Prospective Role of PAK6 and 14-3-3γ as Biomarkers for Parkinson's Disease.

Background: Parkinson's disease is a progressive neurodegenerative disorder mainly distinguished by sporadic etiology, although a genetic component is also well established. Variants in the LRRK2 gene are associated with both familiar and sporadic disease. We have previously shown that PAK6 and 14-3-3γ protein interact with and regulate the activity of LRRK2. Objective: The aim of this study is to quantify PAK6 and 14-3-3γ in plasma as reliable biomarkers for the diagnosis of both sporadic and LRRK2-linked Parkinson's disease. Methods: After an initial quantification of PAK6 and 14-3-3γ expression by means of Western blot in post-mortem human brains, we verified the presence of the two proteins in plasma by using quantitative ELISA tests. We analyzed samples obtained from 39 healthy subjects, 40 patients with sporadic Parkinson's disease, 50 LRRK2-G2019S non-manifesting carriers and 31 patients with LRRK2-G2019S Parkinson's disease. Results: The amount of PAK6 and 14-3-3γ is significantly different in patients with Parkinson's disease compared to healthy subjects. Moreover, the amount of PAK6 also varies with the presence of the G2019S mutation in the LRRK2 gene. Although the generalized linear models show a low association between the presence of Parkinson's disease and PAK6, the kinase could be added in a broader panel of biomarkers for the diagnosis of Parkinson's disease. Conclusions: Changes of PAK6 and 14-3-3γ amount in plasma represent a shared readout for patients affected by sporadic and LRRK2-linked Parkinson's disease. Overall, they can contribute to the establishment of an extended panel of biomarkers for the diagnosis of Parkinson's disease.

Telerehabilitation for Stroke: A Personalized Multi-Domain Approach in a Pilot Study.

Stroke, a leading cause of long-term disability worldwide, manifests as motor, speech language, and cognitive impairments, necessitating customized rehabilitation strategies. In this context, telerehabilitation (TR) strategies have emerged as promising solutions. In a multi-center longitudinal pilot study, we explored the effects of a multi-domain TR program, comprising physiotherapy, speech therapy, and neuropsychological treatments. In total, 84 stroke survivors (74 analyzed) received 20 tailored sessions per domain, addressing individual impairments and customized to their specific needs. Positive correlations were found between initial motor function, cognitive status, independence in activities of daily living (ADLs), and motor function improvement after TR. A lower initial health-related quality of life (HRQoL) perception hindered progress, but improved ADL independence and overall health status, and reduced depression correlated with a better QoL. Furthermore, post-treatment improvements were observed in the entire sample in terms of fine motor skills, upper-limb functionality, balance, independence, and cognitive impairment. This multi-modal approach shows promise in enhancing stroke rehabilitation and highlights the potential of TR in addressing the complex needs of stroke survivors through a comprehensive support and interdisciplinary collaboration, personalized for each individual's needs.

Examining technology-assisted rehabilitation for older adults' functional mobility: a network meta-analysis on efficacy and acceptability.

Technological advancements facilitate feedback adaptation in rehabilitation through virtual reality (VR) exergaming, serious gaming, wearables, and telerehabilitation for older adults fall prevention. Although studies have evaluated these technologies, no comparisons of their effectiveness have been conducted to date. Thus, this study aims to assess the differences in effectiveness of these interventions on balance and functional mobility in the older adults. A systematic review and network meta-analysis (NMA) were conducted to identify the most effective interventions for improving balance and functional mobility in adults aged 60 and over. The search was conducted in five databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science) up to June 10, 2023. The eligibility criteria were: (1) older adults, (2) functional mobility, balance, or gait as the primary outcome, (3) new technology intervention, and (4) randomized study design. New technology interventions were classified into five categories: exergaming with balance platforms or motion capture technologies, other serious gaming, interventions with wearables, and telerehabilitation. Additionally, two categories of control interventions (conventional exercises and no treatment) were extracted. The NMA was performed for the aggregated results of all outcomes, and separately for clinical functional scales, functional mobility, and gait speed results. Fifty-two RCTs with 3081 participants were included. Exergaming with motion capture was found to be statistically significant in producing a better effect than no treatment in the analysis of the functional mobility with an SMD of -0.70 (P < 0.01). The network meta-analysis revealed that exergaming with motion capture offers greater therapeutic benefits for functional mobility and balance compared to no treatment control. The effectiveness of this approach is similar to that of conventional exercises. Further RCTs are needed to provide a more definitive conclusion, particularly with respect to the effectiveness of serious games, telerehabilitation, and interventions with wearables.

Prediction of rehabilitation induced motor recovery after stroke using a multi-dimensional and multi-modal approach.

Background: Stroke is a debilitating disease affecting millions of people worldwide. Despite the survival rate has significantly increased over the years, many stroke survivors are left with severe impairments impacting their quality of life. Rehabilitation programs have proved to be successful in improving the recovery process. However, a reliable model of sensorimotor recovery and a clear identification of predictive markers of rehabilitation-induced recovery are still needed. This article introduces the cross-modality protocols designed to investigate the rehabilitation treatment's effect in a group of stroke survivors. Methods/design: A total of 75 stroke patients, admitted at the IRCCS San Camillo rehabilitation Hospital in Venice (Italy), will be included in this study. Here, we describe the rehabilitation programs, clinical, neuropsychological, and physiological/imaging [including electroencephalography (EEG), transcranial magnetic stimulation (TMS), and magnetic resonance imaging (MRI) techniques] protocols set up for this study. Blood collection for the characterization of predictive biological biomarkers will also be taken. Measures derived from data acquired will be used as candidate predictors of motor recovery. Discussion/summary: The integration of cutting-edge physiological and imaging techniques, with clinical and cognitive assessment, dose of rehabilitation and biological variables will provide a unique opportunity to define a predictive model of recovery in stroke patients. Taken together, the data acquired in this project will help to define a model of rehabilitation induced sensorimotor recovery, with the final aim of developing personalized treatments promoting the greatest chance of recovery of the compromised functions.

Anti-SARS-CoV-2 IgG Antibody Response in Individuals Infected Post Complete Vaccination: A 6-Month Longitudinal Study in Healthcare Professionals.

Serological assays have been used to evaluate the magnitude of naturally acquired and BNT162b2 vaccine-induced immunity. In order to assess the extent to which the antibody response correlates with infection-mediated protection after vaccination, we investigated the kinetics of anti-SARS-CoV-2-S1 IgG in fully vaccinated healthy individuals who did or did not develop COVID-19 within 8 months after the booster dose. The anti-SARS-CoV-2-S1 receptor-binding, domain-specific IgG titer was assessed in serum samples collected at various intervals from 4 months after the second and 6 months after the third dose. The IgG level decreased 33% within 6 months after the second dose and, one month after the third dose, increased dramatically (>300%) compared with the pre-booster time point. COVID-19 infection within two months after the third dose did not cause significant IgG variation, but later viral infections elicited an IgG response similar to the initial response to the booster. The probability of developing COVID-19 and the severity of symptoms were not related to the antibody titer. Our data indicate that repeated exposure to viral antigens by either vaccination or infection at short-term intervals elicits limited boosting effects and that an IgG titer alone is not associated with the prediction of future infections and their symptomatology.

Validity and reliability of the Italian translation of the Yale Pharyngeal Residue Severity Rating Scale.

Objective: In the dysphagic patient, pharyngeal residues (PR) are associated with aspiration and poor quality of life. The assessment of PR using validated scales during flexible endoscopic evaluation of swallowing (FEES) is crucial for rehabilitation. This study aims to validate and test the reliability of the Italian version of the Yale Pharyngeal Residue Severity Rating Scale (IT-YPRSRS). The effects of training and experience in FEES on the scale were also determined. Methods: The original YPRSRS was translated into Italian according to standardised guidelines. Thirty FEES images were selected after consensus and proposed to 22 naive raters who were asked to assess the severity of PR in each image. Raters were divided into two subgroups by years of experience at FEES, and randomly by training. Construct validity, inter-rater, and intra-rater reliability were assessed by kappa statistics. Results: IT-YPRSRS showed substantial to almost perfect agreement (kappa > 0.75) in validity and reliability for both the overall sample (660 ratings), and valleculae/pyriform sinus sites (330 ratings each). No significant differences emerged between groups considering years of experience, and variable differences were observed by training. Conclusions: The IT-YPRSRS demonstrated excellent validity and reliability in identifying location and severity of PR.

Clinical Features to Predict the Use of a sEMG Wearable Device (REMO®) for Hand Motor Training of Stroke Patients: A Cross-Sectional Cohort Study.

After stroke, upper limb motor impairment is one of the most common consequences that compromises the level of the autonomy of patients. In a neurorehabilitation setting, the implementation of wearable sensors provides new possibilities for enhancing hand motor recovery. In our study, we tested an innovative wearable (REMO®) that detected the residual surface-electromyography of forearm muscles to control a rehabilitative PC interface. The aim of this study was to define the clinical features of stroke survivors able to perform ten, five, or no hand movements for rehabilitation training. 117 stroke patients were tested: 65% of patients were able to control ten movements, 19% of patients could control nine to one movement, and 16% could control no movements. Results indicated that mild upper limb motor impairment (Fugl-Meyer Upper Extremity ≥ 18 points) predicted the control of ten movements and no flexor carpi muscle spasticity predicted the control of five movements. Finally, severe impairment of upper limb motor function (Fugl-Meyer Upper Extremity > 10 points) combined with no pain and no restrictions of upper limb joints predicted the control of at least one movement. In conclusion, the residual motor function, pain and joints restriction, and spasticity at the upper limb are the most important clinical features to use for a wearable REMO® for hand rehabilitation training.

Clinical Predictors for Upper Limb Recovery after Stroke Rehabilitation: Retrospective Cohort Study.

After stroke, recovery of upper limb (UL) motor function is enhanced by a high dose of rehabilitation and is supposed to be supported by attentive functions. However, their mutual influence during rehabilitation is not well known yet. The aim of this retrospective observational cohort study was to investigate the association between rehabilitation dose and motor and cognitive functions, during UL motor recovery. Inpatients with first unilateral stroke, without time restrictions from onset, and undergoing at least 15 h of rehabilitation were enrolled. Data on dose and modalities of rehabilitation received, together with motor and cognitive outcomes before and after therapy, were collected. Fugl-Meyer values for the Upper Extremity were the primary outcome measure. Logistic regression models were used to detect any associations between UL motor improvement and motor and cognitive-linguistic features at acceptance, regarding dose of rehabilitation received. Thirty-five patients were enrolled and received 80.57 ± 30.1 h of rehabilitation on average. Manual dexterity, level of independence and UL motor function improved after rehabilitation, with no influence of attentive functions on motor recovery. The total amount of rehabilitation delivered was the strongest factor (p = 0.031) influencing the recovery of UL motor function after stroke, whereas cognitive-linguistic characteristics were not found to influence UL motor gains.

Virtual Feedback for Arm Motor Function Rehabilitation after Stroke: A Randomized Controlled Trial.

A single-blind randomized controlled trial was conducted to compare whether the continuous visualization of a virtual teacher, during virtual reality rehabilitation, is more effective than the same treatment provided without a virtual teacher visualization, for the recovery of arm motor function after stroke. Teacher and no-teacher groups received the same amount of virtual reality therapy (i.e., 1 h/d, 5 dd/w, 4 ww) and an additional hour of conventional therapy. In the teacher group, specific feedback ("virtual-teacher") showing the correct kinematic to be emulated by the patient was always displayed online during exercises. In the no-teacher group patients performed the same exercises, without the virtual-teacher assistance. The primary outcome measure was Fugl-Meyer Upper Extremity after treatment. 124 patients were enrolled and randomized, 62 per group. No differences were observed between the groups, but the same number of patients (χ2 = 0.29, p = 0.59) responded to experimental and control interventions in each group. The results confirm that the manipulation of a single instant feedback does not provide clinical advantages over multimodal feedback for arm rehabilitation after stroke, but combining 40 h conventional therapy and virtual reality provides large effect of intervention (i.e., Cohen's d 1.14 and 0.92 for the two groups, respectively).

Effects of cognitive rehabilitation in Parkinson disease: a meta-analysis.

BACKGROUND AND OBJECTIVES: Cognitive symptoms are common in Parkinson's disease (PD) and affect patients' quality of life. Pharmacological interventions often do not improve such deficits that might benefit of cognitive rehabilitation. However, previous meta-analysis on this topic reported inconsistent results. Clarifying the efficacy of cognitive rehabilitation would be pivotal to optimize treatment and reduce care's costs. This meta-analysis aims at determining whether current literature lays in favor of the effectiveness of cognitive rehabilitation in PD and at understanding whether its effect might change depending on the trained cognitive domain. METHODS: We searched online databases for studies concerning cognitive rehabilitation in PD. Fourteen studies encompassing 767 participants were included. Analyses were conducted for each cognitive domain separately, examining several neuropsychological measures for each function. RESULTS: We found that rehabilitation improves global cognition, executive functions, and long- and short-term memory. CONCLUSION: The current body of research indicates that cognitive rehabilitation improves specific cognitive deficits in PD and that it should be tailored on patients' specific impairments. These interventions should be employed considering that not all the cognitive domains might benefit of a cognitive training. Finally, the high heterogeneity among studies suggests the need for more controlled clinical trials.

Muscle Synergies and Clinical Outcome Measures Describe Different Factors of Upper Limb Motor Function in Stroke Survivors Undergoing Rehabilitation in a Virtual Reality Environment.

Recent studies have investigated muscle synergies as biomarkers for stroke, but it remains controversial if muscle synergies and clinical observation convey the same information on motor impairment. We aim to identify whether muscle synergies and clinical scales convey the same information or not. Post-stroke patients were administered an upper limb treatment. Before (T0) and after (T1) treatment, we assessed motor performance with clinical scales and motor output with EMG-derived muscle synergies. We implemented an exploratory factor analysis (EFA) and a confirmatory factor analysis (CFA) to identify the underlying relationships among all variables, at T0 and T1, and a general linear regression model to infer any relationships between the similarity between the affected and unaffected synergies (Median-sp) and clinical outcomes at T0. Clinical variables improved with rehabilitation whereas muscle-synergy parameters did not show any significant change. EFA and CFA showed that clinical variables and muscle-synergy parameters (except Median-sp) were grouped into different factors. Regression model showed that Median-sp could be well predicted by clinical scales. The information underlying clinical scales and muscle synergies are therefore different. However, clinical scales well predicted the similarity between the affected and unaffected synergies. Our results may have implications on personalizing rehabilitation protocols.

Does the Score on the MRC Strength Scale Reflect Instrumented Measures of Maximal Torque and Muscle Activity in Post-Stroke Survivors?

It remains unknown whether variation of scores on the Medical Research Council (MRC) scale for muscle strength is associated with operator-independent techniques: dynamometry and surface electromyography (sEMG). This study aimed to evaluate whether the scores of the MRC strength scale are associated with instrumented measures of torque and muscle activity in post-stroke survivors with severe hemiparesis both before and after an intervention. Patients affected by a first ischemic or hemorrhagic stroke within 6 months before enrollment and with complete paresis were included in the study. The pre- and post-treatment assessments included the MRC strength scale, sEMG, and dynamometry assessment of the triceps brachii (TB) and biceps brachii (BB) as measures of maximal elbow extension and flexion torque, respectively. Proprioceptive-based training was used as a treatment model, which consisted of multidirectional exercises with verbal feedback. Each treatment session lasted 1 h/day, 5 days a week for a total 15 sessions. Nineteen individuals with stroke participated in the study. A significant correlation between outcome measures for the BB (MRC and sEMG p = 0.0177, ρ = 0.601; MRC and torque p = 0.0001, ρ = 0.867) and TB (MRC and sEMG p = 0.0026, ρ = 0.717; MRC and torque p = 0.0001, ρ = 0.873) were observed post intervention. Regression models revealed a relationship between the MRC score and sEMG and torque measures for both the TB and BB. The results confirmed that variation on the MRC strength scale is associated with variation in sEMG and torque measures, especially post intervention. The regression model showed a causal relationship between MRC scale scores, sEMG, and torque assessments.

Shoulder Pain and Disability Index: Italian cross-cultural validation in patients with non-specific shoulder pain.

BACKGROUND: Health-related patient reported outcome measures are considered essential to determine the impact of disease on the life of individuals. Aim of this study is to culturally adapt the Italian version of the Shoulder Pain and Disability Index (SPADI). The secondary aim is to evaluate psychometric proprieties in patients with non-specific shoulder pain. METHODS: The current study is an analysis of a sample of 59 adult patients with non-specific shoulder pain. The SPADI was translated and cross-culturally adapted, and then psychometric properties were tested. Participants completed the Shoulder Pain and Disability Index-Italian (SPADI-I), 36-item short form health survey, the Oxford Shoulder Score, the Disability of Arm, Shoulder, and Hand scale and a pain intensity visual analogue scale. RESULTS: SPADI-I included two domains. Internal consistency analysis showed good values for total (α = 0.84) and subscales (α = 0.94 and α = 0.76). For construct validity, there was good correlation between the visual analogue scale, the Oxford Shoulder Score, the DASH and the SPADI-I total score and subscales. Standard error of measurement and minimally detectable change were calculated. CONCLUSIONS: The SPADI-I was culturally adapted into Italian. SPADI-I is centred on pain and disability of the shoulder only and can be considered as a useful tool in daily clinical practice for assessing musculoskeletal non-specific shoulder pain because of its good internal consistency and validity. Further studies should focus on other psychometric proprieties such as test re-test reliability, responsiveness and clinical interpretability to improve the available clinimetrics of the tool.

Sensorimotor, Attentional, and Neuroanatomical Predictors of Upper Limb Motor Deficits and Rehabilitation Outcome after Stroke.

The rehabilitation of motor deficits following stroke relies on both sensorimotor and cognitive abilities, thereby involving large-scale brain networks. However, few studies have investigated the integration between motor and cognitive domains, as well as its neuroanatomical basis. In this retrospective study, upper limb motor responsiveness to technology-based rehabilitation was examined in a sample of 29 stroke patients (18 with right and 11 with left brain damage). Pretreatment sensorimotor and attentional abilities were found to influence motor recovery. Training responsiveness increased as a function of the severity of motor deficits, whereas spared attentional abilities, especially visuospatial attention, supported motor improvements. Neuroanatomical analysis of structural lesions and white matter disconnections showed that the poststroke motor performance was associated with putamen, insula, corticospinal tract, and frontoparietal connectivity. Motor rehabilitation outcome was mainly associated with the superior longitudinal fasciculus and partial involvement of the corpus callosum. The latter findings support the hypothesis that motor recovery engages large-scale brain networks that involve cognitive abilities and provides insight into stroke rehabilitation strategies.

Robot-assisted rehabilitation of hand function after stroke: Development of prediction models for reference to therapy.

BACKGROUND: Recovery of hand function after stroke represents the hardest target for clinicians. Robot-assisted therapy has been proved to be effective for hand recovery. Nevertheless, studies aimed to refer patients to the best therapy are missing. METHODS: With the aim to identify which clinical features are predictive for referring to robot-assisted hand therapy, 174 stroke patients were assessed with: Fugl-Meyer Assessment (FMA), Functional Independence Measure (FIM), Reaching Performance Scale (RPS), Box and Block Test (BBT), Modified Ashworth Scale (MAS), Nine Hole Pegboard Test (NHPT). Moreover, patients ability to control the robot with residual force and surface EMG (sEMG) independently, was checked. ROC curves were calculated to determine which of the measures were the predictors of the event. RESULTS: sEMG control (AUC = 0.925) was significantly determined by FMA upper extremity (FMUE) (>24/66) and sensation (>23/24) sections, MAS at Flexor Carpi (<3/4) and total MAS (>4/20). Force control (AUC = 0.928) was correlated only with FMUE (>24/66). CONCLUSIONS: FMUE and MAS were the best predictors of preserved ability to control the device by two different modalities. This finding opens the possibility to plan specific therapies aimed at maximizing the highest functional outcome achievable after stroke.

Functional changes in the lower extremity after non-immersive virtual reality and physiotherapy following stroke.

OBJECTIVE: To analyse the effect of virtual reality (VR) ther-apy combined with conventional physiotherapy on balance, gait and motor functional disturbances, and to determine whether there is an influence on motor recovery in the subacute (< 6 months) or chronic (>> 6 months) phases after stroke. METHODS: A total of 59 stroke inpatients (mean age 60.3 years (standard deviation (SD) 14.8); 14.0 months (SD 25.7) post-stroke) were stratified into 2 groups: subacute (n = 31) and chronic (n = 28). Clinical scales (Fugl-Meyer lower extremity (FM LE); Functional Independence Measure (FIM); Berg Balance Scale (BBS); Functional Ambulation Category (FAC); modified Ashworth scale (MAS); 10-metre walk test (10MWT); and kinematic parameters during specific motor tasks in sitting and standing position (speed; time; jerk; spatial error; length) were applied before and after treatment. The VR treatment lasted for 15 sessions, 5 days/week, 1 h/day. RESULTS: The subacute group underwent significant change in all variables, except MAS and length. The chronic group underwent significant improvement in clinical scales, except MAS and kinematics. Motor impairment improved in the severe ≤ 19 FM LE points, moderate 20-28 FM LE points, mild ≥ 29 FM LE points. Neither time since stroke onset nor affected hemisphere differed significantly between groups. The correlations were investigated between the clinical scales and the kinematic parameters of the whole sample. Moreover, FM LE, BBS, MAS, and speed showed high correlations (R2>> 0.70) with independent variables. CONCLUSION: VR therapy combined with conventional physiotherapy can contribute to func-tional improvement in the subacute and chronic phases after stroke.

Assessment of the cervical spine mobility by immersive and non-immersive virtual reality.

INTRODUCTION: Despite many devices are helpful for motion analysis, there is still no established standard technique for the assessment of cervical spine mobility. OBJECTIVE: To compare differences in using immersive or non-immersive virtual reality (VR) for the assessment of the sensorimotor movement of the cervical spine in healthy subjects. METHODS: Thirty-five healthy adults were asked to perform head rotation, flexion, extension, lateral flexion, reaching and repositioning tasks with the head. The same tasks were performed interacting with both non-immersive and immersive virtual reality. Random sequence determined which of the environments was used as first assessment. Range of motion and kinematics i.e. number of completed targets, time of execution (seconds), spatial length (cm), angle distance (°), jerk of the cervical spine, were automatically computed by a 6D electromagnetic motion tracking system. RESULTS: The following variables were significantly larger in immersive than non-immersive VR: head right rotation (p = 0.027), extension (p = 0.047), flexion (p = 0.000), time (p = 0.001), spatial length (p = 0.004), jerk target (p = 0.032), trajectory repositioning (p = 0.003), jerk target repositioning (p = 0.007). A regression model showed that assessment in both VR environments can be influenced by dependent and independent variables. CONCLUSIONS: Immersive VR provided more accurate measurement of cervical spine than non-immersive VR in healthy adults.

Relationship Between Observational Wisconsin Gait Scale, Gait Deviation Index, and Gait Variability Index in Individuals Poststroke.

OBJECTIVE: To compare results of the observational Wisconsin Gait Scale (WGS) and global gait indexes such as Gait Deviation Index (GDI) and Gait Variability Index (GVI), constituting an objective method of assessing gait, and taking into account parameters identified during 3-dimensional gait analysis (3DGA). DESIGN: A validation study. SETTING: Rehabilitation clinic. PARTICIPANTS: A total of 50 individuals poststroke and 50 individuals without stroke and without gait disorders (N=100). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Gait was evaluated using the WGS. GDI and GVI values were acquired using a movement analysis system. The global gait indexes GDI and GVI were determined based on the kinematic and spatiotemporal parameters, respectively. RESULTS: The study showed statistically significant correlations between the parameters of GDI affected leg and WGS total score (R=-0.87), GVI affected leg and WGS total score (R=-0.93), GVI unaffected leg and WGS total score (R=-0.88), GVI affected/unaffected leg and the total score in the assessment of spatiotemporal parameters on the WGS (R=-0.81) as well as GDI affected leg and the total score in the assessment of kinematics parameters on the WGS (R=-0.85). All correlations were strong (0.7<|R|<0.9) or very strong (0.9<|R|<1). CONCLUSIONS: WGS scores have a strong or very strong correlation with GDI and GVI. The WGS may be recommended as a substitute tool to be used when 3DGA is unavailable, as it is a useful ordinal scale, enabling simple and accurate observational assessment of gait in patients poststroke, with effectiveness that is comparable to the GDI and GVI.