Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease.

INTRODUCTION: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD. METHODS: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing. RESULTS: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant. CONCLUSIONS: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation.

Comparing Essential Tremor with and without Soft Dystonic Signs and Tremor Combined with Dystonia: The TITAN Study.

BACKGROUND: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high. OBJECTIVES: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD). METHODS: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life. RESULTS: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor. CONCLUSIONS: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity.

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.

Tremulous spastic ataxia in a patient with a homozygous truncating SYNE1 variant.

We describe a case of severe adult-onset progressive tremulous cerebellar ataxia with pyramidal signs associated with a rare homozygous truncating pathogenic variant in the SYNE1 gene (p.Arg5371*). This contrasts the initial views on SYNE1-related ataxia as a relatively benign, slowly progressive condition, with important implications for clinic-genetic counselling.

Visuospatial Deficits Are Associated with Pisa Syndrome and not Camptocormia in Parkinson's Disease.

Background: Pisa syndrome (PS) and camptocormia (CC) are postural abnormalities frequently associated with Parkinson's disease (PD). Their pathophysiology remains unclear, but the role of cognitive deficits has been postulated. Objectives: To identify differences in the neuropsychological functioning of patients with PD with PS or CC compared with matched patients with PD without postural abnormalities. Methods: We performed a case-control study including 57 patients with PD with PS (PS+) or CC (CC+) and 57 PD controls without postural abnormalities matched for sex, age, PD duration, phenotype, and stage. Patients were divided into four groups: PS+ (n = 32), PS+ controls (PS-, n = 32), CC+ (n = 25), and CC+ controls (CC-, n = 25). We compared PS+ versus PS- and CC+ versus CC- using a neuropsychological battery assessing memory, attention, executive functions, visuospatial abilities, and language. Subjective visual vertical (SVV) perception was assessed by the Bucket test as a sign of vestibular function; the misperception of trunk position, defined as a mismatch between the objective versus subjective evaluation of the trunk bending angle >5°, was evaluated in PS+ and CC+. Results: PS+ showed significantly worse visuospatial performances (P = 0.025) and SVV perception (P = 0.038) than their controls, whereas CC+ did not show significant differences compared with their control group. Reduced awareness of postural abnormality was observed in >60% of patients with PS or CC. Conclusions: Low visuospatial performances and vestibular tone imbalance are significantly associated with PS but not with CC. These findings suggest different pathophysiology for the two main postural abnormalities associated with PD and can foster adequate therapeutic and prevention strategies.

VPS13C-associated Parkinson's disease: Two novel cases and review of the literature.

VPS13C is a protein-coding gene involved in the regulation of mitochondrial function through the endolysosomal pathway in neurons. Homozygous and compound heterozygous VPS13C mutations are etiologically associated with early-onset Parkinson's disease (PD). Moreover, recent studies linked biallelic VPS13C mutations with the development of dementia with Lewy bodies (DLB). Neuropathological studies on two mutated subjects showed diffuse Lewy body disease. In this article, we report the clinical and genetic findings of two subjects affected by early-onset PD carrying three novel VPS13C mutations (i.e., one homozygous and one compound heterozygous), and review the previous literature on the genetic and clinical findings of VPS13C-mutated patients, contributing to the knowledge of this rare genetic alpha-synucleinopathy.

Continuous subcutaneous apomorphine infusion allowing awake deep brain stimulation in a Parkinson's disease patient.

BACKGROUND: Subthalamic Deep Brain Stimulation (DBS) have demonstrated in the last decades to determine an important clinical improvement in advanced and selected Parkinson's disease (PD) patients. However, only a minority of parkinsonian patients meet the criteria to undergo DBS, and the surgical procedure itself is often stressful, especially for patients experiencing severe OFF state. Subcutaneous Apomorphine continuous administration is suitable as an adjunctive therapy capable of improving a suboptimal DBS result. Here we hypothesize a possible role for subcutaneous apomorphine infusion to alleviate severe OFF state in parkinsonian patients undergoing DBS, thus allowing intraoperative microrecording and patient's collaboration during clinical testing. CASE PRESENTATION: A 68-year-old man, suffering from a very long PD-history, characterized by a severe akinetic status and dramatic non-motor features while in OFF, underwent Subthalamic-DBS keeping a slight but continuous apomorphine infusion (1.8 mg/hour), able to guarantee the right degree of patient's collaboration without interfering with microelectrode recordings. There were no intra or perioperative complications and after the procedure he experienced a marked clinical benefit, being able to stop apomorphine administration. CONCLUSIONS: Here we described the first Subthalamic DBS procedure performed with a low and stable dopaminergic stimulation guaranteed by subcutaneous Apomorphine continuous infusion. For its rapidity of action and prompt reversibility, apomorphine could be particularly suitable for use during difficult surgical procedures in PD, allowing more therapeutic opportunities for patients who would otherwise be excluded from the DBS option.

The Choice of Leg During Pull Test in Parkinson's Disease: Not Mere Chance.

Background: Parkinson's disease (PD) starts asymmetrically and it maintains a certain degree of asymmetry throughout its course. Once functional disability proceeds, people with PD can change their dominant hand due to the increased disease severity. This is particularly true for hand dominance, while no studies have been performed so far exploring the behavioral changes of lower limb utilization in PD according to the lateralized symptom dominance. In the current study, we aim to track the foot preference of participants with PD to respond to the Pull Test. Methods: Forty-one subjects suffering from PD, with a H&Y scale ≤ 2, were recruited. A motor evaluation was performed, including the motor part of the MDS-UPDRS, its axial and lateralized scores (for more and less affected side), two Timed Tests, namely Time to Walk a standard distance (TW, in seconds) and Time Up and Go Test (TUG, in seconds), and the Pull Test. The preferred foot (right or left) involved in the step backward was recorded. Thirty-seven healthy controls underwent a motor assessment which included the Pull Test and the Timed Tests. Both participants with PD and controls were right-handed. To evaluate the relationship between the response to Pull-Test and PD-symptoms, subjects with PD were further divided into two groups: (1) Right more affected side (Right-MAS), and (2) Left more affected side (Left-MAS). Results: Both groups of subjects with PD (Right-MAS and Left-MAS) during the Pull Test shifted significantly their leg use preference toward the opposite side than the more affected side: Right-MAS used preferentially their left leg (71%) and vice versa (p < 0.001). The limb preference shift was especially true for Left-MAS group that almost invariably used their right, dominant leg to respond to the Pull Test (95%). Similar results were obtained comparing people with PD and Controls. Conclusions: This study shows that the limb used to respond to the Pull Test generally predicts the contralateral side of worse PD involvement. As the disease takes place, it prevails over hemispheric dominance: right-handed subjects with left side PD-onset and worse lateralization tend to be hyper-right-dominant, while right-handed subjects with right side PD-onset and worse impairment tend to behave as left-handers. Lateralization of symptoms in PD is still a mysterious phenomenon; more studies are needed to better understand this association and to optimize tailored rehabilitation programs for people with PD.

Bilateral Repetitive Transcranial Magnetic Stimulation With the H-Coil in Parkinson's Disease: A Randomized, Sham-Controlled Study.

Background: Pilot open-label application of high-frequency repetitive transcranial magnetic stimulation (rTMS) with H-coil in Parkinson's Disease (PD) have shown promising results. Objective: To evaluate safety and efficacy of high-frequency rTMS with H-coil in PD in a double-blind, placebo-controlled, randomized study. Methods: Sixty patients with PD were randomized into 3 groups: M1-PFC (real stimulation on primary motor-M1 and pre-frontal cortices-PFC), M1 (real rTMS on M1, sham on PFC), Sham (apparent stimulation). Primary outcome was baseline-normalized percent improvement in UPDRS part III OFF-therapy at the end of treatment (12 rTMS sessions, 4 weeks). Secondary outcomes were improvement in UPDRS part III sub-scores, timed tests, and neuropsychological tests. Statistical analysis compared improvement following real and sham stimulation at the end of the protocol using either a t-test or a Mann-Whitney test. Results: All patients tolerated the treatment and concluded the study. One patient from M1-PFC group was excluded from the analysis due to newly discovered uncontrolled diabetes mellitus. No serious adverse effect was recorded. At the end of treatment, patients receiving real rTMS (M1-PFC and M1 combined) showed significantly greater improvement compared to sham in UPDRS part III total score (p = 0.007), tremor subscore (p = 0.011), and lateralized sub-scores (p = 0.042 for the more affected side; p = 0.012 for the less affected side). No significant differences have been oserved in safety and efficacy outcomes between the two real rTMS groups. Notably, mild, not-distressing and transient dyskinesias occurred in 3 patients after real rTMS in OFF state. Conclusions: The present findings suggest that high-frequency rTMS with H-coil is a safe and potentially effective procedure and prompt larger studies for validation as add-on treatment in PD.

Neurological Involvement in the Course of Scleromyxedema: A Case Report.

Scleromyxedema is a rare disease of unknown etiology primarily affecting the skin, characterized by generalized papular eruption, dermal fibroblast proliferation with mucin deposition, and a monoclonal gammopathy. Neurological impairment is a rare but sometimes fatal complication of scleromyxedema that should be rapidly identified to prevent significant morbidity and mortality. A 63-year-old Caucasian man had a 2-year history of scleromyxedema, and was under immunosuppressive treatment with ciclosporine and methotrexate. The patient came to our attention because of sudden neurological dysfunction with altered sensorium, confusion, and dysarthria. After a few hours since admission, the patient developed left hemiparesis, followed after 2 days by right hemiparesis. The brain computed tomography and cerebrospinal fluid examination results were normal. Brain magnetic resonance imaging (MRI) showed a bilateral cortical hyperintense signal on T2 sequences with leptomeningeal enhancement. Extensive serological and liquoral evaluations were performed without significant findings. After steroid initiation, a remarkable neurological improvement was noticed. The dramatic and immediate response of the patient's to steroid and MRI data strongly suggested a dysimmune etiology. Over the ensuing week, the patient's language, motor, and sensory functions continued to improve. Two weeks after admission, the patient was discharged to home without significant neurological sequelae.

Motor Cortical Plasticity to Training Started in Childhood: The Example of Piano Players.

Converging evidence suggest that motor training is associated with early and late changes of the cortical motor system. Transcranial magnetic stimulation (TMS) offers the possibility to study plastic rearrangements of the motor system in physiological and pathological conditions. We used TMS to characterize long-term changes in upper limb motor cortical representation and interhemispheric inhibition associated with bimanual skill training in pianists who started playing in an early age. Ipsilateral silent period (iSP) and cortical TMS mapping of hand muscles were obtained from 30 strictly right-handed subjects (16 pianists, 14 naïve controls), together with electromyographic recording of mirror movements (MMs) to voluntary hand movements. In controls, motor cortical representation of hand muscles was larger on the dominant (DH) than on the non-dominant hemisphere (NDH). On the contrary, pianists showed symmetric cortical output maps, being their DH less represented than in controls. In naïve subjects, the iSP was smaller on the right vs left abductor pollicis brevis (APB) indicating a weaker inhibition from the NDH to the DH. In pianists, interhemispheric inhibition was more symmetric as their DH was better inhibited than in controls. Electromyographic MMs were observed only in naïve subjects (7/14) and only to voluntary movement of the non-dominant hand. Subjects with MM had a lower iSP area on the right APB compared with all the others. Our findings suggest a more symmetrical motor cortex organization in pianists, both in terms of muscle cortical representation and interhemispheric inhibition. Although we cannot disentangle training-related from preexisting conditions, it is possible that long-term bimanual practice may reshape motor cortical representation and rebalance interhemispheric interactions, which in naïve right-handed subjects would both tend to favour the dominant hemisphere.

Age-related changes in motor cortical representation and interhemispheric interactions: a transcranial magnetic stimulation study.

To better understand the physiological mechanisms responsible for the differential motor cortex functioning in aging, we used transcranial magnetic stimulation to investigate interhemispheric interactions and cortical representation of hand muscles in the early phase of physiological aging, correlating these data with participants' motor abilities. Right-handed healthy subjects were divided into a younger group (n = 15, mean age 25.4 ± 1.9 years old) and an older group (n = 16, mean age 61.1 ± 5.1 years old). Activity of the bilateral abductor pollicis brevis (APB) and abductor digiti minimi (ADM) was recorded. Ipsilateral silent period (ISP) was measured in both APBs. Cortical maps of APB and ADM were measured bilaterally. Mirror movements (MM) were recorded during thumb abductions. Motor abilities were tested using Nine Hole Peg Test, finger tapping, and grip strength. ISP was reduced in the older group on both sides, in terms of duration (p = 0.025), onset (p = 0.029), and area (p = 0.008). Resting motor threshold did not differ between groups. APB and ADM maps were symmetrical in the younger group, but were reduced on the right compared to the left hemisphere in the older group (p = 0.008). The APB map of the right hemisphere was reduced in the older group compared to the younger (p = 0.021). Older subjects showed higher frequency of MM and worse motor abilities (p < 0.001). The reduction of right ISP area correlated significantly with the worsening of motor performances. Our results showed decreased interhemispheric interactions in the early processes of physiological aging and decreased cortical muscles representation over the non-dominant hemisphere. The decreased ISP and increased frequency of MM suggest a reduction of transcallosal inhibition. These data demonstrate that early processes of normal aging are marked by a dissociation of motor cortices, characterized, at least, by a decline of the non-dominant hemisphere, reinforcing the hypothesis of the right hemi-aging model.

Deep repetitive transcranial magnetic stimulation with H-coil on lower limb motor function in chronic stroke: a pilot study.

OBJECTIVES: To assess the efficacy of high-frequency (20 Hz) brain stimulation on lower limb motor function in subjects with chronic (> 6 mo) subcortical stroke. DESIGN: Double-blind, placebo-controlled crossover study. SETTING: University hospital. PARTICIPANTS: Right-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study. INTERVENTIONS: Repetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period. MAIN OUTCOME MEASURES: Lower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up. RESULTS: Real rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation. CONCLUSIONS: These data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment.

Striatal hand in Parkinson's disease: the re-evaluation of an old clinical sign.

Among postural abnormalities in Parkinson's disease (PD), striatal hand (SH) is a particularly underexplored phenomenon. It leads to extreme abnormalities of hand posture, causing altered dexterity, pain and disfigurement. In our study, three blinded investigators examined several pictures of the hands of individuals with PD (N = 40) and controls (N = 15). The investigators quantified postural alterations using the Striatal Hand Score. Demographic and clinical data were also collected. As no differences were detected among investigators agreement, a final Hand Score (HS, range 0-4) was obtained for each hand. The Striatal Hand Score in both the left and right hand was significantly different in PD compared to controls (p < 0.001 for both left and right hand). Striatal hand was significantly worse on the side of PD onset, and on the side with greater PD symptomatology. The finding of a striatal hand was 100 % specific for a diagnosis of PD. Nine PD subjects were evaluated both on and off medication, and dopaminergic treatment did not significantly change the Striatal Hand Score. Our findings suggest that in patients without any explanation for hand deformities other than PD, striatal hand occurs very often, and is highly specific for the side of worst PD involvement. We recommend including an evaluation for SH as part of routine practice. This study emphasizes the importance of a careful observation of the patient in order to improve diagnostic accuracy.

Interhemispheric balance in Parkinson's disease: a transcranial magnetic stimulation study.

BACKGROUND: Parkinson's disease (PD) is characterized by various changes in motor excitability. OBJECTIVE: To examine through Transcranial Magnetic Stimulation (TMS) cortical excitability, specifically addressing interhemispheric connections in PD. METHODS: Nineteen PD patients with a predominant involvement of the left hemibody (7 females, age 61.7 years,) and 13 controls (6 females, age 61.5 years) entered the study. Patients were subdivided into two groups (early and advanced) according to the time from PD diagnosis. Participants underwent evaluation of Resting Motor Threshold (RMT) and ipsilateral Silent Period (iSP), induced by suprathreshold TMS on the ipsilateral-M1, measured as suppression of voluntary EMG activity. Mirror Movements (MM) were EMG-recorded and scored, in three upper limb muscles, during unilateral voluntary hand movement. Patients were studied at baseline (OFF drug) and after acute levodopa challenge (ON). RESULTS: PD patients showed a general reduction in RMT vs controls (P < 0.01 for right and left hemisphere) in both drug conditions. Early PD had a significantly lower RMT over the right vs the left hemisphere (P = 0.027); this difference was no longer significant after levodopa. In early PD patients, MM were mainly observed in the right arm during voluntary activation of the left, more affected side both in OFF (P = 0.033) and in ON (P = 0.046). In PD, RMT of the left, less affected M1 was significantly correlated with the right lateralized motor score (P = 0.011; Spearman's coefficient = -0.585), as well as with disease duration. In PD patients, a shorter (P = 0.039) and smaller (P = 0.037) iSP was detected when the stimulus was applied to the worse M1 (right) compared with the contralateral side. This asymmetry was significant only OFF drug. In the PD group iSP-duration from the right, less affected APB was negatively correlated with the MM recorded from the same side during the voluntary movement of the worse side (Spearman's coefficient = -0.498; P = 0.035). CONCLUSIONS: Increased cortical motor excitability in PD, consistent with previous findings, is more evident in the worse hemisphere, particularly in early PD. Asymmetric motor involvement is also associated with excessive involuntary mirroring and defective interhemispheric inhibition, both unfavoring the more affected side. Altogether, these findings suggest that asymmetric motor involvement in PD, particularly in the earlier phases of the disease, affects the interhemispheric balance of cortical excitability, movement lateralization and transcallosal inhibition.

Mapping early changes of cortical motor output after subcortical stroke: a transcranial magnetic stimulation study.

After acute stroke several changes in cortical excitability occur involving affected (AH) and unaffected hemisphere (UH) but whether they contribute to motor recovery is still controversial. We performed transcranial magnetic stimulation mapping of several upper limb muscles over the two hemispheres in thirteen patients at 4-12 days from subcortical stroke and after 1 month. The occurrence of mirror movements (MMs) on the healthy side during contraction of paretic muscles was measured. At baseline, cortical excitability parameters over the AH decreased in comparison with controls, while excitability over the UH increased correlating with severity of motor deficits of the affected arm at baseline as well as with poor recovery. At follow-up, map parameters of the UH became closer to those of controls independently from recovery, while for the AH the number of responsive sites increased significantly. Ipsilateral motor evoked responses (iMEPs) in the affected arm were never elicited. We observed an early impairment in dexterity of the ipsilesional hand that recovered over-time but persistently differed in comparison with controls. MMs occurrence increased at baseline correlating with reduced cortical excitability of the AH as well as with increased map density over the UH. The acute increased excitability of the UH after stroke has a negative prognostic value on recovery and negatively affects motor performance of the ipsilesional hand. Moreover, the absence of iMEPs and the normalization of motor cortical excitability at follow-up indicate that the UH primary motor area does not contribute to recovery.