between 0.3 and 0.7; p < 0.05). Linear regression models confirmed the relationships. After three months visit, significant worsening from baseline was observed for cadence, cycle duration and PSPrs item 25, while PSPrs item 10 showed a significant improvement., Conclusion: We propose wearable sensors can provide an objective, sensitive quantitative evaluation and immediate notification of gait changes in PSP. Our protocol can be easily introduced in outpatient and research settings as a complementary tool to clinical measures as well as an informative tool on disease severity and progression in PSP., Competing Interests: Declarations of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hyposmia is a common finding in Parkinson's disease (PD) and is usually tested through the University of Pennsylvania Smell Identification Test (UPSIT). The aim of our study is to provide a briefer version of the Italian-adapted UPSIT test, able to discriminate between PD patients and healthy subjects (HS). By means of several univariate and multivariate (machine-learning-based) statistical approaches, we selected 8 items by which we trained a partial-least-square discriminant analysis (PLS-DA) and a decision tree (DT) model: class predictions of both models performed better with the 8-item version when compared to the 40-item version. An area under the receiver operating characteristic (AUC-ROC) curve built with the selected 8 odors showed the best performance (sensitivity 86.8%, specificity 82%) in predicting the PD condition at a cut-off point of ≤ 6. These performances were higher than those previously calculated for the 40-item UPSIT test (sensitivity 82% and specificity 88.2 % with a cut-off point of ≤ 21). Qualitatively, our selection contains one odor (i.e., apple) which is Italian-specific, supporting the need for cultural adaptation of smell testing; on the other hand, some of the selected best discriminating odors are in common with existing brief smell test versions validated on PD patients of other cultures, supporting the view that disease-specific odor patterns may exist and deserve a further evaluation., (© 2022. The Author(s).)

The aim of this study was to determine a gait pattern, i.e., a subset of spatial and temporal parameters, through a supervised machine learning (ML) approach, which could be used to reliably distinguish Parkinson's Disease (PD) patients with and without mild cognitive impairment (MCI). Thus, 80 PD patients underwent gait analysis and spatial-temporal parameters were acquired in three different conditions (normal gait, motor dual task and cognitive dual task). Statistical analysis was performed to investigate the data and, then, five ML algorithms and the wrapper method were implemented: Decision Tree (DT), Random Forest (RF), Naïve Bayes (NB), Support Vector Machine (SVM) and K-Nearest Neighbour (KNN). First, the algorithms for classifying PD patients with MCI were trained and validated on an internal dataset (sixty patients) and, then, the performance was tested by using an external dataset (twenty patients). Specificity, sensitivity, precision, accuracy and area under the receiver operating characteristic curve were calculated. SVM and RF showed the best performance and detected MCI with an accuracy of over 80.0%. The key features emerging from this study are stance phase, mean velocity, step length and cycle length; moreover, the major number of features selected by the wrapper belonged to the cognitive dual task, thus, supporting the close relationship between gait dysfunction and MCI in PD.

Background: Clinical markers of cognitive decline in Parkinson's disease (PD) encompass several mental non-motor symptoms such as hallucinations, apathy, anxiety, and depression. Furthermore, freezing of gait (FOG) and specific gait alterations have been associated with cognitive dysfunction in PD. Finally, although low cerebrospinal fluid levels of amyloid-β42 have been found to predict cognitive decline in PD, hitherto PET imaging of amyloid-β (Aβ) failed to consistently demonstrate the association between Aβ plaques deposition and mild cognitive impairment in PD (PD-MCI)., Aim: Finding significant features associated with PD-MCI through a machine learning approach., Patients and Methods: Patients were assessed with an extensive clinical and neuropsychological examination. Clinical evaluation included the assessment of mental non-motor symptoms and FOG using the specific items of the MDS-UPDRS I and II. Based on the neuropsychological examination, patients were classified as subjects without and with MCI (noPD-MCI, PD-MCI). All patients were evaluated using a motion analysis system. A subgroup of PD patients also underwent amyloid PET imaging. PD-MCI and noPD-MCI subjects were compared with a univariate statistical analysis on demographic data, clinical features, gait analysis variables, and amyloid PET data. Then, machine learning analysis was performed two times: Model 1 was implemented with age, clinical variables (hallucinations/psychosis, depression, anxiety, apathy, sleep problems, FOG), and gait features, while Model 2, including only the subgroup performing PET, was implemented with PET variables combined with the top five features of the former model., Results: Seventy-five PD patients were enrolled (33 PD-MCI and 42 noPD-MCI). PD-MCI vs. noPD-MCI resulted in older and showed worse gait patterns, mainly characterized by increased dynamic instability and reduced step length; when comparing amyloid PET data, the two groups did not differ. Regarding the machine learning analyses, evaluation metrics were satisfactory for Model 1 overcoming 80% for accuracy and specificity, whereas they were disappointing for Model 2., Conclusions: This study demonstrates that machine learning implemented with specific clinical features and gait variables exhibits high accuracy in predicting PD-MCI, whereas amyloid PET imaging is not able to increase prediction. Additionally, our results prompt that a data mining approach on certain gait parameters might represent a reliable surrogate biomarker of PD-MCI., Competing Interests: Unrelated to this study, PB received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie, and Acorda; RE received consultancies from Zambon and honoraria from TEVA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Amboni, Ricciardi, Adamo, Nicolai, Volzone, Erro, Cuoco, Cesarelli, Basso, D'Addio, Salvatore, Pace and Barone.)

Theory of Mind (ToM) is the ability to infer and reason about others' mental states, a process impaired by Parkinson's disease (PD). ToM performance in PD seems to be strongly related to executive functioning but the exact nature of this relationship is still unclear. We aim to investigate the direct impact of several executive dysfunctions on ToM deficits (Affective and Cognitive ToM) in PD patients. Sixty-eight PD patients underwent neuropsychological tests evaluating executive control such as inhibition, cognitive flexibility, processing speed or working memory and Cognitive and Affective ToM. We divided participants into two groups based on their performance on executive tests: PD patients with poor executive functioning (PD-EF-) and those with preserved executive functioning (PD-EF+). To explore the direct impact of executive subdomains on ToM abilities, two mediation models were executed in the whole sample. We found that PD patients with poor executive functioning reported poorer scores on Affective and Cognitive ToM tasks than PD patients with preserved executive functions, controlling for age and education. Moreover, parallel mediation models, conducted in the whole sample, indicated that performance on phonological fluency mediated the relationships between educational level and both Affective and Cognitive ToM, controlling the effect of other executive tests. These findings further support the idea that executive functions are crucial in ToM processes. Particularly, phonological fluency, whose execution requires both verbal abilities and cognitive flexibility, mediated ToM performance controlling the effect of other executive functions. The identification of neuropsychological processes underpinning ToM abilities might represent a plausible target for cognitive training to strengthen ToM abilities in PD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Several MRI techniques have become available to support the early diagnosis of multiple system atrophy (MSA), but few longitudinal studies on both MSA variants have been performed, and there are no established MRI markers of disease progression. We aimed to characterize longitudinal brain changes in 26 patients with MSA (14 MSA-P and 12 MSA-C) over a 1-year follow-up period in terms of local tissue density and T1w/T2w ratio in a-priori regions, namely, bilateral putamen, cerebellar gray matter (GM), white matter (WM), and substantia nigra (SN). A significant GM density decrease was found in cerebellum and left putamen in the entire group (10.7 and 33.1% variation, respectively) and both MSA subtypes (MSA-C: 15.4 and 33.0% variation; MSA-P: 7.7 and 33.2%) and in right putamen in the entire group (19.8% variation) and patients with MSA-C (20.9% variation). A WM density decrease was found in the entire group (9.3% variation) and both subtypes in cerebellum-brainstem (MSA-C: 18.0% variation; MSA-P: 5% variation). The T1w/T2w ratio increase was found in the cerebellar and left putamen GM (6.6 and 24.9% variation), while a significant T1w/T2w ratio decrease was detected in SN in the entire MSA group (31% variation). We found a more progressive atrophy of the cerebellum in MSA-C with a similar progression of putaminal atrophy in the two variants. T1w/T2w ratio can be further studied as a potential marker of disease progression, possibly reflecting decreased neuronal density or iron accumulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ponticorvo, Manara, Russillo, Andreozzi, Forino, Erro, Picillo, Amboni, Cuoco, Di Salle, Di Salle, Barone, Esposito and Pellecchia.)

Introduction: The COVID-19 pandemic led to psychological consequences on people's mental health, representing a condition of increased vulnerability for the weakest sections of population, including elderly patients with Parkinson's disease (PD). This longitudinal study aimed at exploring the impact of the most frequent non-motor symptoms and their contribute on health-related quality of life of PD patients after the COVID-19 outbreak, in comparison with the pre-pandemic status., Methods: Forty-two non-demented PD patients underwent a first assessment between December 2018 and January 2020 (T0). Then, between March and May 2021 (T1), they were contacted again and asked to complete the second assessment. Levels of global functioning, several non-motor symptoms (i.e. depression, apathy, anxiety, anhedonia) and health-related quality of life were investigated., Results: Results of the the paired Wilcoxon signed-rank test showed that at T1, PD patients scored lower on the emotional subscale of the DAS, Z =  - 2.49; p = 0.013; Cohen d z  = 0.691. Higher scores of the TEPS total score, Z =  - 2.38; p = 0.025; Cohen d z  = 0.621, and LEDD, Z =  - 2.63; p = 0.008; Cohen d z  = 0.731, were also reported at T1., Conclusion: The present study suggested that self-isolation at home might lead to a reduction of apathy and anhedonia in PD patients due to the increase in social support provided by families during COVID-19 restrictions. This evidence brings out the need of a consistent and persistent social support which might be represented by caregivers or/and social assistive robotics., (© 2022. The Author(s).)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and gender differences have been described on several aspects of PD. In the present commentary, we aimed to collect and discuss the currently available evidence on gender differences in PD regarding biomarkers, genetic factors, motor and non-motor symptoms, therapeutic management (including pharmacological and surgical treatment) as well as preclinical studies., Methods: A systematic literature review was performed by searching the Pubmed and Scopus databases with the search strings "biomarkers", "deep brain stimulation", "female", "gender", "genetic", "levodopa", "men", "male", "motor symptoms", "non-motor symptoms", "Parkinson disease", "sex", "surgery", and "women"., Results: The present review confirms the existence of differences between men and women in Parkinson Disease, pointing out new information regarding evidence from animal models, genetic factors, biomarkers, clinical features and pharmacological and surgical treatment., Conclusions: The overall goal is to acquire new informations about sex and gender differences in Parkinson Disease, in order to develop tailored intervetions.

Parkinson's Disease (PD) is a neurodegenerative disease which involves both motor and non-motor symptoms. Non-motor mental symptoms are very common among patients with PD since the earliest stage. In this context, gait analysis allows to detect quantitative gait variables to distinguish patients affected by non-motor mental symptoms from patients without these symptoms. A cohort of 68 PD subjects (divided in two groups) was acquired through gait analysis (single and double task) and spatial temporal parameters were analysed; first with a statistical analysis and then with a machine learning (ML) approach. Single-task variables showed that 9 out of 16 spatial temporal features were statistically significant for the univariate statistical analysis (p-value< 0.05). Indeed, a statistically significant difference was found in stance phase (p-value=0.032), swing phase (p-value=0.042) and cycle length (p-value=0.03) of the dual task. The ML results confirmed the statistical analysis, in particular, the Decision Tree classifier showed the highest accuracy (80.9%) and also the highest scores in terms of specificity and precision. Our findings indicate that patients with non-motor mental symptoms display a worse gait pattern, mainly dominated by increased slowness and dynamic instability.

Background: Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug's effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD., Materials and Methods: This is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t 1/2 ), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters., Results: Thirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men ( p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t 1/2 . Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = -0.0970631, 95% CI -0.1733004 -0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t 1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t 1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men., Conclusion: This study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Conti, Izzo, Russillo, Picillo, Amboni, Scaglione, Nicoletti, Cani, Cicero, De Bellis, Charlier, Giudice, Somma, Corbi, Barone, Filippelli and Pellecchia.)

Background: Mild cognitive impairment (MCI) is frequent in Parkinson's disease (PD) and represents a risk factor for the development of dementia associated with PD (PDD). Since PDD has been associated with disability, caregiver burden, and an increase in health-related costs, early detection of MCI associated with PD (PD-MCI) and its biomarkers is crucial., Objective: Given that gait is considered a surrogate marker for cognitive decline in PD, the aim of this study was to compare gait patterns in PD-MCI subtypes in order to verify the existence of an association between specific gait features and particular MCI subtypes., Methods: A total of 67 patients with PD were consecutively enrolled and assessed by an extensive clinical and cognitive examination. Based on the neuropsychological examination, patients were diagnosed as patients with MCI (PD-MCI) and without MCI (no-PD-MCI) and categorized in MCI subtypes. All patients were evaluated using a motion capture system of a BTS Bioengineering equipped with six IR digital cameras. Gait of the patients was assessed in the ON-state under three different tasks (a single task and two dual tasks). Statistical analysis included the t -test, the Kruskal-Wallis test with post hoc analysis, and the exploratory correlation analysis., Results: Gait pattern was poorer in PD-MCI vs. no-PD-MCI in all tasks. Among PD-MCI subtypes, multiple-domain PD-MCI and amnestic PD-MCI were coupled with worse gait patterns, notably in the dual task., Conclusion: Both the magnitude of cognitive impairment and the presence of memory dysfunction are associated with increased measures of dynamic unbalance, especially in dual-task conditions, likely mirroring the progressive involvement of posterior cortical networks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Amboni, Ricciardi, Cuoco, Donisi, Volzone, Ricciardelli, Pellecchia, Santangelo, Cesarelli and Barone.)

Introduction: Mild Cognitive Impairment in Parkinson's Disease (PD-MCI) is a transitional state between normal cognition and dementia. Cross-sectional studies revealed that low Vitamin D levels were associated with worse performance on cognitive tests in Parkinson's Disease. The present longitudinal study aimed to examine the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels at baseline and possible development of PD-MCI at 24 and 48   months., Materials and Methods: Sixty untreated, de novo PD patients underwent clinical and cognitive evaluations and measurement of serum 25(OH)D at baseline assessment (T0). After 24 (T1) and 48   months (T2), cognitive status (presence or absence of PD-MCI) of PD patients were re-evaluated., Results: Vitamin D insufficiency occurred in 93.3% at T0. At T1, significant differences among patients with PD-MCI at both baseline and follow-up, patients with PD-MCI at follow-up and patients who never developed PD-MCI were found on age, age at onset of PD, and education; no significant difference was found on vitamin D levels at T0. A binary logistic regression analysis showed that a lower level of 25(OH)D at T0 (B= -0.158, Wald= 5.280, p   =   0.022, Exp (B)=0.854; CI 95%: 0.746-0.977) and lower education (B= -0.214, Wald= 3.859, p   =   0.049, Exp (B)=0.807; CI 95%: 0652-1.000) were predictors of PD-MCI occurrence at T2., Discussion: Our results demonstrated that a lower level of 25(OH)D is conceivable as a biomarker of development of PD-MCI throughout the disease. Early diagnosis of Vitamin D insufficiency and its management might be useful to prevent cognitive decline in PD patients.

Introduction: The aim of this study is to investigate the impact of orthostatic hypotension (OH) on cognitive functions in patients with multiple system atrophy (MSA) followed over time. Methods: Thirty-two MSA patients were enrolled and underwent a comprehensive neuropsychological battery; at baseline (T 0 ) 15 out of 32 patients presented OH, assessed by means of orthostatic standing test. All patients underwent a follow-up (T 1 ) evaluation 12 months after baseline. Thirteen out of 32 patients also underwent a second follow-up (T 2 ) evaluation at 24 months. Changes over time on different neuropsychological tasks were compared between patients with and without OH by means of Mann-Whitney's U -test. Moreover, clinical categories of normal cognition, mild cognitive impairment, and dementia were determined, and changes at T 1 and T 2 in global cognitive status were compared between patients with and without OH. Results: At T 0 , patients with OH had better performance on words/non-words repetition task ( p = 0.02) compared to patients without OH. Compared to patients without OH, patients with OH performed worse on semantic association task ( p < 0.01) at T 1 and on Stroop test-error effect ( p = 0.04) at T 2 . The percentage of patients with worsened cognitive status at T 1 was higher among patients with OH than among patients without OH (93 vs. 59%, p = 0.03). OH (β = -4.67, p = 0.01), education (β = 0.45, p = 0.02), age (β = 0.19, p = 0.03), and Montreal Cognitive Assessment battery (MOCA) score at T 0 (β = -0.26, p = 0.04) were significant predictors of global cognitive status worsening at T 1 . Discussion: We found that global cognitive status worsened at 1-year follow-up in 93% of patients with OH, and OH, along with age, education, and MOCA score, predicted cognitive worsening over time. To clarify the relationship between OH and cognitive dysfunction in MSA, we suggest the use of clinical categories of normal cognition, mild cognitive impairment, and dementia in further longitudinal studies on MSA patients with and without OH., Competing Interests: Unrelated to this study, PB received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie, and Acorda. RE received consultancies from Zambon and honoraria from TEVA. The other authors report no financial disclosures. The other authors report no financial disclosures. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cuoco, Carotenuto, Cappiello, Scannapieco, Russillo, Andreozzi, Forino, Amboni, Picillo, Erro, Barone and Pellecchia.)

Background: Functional motor disorders (FMD) are highly disabling neurological conditions in which postural control deficits increase the risk of falls and disability in performing daily living activities. Scattered evidence suggests that such disturbances may depend on abnormal attentional focus and might improve with distraction., Research Question: How do motor and cognitive dual tasks performed under two different sensory conditions shape postural control in patients with FMD., Methods: This posturographic study involved 30 patients with FMD (age, 45.20 ± 14.57 years) and 30 healthy controls (age, 41.20 ± 16.50 years). Postural parameters were measured with eyes open, and eyes closed in quiet stance (single task) and on a motor dual task (m-DT) and a calculation (cognitive) dual task (c-DT). The dual task effect (DTE, expressed in percentage) on motor and cognitive performance was calculated for sway area, length of Center of Pressure (CoP), and velocity of CoP displacement., Results: There was a statistically significant three-way interaction between task, condition, and group for the DTE on sway area (p = 0.03). The mean sway area DTE on the motor task in the eyes-closed condition was increased by 70.4 % in the healthy controls, while it was decreased by 1% in the patient group (p = 0.003). No significant three-way interaction was observed for the DTE on length of CoP and velocity of CoP displacement., Significance: This study provides novel preliminary evidence for the benefit of a simple motor dual task in the eyes closed condition as a way to improve postural control in patients with FMD. These findings are relevant for the management of postural control disorders in patients with FMD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The objective of the present study was to describe gait parameters of progressive supranuclear palsy (PSP) phenotypes at early stage verifying the ability of gait analysis in discriminating between disease phenotypes and between the other variant syndromes of PSP (vPSP) and Parkinson's disease (PD). Nineteen PSP (10 PSP-Richardson's syndrome, five PSP-parkinsonism, and four PSP-progressive gait freezing) and nine PD patients performed gait analysis in single and dual tasks. Although phenotypes showed similar demographic and clinical variables, Richardson's syndrome presented worse cognitive functions. Gait analysis demonstrated worse parameters in Richardson's syndrome compared with the vPSP. The overall diagnostic accuracy of the statistical model during dual task was almost 90%. The correlation analysis showed a significant relationship between gait parameters and visuo-spatial, praxic, and attention abilities in PSP-Richardson's syndrome only. vPSP presented worse gait parameters than PD. Richardson's syndrome presents greater gait dynamic instability since the earliest stages than other phenotypes. Computerized gait analysis can differentiate between PSP phenotypes and between vPSP and PD., Competing Interests: MP has been supported by the Michael J. Fox Foundation for Parkinson's research. PB received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie, and Acorda. RE received consultancies from Zambon and honoraria from TEVA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Picillo, Ricciardi, Tepedino, Abate, Cuoco, Carotenuto, Erro, Ricciardelli, Russo, Cesarelli, Barone and Amboni.)

Cervical Dystonia (CD) and Parkinson's disease, particularly tremor-dominant motor phenotype (TD-PD), showed a selective deficit of time-based prospective memory (TBPM). The two movement disorders are mainly characterized by dysfunctions of basal-ganglia and prefrontal cortex but it is reported that cerebellum also plays a key role in their pathogenesis. These cerebral structures are specifically involved in TBPM rather than in event-based PM (EBPM), but until now no study directly compared these two components of PM between CD and TD-PD patients. Therefore, the present study aimed at investigating if differences in PM functioning between CD and TD-PD patients might exist and if the type of movement disorder moderated the relationship between deficit of PM and deficit of executive functions and retrospective memory. Thirty TD-PD, 27CD patients and 29 healthy subjects (HCs), matched for demographic features, underwent neuropsychological tests for PM, executive functions, retrospective memory and self-rated questionnaires. The three groups did not differ on neuropsychological variables except for TBPM where TD-PD and CD patients performed worse than HCs; moreover, TD-PD performed worse than CD patients. Moderation analysis indicated that the type of movement disorder moderated the relationship between executive dysfunction and TBPM, but not EBPM. In conclusion, selective deficit of TBPM characterizes both CD and TD-PD but it is associated with executive dysfunction only in TD-PD. It might be possible to speculate that the involvement of the cerebellum, responsible for internal timing processes, could explain the impairment of TBPM in both movement disorders. This issue deserves to be explored in future neuroimaging studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Progressive supranuclear palsy (PSP) is a rare and rapidly progressing atypical parkinsonism. Albeit existing clinical criteria for PSP have good specificity and sensitivity, there is a need for biomarkers able to capture early objective disease-specific abnormalities. This study aimed to identify gait patterns specifically associated with early PSP. The study population comprised 104 consecutively enrolled participants (83 PD and 21 PSP patients). Gait was investigated using a gait analysis system during normal gait and a cognitive dual task. Univariate statistical analysis and binary logistic regression were used to compare all PD patients and all PSP patients, as well as newly diagnosed PD and early PSP patients. Gait pattern was poorer in PSP patients than in PD patients, even from early stages. PSP patients exhibited reduced velocity and increased measures of dynamic instability when compared to PD patients. Application of predictive models to gait data revealed that PD gait pattern was typified by increased cadence and longer cycle length, whereas a longer stance phase characterized PSP patients in both mid and early disease stages. The present study demonstrates that quantitative gait evaluation clearly distinguishes PSP patients from PD patients since the earliest stages of disease. First, this might candidate gait analysis as a reliable biomarker in both clinical and research setting. Furthermore, our results may offer speculative clues for conceiving early disease-specific rehabilitation strategies.

To evaluate intraocular pressure (IOP) and choroidal thickness (ChT) postural changes in multiple system atrophy (MSA), Parkinson's disease (PD) patients and healthy controls (HC). 20 MSA patients, 21 PD patients and 14 HC, were examined. All subjects underwent a complete examination, including corneal thickness, ChT, IOP and axial length (AL) measurements. IOP measurement was performed in supine, sitting, and standing positions, whereas ChT in sitting and standing positions. Supine to standing IOP variations were significantly higher in MSA vs PD(p = 0.01) and in MSA vs HC (p < 0.0001), whereas no significant differences were observed between PD and HC (p = 0.397). Mean sub-foveal ChT in MSA was 240 ± 92 μm in sitting position, and 215 ± 94 μm in standing position with a significant reduction (p = 0.008). Mean sub-foveal ChT in PD was 258 ± 79 μm in sitting position, and 259 ± 76 μm in standing position (p = 0.887). In HC it was 244 ± 36 μm in sitting position, and 256 ± 37 μm in standing position with a significant increase (p = 0.007). The significant IOP and ChT postural changes can be considered additional hallmarks of autonomic dysfunction in MSA and further studies are needed to consider them as biomarkers in the differential diagnosis with PD.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which environmental (lifestyle, dietary, infectious disease) factors as well as genetic make-up play a role. Metabolomics, an evolving research field combining biomarker discovery and pathogenetics, is particularly useful in studying complex pathophysiology in general and Parkinson's disease (PD) specifically. PD, the second most frequent neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of intraneural inclusions of α-synuclein aggregates. Although considered a predominantly movement disorder, PD is also associated with number of non-motor features. Metabolomics has provided useful information regarding this neurodegenerative process with the aim of identifying a disease-specific fingerprint. Unfortunately, many disease variables such as clinical presentation, motor system involvement, disease stage and duration substantially affect biomarker relevance. As such, metabolomics provides a unique approach to studying this multifactorial neurodegenerative disorder., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Parkinson's disease is the second most frequent neurodegenerative disorder. Its diagnosis is challenging and mainly relies on clinical aspects. At present, no biomarker is available to obtain a diagnosis of certainty in vivo., Objective: The present review aims at describing machine learning algorithms as they have been variably applied to different aspects of Parkinson's disease diagnosis and characterization., Methods: A systematic search was conducted on PubMed in December 2019, resulting in 230 publications obtained with the following search query: "Machine Learning" "AND" "Parkinson Disease"., Results: The obtained publications were divided into 6 categories, based on different application fields: "Gait Analysis - Motor Evaluation", "Upper Limb Motor and Tremor Evaluation", "Handwriting and typing evaluation", "Speech and Phonation evaluation", "Neuroimaging and Nuclear Medicine evaluation", "Metabolomics application", after excluding the papers of general topic. As a result, a total of 166 articles were analyzed after elimination of papers written in languages other than English or not directly related to the selected topics., Conclusion: Machine learning algorithms are computer-based statistical approaches that can be trained and are able to find common patterns from big amounts of data. The machine learning approaches can help clinicians in classifying patients according to several variables at the same time., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Anxiety is a common neuropsychiatric symptom in Parkinson's disease (PD). Until now, anxiety has been consistently related to cognitive deficits and severity of motor symptoms, whereas the association between anxiety and motor subtypes (TD-PD, tremor dominant and PIGD-PD, postural instability/gait disturbances dominant) revealed contrasting results. The present study aims to investigate the relationship between PD motor subtypes and anxiety and to explore whether the relationship between anxiety and cognitive deficits occurs in a specific PD motor subtype. Consecutive PD outpatients were recruited and divided into TD-PD and PIGD-PD groups according to Jankovic et al.'s criteria. All participants underwent a neuropsychological battery to evaluate anxiety, apathy, the global cognitive functioning, memory abilities, executive and visuo-constructional functions. Thirty-six patients with TD-PD and 35 patients with PIGD-PD were enrolled. The two groups did not differ on demographical and clinical variables. As for the severity of anxiety, no significant difference between the two groups was found. Regression analysis revealed that higher anxiety score was associated with poorer performance on constructional visuospatial test in both TD-PD and PIGD-PD. Clinical variables were not associated with anxiety in the two groups. Our findings indicated that the severity of anxiety was not associated with any PD motor subtypes. Moreover, regression analysis revealed that impaired visuo-constructional abilities are related to anxiety independently of PD motor subtypes. Since altered fronto-parietal network might be one of the pathogenetic mechanisms underpinning anxiety and constructional visuospatial deficits, the treatment of cognitive dysfunctions might reduce anxious symptoms.

Background: Progressive supranuclear palsy (PSP) is a rare rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. The use of health-related quality of life (HR-QoL) measures allows assessing changes in health status induced by therapeutic interventions or disease progress in neurodegenerative diseases. The PSP-QoL is a 45-item, self-administered questionnaire designed to evaluate HR-QoL in PSP., Methods and Results: Here, the PSP-QoL was translated into Italian and validated in 190 PSP (96 women and 94 men; mean age ± standard deviation, 72 ± 6.5; mean disease duration, 4.2 ± 2.3) patients diagnosed according to the Movement Disorder Society criteria and recruited in 16 third level movement disorders centers participating in the Neurecanet project. The mean PSP-QoL total score was 77.8 ± 37 (physical subscore, 46.5 ± 18.7; mental subscore, 33.6 ± 19.2). The internal consistency was high (Cronbach's alpha = 0.954); corrected item-total correlation was > 0.40 for the majority of items. The significant and moderate correlation of the PSP-QoL with other HR-QoL measures as well as with motor and disability assessments indicated adequate convergent validity of the scale. Gender and geographic location presented a significant impact on the PSP-QoL in our sample with women and patients from the South of Italy scoring higher than their counterparts., Conclusion: In conclusion, the Italian version of the PSP-QoL is an easy, reliable and valid tool for assessment of HR-QoL in PSP.

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world, while Progressive Supranuclear Palsy (PSP) is an atypical Parkinsonism resembling PD, especially in early stage. Assumed that gait dysfunctions represent a major motor symptom for both pathologies, gait analysis can provide clinicians with subclinical information reflecting subtle differences between these diseases. In this scenario, data mining can be exploited in order to differentiate PD patients at different stages of the disease course and PSP using all the variables acquired through gait analysis., Methods: A cohort of 46 subjects (divided into three groups) affected by PD patients at different stages and PSP patients was acquired through gait analysis and spatial and temporal parameters were analysed. Synthetic Minority Over-sampling Technique was used to balance our imbalanced dataset and cross-validation was applied to provide different training and testing sets. Then, Random Forests and Gradient Boosted Trees were implemented., Results: Accuracy, error, precision, recall, specificity and sensitivity were computed for each group and for both algorithms, including 16 features. Random Forests obtained the highest accuracy (86.4%) but also specificity and sensitivity were particularly high, overcoming the 90% for PSP group., Conclusion: The novelty of the study is the use of a data mining approach on the spatial and temporal parameters of gait analysis in order to classify patients affected by typical (PD) and atypical Parkinsonism (PSP) based on gait patterns. This application would be helpful for clinicians to distinguish PSP from PD at early stage, when the differential diagnosis is particularly challenging., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Prospective memory (PM) is defined as memory for future intentions and it is typically divided into time-based and event-based PM. Deficit of PM has been reported in patients with Parkinson's disease (PD) but no study has yet explored the association between motor subtypes (tremor dominant and rigidity/bradykinesia dominant) and performance on PM tasks. The aim of the study was to explore the role of motor subtypes in the defect of PM., Methods: Consecutive outpatients with tremor dominant (TD-PD) or rigidity/bradykinesia dominant (PIGD-PD) PD and healthy subjects (HCs) were enrolled and underwent a neuropsychological battery assessing PM, verbal memory and executive functions and questionnaires assessing apathy, functional autonomy, and perceived memory disturbances., Results: We enrolled 28 patients with TD-PD, 28 patients with PIGD-PD and 50 HCs. The three groups did not differ on demographic and cognitive variables. Patients with TD-PD performed worse on time-based PM tasks than patients with PIGD-PD and HCs; no significant difference was found among the three groups on event-based PM tasks. Executive dysfunctions contributed to reduced time-based PM scores in TD-PD. Moreover, severe deficit of time-based and more frequency of perceived failures of PM contributed to reduced functional autonomy in TD-PD., Conclusion: The finding of a poorer performance of patients with TD-PD than ones with PIGD-PD and HCs suggests a selective deficit of time-based PM abilities in TD-PD group; therefore, deficit of time-based PM might be considered as a distinctive non-motor symptom of TD-PD and it might affect the functional autonomy in this subtype of PD.

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. Caring for a partner or relative who suffers from PSP entails a strenuous and demanding task, usually lasting for years that affects carers' everyday life routines and emotional and social well-being. The 26-item Parkinsonism Carers QoL (PQoL Carer) is a self-administered, concise instrument evaluating the quality of life of caregivers of patients with atypical parkinsonism (both PSP and multiple system atrophy). Here, the PQoL Carer was translated into Italian and validated in 162 carers of PSP patients (54.3% women; mean age (standard deviation), 62.4 (15.4)) diagnosed according to the Movement Disorder Society criteria and recruited in 16 third-level movement disorders centers participating in the Neurecanet project. The mean PQoL total score was 40.66 ± 19.46. The internal consistency was excellent (Cronbach's alpha = 0.941); corrected item-total correlation was > 0.40 for all the items. A correlation with other health-related quality of life measures as well as with behavioral assessments was shown suggesting adequate convergent validity of the scale. PQoL also correlated with patients' severity of disease. The discriminant validity of the scale was evidenced by its capacity to differentiate between carers with varying levels of self-reported health (p < 0.001). In conclusion, the Italian version of the PQoL Carer is an easy, consistent, and valid tool for the assessment of the quality of life in carers of PSP patients.

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., (© 2019 EAN.)

Introduction: About 90% of cases of Parkinson's disease (PD) are idiopathic and attempts to understand pathogenesis typically assume a multifactorial origin. Multifactorial diseases can be studied using metabolomics, since the cellular metabolome reflects the interplay between genes and environment., Objective: The aim of our case-control study is to compare metabolomic profiles of whole blood obtained from treated PD patients, de-novo PD patients and controls, and to study the perturbations correlated with disease duration, disease stage and motor impairment., Methods: We collected blood samples from 16 drug naïve parkinsonian patients, 84 treated parkinsonian patients, and 42 age matched healthy controls. Metabolomic profiles have been obtained using gas chromatography coupled to mass spectrometry. Multivariate statistical analysis has been performed using supervised models; partial least square discriminant analysis and partial least square regression., Results: This approach allowed separation between discrete classes and stratification of treated patients according to continuous variables (disease duration, disease stage, motor score). Analysis of single metabolites and their related metabolic pathways revealed unexpected possible perturbations related to PD and underscored existing mechanisms that correlated with disease onset, stage, duration, motor score and pharmacological treatment., Conclusion: Metabolomics can be useful in pathogenetic studies and biomarker discovery. The latter needs large-scale validation and comparison with other neurodegenerative conditions.