Unraveling the stride: exploring the influence of neurogenic orthostatic hypotension on gait and balance in Parkinson's disease.

PURPOSE: Neurogenic orthostatic hypotension (nOH) and gait impairment are frequent sources of disability in Parkinson's disease (PD). However, the impact of nOH on balance and gait features remains unclear. This cross-sectional study aimed to assess the influence of nOH on postural and gait parameters in a cohort of patients with PD by means of wearable inertial sensors. METHODS: Gait and balance were assessed using Opal inertial sensors. nOH was defined as sustained systolic blood pressure (BP) drop ≥ 20 mmHg or diastolic BP drop ≥ 10 mmHg within 3 min of standing, with a ΔHR/ΔSBP ratio ≤ 0.5 bpm/mmHg. Analysis of covariance was performed to evaluate differences in gait/balance features between patients with and without nOH, adjusting for age, cognitive status, and motor disability. Moreover, we performed the same analysis considering the presence of hemodynamically relevant nOH (orthostatic mean BP ≤ 75 mmHg). RESULTS: A total of 82 patients were enrolled, 26 with nOH (31.7%), of which 13 presented with hemodynamically relevant nOH. After correcting for confounders, nOH was independently associated with lower gait speed (p = 0.027), shorter stride length (p = 0.033), longer time for postural transitions (p = 0.004), and increased postural sway (p = 0.019). These differences were even more pronounced in patients with hemodynamically relevant nOH. Higher postural sway was associated with a 7.9-fold higher odds of falls (p = 0.040). CONCLUSIONS: Our study presents an objective demonstration of the independent negative impact of nOH on gait and balance in PD, emphasizing the need for careful detection and management of nOH to mitigate gait and balance disturbances in PD.

CACNA1A variant associated with generalized dystonia.

INTRODUCTION: CACNA1A gene variants are correlated with different disorders, including episodic ataxia type 2, spinocerebellar ataxia type 6, and familial hemiplegic migraine type 1. Despite dystonia not being a typical manifestation of CACNA1A variants, there are reports indicating a link between this gene mutation and dystonic features. METHODS: We report the case of a patient with a novel missense variant of the CACNA1A gene presenting headache, head and arm tremor, dystonia, episodic painful focal dystonic attacks, and unexplained falls. RESULTS:  A 57-year-old woman presented with a history of neck dystonia, head and arm tremor, and headaches since age 15. In 2017, she progressively developed dystonic tremor of the head and arms with an unremarkable brain MRI. In 2018 she experienced worsening of tremor and developed painful dystonic attacks, resistant to treatments including clonazepam, trihexyphenidyl, baclofen, and levodopa/benserazide. Botulinum toxin injections for neck dystonia provided limited benefit. The next-generation sequencing exam revealed a CACNA1A gene missense variant (NM_023035.2:c.1630C > T; p.Arg544Trp). In 2021 we observed a worsening of dystonia, accompanied by weight loss, mood changes, and unexplained falls. Deep brain stimulation was considered but ruled out due to cortical atrophy and mild cognitive deficits revealed by the neuropsychological examination. DISCUSSION: Only a few studies reported dystonia as part of the clinical features in carriers of CACNA1A mutations. This case points out the relevance of a need to expand the literature on voltage-dependent P/Q-type Ca2 + channels' role in dystonia's pathogenesis and stresses the complex phenotype-genotype presentation of CACNA1A mutation.

15-Year Subthalamic Deep Brain Stimulation outcome in a Parkinson's disease patient with Parkin gene mutation: a case report.

INTRODUCTION: Parkinson's Disease (PD) patients with Parkin gene (PRKN) mutations show good response to subthalamic deep brain stimulation (STN-DBS). Currently, the longest follow-up available of these patients is 6 years. We report a very long-term outcome (more than 15 years) of a STN-DBS-treated patient with a compound heterozygous deletion of exons 3 and 11 of the PRKN gene. CASE REPORT: In 1993, a 39-year-old male was diagnosed with PD after the onset of resting tremor. Levodopa was started, and during the following 10 years, he reported good motor symptoms control, with only mild modification of levodopa intake and pramipexole introduction. In 2005, he developed disabling motor fluctuations and dyskinesia. In 2007, he underwent bilateral STN-DBS, with a marked improvement of motor symptoms and fluctuations during the following years. After 6 years, he reported mild motor fluctuations, improved after stimulation and treatment modifications. After 10 years he showed diphasic dyskinesias, feet dystonia, postural instability, and gambling (resolved after pramipexole discontinuation). In 2018, he developed a non-amnestic single-domain mild cognitive impairment (MCI). In 2023, after more than 15 years of STN-DBS, motor symptoms and fluctuations are still well controlled. He reports mild dysphagia, mild depression, and multiple-domain MCI. His quality of life is better than before surgery, and he still reports a subjective significant improvement from STN-DBS. CONCLUSION: Confirming the very long-term efficacy of STN-DBS in PRKN-mutated patients, our case report underlines their peculiar suitability for surgical treatment.

Social cognition deficits in amyotrophic lateral sclerosis: A pilot cross-sectional population-based study.

BACKGROUND AND PURPOSE: Social cognition (SC) deficits are included in amyotrophic lateral sclerosis (ALS)-frontotemporal spectrum disorder revised diagnostic criteria. However, SC performance among ALS patients is heterogeneous due to the phenotypic variability of the disease and the wide range of neuropsychological tools employed. The aim of the present study was to assess facial emotion recognition and theory of mind in ALS patients compared to controls and to evaluate correlations with the other cognitive domains and degree of motor impairment. METHODS: Eighty-three patients and 42 controls underwent a cognitive evaluation and SC assessment through the Ekman 60 Faces Test (EK-60F), the Reading the Mind in the Eyes Test-36 Faces (RMET-36), and the Story-Based Empathy Task (SET). RESULTS: ALS patients showed significantly worse performance compared to controls in EK-60F global score (p < 0.001), recognition of disgust (p = 0.032), anger (p = 0.038), fear (p < 0.001), and sadness (p < 0.001); RMET-36 (p < 0.001), and SET global score (p < 0.001). Also, cognitively normal patients (ALS-CN) showed significantly worse performance compared to controls in EK-60F global score (p < 0.001), recognition of fear (p = 0.002), sadness (p < 0.001), and SET (p < 0.001). RMET-36 showed a significant correlation with the Category Fluency Test (p = 0.041). SC tests showed no correlation with motor impairment expressed by Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised. CONCLUSIONS: ALS patients, also when categorized as ALS-CN, may show impairment in SC performance. The frequent identification of early SC impairment in ALS patients supports the need to routinely assess SC for its impact on end-of-life decisions and its potential influence on patients' quality of life.

Burden of caregiving for cardiovascular dysautonomia in Parkinson's disease.

PURPOSE: We sought to estimate the impact of cardiovascular autonomic neuropathy (cAN) on informal caregivers of patients with Parkinson's disease (PD), defined as individuals providing regular care to a friend, partner, or family member with PD, and to evaluate the mutual relationship between caregiver burden and patient health-related quality of life (HRQoL). METHODS: We enrolled 36 consecutive patients with PD and their informal caregivers. Patients underwent a detailed motor, autonomic, cognitive, and functional assessment. Caregivers were assessed using the Zarit Burden Interview (ZBI). Differences in caregiver burden, expressed by the ZBI score, and strength of association between caregiver burden, cAN, and HRQoL were assessed using analysis of covariance (ANCOVA), logistic regression, and linear regression analyses. Analyses were adjusted for patients' age, PD duration, and motor and cognitive disability, as well as caregivers' age. RESULTS: Moderate-severe caregiver burden was reported in 41.7% of PDcAN+ versus 8.7% of PDcAN- (p < 0.001). The ZBI score was increased in PDcAN+ versus PDcAN- (31.5 ± 3.4 versus 15.2 ± 2.3; p < 0.001), with tenfold higher odds (p = 0.012) of moderate-severe caregiver burden in PDcAN+, even after adjusting for potential confounders. The ZBI score correlated with cAN severity (p = 0.005), global autonomic impairment (p = 0.012), and HRQoL impairment (p < 0.001). CONCLUSION: These results highlight the significant impact of cAN on PD caregivers and the need for targeted interventions addressing this frequently overlooked and insufficiently treated source of nonmotor disability in PD.

SARS-CoV-2 vaccination, Parkinson's disease, and other movement disorders: case series and short literature review.

BACKGROUND: Several neurological complications have been reported following SARS-Cov-2 vaccination, without a clear causal relationship ever being verified, including some cases of worsening of Parkinson's disease (PD) symptoms and new onset of movement disorders in non-parkinsonian patients. METHODS: We describe two new cases of PD patients treated with device-aided therapy who developed worsening of parkinsonian symptoms after receiving the third vaccine dose (booster). We also conducted a short review of the cases reported in literature of PD symptoms worsening and new onset of movement disorders in non-parkinsonian patients after SARS-Cov-2 vaccination. RESULTS: The first patient, a 46-year-old man implanted with bilateral Subthalamic Deep Brain Stimulation, experienced temporary motor and non-motor symptoms worsening after mRNA-1273 booster, improved after stimulation settings modification. The second patient, a 55-year-old man implanted with percutaneous endoscopic transgastric jejunostomy (PEG-J) for levodopa-carbidopa intestinal gel (LCIG) infusion experienced severe temporary worsening of dyskinesia and managed through temporary LCIG dose reduction. Other seven cases of vaccine-related movement disorder are currently reported in literature, four describing PD symptoms worsening and three the onset of new movement disorders in otherwise healthy people. CONCLUSION: Both our patients and the cases described so far completely recovered after few days with parkinsonian therapy modification, symptomatic treatment, or even spontaneously, underlining the transient and benign nature of side effects from vaccine. Patients should be reassured about these complications, manageable through a prompt evaluation by the reference neurologist.

Anxiety, depression, and worries in advanced Parkinson disease during COVID-19 pandemic.

BACKGROUND: The psychological impact of the COVID-19 outbreak and lockdown on frail populations with advanced Parkinson disease (APD) and their caregivers may present with peculiar features and require specific interventions. METHODS: We enrolled here 100 APD patients and 60 caregivers. Seventy-four patients were treated with device-aided therapies (DAT) and 26 with standard medical treatment (SMT). Through a telephonic interview, subjects underwent the Hospital Anxiety and Depression Scale (HADS-A; HADS-D), and an ad hoc questionnaire to explore thoughts and emotions related to the pandemic. RESULTS: Depression was observed in 35% of APD patients and anxiety in 39%, with a significant reduction of the latter after the lockdown (p= 0.023). We found a significant correlation between the type of therapy and the HADS-A score (p= 0.004). Patients' main worries were as follows: a possible higher risk of COVID-19 infection (25%), interruption of non-pharmacological treatments (35%), interruption of outpatient clinics (38%), PD complications related to COVID-19 (47%). Patients treated with DAT manifested worries about device-related issues and risk for caregivers' infection. The 40% of caregivers showed anxiety, while the 21.7% of them showed depression. CONCLUSION: Our study reveals a higher prevalence of anxiety and the presence of peculiar worries and needs in APD patients during the pandemic alongside psychological sequelae of their caregivers. These findings are important for neurologists and healthcare services to foster strategies for the management of psychological distress in both patients and caregivers.

Efficacy of safinamide as add-on therapy after subthalamic nucleus deep brain stimulation in Parkinson disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective surgical treatment for advanced Parkinson's disease (PD). However, some patients still experience motor fluctuations or dyskinesia after STN-DBS. Safinamide is approved as add-on treatment to levodopa in fluctuating PD patients. In this study, we evaluated the effect of safinamide as adjunctive therapy in PD patients still experiencing motor fluctuations and dyskinesias after STN-DBS. METHODS: PD patients treated for at least 2 years with bilateral STN-DBST and with troublesome motor fluctuation and/or dyskinesias were examined by means of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the quality of life questionnaire Parkinson's Disease Questionnaire-8 (PDQ-8) and the Non-Motor Symptoms Scale (NMSS) at baseline (T0), after 1 month of treatment with safinamide 50 mg daily (T1) and after another month of treatment with safinamide 100 mg daily (T2). RESULTS: Twenty-nine PD patients were examined. An improvement of the MDS-UPDRS IV score (motor complications) was observed between T0 and T1, T0 and T2, and T1 and T2. The time spent in the OFF state, the functional impact and the complexity of motor fluctuations significantly improved between T0 and T1 and T0 and T2. The mean levodopa equivalent daily dose significantly decreased from T0 to T1 and from T0 to T2. Regarding non-motor symptoms, an improvement on mood and pain was observed. CONCLUSIONS: Safinamide seems to be an effective adjunctive treatment in PD patients treated with bilateral STN-DBS, leading to an improvement of motor complications, mood and pain.

Focal seizures with impaired awareness as long-term neurological complication of COVID-19: a case report.

We report here the first case of a young individual otherwise healthy, who presented with frequent focal seizures with impaired awareness as a possible long-term complication of severe acute respiratory syndrome coronavirus-2 infection. Seizures were documented by electroencephalography and responded clinically and neuro-physiologically to antiseizure therapy. The patient underwent an extensive investigation including cerebrospinal fluid examination, conventional and quantitative brain magnetic resonance imaging, and 18-FDG positron emission tomography. Beyond the clinical interest, this case contributes to clarify the possible pathways by which SARS-CoV-2 may enter the central nervous system and cause long-term neurological complications.

Early reversible leukoencephalopathy and unilateral sixth cranial nerve palsy in mild COVID-19 infection.

OBJECTIVES: To provide new insights into neurological manifestations of COVID-19. We describe a patient with mild COVID-19 associated with diplopia from right sixth cranial nerve palsy and early diffuse leukoencephalopathy, successfully treated with intravenous methylprednisolone. METHODS: The patient was evaluated for diplopia that occurred 1 day after the onset of fever, myalgia, and headache. A complete neurological workup, including neurological examination, cerebrospinal fluid (CSF) analysis with viral polymerase chain reaction (PCR), serum autoimmune encephalitis, and anti-nerve antibodies and brain magnetic resonance imaging (MRI), was performed. RESULTS: Clinical examination revealed incomplete right sixth cranial nerve palsy. Brain MRI showed diffuse confluent fluid-attenuated inversion recovery (FLAIR) hyperintense white matter abnormalities, while CSF analysis showed mild hyperproteinorrachia (61 mg/dL) without pleocytosis. The patients were treated with high-dose intravenous methylprednisolone with rapid improvement of neurological symptoms and resolution of CSF and MRI abnormalities. DISCUSSION: Our report shows that COVID-19 may predominantly present with neurological symptoms; furthermore, it argues the notion of leukoencephalopathy as a typical feature of a severe case of the disease. Mechanisms underpinning neurological symptoms in COVID-19 still need to be elucidated; nonetheless, early recognition and prompt management may ensure their improvement or even complete recovery and are therefore recommended.

Should We Consider Deep Brain Stimulation Discontinuation in Late-Stage Parkinson's Disease?

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson's disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of "poor stimulation responders" among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered. METHODS: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale <50 in medication on/stimulation on condition) treated with STN-DBS for at least 5 years underwent a crossover, double-blind, randomized evaluation of acute effects of stimulation. Physicians, caregivers, and patients were blinded to stimulation conditions. Poor stimulation responders (MDS-UPDRS part III change <10% between stimulation on/medication off and stimulation off/medication off) maintained the stimulation off/medication on condition for 1 month for open-label assessment. RESULTS: Thirty-six patients were included. The acute effect of stimulation was significant (17% MDS-UPDRS part III), with 80% of patients classified as "good responders." Seven patients were classified as "poor stimulation responders," and the stimulation was switched off, but in 4 cases the stimulation was switched back "on" because of worsening of parkinsonism and dysphagia with a variable time delay (up to 10 days). No serious adverse effects occurred. CONCLUSIONS: The vast majority of late-stage PD patients (92%) show a meaningful response to STN-DBS. Effects of stimulation may take days to disappear after its discontinuation. We present a safe and effective decisional algorithm that could guide physicians and caregivers in making challenging therapeutic decisions in late-stage PD. © 2020 International Parkinson and Movement Disorder Society.

Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges.

OBJECTIVE: Comprehensively describe the phenotypic spectrum of sporadic fatal insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder. METHODS: A survey among major prion disease reference centers in Europe identified 13 patients diagnosed with sFI in the past 20 years. We undertook a detailed analysis of clinical and histopathological features and the results of diagnostic investigations. RESULTS: Mean age at onset was 43 years, and mean disease duration 30 months. Early clinical findings included psychiatric, sleep, and oculomotor disturbances, followed by cognitive decline and postural instability. In all tested patients, video-polysomnography demonstrated a severe reduction of total sleep time and/or a disorganized sleep. Cerebrospinal fluid (CSF) levels of proteins 14-3-3 and t-tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real-time quaking-induced conversion assay (RT-QuIC) revealed a positive prion seeding activity in 60% of cases. Electroencephalography and magnetic resonance imaging showed nonspecific findings, whereas fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrPSc type 2 and methionine homozygosity at PRNP codon 129 in all cases. INTERPRETATION: sFI is a disease of young or middle-aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age-related PrP misfolding. The combination of psychiatric and/or sleep-related symptoms with oculomotor abnormalities represents an early peculiar clinical feature of sFI to be valued in the differential diagnosis. Video-polysomnography, FDG-PET, and especially CSF prion RT-QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. Ann Neurol 2018;84:347-360.

Long-term effect of levodopa-carbidopa intestinal gel on axial signs in Parkinson's disease.

BACKGROUND: Few studies have suggested that levodopa-carbidopa intestinal gel (LCIG) may have a benefit on Parkinson's disease (PD) axial signs. AIMS OF THE STUDY: To investigate the long-term effect of LCIG on axial signs and the related prognostic factors. METHODS: A retrospective study on 49 PD patients treated with LCIG. Axial signs as per the Unified Parkinson Disease Rating Scale axial score (AS), Hoehn and Yahr (H&Y) scale, and levodopa equivalent daily dose (LEDD) were assessed at baseline (before starting LCIG treatment) and at the last follow-up (FU). RESULTS: After 47.6 ± 30 months of treatment, total AS deteriorated while motor complications still improved, in spite of a significant LEDD/Kg increment. When adjusted for LCIG treatment duration, a higher AS and freezing of gait severity at FU were predicted by a baseline lower response to l-dopa and higher H&Y (P < 0.01) and they were related to a lower independency in activity of daily life at FU (P < 0.001). Single axial items remain stable up to one year and postural instability up to four years. CONCLUSION: Baseline disease severity and the magnitude of l-dopa response predict axial signs' severity after around four years of LCIG treatment, with consequent implication on patients' functional independence.

Medical therapy and subthalamic deep brain stimulation in advanced Parkinson's disease: a different long-term outcome?

OBJECTIVES: Few clinical trials reported the comparative short-term efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) versus medical therapy in advanced Parkinson's disease (PD). However, the comparative efficacy, safety and the potential disease-modifying effect of these treatments have not been investigated over a longer follow-up period. METHODS: In this study, we organised a 'retrospective control group' to compare medical and surgical therapies over a long-term period. We assessed a group of PD patients suitable for STN-DBS but successively treated with medical therapies for reasons not related to PD, and a group of similar consecutive STN-DBS patients. We thus obtained two groups comparable at baseline, which were re-evaluated after an average follow-up of 6 years (range 4-11). RESULTS: Patients treated with STN-DBS showed a long-lasting superior clinical efficacy on motor fluctuations, with a significant reduction in the average percentage of the waking day spent in 'OFF' and in the duration and disability of dyskinesia. Moreover, operated patients showed a better outcome in the activities of daily living in 'Medication-OFF' condition. On the other hand, a similar progression of motor score and cognitive/behavioural alterations was observed between the two groups, apart from phonemic verbal fluency, which significantly worsened in STN-DBS patients. CONCLUSIONS: To our knowledge, this is the first long-term comparison between medical and surgical therapies; a superior efficacy of STN-DBS was observed on motor disability, while no significant differences were observed in the progression of motor symptoms and, apart from phonemic verbal fluency, of neuropsychological alterations.

Effects of Continuous Dopaminergic Stimulation on Parkinson's Disease Gait: A Longitudinal Prospective Study with Levodopa Intestinal Gel Infusion.

Background: Gait issues, including reduced speed, stride length and freezing of gait (FoG), are disabling in advanced phases of Parkinson's disease (PD), and their treatment is challenging. Levodopa/carbidopa intestinal gel (LCIG) can improve these symptoms in PD patients with suboptimal control of motor fluctuations, but it is unclear if continuous dopaminergic stimulation can further improve gait issues, independently from reducing Off-time. Objective: To analyze before (T0) and after 3 (T1) and 6 (T2) months of LCIG initiation: a) the objective improvement of gait and balance; b) the improvement of FoG severity; c) the improvement of motor complications and their correlation with changes in gait parameters and FoG severity. Methods: This prospective, longitudinal 6-months study analyzed quantitative gait parameters using wearable inertial sensors, FoG with the New Freezing of Gait Questionnaire (NFoG-Q), and motor complications, as per the MDS-UPDRS part IV scores. Results: Gait speed and stride length increased and duration of Timed up and Go and of sit-to-stand transition was significantly reduced comparing T0 with T2, but not between T0-T1. NFoG-Q score decreased significantly from 19.3±4.6 (T0) to 11.8±7.9 (T1) and 8.4±7.6 (T2) (T1-T0 p = 0.018; T2-T0 p < 0.001). Improvement of MDS-UPDRS-IV (T0-T2, p = 0.002, T0-T1 p = 0.024) was not correlated with improvement of gait parameters and NFoG-Q from T0 to T2. LEDD did not change significantly after LCIG initiation. Conclusion: Continuous dopaminergic stimulation provided by LCIG infusion progressively ameliorates gait and alleviates FoG in PD patients over time, independently from improvement of motor fluctuations and without increase of daily dosage of dopaminergic therapy.

Effects of dopaminergic therapy on sleep quality in fluctuating Parkinson's disease patients.

BACKGROUND: Sleep disorders negatively impact quality of life in Parkinson's disease (PD), yet the role of antiparkinsonian drugs on sleep quality is still unclear. We aimed to explore the correlation between sleep dysfunction and dopaminergic therapy in a large cohort of advanced PD patients. METHODS: Patients consecutively evaluated for device-aided therapies eligibility were evaluated by means of the PD Sleep Scale (PDSS-2; score ≥ 18 indicates poor sleep quality), and the Epworth Sleepiness Scale (ESS score ≥ 10 indicates excessive daytime sleepiness-EDS). Binary logistic regression analysis, adjusting for age, sex, disease duration, motor impairment, and sleep drugs, was employed to evaluate the association between dopaminergic therapy and PDSS-2 and ESS scores. Analysis of covariance assessed differences in PDSS-2 and ESS scores between patients without DA, and between patients treated with low or high doses of DA (cut-off: DA-LEDD = 180 mg). RESULTS: In a cohort of 281 patients, 66.2% reported poor sleep quality, and 34.5% reported EDS. DA treatment demonstrated twofold lower odds of reporting relevant sleep disturbances (OR 0.498; p = 0.035), while DA-LEDD, levodopa-LEDD, total LEDD, and extended-release levodopa were not associated with disturbed sleep. EDS was not influenced by dopaminergic therapy. Patients with DA intake reported significant lower PDSS-2 total score (p = 0.027) and "motor symptoms at night" domain score (p = 0.044). Patients with higher doses of DA showed lower PDSS-2 total score (p = 0.043). CONCLUSION: Our study highlights the positive influence of DA add-on treatment on sleep quality in this group of advanced fluctuating PD patients.

NoMoFa as a new tool to evaluate the impact of deep brain stimulation on non-motor fluctuations: A new perspective.

BACKGROUND: Non-motor symptoms and non-motor fluctuations (NMF) in Parkinson's disease (PD) strongly affect health-related quality of life (HRQoL) and disability. The impact of deep brain stimulation (DBS) on NMF remains an area of uncertainty. The aim is to evaluate the impact of DBS on NMF, using the recently validated Non-Motor Fluctuation Assessment (NoMoFa), and to explore the correlation between NMF and motor symptoms, motor complications (MC), and HRQoL post-surgical improvement. METHODS: We prospectively evaluated consecutive patients undergoing subthalamic DBS (STN-DBS), at baseline and 6-months after surgery. Assessments included the NoMoFa questionnaire, the MDS-sponsored Unified Parkinson's Disease Rating Scale, and the 39-Item Parkinson's Disease Questionnaire. Pre- and post-surgical NoMoFa scores were compared using the Wilcoxon Signed rank-test. Linear regression analysis evaluated: a) the correlation between NoMoFa scores, motor and MC improvement, correcting for age, disease duration, and dopaminergic therapy reduction; b) the correlation between HRQoL and NMF improvement, correcting for age, disease duration, motor and MC improvement. RESULTS: Twenty patients were evaluated. Total NMF score significantly improved (44.6 %, [IQR = 18.3-100]; p = 0.022), particularly in Off condition (52.0 %, [IQR = 25.4-100]; p = 0.009); we observed strong correlation between NMF and MC improvement (Beta = 0.728; p = 0.006), mainly driven by the mitigation of unpredictable Off (Beta = 0.905; p < 0.001). Even after adjusting for potential confounders, the reduction of NMF independently correlated with increased HRQoL (Beta = 0.714; p = 0.010). CONCLUSIONS: STN-DBS demonstrated strong beneficial effect on NMF, resulting in significant improvement of HRQoL. This underlines the importance of recognizing NMF as a significant factor to be considered in the selection of patients eligible for STN-DBS.

Incidence and predictors of postural abnormalities in Parkinson's disease: a PPMI cohort study.

BACKGROUND: Axial postural abnormalities (PA) are invalidating symptoms of Parkinson's disease (PD). Risk factors for PA are unknown. OBJECTIVES: We sought to evaluate PA incidence and risk factors over the first 4-6 years of PD. METHODS: We included 441 PD patients from the Parkinson's Progression Markers Initiative (PPMI) cohort with data at diagnosis and after 4-year follow-up. PA was defined according to a posture item ≥ 2 at the Movement Disorder Society-sponsored-revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) in Off therapeutic condition. The Kruskal-Wallis test was used to compare characteristics of patients without PA ('no-PA'), with PA at disease onset ('baseline-PA'), and PA developed during follow-up ('develop-PA'). To identify predictors of PA development, univariate and multivariate Cox regression analyses were performed considering demographic, clinical and therapeutic variables. RESULTS: 10.9% of patients showed PA at baseline and 23.7% developed PA within the first 4-6 years since diagnosis. Older age, malignant phenotype, higher MDS-UPDRS part III, Hoehn & Yahr, and dysautonomia (SCOPA-AUT) score, and lower levels of physical activity were predictors of PA development at the univariate analysis. Older age (Hazard ratio [HR] per year: 1.041) and higher MDS-UPDRS part III score (HR per point: 1.035) survived as PA development predictors in the multivariate analysis. CONCLUSIONS: PPMI cohort data show that > 30% of PD patients present PA within the first 4-6 years of disease. Older age at onset and higher motor burden are associated with a higher risk for PA development. The protective role of physical activity merits to be further investigated.

Axial symptoms as main predictors of short-term subthalamic stimulation outcome in Parkinson's disease.

Deep brain stimulation (DBS) is an established therapeutic option for Parkinson's disease (PD) patients; however, a clear-cut definition of subthalamic (STN) DBS predictors in PD is lacking. We analyzed a cohort of 181 STN-treated PD patients and compared pre- vs. 1-year post-surgical motor, dyskinesia, Off time, and daily-life activities (ADL) scores. A multivariate linear regression analysis was used to evaluate the association between clinical/demographic characteristics and the extent of STN-DBS response for outcomes proving a significant change after surgery. After STN-DBS, we observed a significant improvement of motor symptoms (P < 0.001), dyskinesia (P < 0.001), and daily Off time (P < 0.001). Sex, PD duration, cognitive status, and the motor and axial response to levodopa significantly explained the motor improvement (R = 0.360, P = 0.002), with presurgical response of axial symptoms (Beta = 0.203, P = 0.025) and disease duration (Beta = 0.205, P = 0.013) being the strongest predictors. Considering the daily Off time improvement, motor and axial response at the levodopa challenge test and disease duration explained 10.6% of variance (R = 0.326, p < 0.001), with disease duration being the strongest predictor of improvement (Beta = 0.253, p: 0.001) and axial levodopa response showing a trend of significance in explaining the change (Beta = 0.173, p: 0.056). Dyskinesia improvement was not significantly explained by the model. Our findings highlight the emerging role of axial symptoms in PD and their response to levodopa as potentially pivotal also in the DBS selection process.

Shared and Unique Disease Pathways in Amyotrophic Lateral Sclerosis and Parkinson's Disease Unveiled in Peripheral Blood Mononuclear Cells.

Recent evidence supports an association between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Indeed, prospective population-based studies demonstrated that about one-third of ALS patients develop parkinsonian (PK) signs, even though different neuronal circuitries are involved. In this context, proteomics represents a valuable tool to identify unique and shared pathological pathways. Here, we used two-dimensional electrophoresis to obtain the proteomic profile of peripheral blood mononuclear cells (PBMCs) from PD and ALS patients including a small cohort of ALS patients with parkinsonian signs (ALS-PK). After the removal of protein spots correlating with confounding factors, we applied a sparse partial least square discriminant analysis followed by recursive feature elimination to obtain two protein classifiers able to discriminate (i) PD and ALS patients (30 spots) and (ii) ALS-PK patients among all ALS subjects (20 spots). Functionally, the glycolysis pathway was significantly overrepresented in the first signature, while extracellular interactions and intracellular signaling were enriched in the second signature. These results represent molecular evidence at the periphery for the classification of ALS-PK as ALS patients that manifest parkinsonian signs, rather than comorbid patients suffering from both ALS and PD. Moreover, we confirmed that low levels of fibrinogen in PBMCs is a characteristic feature of PD, also when compared with another movement disorder. Collectively, we provide evidence that peripheral protein signatures are a tool to differentially investigate neurodegenerative diseases and highlight altered biochemical pathways.