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.

No evidence for an association of voxel-based morphometry with short-term non-motor outcomes in deep brain stimulation for Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy in advanced Parkinson's disease (PD). Motor and non-motor outcomes, however, show considerable inter-individual variability. Preoperative morphometry-based metrics have recently received increasing attention to explain treatment effects. As evidence for the prediction of non-motor outcomes is limited, we sought to investigate the association between metrics of voxel-based morphometry and short-term non-motor outcomes following STN-DBS in this prospective open-label study. Forty-nine PD patients underwent structural MRI and a comprehensive clinical assessment at preoperative baseline and 6-month follow-up. Voxel-based morphometry was used to assess associations between cerebral volume and non-motor outcomes corrected for multiple comparisons using a permutation-based approach. We replicated existing results associating volume loss of the superior frontal cortex with subpar motor outcomes. Overall non-motor burden, however, was not significantly associated with morphometric features, limiting its use as a marker to inform patient selection and holistic preoperative counselling.

Role of zonisamide in advanced Parkinson's disease: a randomized placebo-controlled study.

BACKGROUND: Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD. METHODS: PD patients with Hoehn and Yahr stage ≥ 2 ("On" state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III "On", while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson's disease questionnaire-39 at the final assessment. RESULTS: Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation. CONCLUSION: ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04182399, in 24/11/2019.

Facial emotion recognition in individuals with mild cognitive impairment: An exploratory study.

Understanding facial emotions is fundamental to interact in social environments and modify behavior accordingly. Neurodegenerative processes can progressively transform affective responses and affect social competence. This exploratory study examined the neurocognitive correlates of face recognition, in individuals with two mild cognitive impairment (MCI) etiologies (prodromal to dementia - MCI, or consequent to Parkinson's disease - PD-MCI). Performance on the identification and memorization of neutral and emotional facial expressions was assessed in 31 individuals with MCI, 26 with PD-MCI, and 30 healthy controls (HC). Individuals with MCI exhibited selective impairment in recognizing faces expressing fear, along with difficulties in remembering both neutral and emotional faces. Conversely, individuals with PD-MCI showed no differences compared with the HC in either emotion recognition or memory. In MCI, no significant association emerged between the memory for facial expressions and cognitive difficulties. In PD-MCI, regression analyses showed significant associations with higher-level cognitive functions in the emotional memory task, suggesting the presence of compensatory mechanisms. In a subset of participants, voxel-based morphometry revealed that the performance on emotional tasks correlated with regional changes in gray matter volume. The performance in the matching of negative expressions was predicted by volumetric changes in brain areas engaged in face and emotional processing, in particular increased volume in thalamic nuclei and atrophy in the right parietal cortex. Future studies should leverage on neuroimaging data to determine whether differences in emotional recognition are mediated by pathology-specific atrophic patterns.

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

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

How to Use the New European Academy of Neurology/Movement Disorder Society European Section Guideline for Invasive Therapies in Parkinson's Disease.

BACKGROUND: The decision to choose invasive treatments for Parkinson's disease (PD) is complex and needs careful consideration. OBJECTIVES: Although the recommendations of the European Academy of Neurology/Movement Disorder Society European Section guideline for invasive therapies of PD are useful, the different clinical profiles of people with PD who seek advice for possible invasive therapy need further attention. METHODS AND RESULTS: Here we describe 8 clinical standard situations of people with PD unsatisfied with their current oral treatment where invasive therapies may be considered. These are PD patients presenting with the following symptoms: (1) severe motor fluctuations, (2) beginning of levodopa-responsive fluctuations, severe tremor at (3) young or (4) advanced age, (5) impulse control disorders and related behavioral disorders, (6) hallucinations and psychosis, (7) minimal cognitive impairment or mild dementia, and (8) patients in need of palliative care. For some of these conditions, evidence at lower level or simple clinical considerations exist. CONCLUSIONS: There are no one-fits-all answers, but physician and patient should discuss each option carefully considering symptom profile, psychosocial context, availability of therapy alternatives, and many other factors. The current paper outlines our proposed approach to these circumstances.

Neurostimulation for Advanced Parkinson Disease and Quality of Life at 5 Years: A Nonrandomized Controlled Trial.

Importance: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life (QOL) in patients with advanced Parkinson disease (PD). However, controlled studies with more than 3 years of follow-up are lacking. Objective: To investigate the long-term effects of STN-DBS on QOL compared with standard-of-care medication (MED). Design, Setting, and Participants: In this prospective, observational, quasi-experimental, longitudinal nonrandomized controlled trial, 183 patients were screened for eligibility and 167 were enrolled from March 1, 2011, to May 31, 2017, at 3 European university centers. Propensity score matching for demographic and clinical characteristics was applied to 108 patients with PD (62 in the STN-DBS group and 46 in the MED group), resulting in a well-balanced, matched subcohort of 25 patients per group. Data analysis was performed from September 2022 to January 2023. Exposure: Treatment for PD of STN-DBS or MED. Main Outcomes and Measures: Assessments included Parkinson's Disease Questionnaire 8 (PDQ-8), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-activities of daily living (ADL) and motor complications, and levodopa-equivalent daily dose. Within-group longitudinal outcome changes, between-group differences, and correlations of change scores were analyzed. Results: The study population in the analysis included 108 patients (mean [SD] age, 63.7 [8.3] years; 66 [61.1%] male). At 5-year follow-up, PDQ-8 and ADL worsened only in the MED group (PDQ-8 change, -10.9; 95% CI, -19.0 to -2.7; P = .01; ADL change: -2.0; 95% CI, -3.1 to -0.8; P = .002), whereas both outcomes remained stable in the STN-DBS group (PDQ-8 change, -4.3; 95% CI, -13.2 to 4.7; P = .34; ADL change, -0.8; 95% CI, -2.5 to 1.0; P = .38). Changes in PDQ-8 and ADL correlated moderately (rs = .40, P = .008). Furthermore, STN-DBS outcomes were favorable for motor complications (median difference in change scores between STN-DBS and MED, -2.0; 95% CI, -4.0 to -1.0; P = .003), mobility (-1.0; 95% CI, -2.0 to 0; P = .03), and levodopa-equivalent daily dose reduction (-821.4; 95% CI, -1111.9 to -530.8; P < .001). Conclusions and Relevance: This study provides evidence of differences in QOL outcomes at 5-year follow-up between STN-DBS (stable) and MED (worsened), mainly driven by the favorable effect of STN-DBS on mobility (class IIb evidence). The association between changes in QOL and ADL, but not motor impairment or complications, highlights the relative importance of ADL outcomes for long-term DBS assessments. Trial Registration: German ClinicalTrials Registry: DRKS00006735.

Objective assessment of the effects of opicapone in Parkinson's disease through kinematic analysis.

BACKGROUND: Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. OBJECTIVES: In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. METHODS: We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). RESULTS: Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. CONCLUSIONS: This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

Rapidly progressive multiple system atrophy in a patient carrying LRRK2 G2019S mutation.

BACKGROUND: Multiple system atrophy (MSA) is considered a primarily sporadic neurodegenerative disease, but the role of genetic is poorly understood. CASE: We present a female patient of Moroccan origin who developed a rapidly progressive non-levodopa responsive parkinsonism, gait and balance problems, and dysautonomia including severe bulbar symptoms. She was diagnosed with MSA Parkinsonian-type (MSA-P) and suddenly died at night at 58 years of age. Reduced striatal DAT-SPECT, putaminal hyperintensity on T2-MRI, and hypometabolism with FDG-PET were present. Genetic testing documented a G2019S mutation in the LRRK2 gene. A skin biopsy was obtained and used to perform alpha-synuclein RT-QuIC, which was negative, and immunohistochemical analysis, which demonstrated abnormal alpha-synuclein deposits in cutaneous nerves. Elevated blood neurofilament light chain levels were also documented. CONCLUSIONS: LRRK2 mutations are the most common cause of monogenic Parkinson's disease (PD) and G2019S is the most frequent variant. Our patient presented with biological, clinical, and radiological features of MSA, but genetic testing revealed a G2019S LRRK2 mutation, which has been previously reported only in one other case of pathologically proven MSA but with mild progression. In our patient, post-mortem confirmation could not be performed, but RT-QuIC and immunohistochemical findings on skin biopsy support the diagnosis of MSA. G2019S LRRK2 may be linked to an increased risk of MSA. Cases of atypical parkinsonism with rapid disease course should be screened for PD-related genes especially in populations with a high prevalence of mutations in known genes.

Deep brain stimulation of globus pallidus internus and subthalamic nucleus in Parkinson's disease: a multicenter, retrospective study of efficacy and safety.

BACKGROUND: Deep brain stimulation (DBS) is an established therapeutic option in advanced Parkinson's disease (PD). Literature data and recent guidelines remain inconclusive about the best choice as a target between the subthalamic nucleus (STN) and the globus pallidus internus (GPi). MATERIALS AND METHODS: We retrospectively reviewed the clinical efficacy outcomes of 48 DBS-implanted patients (33 STN-DBS and 15 GPi-DBS) at a short- (<1 year from the surgery) and long-term (2-5 years) follow-up. Also, clinical safety outcomes, including postoperative surgical complications and severe side effects, were collected. RESULTS: We found no difference between STN-DBS and GPi-DBS in improving motor symptoms at short-term evaluation. However, STN-DBS achieved a more prominent reduction in oral therapy (L-DOPA equivalent daily dose, P = .02). By contrast, GPi-DBS was superior in ameliorating motor fluctuations and dyskinesia (MDS-UPDRS IV, P < .001) as well as motor experiences of daily living (MDS-UPDRS II, P = .03). The greater efficacy of GPi-DBS on motor fluctuations and experiences of daily living was also present at the long-term follow-up. We observed five serious adverse events, including two suicides, all among STN-DBS patients. CONCLUSION: Both STN-DBS and GPi-DBS are effective in improving motor symptoms severity and complications, but GPi-DBS has a greater impact on motor fluctuations and motor experiences of daily living. These results suggest that the two targets should be considered equivalent in motor efficacy, with GPi-DBS as a valuable option in patients with prominent motor complications. The occurrence of suicides in STN-treated patients claims further attention in target selection.

A systematic practice review: Providing palliative care for people with Parkinson's disease and their caregivers.

BACKGROUND: People with Parkinson's disease has significant and increasing physical, psychosocial and spiritual needs, as well as problems with coordination and continuity of care. Despite the benefits that palliative care could offer, there is no consensus on how it should be delivered. AIM: The aim of this study is to provide a pragmatic overview of the evidence to make clinical recommendations to improve palliative care for people with Parkinson's disease and their caregivers. DESIGN: A systematic review method was adopted to determine the strength of evidence, supported by feedback from an expert panel, to generate the 'do', 'do not do' and 'do not know' recommendations for palliative care. DATA SOURCES: Searches were conducted via OVID to access CINAHL, MEDLINE, EMBASE and the Cochrane Library from 01/01/2006 to 31/05/2021. An additional search was conducted in December 2022. The search was limited to articles that included empirical studies of approaches to enabling palliative care. RESULTS: A total of 62 studies met inclusion criteria. There is evidence that education about palliative care and movement disorders is essential. palliative care should be multi-disciplinary, individualised and coordinated. Proactive involvement and support of caregivers throughout the illness is recommended. Limited data provide referral indicators for palliative care integration. Discussions about advance care planning should be held early. CONCLUSIONS: Consideration of palliative care integration based on symptom burden and personal preferences, coordination and continuity of care are needed to maintain the quality of life of people with Parkinson's disease and their caregivers.

Brain Dynamics Complexity as a Signature of Cognitive Decline in Parkinson's Disease.

BACKGROUND: Higuchi's fractal dimension (FD) captures brain dynamics complexity and may be a promising method to analyze resting-state functional magnetic resonance imaging (fMRI) data and detect the neuronal interaction complexity underlying Parkinson's disease (PD) cognitive decline. OBJECTIVES: The aim was to compare FD with a more established index of spontaneous neural activity, the fractional amplitude of low-frequency fluctuations (fALFF), and identify through machine learning (ML) models which method could best distinguish across PD-cognitive states, ranging from normal cognition (PD-NC), mild cognitive impairment (PD-MCI) to dementia (PDD). Finally, the aim was to explore correlations between fALFF and FD with clinical and cognitive PD features. METHODS: Among 118 PD patients age-, sex-, and education matched with 35 healthy controls, 52 were classified with PD-NC, 46 with PD-MCI, and 20 with PDD based on an extensive cognitive and clinical evaluation. fALFF and FD metrics were computed on rs-fMRI data and used to train ML models. RESULTS: FD outperformed fALFF metrics in differentiating between PD-cognitive states, reaching an overall accuracy of 78% (vs. 62%). PD showed increased neuronal dynamics complexity within the sensorimotor network, central executive network (CEN), and default mode network (DMN), paralleled by a reduction in spontaneous neuronal activity within the CEN and DMN, whose increased complexity was strongly linked to the presence of dementia. Further, we found that some DMN critical hubs correlated with worse cognitive performance and disease severity. CONCLUSIONS: Our study indicates that PD-cognitive decline is characterized by an altered spontaneous neuronal activity and increased temporal complexity, involving the CEN and DMN, possibly reflecting an increased segregation of these networks. Therefore, we propose FD as a prognostic biomarker of PD-cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Poor reactivity of posterior electroencephalographic alpha rhythms during the eyes open condition in patients with dementia due to Parkinson's disease.

Here, we hypothesized that the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms during the transition from eyes-closed to -open condition might be lower in patients with Parkinson's disease dementia (PDD) than in patients with Alzheimer's disease dementia (ADD). A Eurasian database provided clinical-demographic-rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources. Results showed substantial (greater than -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the healthy control seniors and the ADD patients. These results suggest that PDD patients show poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. That neurophysiological biomarker may provide an endpoint for (non) pharmacological interventions for improving vigilance regulation in those patients.

SARS-CoV-2-Mimicking Pseudoviral Particles Accelerate α-Synuclein Aggregation In Vitro.

Since the SARS-CoV-2 virus started spreading worldwide, evidence pointed toward an impact of the infection on the nervous system. COVID-19 patients present neurological manifestations and have an increased risk of developing brain-related symptoms in the long term. In fact, evidence in support of the neuroinvasive potential of SARS-CoV-2 has emerged. Considering that viral parkisonism was observed as a consequence of encephalopathies caused by viral infections, it has been already suggested that COVID-19 could affect the dopaminergic neurons and contribute to neurodegeneration in Parkinson's disease (PD), by promoting the formation of amyloid fibrils constituted by the PD-related protein α-synuclein. Here, we observe not only that SARS-CoV-2 viral spike protein and nucleocapsid protein can alone promote α-synuclein aggregation but also that the spike protein organization in a corona shape on the viral envelope may be crucial in triggering fast amyloid fibrils formation, thus possibly contributing to PD pathogenesis.

Stratifying quality of life outcome in subthalamic stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%-49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. METHODS: This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified 'QoL responders' in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. RESULTS: All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as 'QoL responders'. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. CONCLUSIONS: Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. TRIAL REGISTRATION NUMBER: GermanClinicalTrialsRegister: #6735.

A Paradigm Shift in the Management of Patients with Parkinson's Disease.

BACKGROUND: Technological evolution leads to the constant enhancement of monitoring systems and recording symptoms of diverse disorders. SUMMARY: For Parkinson's disease, wearable devices empowered with machine learning analysis are the main modules for objective measurements. Software and hardware improvements have led to the development of reliable systems that can detect symptoms accurately and be implicated in the follow-up and treatment decisions. KEY MESSAGES: Among many different devices developed so far, the most promising ones are those that can record symptoms from all extremities and the trunk, in the home environment during the activities of daily living, assess gait impairment accurately, and be suitable for a long-term follow-up of the patients. Such wearable systems pave the way for a paradigm shift in the management of patients with Parkinson's disease.

Current and novel infusion therapies for patients with Parkinson's disease.

Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.