Monika Rudzińska

An exploratory double‐blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease

AIMSnSelisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntingtons disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers.nnnMETHODSnThis was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers.nnnRESULTSnSelisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen.nnnCONCLUSIONSnSelisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.

Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients.

AIMnParkinson disease (PD) is the common neurodegenerative disease with motor and numerous non-motor symptoms, including cognitive impairment. Mutation of glucocerebrosidase (GBA) gene is the most common genetic risk factor of sporadic PD. The aim of this study was to assess clinical features of PD associated with GBA mutation.nnnMETHODSnOne hundred and thirty-eight PD patients were involved and examined by the movement disorder specialist using several scales including Unified Parkinson Disease Rating Scale (UPDRS) part II and III, Hoehn and Yahr (H&Y) staging, Mini-Mental State Examination (MMSE) and Hamilton Depression Scale (HDS). The exons 8 and 9 of GBA was sequenced and screened for variants.nnnRESULTSnThe GBA variants were found in 16 (11.6%) PD patients: N370S mutation in 5 (3.6%) and T369M variant in 11 (7.9%). No significant differences between the group of mutation carriers and non-carriers were found in relation to clinical features except for dementia (MMSE score<26) occurring more often in N370S mutation carriers (60.0% vs 19.6%, p=0.03).nnnCONCLUSIONnThe N370S GBA mutation is the risk factor for cognitive impairment in PD patients.

Long-Term Treatment with Extended-Release Carbidopa–Levodopa (IPX066) in Early and Advanced Parkinson’s Disease: A 9-Month Open-Label Extension Trial

Background and ObjectiveIPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD).MethodsParticipants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings.ResultsAmong 268 early PD patients, 53.4xa0% reported adverse events (AEs) and 1.1xa0% (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6xa0%) and insomnia (5.6xa0%). Among 349 advanced patients, 60.2xa0% reported AEs and 3.7xa0% (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9xa0%) and fall (6.6xa0%). At month 9 (or early termination), 78.3xa0% of early patients were taking IPX066 three times daily (median: 720xa0mg/day) and 87.7xa0% of advanced patients were taking IPX066 three or four times daily (median: 1450xa0mg/day). Adjusting for 70xa0% bioavailability relative to immediate-releasexa0(IR) carbidopa–levodopa, the median dosages correspond to ~500 and ~1015xa0mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension.ConclusionDuring 9xa0months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.

Deep brain stimulation in the treatment of Holmes tremor - a long-term case observation.

We present the patient with Holmes tremor secondary to the infarction of thalamus, successfully treated with the deep brain stimulation (DBS) of the area between ventralis oralis anterior and zona incerta for a long time, in whom the severe tremor reappeared after removal of the DBS lead. This is the first presentation of the effective DBS on this location. Our case does not support the hypothesis that the DBS treatment could lead to sustained relief of symptoms after cessation of stimulation.

Saccadic eye movements in juvenile variant of Huntington disease

BACKGROUND AND PURPOSEnHuntington disease (HD) is a neurodegenerative disease leading to involuntary movements, cognitive and behavior decline. The juvenile variant of HD (JHD) manifests in people younger than 21 and is characterized by a different clinical presentation, i.e. rigidity and bradykinesia. Rapid eye movements were not extensively studied in patients with JHD. Aims of our study were to describe the saccadic eye movements in JHD patients and to find a correlation between the saccade abnormalities, severity of the disease and cognitive and behavior deterioration.nnnMATERIALS AND METHODSnWe studied 10 patients with JHD and 10 healthy subjects. Reflexive and volitional saccades were assessed with the Saccadometer Advanced. The battery of cognitive and behavior tests was performed as well.nnnRESULTSnWe found a prolonged latency, slowness and decreased velocity of reflexive and voluntary saccades and reduced amplitude of voluntary saccades. Moreover, patients with JHD executed a significantly lower number of volitional saccades and made more incorrect cued saccades than controls. We noted a significant correlation between prolonged latency of reflexive saccades with gap task and disease severity and significant inverse correlation between prolonged latency of reflexive saccades with overlap task, an increased number of incorrect saccades made on a cue and impairment in working memory.nnnCONCLUSIONnAbnormalities of saccade eye movements in patients with JHD were similar to those reported in patients with HD. Our findings did not confirm abnormalities previously reported in patients with early onset HD. Abnormal saccade parameters correlated also with a disease severity and cognitive deterioration.

The effect of the rehabilitation program on balance, gait, physical performance and trunk rotation in Parkinson's disease.

BackgroundParkinson’s disease (PD) is a progressive, neurodegenerative disease which leads to postural and gait disorders, limitation in mobility, activities of daily living and disability.AimsThe aim of the study is to assess the effects of the rehabilitation program on balance, gait, motor performance and trunk rotations in PD patients.MethodsSixty-four patients with 1.5–3.0 stage PD in the Hoehn and Yahr scale were randomly allocated to rehabilitation and control groups. Sixty-one patients completed the study. Patients were assessed three times, at month intervals. Between the first and second assessments, the rehabilitation group participated in a rehabilitation training program focused on mobility, balance and gait exercises, consisting of 28 sessions. Balance was assessed with tandem stance and the Pastor test (shoulder tug). Gait was assessed with a 10xa0m walk at preferred speed and 360° turn. Motor performance was evaluated by means of the Physical Performance Test (PPT) and timed motor activities. The trunk rotations were measured in the lumbar and thoraco-lumbar spine with a tape measure.ResultsThe rehabilitation group significantly improved (pxa0<xa00.05) in balance and gait outcomes, PPT score, timed activities and trunk rotations both in comparison to the control group and baseline results. The positive effects of the exercise program maintained for at least 1xa0month.ConclusionThe 4-week rehabilitation training program focused on mobility, balance and gait exercises improved balance, gait, physical performance and trunk rotations in patients with PD.

Is hypertension a risk factor of hemifacial spasm

OBJECTIVESnThe published data on the relation between arterial hypertension (AH) and hemifacial spasm (HFS) are controversial. The aim of the study was to determine the prevalence of AH in HFS patients and the relation of AH and compression of the brainstem at the region of vasomotor center.nnnMATERIALS AND METHODSnThe study included 60 of primary HFS patients and 60 healthy controls matched by age. AH was defined according to WHO criteria. The vessel compression of the brainstem was measure on MRI scans in selected region of vasomotor center located in the ventro-lateral medulla (VLM), between the pontomedullary junction, retro-olivary sulcus and the root entry zone (REZ) of the IX and X nerves. Modeling and compression severity of the VLM was graded in the 0-3 scale.nnnRESULTSnThe prevalence of AH in HFS patients did not differ significantly from the control group (61.6% vs 45.0%, p=ns). VML compression by vessel was frequently found in HFS patients with AH than without AH (97.2% vs 60.9%, χ(2)=11.0, p=0.0009). A similar relation was also found in the control group. The higher rate of VML vascular compression was related to the presence of AH in both, HFS patients and control group.nnnCONCLUSIONnThe prevalence of AH in HFS patients does not differ from controls. The VLM compression in HFS patients and controls is related to AH diagnosis. The association between AH and VLM compression is stronger in patients with higher degree of VLM compression.

Assessment of Gait Therapy Effectiveness in Patients with Parkinson’s Disease on the Basis of Three-Dimensional Movement Analysis

Objective The aim of this study was to assess the effect of physical exercise on gait pattern disorders, based on three-dimensional gait analysis in the sagittal plane in a group of people with Parkinson’s disease (PD). Methods Thirty-two subjects with PD (14 women and 18 men; age: 50–75u2009years) were qualified for the study, which ran for 3u2009weeks and included 18 therapeutic sessions. Thirty-five control subjects were included in the research (13 women and 19 men; age: 52–77u2009years). Gait analysis using the Vicon 3D system took place in the Biokinetics Laboratory. The research group was tested before and after treatment, and the control group was tested once. Results Comparing the average peak angle changes and average standard time results (% gait cycle) corresponding with angles of movement in the lumbar spine, cervical spine, elbow joint, and shoulder joint, statistically significant changes were observed. The study results are indicative of differences in spatiotemporal parameters and angular changes in gait for both groups. After therapeutic treatment, we observed improvement in the angular range of changes in thorax tilting, but there were no difference between the most affected and less affected side. For the cervical spine, a significant reduction in flexion during dual support was observed. The angular range of changes in shoulder joint was significant only in less affected shoulder during the initial contact (F1), terminal stance (F4), and terminal stance (F8) phases of gait (pu2009<u20090.05). After therapeutic treatment, significant angle and setting changes in the most affected limb of the elbow joint occurred during the initial contact and terminal swing phases (F1, F8). In the terminal stance phase (F4), an increase in range of motion by about ±4° was observed (pu2009<u20090.05). Conclusion Exercise therapy slightly increased the range of movement in the examined joints of PD’s patients. Results of pathological walking patterns occurring prior to treatment improved after treatment and moved closer to the physiological gait pattern.

The effects of physiotherapy with PNF concept on gait and balance of patients with Huntington's disease - pilot study.

BACKGROUND AND PURPOSEnHuntingtons disease (HD) is a neurodegenerative, progressive disorder of the central nervous system which causes significant gait and balance disturbances. This is a pilot study which aims to determine the effects of a physiotherapy programme with use of Proprioceptive Neuromuscular Facilitation (PNF) on gait and balance in HD patients.nnnMATERIAL AND METHODSn30 HD patients aged 21-60 with genetically confirmed diagnosis participated in the study. Participants followed a 3-week-long PNF-based physiotherapy programme. Gait and balance were evaluated twice in each participant: first at baseline and then after the course of physiotherapy. The following methods were used for gait disturbances: Tinetti Gait Assessment Tool, Up and Go Test, Timed Walking Tests for 10m and 20m (TWT10m, TWT20m). Balance was assessed with use of Berg Balance Scale, Pastor Test and Functional Reach Test.nnnRESULTSnThere was a significant improvement in all measures of balance and gait.nnnCONCLUSIONnPNF-based physiotherapy is effective and safe in HD patients.

Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients.

Hereditary spastic paraplegias (HSPs) consist of a heterogeneous group of genetically determined neurodegenerative disorders. Progressive lower extremity weakness and spasticity are the prominent features of HSPs resulting from retrograde axonal degeneration of the corticospinal tracts. Three genetic types, SPG3 (ATL1), SPG4 (SPAST) and SPG31 (REEP1), appear predominantly and may account for up to 50% of autosomal dominant hereditary spastic paraplegias (AD-HSPs). Here, we present the results of genetic testing of the three mentioned SPG genetic types in a group of 216 unrelated Polish patients affected with spastic paraplegia. Molecular evaluation was performed by multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing. Nineteen novel mutations: 13 in SPAST, 4 in ATL1 and 2 in REEP1, were identified among overall 50 different mutations detected in 57 families. Genetic analysis resulted in the identification of molecular defects in 54% of familial and 8.4% of isolated cases. Our research expanded the causative mutations spectrum of the three most common genetic forms of HSPs found in a large cohort of probands originating from the Central Europe.