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Background: Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect., Objectives: We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD)., Methods: A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected., Results: Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group., Conclusions: fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Valence (positive and negative) and content (embodied vs non-embodied) characteristics of visual stimuli have been shown to influence motor readiness, as tested with response time paradigms. Both embodiment and emotional processing are affected in Parkinson's disease (PD) due to basal ganglia dysfunction. Here we aimed to investigate, using a two-choice response time paradigm, motor readiness when processing embodied (emotional body language [EBL] and emotional facial expressions [FACS]) vs non-embodied (emotional scenes [IAPS]) stimuli with neutral, happy, and fearful content. We enrolled twenty-five patients with early-stage PD and twenty-five age matched healthy participants. Motor response during emotional processing was assessed by measuring response times (RTs) in a home-based, forced two-choice discrimination task where participants were asked to discriminate the emotional stimulus from the neutral one. Rating of valence and arousal was also performed. A clinical and neuropsychological evaluation was performed on PD patients. Results showed that RTs for PD patients were longer for all conditions compared to HC and that RTs were generally longer in both groups for EBL compared to FACS and IAPS, with the sole exception retrieved for PD, where in discriminating fearful stimuli, RTs for EBL were longer compared to FACS but not to IAPS. Furthermore, in PD only, when discriminating fearful respect to neutral stimuli, RTs were shorter when discriminating FACS compared to IAPS. This study shows that PD patients were faster in discriminating fearful embodied stimuli, allowing us to speculate on mechanisms involving an alternative, compensatory, emotional motor pathway for PD patients undergoing fear processing., (© 2024. The Author(s).)

Background: The burden of Parkinson Disease (PD) represents a key public health issue and it is essential to develop innovative and cost-effective approaches to promote sustainable diagnostic and therapeutic interventions. In this perspective the adoption of a P3 (predictive, preventive and personalized) medicine approach seems to be pivotal. The NeuroArtP3 (NET-2018-12366666) is a four-year multi-site project co-funded by the Italian Ministry of Health, bringing together clinical and computational centers operating in the field of neurology, including PD., Objective: The core objectives of the project are: i) to harmonize the collection of data across the participating centers, ii) to structure standardized disease-specific datasets and iii) to advance knowledge on disease's trajectories through machine learning analysis., Methods: The 4-years study combines two consecutive research components: i) a multi-center retrospective observational phase; ii) a multi-center prospective observational phase. The retrospective phase aims at collecting data of the patients admitted at the participating clinical centers. Whereas the prospective phase aims at collecting the same variables of the retrospective study in newly diagnosed patients who will be enrolled at the same centers., Results: The participating clinical centers are the Provincial Health Services (APSS) of Trento (Italy) as the center responsible for the PD study and the IRCCS San Martino Hospital of Genoa (Italy) as the promoter center of the NeuroartP3 project. The computational centers responsible for data analysis are the Bruno Kessler Foundation of Trento (Italy) with TrentinoSalute4.0 -Competence Center for Digital Health of the Province of Trento (Italy) and the LISCOMPlab University of Genoa (Italy)., Conclusions: The work behind this observational study protocol shows how it is possible and viable to systematize data collection procedures in order to feed research and to advance the implementation of a P3 approach into the clinical practice through the use of AI models., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Malaguti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is clinically characterized by the presence of motor (bradykinesia, rigidity, rest tremor and postural instability) and non-motor symptoms (cognitive impairment, autonomic dysfunction, sleep disorders, depression and hyposmia). The aetiology of PD is unknown except for a small but significant contribution of monogenic forms., Sources of Data: No new data were generated or analyzed in support of this review., Areas of Agreement: Up to 15% of PD patients carry pathogenic variants in PD-associated genes. Some of these genes are associated with mendelian inheritance, while others act as risk factors. Genetic background influences age of onset, disease course, prognosis and therapeutic response., Areas of Controversy: Genetic testing is not routinely offered in the clinical setting, but it may have relevant implications, especially in terms of prognosis, response to therapies and inclusion in clinical trials. Widely adopted clinical guidelines on genetic testing are still lacking and open to debate. Some new genetic associations are still awaiting confirmation, and selecting the appropriate genes to be included in diagnostic panels represents a difficult task. Finally, it is still under study whether (and to which degree) specific genetic forms may influence the outcome of PD therapies., Growing Points: Polygenic Risk Scores (PRS) may represent a useful tool to genetically stratify the population in terms of disease risk, prognosis and therapeutic outcomes., Areas Timely for Developing Research: The application of PRS and integrated multi-omics in PD promises to improve the personalized care of patients., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Real-world monitoring using wearable sensors has enormous potential for assessing disease severity and symptoms among persons with Parkinson's disease (PD). Many distinct features can be extracted, reflecting multiple mobility domains. However, it is unclear which digital measures are related to PD severity and are sensitive to disease progression., Objectives: The aim was to identify real-world mobility measures that reflect PD severity and show discriminant ability and sensitivity to disease progression, compared to the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scale., Methods: Multicenter real-world continuous (24/7) digital mobility data from 587 persons with PD and 68 matched healthy controls were collected using an accelerometer adhered to the lower back. Machine learning feature selection and regression algorithms evaluated associations of the digital measures using the MDS-UPDRS (I-III). Binary logistic regression assessed discriminatory value using controls, and longitudinal observational data from a subgroup (n = 33) evaluated sensitivity to change over time., Results: Digital measures were only moderately correlated with the MDS-UPDRS (part II-r = 0.60 and parts I and III-r = 0.50). Most associated measures reflected activity quantity and distribution patterns. A model with 14 digital measures accurately distinguished recently diagnosed persons with PD from healthy controls (81.1%, area under the curve: 0.87); digital measures showed larger effect sizes (Cohen's d: [0.19-0.66]), for change over time than any of the MDS-UPDRS parts (Cohen's d: [0.04-0.12])., Conclusions: Real-world mobility measures are moderately associated with clinical assessments, suggesting that they capture different aspects of motor capacity and function. Digital mobility measures are sensitive to early-stage disease and to disease progression, to a larger degree than conventional clinical assessments, demonstrating their utility, primarily for clinical trials but ultimately also for clinical care. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Action observation (AO) and motor imagery (MI) has emerged as promising tool for physiotherapy intervention in Parkinson's disease (PD). This narrative review summarizes why, how, and when applying AO and MI training in individual with PD. We report the neural underpinning of AO and MI and their effects on motor learning. We examine the characteristics and the current evidence regarding the effectiveness of physiotherapy interventions and we provide suggestions about their implementation with technologies. Neurophysiological data suggest a substantial correct activation of brain networks underlying AO and MI in people with PD, although the occurrence of compensatory mechanisms has been documented. Regarding the efficacy of training, in general evidence indicates that both these techniques improve mobility and functional activities in PD. However, these findings should be interpreted with caution due to variety of the study designs, training characteristics, and the modalities in which AO and MI were applied. Finally, results on long-term effects are still uncertain. Several elements should be considered to optimize the use of AO and MI in clinical setting, such as the selection of the task, the imagery or the video perspectives, the modalities of training. However, a comprehensive individual assessment, including motor and cognitive abilities, is essential to select which between AO and MI suite the best to each PD patients. Much unrealized potential exists for the use AO and MI training to provide personalized intervention aimed at fostering motor learning in both the clinic and home setting.

The difficulty in assessing FOG and the variety of existing cues, hamper to determine which cueing modality should be applied and which FOG-related aspect should be targeted to reach personalized treatments for FOG. This systematic review aimed to highlight: i) whether cues could reduce FOG and improve FOG-related gait parameters, ii) which cues are the most effective, iii) whether medication state (ON-OFF) affects cues-related results. Thirty-three repeated measure design studies assessing cueing effectiveness were included and subdivided according to gait tasks (gait initiation, walking, turning) and to the medication state. Main results reveal that: preparatory phase of gait initiation benefit from visual and auditory cues; spatio-temporal parameters (e.g., step and stride length) are improved by visual cues during walking; turning time and step time variability are reduced by applying auditory and visual cues. Some findings on the potential benefits of cueing on FOG and FOG gait-related parameters were found. Questions remain about which are the best behavioral strategies according to FOG features and PD clinical characteristics., Competing Interests: Conflict of interest The Authors have no financial or other conflicts of interest associated with this publication to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In healthy people, motor resonance mechanisms are flexible to negative emotional contextual clues with greater motor resonance during the observation of a reach to grasp movement performed in an environment eliciting disgust. The link between emotion and motor control has become an interesting topic in Parkinson's disease (PD). Here, we aimed to study the response of the mirror neuron system, specifically motor resonance, to an emotion-enriched context in people with PD. Corticospinal excitability was recorded in a total of 44 participants, divided into two groups (23 PD patients and 21 healthy subjects). We recorded motor-evoked potentials from a muscle involved in the grasping movement while participants were watching the same reach-to-grasp movement embedded in surrounds with negative emotional valence, but different levels of arousal: sadness (low arousal) and disgust (high arousal). Basic motor resonance mechanisms were less efficient in PD than controls. Responsiveness to emotional contextual clues eliciting sadness was similar between PD and controls, whereas responsiveness to emotional contextual clues eliciting disgust was impaired in PD patients. Our findings show reduced motor resonance flexibility to the disgusting context, supporting the hypothesis that PD patients may have a deficit in "translating" an aversive motivational state into a physiologic response. The amygdala, which is implicated in the appraisal of fearful stimuli and response to threatening situations, might be implicated in this process., Competing Interests: The study's authors affirm that there were no financial or commercial relationships that might be viewed as having a potential conflict of interest., (Copyright © 2022 Giovanna Lagravinese et al.)

The diagnostic framework and the therapeutic management of patients with adult dystonia can represent a challenge for clinical neurologists. The objective of the present paper is to delineate diagnostic and therapeutic recommendations for dystonia provided by a panel of Italian experts afferent to the Italian Society of Neurology, the Italian Academy for the Study of Parkinson's Disease and Movement Disorders, and the Italian Network on Botulinum Toxin. We first discuss the clinical approach and the instrumental assessment useful for diagnostic purpose. Then, we analyze the pharmacological, surgical, and rehabilitative therapeutic options for adult dystonia. Finally, we propose a hospital-territory network model for adult dystonia management., (© 2022. Fondazione Società Italiana di Neurologia.)

Purpose: Strong evidence shows that symptoms in individuals with Parkinson's Disease (PD) restrict both their independence and social participation, leading to a low Quality of Life (QoL). Conversely, a reduced QoL has a negative impact on symptoms. The aim is to evaluate the correlation between QoL and severity of PD by assessing the presence of an optimal cut-off point on the Parkinson's disease questionnaire (PDQ-39) as related to the Hoehn &Yahr (H&Y) scale in a cohort of Italian adults with PD., Methods: A multicenter, cross-sectional study was performed. This study was conducted on a cohort of consecutive individuals. All participants were evaluated with the PDQ-39, and the severity of PD was recorded according to the H&Y scale by a neurologist. Receiver op-erating characteristic (ROC) curves and coordinates, visually inspected, were used to find cut-off points with optimal sensitivity and specificity. These were in turn used to determine the optimal PDQ-39 cut-off score for identifying disease severity according to H&Y stages., Results: 513 individuals were included in the study. The ROC curve analysis showed that QoL worsened with an increase in disease severity and age. Moreover, QoL was worse in females., Conclusions: The results of this study allowed for the correlation of QoL and disease severity in a cohort of individuals with PD. With this cut-off point, it is now possible to make a determination of QoL of an individual with PD at a certain stage of the disease, in a specific age range, and of a particular gender.

Introduction: Emotional states have been shown to influence cognitive processes including visual-spatial learning. Parkinson's Disease (PD), besides manifesting with the cardinal motor symptoms, presents cognitive and affective disturbances. Here we aimed at investigating whether manipulation of the emotional state by means of music was able to influence the performance of a visual-spatial learning task in a group of PD participants., Methods: Ten PD patients and 11 healthy elderly (ELD) were asked to perform a visual-spatial learning task while listening two musical pieces evoking a neutral emotion or fear. Targets were presented on a screen in a preset order over four blocks and subjects were asked to learn the sequence order by attending to the display. At the end of each block, participants were asked to verbally recall the sequence and a score was assigned (Verbal Score, VS)., Results: Analysis of variance-type statistic test on the VS disclosed a significant effect of Music and sequence Blocks (p = 0.01 and p < 0.001, respectively) and a significant interaction between Group and sequence Blocks. Sequence learning occurred across the training period in both groups, but PD patients were slower than ELD and at the end of the training period learning performance was worse in PD with respect to ELD. In PD patients, like in ELD, fear-inducing music has a detrimental effect on visual-spatial learning performances, which are slower and decreased., Conclusion: These findings confirm an impairment in visual-spatial learning in PD and indicates that the emotional state influences this learning ability similarly to healthy controls., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: It is not clear how specific gait measures reflect disease severity across the disease spectrum in Parkinson's disease (PD)., Objective: To identify the gait and mobility measures that are most sensitive and reflective of PD motor stages and determine the optimal sensor location in each disease stage., Methods: Cross-sectional wearable-sensor records were collected in 332 patients with PD (Hoehn and Yahr scale I-III) and 100 age-matched healthy controls. Sensors were adhered to the participant's lower back, bilateral ankles, and wrists. Study participants walked in a ~15-meter corridor for 1 minute under two walking conditions: (1) preferred, usual walking speed and (2) walking while engaging in a cognitive task (dual-task). A subgroup (n = 303, 67% PD) also performed the Timed Up and Go test. Multiple machine-learning feature selection and classification algorithms were applied to discriminate between controls and PD and between the different PD severity stages., Results: High discriminatory values were found between motor disease stages with mean sensitivity in the range 72%-83%, specificity 69%-80%, and area under the curve (AUC) 0.76-0.90. Measures from upper-limb sensors best discriminated controls from early PD, turning measures obtained from the trunk sensor were prominent in mid-stage PD, and stride timing and regularity were discriminative in more advanced stages., Conclusions: Applying machine-learning to multiple, wearable-derived features reveals that different measures of gait and mobility are associated with and discriminate distinct stages of PD. These disparate feature sets can augment the objective monitoring of disease progression and may be useful for cohort selection and power analyses in clinical trials of PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Language impairment in Parkinson's disease (PD) has been investigated at different levels of linguistic skills. Only a few studies dealt with pragmatic abilities in PD, and these suggest an impairment of pragmatic skills, which might affect quality of life. However, previous studies enrolled patients with heterogeneous symptom severity. The goal of this study is twofold: first, to investigate whether pragmatic skills are compromised at the early stage of PD; second, to explore whether an early pragmatic impairment is explained by a decay of a specific cognitive function. We assessed pragmatic abilities (discourse production, comprehension of narratives, humour, and figurative language), and a cluster of cognitive functions (memory, verbal fluency, inhibition, shifting, and ToM) in a sample of early PD patients and a group of age-matched healthy controls. Early PD patients showed impaired general pragmatic skills (the ability to perform different pragmatic tasks in language production and comprehension), as well as a deficit in the production and comprehension individual scores. Our results suggest that good general cognitive skills (a good overall cognitive level) and high education support patients' pragmatic competence. Inhibitory processes have been found to predict patients' ability to understand figurative language, such as metaphors, and this might be related to frontal lobe dysfunctions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Action observation (AO) relies on the mirror neuron system (MNS) and has been proposed as a rehabilitation tool in Parkinson's disease (PD), in particular for gait disorder such as freezing of gait (FOG). In this study, we aimed to explore the brain functional correlates of the observation of human gait in PD patients with (FOG+) and without (FOG-) FOG and to investigate a possible relationship between AO-induced brain activation and gait performance., Methods: Fifty-four participants were enrolled in the study (15 PD FOG+; 18 PD FOG-; 21 healthy subjects (HS)) which consisted of two tasks in two separate days: (i) gait assessment and (ii) task-fMRI during AO of gait. Differences between patients with PD (FOG+ and FOG-) and HS were assessed at the level of behavioral and functional analysis., Results: Gait parameters, including gait velocity, stride length, and their coefficients of variability (CV), were different in PD patients compared to HS, whereas gait performance was similar between FOG+ and FOG-. The PD group, compared to HS, presented reduced functional activation in the frontal, cingulum, and parietooccipital regions. Reduced activity was more pronounced in the FOG+ group, compared to both HS and FOG- groups. Gait variability positively correlated with precuneus neural activity in the FOG+ group. Discussion . Patients with PD present a reduced functional activity during AO of gait, especially if FOG+. A baseline knowledge of the neural correlates of AO of gait in the clinical routine "on" status would help for the design of future AO rehabilitative interventions., Competing Interests: EP reports grant from Michael J. Fox Foundation; EP and LA report honoraria for participating at Fox Trial Finder projects of the MJF Foundation; MI received research grants from NIH, DOD, NMSS, FISM, and Teva Neuroscience; RM, GB, MP, CC, and AB have no conflict of interest to report., (Copyright © 2020 Giulia Bommarito et al.)

Background: Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum., Objectives: We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication., Methods: A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements., Results: Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication., Conclusions: Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background . People with Parkinson's disease and freezing of gait (FOG+) have more falls, postural instability and cognitive impairment compared with FOG-. Objective . To conduct a secondary analysis of the V-TIME study, a randomized, controlled investigation showing a greater reduction of falls after virtual reality treadmill training (TT + VR) compared with usual treadmill walking (TT) in a mixed population of fallers. We addressed whether these treadmill interventions led to similar gains in FOG+ as in FOG-. Methods . A total of 77 FOG+ and 44 FOG- were assigned randomly to TT + VR or TT. Participants were assessed pre- and posttraining and at 6 months' follow-up. Main outcome was postural stability assessed by the Mini Balance Evaluation System Test (Mini-BEST) test. Falls were documented using diaries. Other outcomes included the New Freezing of Gait Questionnaire (NFOG-Q) and the Trail Making Test (TMT-B). Results . Mini-BEST scores and the TMT-B improved in both groups after training ( P = .001), irrespective of study arm and FOG subgroup. However, gains were not retained at 6 months. Both FOG+ and FOG- had a greater reduction of falls after TT + VR compared with TT ( P = .008). NFOG-Q scores did not change after both training modes in the FOG+ group. Conclusions . Treadmill walking (with or without VR) improved postural instability in both FOG+ and FOG-, while controlling for disease severity differences. As found previously, TT + VR reduced falls more than TT alone, even among those with FOG. Interestingly, FOG itself was not helped by training, suggesting that although postural instability, falls and FOG are related, they may be controlled by different mechanisms.

Freezing of gait is considered one of the most disabling gait disorders in patients with PD. An effective treatment for freezing of gait is missing, thus current management requires a multidisciplinary approach. Among treatment options, physiotherapy is acknowledged to be crucial; however, a systematic review that demonstrates its efficacy is missing. This review aims at examining the short- and long-term effects of physiotherapy in improving freezing of gait in PD patients. Five electronic databases were searched for English-language full-text articles, and only randomized controlled trials were considered. The freezing of gait questionnaire was selected as the primary outcome measure because it is the only validated measure used to evaluate the severity and impact of freezing of gait on patients' daily life. From 1,130 trials, 19 relevant studies, including 913 patients, were selected. The included studies varied for sample size, methodology, and type of intervention. None of the studies had a low risk of bias, but the majority of randomized control trials presented a low risk for at least 6 of 13 biases. Our findings provide evidence for short-term effectiveness of physiotherapy in improving freezing of gait (physiotherapy vs. no treatment: effect size = -0.28 [-0.45, -0.11], P = 0.001; physiotherapy vs. control: effect size = 0.43 [-0.65, -0.21], P < 0.0001), particularly when tailored interventions are applied. These results seem to be maintained at the follow-up examinations (effect size = -0.52 [-0.78, -0.26]; P = 0.001). Promising findings on the potential benefits of physiotherapy in improving freezing of gait were found, although further randomized control trial studies are still needed. Questions remain on the type and duration of intervention that best fits for treating freezing of gait symptom in PD. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Falls are frequent in Parkinson's disease and aging. Impairments in the cholinergic-mediated attentional supervision of gait may contribute to increased fall risk, especially when obstacles challenge gait. Interventions combining motor-cognitive approaches have been shown to improve motor performance, cognitive skills, and falls number. Here, we hypothesized that an intervention simulating an attention-demanding walking condition could affect not only complex gait performance and fall risk but also short-latency afferent inhibition (SAI), as a marker of cholinergic activity., Methods: Thirty-nine participants at falls risk (24 Parkinson's disease participants and 15 older adults) were recruited in a randomized controlled trial. Participants were assigned to treadmill training or treadmill training with non-immersive virtual reality intervention and trained three times a week for 6 weeks. SAI, a transcranial magnetic stimulation paradigm, was used to assess cholinergic activity. Gait kinematics was measured during usual walking and while negotiating physical obstacles. Transcranial magnetic stimulation and gait assessments were performed pre, post, and 6 months post-intervention., Results: Treadmill training combined with non-immersive virtual reality induced an increase in inhibition of the SAI protocol on cortical excitability, improved obstacle negotiation performance, and induced a reduction of the number of falls compared with treadmill training. Furthermore, the more SAI increased after training, the more the obstacle negotiation performance improved and fall rate decreased., Conclusions: We provide evidence that an innovative rehabilitation approach targeting cognitive components of complex motor actions can induce changes in cortical cholinergic activity, as indexed by SAI, thereby enabling functional gait improvements., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Perception of verticality is fundamental for postural stability that is often impaired in patients with Parkinson's disease (PD). Haptic perception of verticality has not been fully investigated in PD. The aim of the study was to assess subjective haptic vertical (SHV) in PD patients in relation to postural and balance impairments., Methods: 39 PD patients (mean age 72.87 ± 5.78) and 28 gender and age-matched healthy elderly (ELD, mean age 69.16 ± 13.89) were enrolled. The Pull test and the Activities-specific Balance Confidence (ABC) were used for evaluating balance performance, whereas measurement of posture was performed using the Physical Analyzer System ® . For evaluating SHV, participants were instructed to provide their subjective vertical by manipulating with two hands a road while standing with their eyes closed., Results: SHV data showed that PD subjects had a greater deviation from the objective vertical than controls (p < 0.001). Significant differences in balance performance (ABC and Pull test) and postural alignment were found between PD and ELD. Only in PD participants, SHV deviations significantly correlated with the lateral inclination of the trunk (r = 0.618, p < 0.001), pull test (r = 0.519; p = 0.001) and ABC (r = 0.471, p = 0.002) scores., Conclusions: The perception of verticality, driven by multimodal sensory integration, is defective in PD subjects. Deficits in SHV correlated with postural alignment and balance performances, independently from age, disease severity or cognitive decline. Our findings support that PD pathology is associated with a decline in haptic perception suggesting that perception per se might have a causal role in postural and balance deficits., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Recent work suggests that wearables can augment conventional measures of Parkinson's disease (PD). We evaluated the relationship between conventional measures of disease and motor severity (e.g., MDS-UPDRS part III), laboratory-based measures of gait and balance, and daily-living physical activity measures in patients with PD., Methods: Data from 125 patients (age: 71.7 ± 6.5 years, Hoehn and Yahr: 1-3, 60.5% men) were analyzed. The MDS-UPDRS-part III was used as the gold standard of motor symptom severity. Gait and balance were quantified in the laboratory. Daily-living gait and physical activity metrics were extracted from an accelerometer worn on the lower back for 7 days., Results: In multivariate analyses, daily-living physical activity and gait metrics, laboratory-based balance, demographics and subject characteristics together explained 46% of the variance in MDS-UPDRS-part III scores. Daily-living measures accounted for 62% of the explained variance, laboratory measures 30%, and demographics and subject characteristics 7% of the explained variance. Conversely, demographics and subject characteristics, laboratory-based measures of gait symmetry, and motor symptom severity together explained less than 30% of the variance in total daily-living physical activity. MDS-UPDRS-part III scores accounted for 13% of the explained variance, i.e., <4% of all the variance in total daily-living activity., Conclusions: Our findings suggest that conventional measures of motor symptom severity do not strongly reflect daily-living activity and that daily-living measures apparently provide important information that is not captured in a conventional one-time, laboratory assessment of gait, balance or the MDS-UPDRS. To provide a more complete evaluation, wearable devices should be considered., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Disturbance of gait is a key feature of Parkinson's disease (PD) and has a negative impact on quality of life. Deficits in cognition and sensorimotor processing impair the ability of people with PD to walk quickly, efficiently and safely. Recent evidence suggests that emotional disturbances may also affect gait in PD., Research Question: We explored if there were relationships between walking ability, emotion and cognitive impairment in people with PD., Methods: The literature was firstly reviewed for unimpaired individuals. The recent experimental evidence for the influence of emotion on gait in people with PD was then explored. The contribution of affective disorders to continuous gait disorders was investigated, particularly for bradykinetic and hypokinetic gait. In addition, we investigated the influence of emotional processing on episodic gait disturbances, such as freezing of gait. Potential effects of pharmacological, surgical and physical therapy interventions were also considered., Results: Emerging evidence showed that emotional disturbances arising from affective disorders such as anxiety and depression, in addition to cognitive impairment, could contribute to gait disorders in some people with PD. An analysis of the literature indicated mixed evidence that improvements in affective disorders induced by physical therapy, pharmacological management or surgery improve locomotion in PD., Significance: When assessing and treating gait disorders in people with PD, it is important to take into the account non-motor symptoms such as anxiety, depression and cognitive impairment, in addition to the motor sequalae of this progressive neurological condition., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Freezing of gait (FoG) is among the most disabling symptoms of Parkinson's disease (PD) patients. Recent studies showed that action observation training (AOT) with repetitive practice of the observed actions represents a strategy to induce longer-lasting effects compared with standard physiotherapy. We investigated whether AOT may improve FoG and mobility in PD, when AOT is applied in a group-based setting. Sixty-four participants with PD and FoG were assigned to the experimental (AO) or control groups and underwent a 45-minute training session, twice a week, for 5 weeks. AOT consisted in physical training combined with action observation whereas the control group executed the same physical training combined with landscape-videos observation. Outcome measures (FoG questionnaire, Timed Up and Go test, 10-meter walking test, and Berg balance scale) were evaluated before training, at the end of training, and 4 weeks later (FU-4w). Both groups showed positive changes in all outcome measures at posttraining assessment. Improvements in FoG questionnaire, Timed Up and Go test, and Berg balance scale were retained at FU-4w evaluation only in the AOT group. AOT group-based training is feasible and effective on FoG and motor performance in PD patients and may be introduced as an adjunctive option in PD rehabilitation program.

Background: The use of miniaturized magneto-inertial measurement units (MIMUs) allows for an objective evaluation of gait and a quantitative assessment of clinical outcomes. Spatial and temporal parameters are generally recognized as key metrics for characterizing gait. Although several methods for their estimate have been proposed, a thorough error analysis across different pathologies, multiple clinical centers and on large sample size is still missing. The aim of this study was to apply a previously presented method for the estimate of spatio-temporal parameters, named Trusted Events and Acceleration Direct and Reverse Integration along the direction of Progression (TEADRIP), on a large cohort (236 patients) including Parkinson, mildly cognitively impaired and healthy older adults collected in four clinical centers. Data were collected during straight-line gait, at normal and fast walking speed, by attaching two MIMUs just above the ankles. The parameters stride, step, stance and swing durations, as well as stride length and gait velocity, were estimated for each gait cycle. The TEADRIP performance was validated against data from an instrumented mat., Results: Limits of agreements computed between the TEADRIP estimates and the reference values from the instrumented mat were - 27 to 27 ms for Stride Time, - 68 to 44 ms for Stance Time, - 31 to 31 ms for Step Time and - 67 to 52 mm for Stride Length. For each clinical center, the mean absolute errors averaged across subjects for the estimation of temporal parameters ranged between 1 and 4%, being on average less than 3% (< 30 ms). Stride length mean absolute errors were on average 2% (≈ 25 mm). Error comparisons across centers did not show any significant difference. Significant error differences were found exclusively for stride and step durations between healthy elderly and Parkinsonian subjects, and for the stride length between walking speeds., Conclusions: The TEADRIP method was effectively validated on a large number of healthy and pathological subjects recorded in four different clinical centers. Results showed that the spatio-temporal parameters estimation errors were consistent with those previously found on smaller population samples in a single center. The combination of robustness and range of applicability suggests the use of the TEADRIP as a suitable MIMU-based method for gait spatio-temporal parameter estimate in the routine clinical use. The present paper was awarded the "SIAMOC Best Methodological Paper 2017".

Background: Freezing of gait is a symptom that affects more than 50% of Parkinson's disease (PD) patients and increasing evidence suggests that nonmotor systems (i.e., limbic system) are involved in its underlying mechanisms., Objective: The objective of this study was to investigate whether gait initiation characteristics are influenced by emotional stimuli in patients with PD, with or without freezing of gait., Methods: A total of 44 participants, divided into 3 groups (15 PD patients with and 15 PD patients without freezing of gait and 14 controls), stood on a sensorized mat and were asked to take a step forward in response to a pleasant image and a step backward in response to an unpleasant one (congruent task, low cognitive load) or to take a step backward in response to a pleasant image and a step forward in response to an unpleasant one (incongruent task, high cognitive load). Reaction time, step size, anticipatory postural adjustments, and sway path were measured., Results: In PD with freezing of gait, the reaction time was longer and the step size was shorter than in the other groups when they took a step forward in response to an unpleasant image (incongruent task). Changes in reaction time performance in response to unpleasant images remained significant after having adjusted for executive dysfunction and positively correlated with the "frequency" of freezing episodes., Conclusions: This study demonstrates that gait initiation was influenced by the emotional valence of visual stimuli in addition to the cognitive load of the task suggesting that the limbic system may be involved in freezing of gait. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Treadmill training (TT) has been indicated as a potential therapeutic tool for improving balance and gait in patients with Parkinson's disease (PD). However, the lack of evidences about the best modality of intervention (e.g.: number of sessions) and the lack of reliable follow-up measures, made difficult to hand down these results into the clinical practice., Aim: The aim of this study was to compare the efficacy of 3 different modalities of TT program on gait performance in PD patients., Design: A randomized, single-blind pilot study., Setting: Outpatients clinic, Department of Neuroscience, University of Genoa., Population: Thirty patients (out of 42 screened) with PD were randomized., Methods: Participants underwent the same TT program (ten sessions, 45 minute each) but with a different frequency throughout a week: 1) low-frequency (LF) group: 2-times a week; 2) intermediate-frequency (IF) group: 3-times a week; and 3) high-frequency (HF) group: 5-times a week. Patients were evaluated by Timed Up and Go (TUG) test, 10-meter walking test (10M-WT), Berg Balance Scale (BBS), Falls Efficacy Scale (FES) and falls diary before TT, immediately after the training was stopped, and 2 and 4 months later., Results: At baseline, no significant differences were found among groups. Immediately after the end of the TT, TUG Test, 10 MWT, FES and falls diary scores significantly improved in the LF and IF groups, whereas they did not change in the HF group. Improvements were sustained for up 2-months in the IF and LF groups. At 4-months evaluation, outcome measures were either comparable or sometimes even better than at baseline in the LF and IF groups, whereas in the HF group, 10M-WT and FES score worsened., Conclusions: According to the results of this study, we might postulate that the frequency of TT influences short and long-lasting effects on walking performance and falls., Clinical Rehabilitation Impact: The present study confirms that TT is effective in improving gait disturbances and reducing falls risk in patients with PD. The short- and long-lasting effects induced by TT on walking performance are specifically affected by the frequency of training, possibly in relationship to learning mechanisms and fatigue.

Background: Objective measures of physical and cognitive fatigability do not correlate with subjective Parkinson's disease (PD)-related fatigue. The relationship of subjective PD-related fatigue to tasks combining cognitive and motor effort has never been explored., Methods: Forty-four right-handed, non-demented PD patients, 22 with (PD-F) and 22 without (PD-NF) fatigue, were tested using a sensor-engineered glove on their more affected hand. Patients performed sequential opposition finger movements following a metronome at 2 Hz for 5 min (cued task), and for another minute following a 2-min rest. The same task was repeated without sustained auditory cueing. Movement time (inter-tapping interval, ITI) and rate, touch duration, percentage of correct sequences and clinical measures (motor and fatigue severity, depression, sleep impairment and apathy) were analysed., Results: In the cued task, motor performance worsened over time (significantly increased ITI and decreased movement rate on the third to fifth minute) in PD-F patients only. In the uncued task, motor performance deteriorated similarly in the two groups. PD-F and PD-NF patients differed in ITI and movement rate deterioration over time only in the cued task, independently from motor severity, depression and sleep impairment. The severity of subjective fatigue complaints significantly correlated with motor performance deterioration in the cued task., Conclusions: PD-related fatigue is associated with performance on an externally cued, attention-controlled motor task, but not with an uncued version of the same task. The finding supports a link between PD-related fatigue and attention-demanding motor tasks, proposing a model of inducible fatigue applicable to future clinical and neuroimaging research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Mirror visual feedback (MVF) therapy has been applied to improve upper limb function in stroke. When combined with motor training, MVF improves the performance of the trained and untrained hand by enhancing the excitability of both primary motor cortices (M1s). Bradykinesia is a typical feature of Parkinson's disease (PD), characterized by slowness in the execution of movement. This condition is often asymmetrical and possibly supported by a volitional hypoactivation of M1. MVF therapy could tentatively treat bradykinesia since the untrained hand, which benefits from the exercise, is generally more severely impaired in undertaking sequential movements. Aim of the study was to evaluate whether MVF therapy may improve bradykinesia of the more affected hand in PD patients. Twelve PD patients and twelve healthy controls performed for 10 minutes a finger sequence, receiving MVF of the more affected/nondominant hand. Before and after MVF training, participants performed a finger sequence at their spontaneous pace with both hands. M1 excitability was assessed in the trained and untrained hemispheres by means of transcranial magnetic stimulation. Movement speed increased after MVF training in either hand of both groups. MVF therapy enhanced cortical excitability of M1s in both groups. Our preliminary data support the use of MVF therapy to improve bradykinesia in PD patients.

Rehabilitation is considered as an adjuvant to pharmacological and surgical treatments for Parkinson's disease (PD) to maximize functional ability and minimize secondary complications. Originally, approaches were based on empirical experience, but growing evidence suggests that exercise-dependent plasticity constitutes the main mechanism underlying the effects of physiotherapy. Exercise increases synaptic strength and influences neurotransmission, thus potentiating functional circuitry in PD. In addition, exercise is a pivotal element of motor learning. PD patients retain a sufficient capacity of motor learning, though learning rates and performance are reduced in comparison to normal controls. Recent meta-analyses demonstrated that rehabilitation could induce short-lasting, but clinically important benefits, particularly for gait and balance. However, the interventions are largely heterogeneous (stretching, muscle strengthening, balance, postural exercises, occupational therapy, cueing, treadmill training), and there is still no consensus about the optimal approach. Innovative techniques have been recently proposed: virtual reality and exergaming, motor imagery and action observation, robot-assisted physiotherapy and non-conventional therapies (e.g.: dance, martial arts). The rehabilitative program for PD should be "goal-based" (targeted to practicing and learning specific activities in the core areas), but a number of practice variables (intensity, specificity, complexity) need to be identified and the program should tailored to the individual patients' characteristics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Affective "Theory of Mind" (ToM) is the specific ability to represent own and others' emotional states and feelings. Several studies examined affective ToM ability in patients with Parkinson's disease (PD), using the "Reading the Mind in the Eyes test" (RMET). However, there has been no agreement as to whether or not affective ToM ability is impaired in PD and such discrepancy may be due to the heterogeneous clinical presentation of PD. Affective disturbance has been linked to the akinetic-rigid form of PD and to gait disturbances, like freezing of gait (FOG). Particularly, FOG has been associated with dysfunction in striatum ability of processing affective inputs. Here we hypothesized that the presence of FOG can be associated with impaired affective ToM ability in PD patients., Methods: We evaluated ToM by means of RMET and executive functions using the Tower Of London (ToL) test in 29 PD patients (15 with FOG and 14 without FOG) and 19 healthy age-matched subjects., Results: Our results showed that affective ToM is abnormal in PD patients, compared to healthy subjects and that it is more impaired in patients with FOG than in patients without FOG. Further, PD patients with FOG performed worse than PD patients without FOG on the ToL test., Conclusion: The affective aspects of ToM can be associated to FOG in patients with PD, thus supporting the idea that FOG is caused by a complex interplay between motor, cognitive and affective factors, rather than being a pure motor problem., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Timing of sequential movements is altered in Parkinson disease (PD). Whether timing deficits in internally generated sequential movements in PD depends also on difficulties in motor planning, rather than merely on a defective ability to materially perform the planned movement is still undefined. To unveil this issue, we adopted a modified version of an established test for motor timing, i.e. the synchronization-continuation paradigm, by introducing a motor imagery task. Motor imagery is thought to involve mainly processes of movement preparation, with reduced involvement of end-stage movement execution-related processes. Fourteen patients with PD and twelve matched healthy volunteers were asked to tap in synchrony with a metronome cue (SYNC) and then, when the tone stopped, to keep tapping, trying to maintain the same rhythm (CONT-EXE) or to imagine tapping at the same rhythm, rather than actually performing it (CONT-MI). We tested both a sub-second and a supra-second inter-stimulus interval between the cues. Performance was recorded using a sensor-engineered glove and analyzed measuring the temporal error and the interval reproduction accuracy index. PD patients were less accurate than healthy subjects in the supra-second time reproduction task when performing both continuation tasks (CONT-MI and CONT-EXE), whereas no difference was detected in the synchronization task and on all tasks involving a sub-second interval. Our findings suggest that PD patients exhibit a selective deficit in motor timing for sequential movements that are separated by a supra-second interval and that this deficit may be explained by a defect of motor planning. Further, we propose that difficulties in motor planning are of a sufficient degree of severity in PD to affect also the motor performance in the supra-second time reproduction task.

Background: Action observation influences motor performance in healthy subjects and persons with motor impairments., Objective: To understand the effects of action observation on the spontaneous rate of finger movements in patients with Parkinson disease (PD)., Methods: Participants, 20 with PD and 14 healthy controls, were randomly divided into 2 groups. Those in the VIDEO group watched video clips showing repetitive finger movements paced at 3 Hz, whereas those in the ACOUSTIC group listened to an acoustic cue paced at 3 Hz. All participants performed a finger sequence at their spontaneous pace at different intervals (before, at the end of, 45 minutes after, and 2 days after training); 8 participants with PD were recruited for a sham intervention, watching a 6-minute video representing a static hand. Finally, 10 patients participated in the same protocol used for the VIDEO group but were tested in the on and off medication states., Results: Both VIDEO and ACOUSTIC training increased the spontaneous rate in all participants. VIDEO intervention showed a greater effect over time, improving the spontaneous rate and reducing the intertapping interval to a larger extent than ACOUSTIC 45 minutes and 2 days after training. Action observation significantly influenced movement rate in on and off conditions, but 45 minutes after training, the effect was still present only in the on condition. No effect was observed after sham intervention., Conclusions: These findings suggest that the dopaminergic state contributes to the effects of action observation, and this training may be a promising approach in the rehabilitation of bradykinesia in PD.

Objective: Depression is a comorbidity affecting quality of life (QoL) in patients with Parkinson's disease (PD) and requires appropriate treatment. This study evaluated the tolerability, safety, and efficacy of duloxetine 60 mg once daily for 12 weeks in PD patients with major depressive disorder (MDD)., Research and Design Methods: Non-comparative, open-label, multi-center study., Main Outcome Measures: Tolerability was evaluated by discontinuation rate (acceptable if ≤ 19%) due to treatment-emergent adverse events (TEAEs) and motor symptoms (UPDRS). Safety measures were TEAEs, the UKU side effect rating scale, vital signs, weight, laboratory tests, and ECG. Efficacy measures included HAMD-17, BDI, CGI-S, PGI-I, and pain VAS. QoL was measured by PDQ-39., Results: Of the 151 patients enrolled, 8.6% (95% upper CI: 13.3%) discontinued the study due to TEAEs. Worsening in PD-related tremor and rigidity was not observed, activities of daily living significantly improved and UKU subscales progressively decreased. Clinically significant abnormalities in laboratory findings were limited to four cases of hypercholesterolemia and one increase of total bilirubin, CPK, and fasting glucose. Blood pressure, weight, and ECG did not change from baseline. HAMD-17 and PDQ-39 total score and individual domains, BDI, CGI-S, and PGI-I total scores significantly improved., Conclusions: Duloxetine seems well tolerated and likely effective in the treatment of depression associated with PD, with no detrimental effects in PD signs and symptoms.

This study investigated how Parkinson's disease alters haptic perception and the underlying mechanisms of somatosensory and sensorimotor integration. Changes in haptic sensitivity and acuity (the abilities to detect and to discriminate between haptic stimuli) due to Parkinson's disease were systematically quantified and contrasted to the performance of healthy older and young adults. Using a robotic force environment, virtual contours of various curvatures were presented. Participants explored these contours with their hands and indicated verbally whether they could detect or discriminate between two contours. To understand what aspects of sensory or sensorimotor integration are altered by ageing and disease, we manipulated the sensorimotor aspect of the task: the robot either guided the hand along the contour or the participant actively moved the hand. Active exploration relies on multimodal sensory and sensorimotor integration, while passive guidance only requires sensory integration of proprioceptive and tactile information. The main findings of the study are as follows: first, a decline in haptic precision can already be observed in adults before the age of 70 years. Parkinson's disease may lead to an additional decrease in haptic sensitivity well beyond the levels typically seen in middle-aged and older adults. Second, the haptic deficit in Parkinson's disease is general in nature. It becomes manifest as a decrease in sensitivity and acuity (i.e. a smaller perceivable range and a diminished ability to discriminate between two perceivable haptic stimuli). Third, thresholds during both active and passive exploration are elevated, but not significantly different from each other. That is, active exploration did not enhance the haptic deficit when compared to passive hand motion. This implies that Parkinson's disease affects early stages of somatosensory integration that ultimately have an impact on processes of sensorimotor integration. Our results suggest that the known motor problems in Parkinson's disease that are generally characterized as a failure of sensorimotor integration may, in fact, have a sensory origin.

Background: Freezing of gait (FOG) is a disabling impairment for people with Parkinson's disease (PD) and may not respond to medications. The effectiveness of physical therapy for FOG is debatable. Action observation strategies to overcome FOG may enhance physical training., Objective: To assess whether action observation, combined with practicing the observed actions, may reduce FOG episodes., Methods: Twenty patients with PD entered a single-blind trial and were randomly assigned to the experimental (Action) or control (Landscape) groups. Those in the Action group watched video clips showing specific movements and strategies to circumvent FOG episodes, whereas those in the Landscape group watched video clips of static pictures showing different landscapes. All patients underwent identical physical therapy training, 3 sessions a week for 4 weeks., Results: The FOG Questionnaire score and the number of FOG episodes were significantly reduced in both groups after the training period. At follow-up examination (4 weeks after the end of the intervention), a significant reduction in the number of FOG episodes was observed only in the Action group. Motor performance (walking and balance) and quality-of-life assessments were significantly improved in both groups at the end of training and at follow-up., Conclusions: Our results suggest that action observation has a positive additional effect on recovery of walking ability in PD patients with FOG. Further studies on the combination of observation and imitation to supplement a physical training program may result in an innovative rehabilitative approach for FOG.

Gait disturbances are frequent in Parkinson's disease (PD) and are associated with increased energy expenditure during walking. This study evaluated whether the effects of treadmill training are associated with an improvement of walking economy. Ten patients with idiopathic PD underwent treadmill training (30 min, three times a week for 4 weeks). Walking performance (Tauimed Up and Go, 6-min and 10-m walking tests) and metabolic function (oxygen uptake, heart and respiratory rate) were evaluated before training, at the end of treatment and after 30 days with two different graded exercises (treadmill and cycloergometer). Training significantly improved walking performance. Oxygen uptake, and heart and respiratory rates were significantly decreased only during graded exercise on the treadmill, but not on the cycloergometer. Treadmill training reduces energy expenditure during walking in PD, but the improvements of metabolic walking economy are associated with the specifically trained motor activity.