Olga Ulmanová

Quantitative assessment of motor speech abnormalities in idiopathic rapid eye movement sleep behaviour disorder

OBJECTIVE Patients with idiopathic rapid eye movement sleep behaviour disorder (RBD) are at substantial risk for developing Parkinsons disease (PD) or related neurodegenerative disorders. Speech is an important indicator of motor function and movement coordination, and therefore may be an extremely sensitive early marker of changes due to prodromal neurodegeneration. METHODS Speech data were acquired from 16 RBD subjects and 16 age- and sex-matched healthy control subjects. Objective acoustic assessment of 15 speech dimensions representing various phonatory, articulatory, and prosodic deviations was performed. Statistical models were applied to characterise speech disorders in RBD and to estimate sensitivity and specificity in differentiating between RBD and control subjects. RESULTS Some form of speech impairment was revealed in 88% of RBD subjects. Articulatory deficits were the most prominent findings in RBD. In comparison to controls, the RBD group showed significant alterations in irregular alternating motion rates (p = 0.009) and articulatory decay (p = 0.01). The combination of four distinctive speech dimensions, including aperiodicity, irregular alternating motion rates, articulatory decay, and dysfluency, led to 96% sensitivity and 79% specificity in discriminating between RBD and control subjects. Speech impairment was significantly more pronounced in RBD subjects with the motor score of the Unified Parkinsons Disease Rating Scale greater than 4 points when compared to other RBD individuals. CONCLUSION Simple quantitative speech motor measures may be suitable for the reliable detection of prodromal neurodegeneration in subjects with RBD, and therefore may provide important outcomes for future therapy trials.

Low incidence of restrictive valvulopathy in patients with Parkinson's disease on moderate dose of pergolide

AbstractRestrictive valvular heart disease (VHD) has recently been reported in Parkinsons disease (PD) patients treated with ergot dopamine agonists. The aim of the present study was to detect valvular changes in our patients and to investigate their relationship to long-term use of pergolide.We examined 90 patients (mean age 60.8 ± SD 9.5 years) with PD, average duration 10.0 ± 5.1 years. Mean pergolide dose was 2.93 ± 0.75 (range 0.75 to 5) mg per day. 36 subjects (mean age 55.0 ± 12.8 years) served as controls. All subjects underwent transthoracic echo-Doppler examination. Valve morphology was rated as normal, fibrotic, restrictive, or degenerative. In addition, the mitral tenting area (TA) and tenting distance (TD) were assessed.In 40 out of 90 (45%) PD patients and in 13 out of 36 (36%) controls, mild mitral regurgitation was observed. In 1 PD patient, a moderate mitral regurgitation was recorded. However, no case of restrictive VHD was found. Neither the TA (1.44 ± 0.24cm2 vs 1.33 ± 0.44cm2) nor the TD (0.73 ± 0.10 cm vs. 0.72 ± 0.30 cm) differed from controls. There were no correlations between the current or cumulative dose of pergolide and TA or TD. Discrete fibrotic changes on valves were found in 10 out of 90 (11%) patients. Degenerative changes of valves were found in 11 (12%) patients and in 7 (19 %) controls.Thus in contrast to earlier findings of restrictive VHD in up to one-third of PD patients on pergolide, we did not find any significant heart disease. We only observed mild to moderate mitral regurgitation and clinically insignificant valvular fibrosis. A possible reason for such a discrepancy is that the daily doses of pergolide in our patients were inferior to those reported previously. In conclusion, the prevalence of restrictive VHD has been lower than expected in our patients with PD, probably in relation to moderate daily doses of pergolide.

NovelOPA1missense mutation in a family with optic atrophy and severe widespread neurological disorder

Purpose:  To identify the underlying molecular genetic cause in a Czech family with optic atrophy, deafness, ptosis, ophthalmoplegia, polyneuropathy and ataxia transmitted as an autosomal dominant trait.

Validation of a new tool for automatic assessment of tremor frequency from video recordings

We present a validation study for TremAn--a tool for automatic detection of tremor and measurement of its frequency from video recordings. To assess the validity of TremAn we designed a study consisting of tremor assessment from video, by accelerometry and by clinical evaluation using Fahn-Tolosa-Marin scale. 26 patients with essential tremor and 5 healthy volunteers underwent the examination in four standardized positions with focus on the hand tremor. Results showed that the frequencies of tremor measured with TremAn and with accelerometry are closely related, attaining agreement with less than 0.1 Hz difference in 80% and less than 0.5 Hz in 94% of measured samples. The reproducibility of frequency measurements using TremAn was comparable to the accelerometry, with the TremAn/accelerometry ratio of measurement error standard deviations equal to 0.99 (95% confidence interval (0.84, 1.17)).

Tremor analysis by decomposition of acceleration into gravity and inertial acceleration using inertial measurement unit

Decomposition of acceleration was investigated as an alternative to commonly used direct spectral analysis of measured acceleration or angular velocity for tremor quantification. Orientation estimation algorithm was devised to decompose the measured acceleration into inertial acceleration caused by sensor movement in inertial reference frame and gravitational artifact. Resulting signals, beside measured acceleration and angular velocity, were used to assess tremor amplitude and frequency by spectral peak detection. The algorithm was tested on experimental data from a clinical study including patients with essential tremor. Influence of sensor calibration and connections of results to analytic approach are analyzed briefly.

Changes of Retina Are Not Involved in the Genesis of Visual Hallucinations in Parkinson’s Disease

Parkinsons disease (PD) is characterized by motor and nonmotor symptoms. Nonmotor symptoms include primarily visual hallucinations (VH). The aim of our study was to establish whether patients with PD and visual hallucinations (PDH+) have structural changes of retina detected by an optical coherence tomography (OCT) in comparison with PD patients without visual hallucinations (PDH−). We examined 52 PD patients (18 with VH, 34 without VH) and 15 age and sex matched healthy controls. Retinal nerve fiber layer (RNFL) thickness and macular thickness and volume were assessed by OCT. Functional impairment of retina was assessed using 2.5% contrast sensitivity test. For OCT outcomes we analyzed 15 PDH+ and 15 PDH− subjects matched for age, gender, and PD duration. For contrast sensitivity we analyzed 8 pairs of patients matched for age, gender, and visual acuity. There was no significant difference in RNFL thickness and macular thickness and macular volume between 15 PDH+ and 15 PDH− subjects, and also between a group of 44 PD patients (both PDH+ and PDH−) and 15 age and gender matched healthy controls. No significant difference was found for 2.5% contrast sensitivity test values between PDH+ and PDH− subjects. Therefore we conclude that functional and structural changes in retina play no role in genesis of VH in PD.

Intermittent bilateral coherence in physiological and essential hand tremor

OBJECTIVE To investigate the prevalence and the temporal structure of bilateral coherence in physiological (PT) and essential (ET) hand tremor. METHODS Triaxial accelerometric recordings from both hands in 30 healthy subjects and 34 ET patients were analyzed using spectral coherence and wavelet coherence methods. In 12 additional healthy subjects, the relation between the hand tremor and the chest wall acceleration was evaluated using partial coherence analysis. RESULTS The majority of both PT and ET subjects displayed significant bilateral coherence. While in PT, bilateral coherence was most frequently found in resting hand position (97% of subjects), in ET the prevalence was comparable for resting (54%) and postural (49%-57%) positions. In both PT and ET, epochs of strong coherence lasting several to a dozen seconds were separated by intervals of insignificant coherence. In PT, bilateral coherence at the main tremor frequency (8-12Hz) was coupled with the ballistocardiac rhythm. CONCLUSION The oscillations of the two hands are intermittently synchronized in both PT and ET. We propose that in postural PT, bilateral coherence at the main tremor frequency arises from transient simultaneous entrainment of the left and right hand oscillations to ballistocardiac forcing. SIGNIFICANCE Bilateral coherence of hand kinematics provides a sensitive measure of synchronizing influences on the left and right tremor oscillators.

General and selective brain connectivity alterations in essential tremor: A resting state fMRI study

Although essential tremor is the most common movement disorder, there is little knowledge about the pathophysiological mechanisms of this disease. Therefore, we explored brain connectivity based on slow spontaneous fluctuations of blood oxygenation level dependent (BOLD) signal in patients with essential tremor (ET). A cohort of 19 ET patients and 23 healthy individuals were scanned in resting condition using functional magnetic resonance imaging (fMRI). General connectivity was assessed by eigenvector centrality (EC) mapping. Selective connectivity was analyzed by correlations of the BOLD signal between the preselected seed regions and all the other brain areas. These measures were then correlated with the tremor severity evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTS). Compared to healthy subjects, ET patients were found to have lower EC in the cerebellar hemispheres and higher EC in the anterior cingulate and in the primary motor cortices bilaterally. In patients, the FTMTS score correlated positively with the EC in the putamen. In addition, the FTMTS score correlated positively with selective connectivity between the thalamus and other structures (putamen, pre-supplementary motor area (pre-SMA), parietal cortex), and between the pre-SMA and the putamen. We observed a selective coupling between a number of areas in the sensorimotor network including the basal ganglia and the ventral intermediate nucleus of thalamus, which is widely used as neurosurgical target for tremor treatment. Finally, ET was marked by suppression of general connectivity in the cerebellum, which is in agreement with the concept of ET as a disorder with cerebellar damage.

Eye movements in idiopathic rapid eye movement sleep behaviour disorder: High antisaccade error rate reflects prefrontal cortex dysfunction

Abnormalities of eye movements have been reported in patients with Parkinsons disease (PD). However, it is unclear if they occur in the prodromal stage of synucleinopathy represented by idiopathic rapid eye movement sleep behaviour disorder (iRBD). We thus aimed to study eye movements in subjects with iRBD and in de novo PD, to assess if their abnormalities may serve as a clinical biomarker of neurodegeneration. Fifty subjects with polysomnography‐confirmed iRBD (46 male, age 40–79 years), 18 newly diagnosed, untreated PD patients (13 male, age 43–75 years) and 25 healthy controls (20 male, age 42–79 years) were prospectively enrolled. Horizontal and vertical ocular prosaccades and antisaccades were investigated with video‐oculography. All patients completed the MDS‐UPDRS and the Montreal Cognitive Assessment. In addition, a neuropsychological battery was performed on iRBD subjects. When compared with healthy controls, both de novo PD patients and iRBD subjects showed increased error rates in the horizontal antisaccade task (p < 0.01, p < 0.05 respectively). In the iRBD group, the error rates in horizontal and vertical antisaccades correlated with performances in the Prague Stroop Test and the Grooved Pegboard Test, as well as with motor scores of the MDS‐UPDRS. De novo PD patients showed a lower gain (p < 0.01) compared with controls. In conclusion, the increased error rate in the antisaccade task of iRBD and PD patients reflects a dysfunction of the dorsolateral prefrontal cortex and is related to the impairment of executive functions and attention.

Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56∗) CRYGD variant in a family with dominantly inherited congenital cataracts

A bilaterally blind woman, with a three generation family history of autosomal dominant congenital cataracts, variably associated with iris colobomata and microcornea, sought preconception genetic consultation. Whole-exome sequencing was performed in three affected family members, one unaffected first degree relative, and one spouse. The sequence variant c.168C>G; p.(Tyr56∗) in CRYGD, previously reported as pathogenic, and a novel mutation c.809C>A; p.(Ser270Tyr) in MAF, were identified in two affected family members; the grandmother, and half-brother of the proband. The proband inherited only the MAF mutation, whereas her clinically unaffected sister had the CRYGD change. In silico analysis supported a pathogenic role of p.(Ser270Tyr) in MAF, which was absent from publicly available whole-exome datasets, and 1161 Czech individuals. The frequency of CRYGD p.(Tyr56∗) in the ExAC dataset was higher than the estimated incidence of congenital cataract in the general population. Our study highlights that patients with genetically heterogeneous conditions may exhibit rare variants in more than one disease-associated gene, warranting caution with data interpretation, and supporting parallel screening of all genes known to harbour pathogenic mutations for a given phenotype. The pathogenicity of sequence variants previously reported as cataract-causing may require re-assessment in light of recently released datasets of human genomic variation.