A "glympse" into neurodegeneration: Diffusion MRI and cerebrospinal fluid aquaporin-4 for the assessment of glymphatic system in Alzheimer's disease and other dementias.

The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage.

Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort.

BACKGROUND: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. OBJECTIVE: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. METHODS: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. RESULTS: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. CONCLUSIONS: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

The impact of patients' pre-treatment expectations on immunosuppressive treatment outcomes in myasthenia gravis: A pilot correlational study.

INTRODUCTION/AIMS: The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes. METHODS: This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months. RESULTS: Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations. DISCUSSION: Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

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.

Hypotensive episodes at 24-h ambulatory blood pressure monitoring predict adverse outcomes in Parkinson's disease.

PURPOSE: Neurogenic orthostatic hypotension (nOH) is a frequent nonmotor feature of Parkinson's disease (PD), associated with adverse outcomes. Recently, 24-h ambulatory blood pressure monitoring (ABPM) showed good accuracy in diagnosing nOH. This study aims at evaluating the prognostic role of ABPM-hypotensive episodes in predicting PD disability milestones and mortality and comparing it to the well-defined prognostic role of bedside nOH. METHODS: Patients with PD who underwent ABPM from January 2012 to December 2014 were retrospectively enrolled and assessed for the development of falls, fractures, dementia, bed/wheelchair confinement, hospitalization, and mortality, during an up-to-10-year follow-up. Significant ABPM-hypotensive episodes were identified when greater than or equal to two episodes of systolic BP drop ≥ 15 mmHg (compared with the average 24 h) were recorded during the awakening-to-lunch period. RESULTS: A total of 99 patients (74% male, age 64.0 ± 10.1 years, and PD duration 6.4 ± 4.0 years) were enrolled. At baseline, 38.4% of patients had ABPM-hypotensive episodes and 46.5% had bedside nOH. On Kaplan-Meier analysis, patients with ABPM-hypotensive episodes showed earlier onset of falls (p = 0.001), fractures (p = 0.004), hospitalizations (p = 0.009), bed/wheelchair confinement (p = 0.032), dementia (p = 0.001), and shorter survival (8.0 versus 9.5 years; p = 0.009). At Cox regression analysis (adjusted for age, disease duration, Charlson Comorbidity Index, and Hoehn and Yahr stage) a significant association was confirmed between ABPM-hypotensive episodes and falls [odds ratio (OR) 3.626; p = 0.001), hospitalizations (OR 2.016; p = 0.038), and dementia (OR 2.926; p = 0.008), while bedside nOH was only associated with falls (OR 2.022; p = 0.039) and dementia (OR 1.908; p = 0.048). CONCLUSIONS: The presence of at least two ABPM-hypotensive episodes independently predicted the development of falls, dementia, and hospitalization, showing a stronger prognostic value than the simple bedside assessment.

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.

How resistant are levodopa-resistant axial symptoms? Response of freezing, posture, and voice to increasing levodopa intestinal infusion rates in Parkinson disease.

BACKGROUND AND PURPOSE: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. METHODS: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. RESULTS: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2 ± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean = 2.3 at T1, 1.7 at T2, 1.2 at T3; p = 0.013). Posture and speech features did not show significant changes, whereas stride length (p = 0.049), turn duration (p = 0.001), and turn velocity (p = 0.024) significantly improved on doubling the levodopa infusion rate. CONCLUSIONS: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

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.

Camera- and Viewpoint-Agnostic Evaluation of Axial Postural Abnormalities in People with Parkinson's Disease through Augmented Human Pose Estimation.

Axial postural abnormalities (aPA) are common features of Parkinson's disease (PD) and manifest in over 20% of patients during the course of the disease. aPA form a spectrum of functional trunk misalignment, ranging from a typical Parkinsonian stooped posture to progressively greater degrees of spine deviation. Current research has not yet led to a sufficient understanding of pathophysiology and management of aPA in PD, partially due to lack of agreement on validated, user-friendly, automatic tools for measuring and analysing the differences in the degree of aPA, according to patients' therapeutic conditions and tasks. In this context, human pose estimation (HPE) software based on deep learning could be a valid support as it automatically extrapolates spatial coordinates of the human skeleton keypoints from images or videos. Nevertheless, standard HPE platforms have two limitations that prevent their adoption in such a clinical practice. First, standard HPE keypoints are inconsistent with the keypoints needed to assess aPA (degrees and fulcrum). Second, aPA assessment either requires advanced RGB-D sensors or, when based on the processing of RGB images, they are most likely sensitive to the adopted camera and to the scene (e.g., sensor-subject distance, lighting, background-subject clothing contrast). This article presents a software that augments the human skeleton extrapolated by state-of-the-art HPE software from RGB pictures with exact bone points for posture evaluation through computer vision post-processing primitives. This article shows the software robustness and accuracy on the processing of 76 RGB images with different resolutions and sensor-subject distances from 55 PD patients with different degrees of anterior and lateral trunk flexion.

Do demographic and clinical features and comorbidities affect the risk of spread to an additional body site in functional motor disorders?

The aim of this study is to assess changes in the body distribution and the semeiology of functional motor disorder (FMD) in patients who reported only one or more than one body site affected at FMD onset. Data were obtained from the Italian Registry of Functional Motor Disorders, which included patients with a diagnosis of clinically definite FMDs. The relationship between FMD features and spread to other body sites was estimated by multivariate Cox regression analysis. We identified 201 (49%) patients who reported only one body site affected at FMD onset and 209 (51%) who reported multiple body sites affected at onset. FMD spread from the initial site to another site in 43/201 (21.4%) patients over 5.7 ± 7.1 years in those with only one site affected at FMD onset; FMD spread to an another body site in 29/209 (13.8%) over 5.5 ± 6.5 years. The spread of FMD was associated with non-motor functional symptoms and psychiatric comorbidities only in the patients with one body site affected at FMD onset. Our findings provide novel insight into the natural history of FMD. The number of body sites affected at onset does not seem to have a consistent influence on the risk of spread. Furthermore, our findings suggest that psychiatric comorbidities and non-motor functional symptoms may predict the spread of FMD symptoms, at least in patients with one body site affected at onset.

Efficacy of rituximab in anti-myelin-associated glycoprotein demyelinating polyneuropathy: Clinical, hematological and neurophysiological correlations during 2 years of follow-up.

BACKGROUND AND PURPOSE: We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy. METHODS: Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m2 . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment. RESULTS: At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%). CONCLUSIONS: This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy.

Criteria for identification of advanced Parkinson's disease: the results of the Italian subgroup of OBSERVE-PD observational study.

BACKGROUND: Frequency of Advanced Parkinson's Disease (APD) and its clinical characteristics are still not well defined. Here, we aimed to assess APD prevalence in the Italian OBSERVE-PD cohort, as well as treatment eligibility to device-aided therapies (DAT), and to compare the APD clinical judgment with the established Delphi criteria. METHODS: This sub-group analysis of the OBSERVE-PD study was performed on patients enrolled by 9 Movement Disorders centers in Italy. Motor and non-motor symptoms, PD characteristics, activities of daily living, and quality of life were assessed. Patient eligibility for DAT, response to current PD treatments, referral process, and the concordance between APD physician's judgment and Delphi criteria were also assessed. RESULTS: According to physician's judgment, 60 out of 140 patients (43%) had APD. The correlation between physician's judgment and the overall APD Delphi criteria was substantial (K = 0.743; 95%CI 0.633-0.853), mainly driven by a discrete concordance found for the presence of ≥ 2 h of daily OFF time, presence of troublesome dyskinesia, ≥ 5 times daily oral levodopa dosing, and activities of daily living limitation. Forty-four (73%) APD patients were considered eligible to DAT but only 18 of them (41%) used these therapies, while most patients, independently from their eligibility, continued to use 3-5 oral daily medications, due to fear of invasive solutions and need to have a longer time to decide. CONCLUSION: APD was frequent in the Italian OBSERVE-PD population. DAT in the eligible APD population proved to be underused, in spite of unsatisfactory symptoms control with oral medications in 67% of patients.

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.

Gut microbiota and metabolome distinctive features in Parkinson disease: Focus on levodopa and levodopa-carbidopa intrajejunal gel.

BACKGROUND AND PURPOSE: Recent data suggest that imbalances in the composition of the gut microbiota (GM) could exacerbate the progression of Parkinson disease (PD). The effects of levodopa (LD) have been poorly assessed, and those of LD-carbidopa intestinal gel (LCIG) have not been evaluated so far. The aim of this study was to identify the effect of LD and LCIG, in particular, on the GM and metabolome. METHODS: Fecal DNA samples from 107 patients with a clinical diagnosis of PD were analyzed by next-generation sequencing of the V3 and V4 regions of the 16S rRNA gene. PD patients were classified in different groups: patients on LCIG (LCIG group, n = 38) and on LD (LD group, n = 46). We also included a group of patients (n = 23) without antiparkinsonian medicaments (Naïve group). Fecal metabolic extracts were evaluated by gas chromatography mass spectrometry. RESULTS: The multivariate analysis showed a significantly higher abundance in the LCIG group of Enterobacteriaceae, Escherichia, and Serratia compared to the LD group. Compared to the Naïve group, the univariate analysis showed a reduction of Blautia and Lachnospirae in the LD group. Moreover, an increase of Proteobacteria, Enterobacteriaceae, and a reduction of Firmicutes, Lachnospiraceae, and Blautia was found in the LCIG group. No significant difference was found in the multivariate analysis of these comparisons. The LD group and LCIG group were associated with a metabolic profile linked to gut inflammation. CONCLUSIONS: Our results suggest that LD, and mostly LCIG, might significantly influence the microbiota composition and host/bacteria metabolism, acting as stressors in precipitating a specific inflammatory intestinal microenvironment, potentially related to the PD state and progression.

Functional motor disorders associated with other neurological diseases: Beyond the boundaries of "organic" neurology.

BACKGROUND AND PURPOSE: The aims of this study were to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases ("comorbid FMDs"), and to compare comorbid FMDs with FMDs not overlapping with other neurological diseases ("pure FMDs"). METHODS: For this multicenter observational study, we enrolled outpatients with a definite FMD diagnosis attending 25 tertiary movement disorder centers in Italy. Each patient with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Group comparisons (comorbid FMDs vs. pure FMDs) were performed in order to compare demographic and clinical variables. Logistic regression models were created to estimate the adjusted odds ratios (95% confidence intervals) of comorbid FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables). RESULTS: Out of 410 FMDs, 21.7% of patients (n = 89) had comorbid FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%), FMDs appeared after the diagnosis of a neurological disease. Patients with comorbid FMDs were older, and more frequently had tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid FMDs was more likely associated with longer time lag until the final diagnosis of FMD, presence of tremor and non-neurological comorbidities. CONCLUSIONS: Our findings highlight the need for prompt diagnosis of FMDs, given the relatively high frequency of associated neurological and non-neurological diseases.

Safety and efficacy of tolcapone in Parkinson's disease: systematic review.

PURPOSE: Tolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson's disease (PD). However, safety issues hampered its use in clinical practice. We aimed to provide evidence of safety and efficacy of tolcapone by a systematic literature review to support clinicians' choices in the use of an enlarging PD therapeutic armamentarium. METHODS: We searched PubMed for studies on PD patients treated with tolcapone, documenting the following outcomes: liver enzyme, adverse events (AEs), daily Off-time, levodopa daily dose, unified Parkinson's disease rating scale (UPDRS) part-III, quality of life (QoL), and non-motor symptoms. FAERS and EudraVigilance databases for suspected AEs were interrogated for potential additional cases of hepatotoxicity. RESULTS: Thirty-two studies were included, for a total of 4780 patients treated with tolcapone. Pertaining safety, 0.9% of patients showed liver enzyme elevation > 2. Over 23 years, we found 7 cases of severe liver injury related to tolcapone, 3 of which were fatal. All fatal cases did not follow the guidelines for liver function monitoring. FAERS and EudraVigilance database search yielded 61 reports of suspected liver AEs possibly related to tolcapone. Pertaining efficacy, the median reduction of hours/day spent in Off was 2.1 (range 1-3.2), of levodopa was 108.9 mg (1-251.5), of "On" UPDRS-III was 3.6 points (1.1-6.5). Most studies reported a significant improvement of QoL and non-motor symptoms. CONCLUSION: Literature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium.