Staging Parkinson’s disease according to the MNCD classification correlates with caregiver burden

Malaltia de Parkinson; Cuidador; Símptomes no motorsParkinson's disease; Caregiver; Non-motor symptomsEnfermedad de Parkinson; Cuidador; Síntomas no motoresBackground and objective: Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients’ quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status. Patients and methods: Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8). Results: Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4–5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers.Conclusion: Staging PD according to the MNCD classification is correlated with caregivers’ strain and burden.Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético; Alpha Bioresearch; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: PI16/0157

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Epoxomicin and trehalose differential effects in cellular viability on control and HD human skin fibroblasts.

<p>(A) Dose-dependent effects of epoxomicin in caspase-3 activation, an indicator of apoptosis. (B) Photomicrographs of activated caspase-3⁺ cells (green) and total nuclei stained with bis-benzimide (blue) after epoxomicin and trehalose treatments. (Scale bar  = 20 µm). (C) Percent of activated caspase-3⁺ cells in control and HD fibroblasts after epoxomicin and trehalose treatments. Values are expressed as the mean ± SD, <i>n</i> = 4 patients. Control cell number (mean per field) 31.87±1.124, <i>n</i> = 4. HD cell number (mean per field) 44.75±2.456, <i>n</i> = 4. The data of each patient was obtained using 4 replicates. Statistical analysis was performed by one-way ANOVA with repeated measures followed by Bonferroni multiple comparison test: *p<0.05, **p<0.01, ***p<0.001 <i>vs</i> Solvent; +p<0.05, ++p<0.01, +++p<0.001 HD <i>vs</i> controls; ΔΔp<0.01, ΔΔΔp<0.001 trehalose + epoxomicin <i>vs</i> epoxomicin; δδδp<0.001 3-methyladenine + trehalose + epoxomicin <i>vs</i> trehalose + epoxomicin.</p

Effects of epoxomicin and trehalose in skin fibroblast cell cycle.

<p>(A) Photomicrographs of BrdU positive cells of dividing cells (green) and total nuclei stained with bis-benzimide (blue) from control and HD patients. (Scale bar  = 20 µm). (B) Percentage of BrdU positive cells with respect to the total number. (C) Comparison of the percentage of BrdU positive cells in early and late cell passage numbers. Values are expressed as the mean ± SD, <i>n</i> = 4 patients. Control cell number (mean per field) 33.80±1.417, <i>n</i> = 4. HD cell number (mean per field) 41.56±2.025, <i>n</i> = 4. The data of each patient was obtained using 4 replicates. Statistical analysis was performed by one-way ANOVA with repeated measures followed by Bonferroni multiple comparison test: *p<0.05, ***p<0.001 <i>vs</i> Solvent; +p<0.05, ++p<0.01, +++p<0.001 HD <i>vs</i> controls.</p

Effects of epoxomicin and trehalose on ERK-1/2 and HSP70 chaperone protein activation in HD fibroblasts.

<p>(A) Western blot of p-ERK-1/2 expression with regard to total ERK and its corresponding densitometric analysis in control and HD fibroblasts. (B) Western blot of HSP70 expression and its corresponding densitometric analysis. Values are expressed as the mean ± SD, <i>n</i> = 4 patients. The data of each patient was obtained using 4 replicates. Statistical analysis was performed by one-way ANOVA with repeated measures followed by Bonferroni multiple comparison test: *p<0.05, ***p<0.001 <i>vs</i> Solvent; +++p<0.001 HD <i>vs</i> controls, ΔΔΔp<0.001 trehalose + epoxomicin <i>vs</i> epoxomicin. There is an interaction between epoxomicin effect and genotype in ERK activation (F = 71.13 with a p value  = <0.0001). In HD, there is an interaction between the epoxomicin and trehalose effects in ERK activation (F = 12.67 with a p value  = 0.0013).</p

Trehalose protects against accumulation of Huntingtin and poly-ubiquitinated protein induced by epoxomicin and increases UPS activity.

<p>(A) Huntingtin immunocytochemistry (green) and total nuclei stained with bis-benzimide (blue). The histogram shows the ratio of Huntingtin (IOD) with respect to the total cell number. (Scale bar  = 20 µm) (B) Ubiquitinated protein accumulation and its corresponding densitometric analysis. (C) Chymotrypsin-like proteasome activity. Values are expressed as the mean ± SD, <i>n</i> = 4 patients. Control cell number (mean per field) 32,66±1.472, <i>n</i> = 4. HD cell number (mean per field) 44,67±0.3405, <i>n</i> = 4. The data of each patient was obtained using 4 replicates. Statistical analysis was performed by one-way ANOVA with repeated measures followed by Bonferroni multiple comparison test: *p<0.05, ***p<0.001 <i>vs</i> solvent; +p<0.05, +++p<0.001 HD <i>vs</i> controls; ΔΔΔp<0.001 trehalose + epoxomicin <i>vs</i> epoxomicin.</p

Macroautophagyc pathway and chaperone-mediated autophagy in control and HD human skin fibroblasts.

<p>(A) LC3 immunocytochemistry (green) and total nuclei stained with bis-benzimide (blue) and the percentage of LC3 positive cells with respect to the total cell number. (B) LAMP2A immunocytochemistry (green) and total nuclei stained with bis-benzimide (blue) and percentage of LAMP2A positive cells. (C) LAMP2A (green) and HSC70 (red) colocalization (yellow) and percentage of LAMP2A and HSC70 colocalization respect to the total cell number. (Scale bar  = 20 µm). Values are expressed as the mean ± SD, <i>n</i> = 4 patients. Control cell number (mean per field) 30.94±2.012, <i>n</i> = 4. HD cell number (mean per field) 46.89±4.587, <i>n</i> = 4. The data of each patient was obtained using 4 replicates. Statistical analysis was performed by one-way ANOVA with repeated measures followed by Bonferroni multiple comparison test: **p<0.01, ***p<0.001 <i>vs</i> Solvent; +<0.05, +p<0.05, ++p<0.01, +++p<0.001 HD <i>vs</i> controls; ΔΔΔp<0.001 trehalose + epoxomicin <i>vs</i> epoxomicin.</p

Epoxomicin increases ROS levels, which are reduced by trehalose in HD firboblasts.

<p>(A) 2′, 7′–dichlorofluorescin (DCF) immunocytochemistry (green) and total nuclei stained with bis-benzimide (blue) in control and HD fibroblasts and (B) percentage of DCF positive cells respect to the total number. (Scale bar  = 20 µm). Values are expressed as the mean ± SD, <i>n</i> = 4 patients. Control cell number (mean per field) 28.83±0.9280, <i>n</i> = 4. HD cell number (mean per field) 46.40±5.247, <i>n</i> = 4. The data of each patient was obtained using 4 replicates. Statistical analysis was performed by one-way ANOVA with repeated measures followed by Bonferroni multiple comparison test: ***p<0.001 <i>vs</i> solvent; +p<0.05, +++p<0.001 HD <i>vs</i> controls; ΔΔΔp<0.001 trehalose + epoxomicin <i>vs</i> epoxomicin.</p

Ritme i dansa a l'aula

Resumen tomado de la publicación. Revisión de los textos: Margalida Barceló. Los archivos se pueden visualizar mediante un reproductor de DVD o bién con el reproductor Windows Media Player (archivos .dat de la carpeta MPEGAV)Se recogen las danzas trabajadas en el curso 'Ritme i dansa a l'aula de música', realizado en el CEP de Manacor durante el curso escolar 2004-2005. El objetivo es trabajar la coordinación de los movimientos con el ritmo de la música. Se presentan un total de 15 danzas y se plantea una actividad para cada una de ellas. Los fragmentos musicales son de estilo clásico (A. Vivaldi, W.A. Mozart, F. Shubert y G. Bizet), contemporáneo (Banda sonora de París-Texas, Halkias Tassos y Pascal Camalde) y tradicional catalán (La masovera del Galop, La balanguera de Linyola y La polca del ball de gitanes de Sant Esteve de Palautardera). Las actividades se desarrollan en grupo mediante círculos y_o parejas y se trabaja la improvisación, expresión corporal, imitación de movimientos de la figura-guía y el seguimiento del ritmo de las notas musicales mediante pulsaciones.BalearesUniversitat de les Illes Balears. Redined Balears; Edifici Guillem Cifre de Colonya. Ctra. de Valldemossa, Km 7,5; 07122 Palma; +34971172792; +34971173190; [email protected]