Pavel Dusek

Aim of the study: Comparative cross-sectional study of retinal parameters in Huntington’s disease and their evaluation as marker of disease progression. Clinical rationale for the study: Huntington’s disease (HD) is a neurodegenerative disorder with dominant motor and neuropsychiatric symptoms. Involvement of sensory functions in HD has been investigated, however studies of retinal pathology are incongruent. Effect sizes of previous findings were not published. OCT data of the subjects in previous studies have not been published. Additional examination of structural and functional parameters of retina in larger sample of patients with HD is warranted. Materials and methods: This is a prospective cross-sectional study that included: peripapillary retinal nerve fiber layer thickness (RNFL) and total macular volume (TMV) measured by spectral domain optical coherence tomography (OCT) of retina, Pelli-Robson Contrast Sensitivity test, Farnsworth 15 Hue Color discrimination test, ophthalmology examination and Unified Huntington’s disease Rating Scale (UHDRS). Ninety-four eyes of 41 HD patients examined in total 47 visits and 82 eyes of 41 healthy controls (HC) examined in total 41 visits were included. Analyses were performed by repeated measures linear mixed effects model with age and gender as covariates. False discovery rate was corrected by Benjamini-Hochberg procedure. Results: HD group included 21 males and 20 females (age 50.6±12.0 years [mean ± standard deviation], disease duration 7.1±3.6 years, CAG triplet repeats 44.1±2.4). UHDRS Total Motor Score (TMS) was 30.0±12.3 and Total Functional Capacity 8.2±3.2. Control group (HC) included 19 males and 22 females with age 48.2±10.3 years. There was no statistically significant difference between HD and HC in age. The effect of the disease was not significant in temporal segment RNFL thickness. It was significant in the mean RNFL thickness and TMV, however not passing false discovery rate adjustment and with small effect size. In the HD group, the effect of disease duration and TMS was not significant. The Contrast Sensitivity test in HD was within normal limits and the 15-hue-test in HD did not reveal any specific pathology. Conclusions: The results of our study support possible diffuse retinal changes in global RNFL layer and in macula in Huntington’s disease, however, these changes are small and not suitable as a biomarker for disease progression. We found no other structural or functional changes in retina of Huntington’s disease patients using RNFL layer and macular volume spectral domain OCT and Contrast Sensitivity Test and 15-hue-test. Clinical implications: Current retinal parameters are not appropriate for monitoring HD disease progression.

The potentional benefit of symptomatic treatment of motor impairment in Huntington´s disease (HD) is still discussed. The aim of this study was to find out the effect of medication at different stages of this disease, In our Registry database containing 309 examinations of patients (aged 50.3±13.4 years, disease duration 9.13±3.51 years, CAG ranging from 40 to 70 repeats) was analysed usage of different drugs in comparison. To objectify performance of patients, Unified Huntington´s Disease Rating Scale – total motor score, motor scale subscores (voluntary, occulomotor, chorea, dystonia, rigidity), Total Functional Capacity and Functional Assessment were used. Risperidone was the most used medication with 154 assessements with this treatment and 155 without. Other preparates with the strongest representation were amantadine (97:212 events), clonazepam (56:253), tiapride (49:260), tetrabenazine (13:296) and haloperidol (11:298). Statistically (Mann-Whitney U-test) were compared patients with and without particular medical treatement, with only significant results in patients with clonazepam therapy, who had only significantly higher voluntary motor subscore (p<0.001). Additionally, we performed a linear model using ordinary least squares calculation to count for the effect of disease progression (age, disease duration, CAG repeats). The difference in voluntary motor subscore was independent on the disease progression. Although a longitudinal study should be performed to prove causality of clonazepam, caution should be used when prescribing clonazepam in HD.

Background Huntington’s disease (HD) is a neurodegenerative disorder with dominant motor and neuropsychiatric symptoms. A few studies found that visual symptoms may also be affected in HD. Aims To assess the structural changes in retina by spectral domain optical coherence tomography (OCT). Methods 21 patients with genetically verified HD were included in the study (11 males and 10 females, CAG triplet repeats 44.5±2.6 [mean ±standard deviation], age 50.2±10.10.8 years [mean ±standard deviation], disease duration 5.9±3.8 years [mean ±standard deviation]). All patients were assessed by Unified Huntington’s disease Rating Scale (UHDRS). Ophtalmological examination included visual acuity (100% contrast), intraocular pressure measurement and fundus examination. Spectral domain OCT was performed to evaluate the peripapillary retinal nerve fiber layer (RNFL) thickness in nasal-superior (NS), nasal (N), nasal-inferior (NI), temporal-inferior (TI), temporal (T), temporal-superior (TS) sectors and with nasal-temporal ratio (N/T) and with papillo-macular bundle. Results Peripapillary RNFL thickness measurements were performed in 33 eyes of 21 patients. Age, disease duration, the number of CAG triplet repeats, UHDRS total motor score (TMS) and UHDRS total functional capacity (TFC) were tested for a relationship with global RNFL thickness (G) and with RNFL thickness in NS, N, NI, TI, T, TS sectors, N/T ratio and with papillo-macular bundle using a Pearson’s r coefficient. Correlations of NS and N/T with disease duration and T with UHDRS TFC and UHDRS TMS were found to be significant. However, no correlation did pass the Bonferroni correction for multiple comparison. Conclusions We found significant correlations between RNFL thickness in NS and N/T with disease length and between RNFL thickness in T with UHDRS TFC and UHDRS TMS. Patients with HD with longer disease duration had thinner RNFL thickness in NS and N/T. Patients with lower TFC and higher TMS had thinner RNFL thickness in T. Nevertheless, in case of using the Bonferroni correction for multiple comparison, we found no correlation.

Unintended weight loss is a negative prognostic factor in Huntington’s disease (HD). Exact mechanism of weight loss and influence of therapeutic intervention on this symptom is still unclear. In Prague centre Registry database containing 309 examinations of patients (age 50.3±13.4 years, disease duration 9.13±3.51 years, number of CAG repeats from 40 to 70) were analysed. Correlation analysis was performed between body mass index (BMI) and Unified Huntington’s Disease Rating Scale – motor subscores (voluntary, oculomotor, chorea, dystonia, rigidity) and functional scales were used. None of the Pearson’s correlation were significant. Our results may indicate that BMI may be independent parameter in this particular stage of the disease course. Of the database, 154 examinations were on risperidone and 155 were without risperidone therapy. Age, CAG repeats and disease duration did not differ between the two groups (p=0.1, p=0.9, p=0.26 respectively). Patients on risperidone therapy had significantly higher weight (Mann-Whitney U-test, p<0.0001). Additionally, we performed a linear model using ordinary least squares calculation to count for the effect of disease progression and motor subscores. The effect of risperidone was independent on the disease progression (i.e. disease duration, CAG expansion, age) and voluntary and involuntary movements. In subsequent analysis, 49 events on tiapride therapy and 260 events off tiapride therapy were compared, weight in those two groups did not differ. A longitudinal study must be performed to prove the causality of risperidone effect on weight in HD.

Alterations in mitochondrial parameteres are an important hallmark of Huntington’s disease (HD). Given the ubiquitous expression of mutant huntingtin raises the prospect that mitochondrial disturbancies can be detected and monitored also in buccal epithelial cells. In a group of 34 patients with Huntington’s disease and a group of 22 age-related healthy volunteers, respiratory complex I and IV protein quantities in buccal epithelial cells were measured using dipstick immunocapture assay. The protein quantity of respiratory complex I is correlated with age (r=0.427, p=0.026, FWE-p=0.156) in the patient group, but not in the group of healthy subjects. Our non-invasive approach allows to obtain valuable materials for studies on mitochondrial biochemical parameters in patients with neurodegenerative diseases and could be be useful in epidemiological studies.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.

The aim of the present study was to investigate if prospective memory (PM) is impaired in idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). RBD is a parasomnia characterized by dream enactment and by REM sleep without muscle atonia. iRBD is considered as the initial stage of neurodegeneration with pathological storage of alpha-synuclein. Sixty iRBD patients with polysomnography-confirmed RBD without parkinsonism and dementia and 30 demographically matched normal controls (NC) were enrolled in the present study. Clinical assessment included Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), dopamine transporter single-photon emission computed tomography (DaT-SPECT) for imaging synapses of dopaminergic neurons in the striatum and a neuropsychological battery with embedded time-based and event-based PM measures. iRBD differed significantly from NC in event-based PM, a number of event-based failures to recall intention and total PM performance (all p < .001) but did not differ in time-based PM and recognition. PM did not contribute to impairment of instrumental activities of daily living in iRBD. Despite being preserved in iRBD in comparison to NC, time-based PM correlated significantly with dopaminergic neuronal loss measured by DaT-SPECT. We show evidence for a differential pattern of PM impairment in iRBD with severe impairment of event-based and concurrent preservation of time-based PM. We theorize that event-based PM impairment in iRBD is caused by severe impairment of retention and recognition mechanisms in episodic memory whereas time-based PM seems to be affected by reduced striatal dopaminergic synapses.

Objectives: Executive dysfunction is a common feature in Parkinson’s disease (PD). However, there is a lack of brief validated instruments for executive dysfunction in PD. Methods: The aim of the present study was to assess the relation of Frontal Assessment Battery (FAB) scores to age and education, to verify the utility of FAB in the evaluation of executive dysfunction in PD and to differentiate between controls (n=41), PD patients with normal cognition (PD-NC; n=41; Hoehn and Yahr stages 2–3) and PD with mild cognitive impairment (PD-MCI; n=32; Hoehn and Yahr stages 2–3). In addition, we studied the relation between voxel-based morphometric (VBM) data and FAB results in PD. Results: We found that FAB scores are significantly related to age and education. The FAB has shown discriminative validity for the differentiation of PD-MCI from PD-NC and controls (area under the curve >.80). Also, the VBM analysis revealed lower FAB scores are specifically related to lower gray matter density in the right ventromedial prefrontal areas and precuneus. Conclusions: The FAB can be recommended as a valid instrument for PD-MCI Level I screening. FAB is sensitive to frontal lobe involvement in PD as reflected by lower gray matter density in prefrontal areas. (JINS, 2017, 23, 675–684)