Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag

Staging Parkinson’s Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life

Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL: 1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). Results: Four hundred and thirty-nine PD patients (62.05 +/- 7.84 years old; 59% males) were included. MNCD stage was: stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advanced MNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p < 0.0001) and EUROHIS-QOL8 (p < 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD

Cognitive impairment and dementia in young onset Parkinson’s disease

[Background and objective] Patients with young-onset Parkinson’s disease (YOPD) have a slower progression. Our aim was to analyze the change in cognitive function in YOPD compared to patients with a later onset and controls.[Patients and methods] Patients with Parkinson’s disease (PD) and controls from the COPPADIS cohort were included. Cognitive function was assessed with the Parkinson’s Disease Cognitive Rating Scale (PD-CRS) at baseline (V0), 2-year ± 1 month (V2y), and 4-year ± 3 months follow-up (V4y). Regarding age from symptoms onset, patients were classified as YOPD (< 50 years) or non-YOPD (≥ 50). A score in the PD-CRS < 81 was defined as cognitive impairment (CI): ≤ 64 dementia; 65–80 mild cognitive impairment (MCI).[Results] One-hundred and twenty-four YOPD (50.7 ± 7.9 years; 66.1% males), 234 non-YOPD (67.8 ± 7.8 years; 59.3% males) patients, and 205 controls (61 ± 8.3 years; 49.5% males) were included. The score on the PD-CRS and its subscore domains was higher at all visits in YOPD compared to non-YOPD patients and to controls (p < 0.0001 in all analysis), but no differences were detected between YOPD patients and controls. Only non-YOPD patients had significant impairment in their cognitive function from V0 to V4y (p < 0.0001). At V4y, the frequency of dementia and MCI was 5% and 10% in YOPD compared to 25.2% and 22.3% in non-YOPD patients (p < 0.0001). A lower score on the Parkinson’s Disease Sleep Scale at baseline was a predictor of CI at V4y in YOPD patients (Adjusted R2 = 0.61; OR = 0.965; p = 0.029).[Conclusion] Cognitive dysfunction progressed more slowly in YOPD than in non-YOPD patients.COPPADIS and the present study were developed with the help of Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético (https://fundaciondegen.org/) and Alpha Bioresearch (www.alphabioresearch.com). Also, we received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesión de subvenciones de Proyectos de Investigación en Salud de la convocatoria 2020 de la Acción Estratégica en Salud 2017–2020 por el Proyecto “PROGRESIÓN NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) to develop a part of the COPPADIS project.Peer reviewe

Multicentre, randomised, single-blind, parallel group trial to compare the effectiveness of a Holter for Parkinson's symptoms against other clinical monitoring methods: study protocol

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson's disease patients (Parkinson's Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson?s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson?s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor?patient contacts will be analysed. The noninferiority of the Parkinson's Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson's Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Funding This work is supported by AbbVie S.L.U, the Instituto de Salud Carlos III [DTS17/00195] and the European Fund for Regional Development, 'A way to make Europe'

Staging Parkinson’s Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life

© 2023 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD).Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity.Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8).Results: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages.Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.COPPADIS and the present study were developed with the help of Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético (https://fundaciondegen.org/) and Alpha Bioresearch (www.alphabioresearch.com). Also, we received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesión de subvenciones de Proyectos de Investigación en Salud de la convocatoria 2020 de la Acción Estratégica en Salud 2017-2020 por el Proyecto “PROGRESION NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) to develop a part of the COPPADIS project.Peer reviewe

Nonmotor Symptoms In Lrrk2 G2019s Associated Parkinson's Disease

Background: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. Objective: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. Methods: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. Results: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5 +/- 6.8 vs 18.4 +/- 6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9 +/- 4.7 vs 19.4 +/- 6.8; p < 0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. Conclusion: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD

Comparison of the Results of a Parkinson's Holter Monitor With Patient Diaries, in Real Conditions of Use : A Sub-analysis of the MoMoPa-EC Clinical Trial

Altres ajuts: the European Fund for Regional Development ('A way to make Europe'); AbbVie S.L.U.Background: For specialists in charge of Parkinson's disease (PD), one of the most time-consuming tasks of the consultations is the assessment of symptoms and motor fluctuations. This task is complex and is usually based on the information provided by the patients themselves, which in most cases is complex and biased. In recent times, different tools have appeared on the market that allow automatic ambulatory monitoring. The MoMoPa-EC clinical trial (NCT04176302) investigates the effect of one of these tools-Sense4Care's STAT-ON-can have on routine clinical practice. In this sub-analysis the agreement between the Hauser diaries and the STAT-ON sensor is analyzed. Methods: Eighty four patients from MoMoPa-EC cohort were included in this sub-analysis. The intraclass correlation coefficient was calculated between the patient diary entries and the sensor data. Results: The intraclass correlation coefficient of both methods was 0.57 (95% CI: 0.3-0.73) for the OFF time (%), 0.48 (95% CI: 0.17-0.68) for the time in ON (%), and 0.65 (95% CI%: 0.44-0.78) for the time with dyskinesias (%). Furthermore, the Spearman correlations with the UPDRS scale have been analyzed for different parameters of the two methods. The maximum correlation found was −0.63 (p < 0.001) between Mean Fluidity (one of the variables offered by the STAT-dON) and factor 1 of the UPDRS. Conclusion: This sub-analysis shows a moderate concordance between the two tools, it is clearly appreciated that the correlation between the different UPDRS indices is better with the STAT-ON than with the Hauser diary. Trial Registration: https://clinicaltrials.gov/show/NCT04176302 (NCT04176302)

Utilidad clínica del dispositivo para la monitorización personalizada de la enfermedad de Parkinson, STAT-ON, en condiciones de práctica clínica diaria: resultados de una encuesta de opinión de neurólogos expertos

Background: STAT-ONTM is an objective tool that registers ON-OFF fluctuations making possible to know the state of the patient at every moment of the day in normal life. Our aim was to analyze the opinion of different Parkinson’s disease experts about the STAT-ONTM tool after using the device in a real clinical practice setting (RCPS). Methods: STAT-ONTM was provided by the Company Sense4Care to Spanish neurologists for using it in a RCPS. Each neurologist had the device for at least three months and could use it in PD patients at his/her own discretion. In February 2020, a survey with 30 questions was sent to all participants. Results: Two thirds of neurologists (53.8% females; mean age 44.9 ± 9 years old) worked in a Movement Disorders Unit, the average experience in PD was 16 ± 6.9 years, and 40.7% of them had previously used other devices. A total of 119 evaluations were performed in 114 patients (range 2—9 by neurologist; mean 4.5 ± 2.3). STAT-ONTM was considered ‘‘quite’’ to ‘‘very useful’’ by 74% of the neurologists with an overall opinion of 6.9 ± 1.7 (0, worst; 10, best). STAT-ONTM was considered better than diaries by 70.3% of neurologists and a useful tool for the identification of patients with advanced PD by 81.5%. Proper identification of freezing of gait episodes and falls were frequent limitations reported. Conclusion: STAT-ONTM could be a useful device for using in PD patients in clinical practice.Introducción: STAT-ON es un dispositivo que registra las fluctuaciones on-off que permite conocer el estado del paciente con enfermedad de Parkinson (EP) en cada momento del día. Nuestro objetivo fue analizar la opinión de diferentes expertos en EP sobre STAT-ON, después de usar el dispositivo en un entorno de práctica clínica real (PCR). Métodos: STAT-ON fue proporcionado por la companía ˜ Sense4Care a neurólogos espanoles ˜ para usarlo en PCR. Cada neurólogo dispuso del dispositivo durante al menos tres meses y podía usarlo en pacientes con EP, según su criterio. En febrero de 2020, se envió una encuesta con 30 preguntas a todos los participantes. Resultados: Dos tercios de los neurólogos (53,8% mujeres; edad promedio 44,9 ± 9 anos) ˜ trabajaban en una Unidad de Trastornos del Movimiento, con una experiencia en EP de 16 ± 6,9 anos, ˜ habiendo el 40,7% usado otros dispositivos previamente. Se realizaron un total de 119 evaluaciones en 114 pacientes (rango dos a nueve por neurólogo; media 4,5 ± 2,3). STAT-ON fue considerado «bastante» a «muy útil» por el 74% de los neurólogos, con una opinión general de 6,9 ± 1,7 (0, peor; 10, mejor). STAT-ON fue considerado mejor que los diarios por el 70,3% de los neurólogos y una herramienta útil para la identificación de pacientes con EP avanzada por un 81,5%. La identificación adecuada de los episodios de congelación de la marcha y las caídas fueron las limitaciones más reportadas. Conclusiones: STAT-ON podría ser un dispositivo útil para usar en la PC

Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies

[Background] Previous studies suggest a link between CAG repeat number in the HTT gene and non-Huntington neurodegenerative diseases.[Objective] The aim is to analyze whether expanded HTT CAG alleles and/or their size are associated with the risk for developing α-synucleinopathies or their behavior as modulators of the phenotype.[Methods] We genotyped the HTT gene CAG repeat number and APOE-Ɛ isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of α-synucleinopathy.[Results] We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA.[Conclusions] Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways.This work is supported by the Fondo de Investigaciones Sanitarias' Spanish government ICIII FIS-FEDER grants (ID grants: PI21/0467 to V.A., and PI21/00886 to P.P.). Sergio Pérez-Oliveira is supported by Fundación Parkinson Asturias-Obra Social Cajastur. M.T.P. was supported by the Spanish Ministry of Education, Culture and Sports [FPU16/05061]. D.M.-G. was supported by the “Río Hortega” program [CM18/00142] from the Instituto de Salud Carlos III (ISCIII-FEDER). P.G.-G. was supported by the “Nicolás Monardes” program [C-0048-2017] from the Andalusian Regional Ministry of Health. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa,” Fundació ACE, and CIBERNED. P.G. is supported by CIBERNED employment plan CNV-304-PRF-866. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by National Grants (PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301). Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”).Peer reviewe