Cognition and Other Non-Motor Symptoms in an At-Risk Cohort for Parkinson's Disease Defined by REM-Sleep Behavior Disorder and Hyposmia.

Background: REM-sleep behavior disorder (RBD) and other non-motor symptoms such as hyposmia were proposed by the Movement Disorder Society as research criteria for prodromal Parkinson's disease (P-PD). Global cognitive deficit was later added. Objective: To compare non-motor symptoms, focusing on cognition, between a P-PD group and a matched control group. Methods: In this cross-sectional, case-control study, in a first set of analyses, we performed extensive cognitive testing on people with (n = 76) and a control group without (n = 195) probable RBD and hyposmia. Furthermore, we assessed motor and non-motor symptoms related to Parkinson's Disease (PD). After propensity score matching, we compared 62 P-PD with 62 age- and sex-matched controls. In addition, we performed regression analyses on the total sample (n = 271). In a second set of analyses, we used, a.o., the CUPRO to evaluate retrograde procedural memory and visuo-constructive functions. Results: People with P-PD showed significantly poorer performances in global cognition, visuo-constructive and executive functions, mainly in mental flexibility (p < 0.001; p = 0.004; p = 0.003), despite similar educational levels (p = 0.415). We observed significantly more motor and non-motor symptoms (p < 0.001; p = 0.004), higher scores for depression (p = 0.004) and apathy (p < 0.001) as well as lower quality of life (p < 0.001) in P-PD. CONCLUSIONS: Our findings confirm that global cognitive, executive, and visuo-constructive deficits define the P-PD group. In addition, depression, apathy, and lower quality of life were more prevalent in P-PD. If replicated in other samples, executive and visuo-constructive deficits should be considered in non-motor P-PD. Determining specific patterns will support early recognition of PD, secondary prevention of complications and the development of neuroprotective treatments.

Creation of a pandemic memory by tracing COVID-19 infections and immunity in Luxembourg (CON-VINCE).

BACKGROUND: During the COVID-19 pandemic swift implementation of research cohorts was key. While many studies focused exclusively on infected individuals, population based cohorts are essential for the follow-up of SARS-CoV-2 impact on public health. Here we present the CON-VINCE cohort, estimate the point and period prevalence of the SARS-CoV-2 infection, reflect on the spread within the Luxembourgish population, examine immune responses to SARS-CoV-2 infection and vaccination, and ascertain the impact of the pandemic on population psychological wellbeing at a nationwide level. METHODS: A representative sample of the adult Luxembourgish population was enrolled. The cohort was followed-up for twelve months. SARS-CoV-2 RT-qPCR and serology were conducted at each sampling visit. The surveys included detailed epidemiological, clinical, socio-economic, and psychological data. RESULTS: One thousand eight hundred sixty-five individuals were followed over seven visits (April 2020-June 2021) with the final weighted period prevalence of SARS-CoV-2 infection of 15%. The participants had similar risks of being infected regardless of their gender, age, employment status and education level. Vaccination increased the chances of IgG-S positivity in infected individuals. Depression, anxiety, loneliness and stress levels increased at a point of study when there were strict containment measures, returning to baseline afterwards. CONCLUSION: The data collected in CON-VINCE study allowed obtaining insights into the infection spread in Luxembourg, immunity build-up and the impact of the pandemic on psychological wellbeing of the population. Moreover, the study holds great translational potential, as samples stored at the biobank, together with self-reported questionnaire information, can be exploited in further research. TRIAL REGISTRATION: Trial registration number: NCT04379297, 10 April 2020.

Determinants of patient-reported functional mobility in people with Parkinson's disease: A systematic review.

BACKGROUND: Information on determinants of patient-reported functional mobility is lacking but would inform the planning of healthcare, resources and strategies to promote functional mobility in people with Parkinson's disease (PD). RESEARCH QUESTION: To identify the determinants of patient-reported functional mobility of people with PD. METHODS: Eligible: Randomized Controlled Trials, cohort, case-control, or cross-sectional analyses in people PD without date or setting restrictions, published in English, German, or French. Excluded: instruments with under 50 % of items measuring mobility. On August 9th 2023 we last searched Medline, CINAHL and PsychInfo. We assessed risk of bias using the mixed-methods appraisal tool. Results were synthesized by tabulating the determinants by outcomes and study designs. RESULTS: Eleven studies published 2012-2023 were included (most in Swedish outpatient settings). Samples ranged from 9 to 255 participants. Follow-up varied from 1.5 to 36 months with attrition of 15-42 %. Heterogenic study designs complicated results synthesis. However, determinants related to environment seem to associate the strongest with patient-reported functional mobility, although determinants related to body structures and functions were most investigated. We identified disease duration, the ability to drive, caregiving, sex, age, cognitive impairment, postural instability and social participation as determinants of patient-reported functional mobility. DISCUSSION: Methodological quality of the studies was limited. No study reported an a priori power calculation. Three studies controlled for confounders. The included studies lack representativeness of the population of people living with PD. Standardized sets of outcomes could enable more systematic research synthesis. CONCLUSIONS: Future research should focus on activities, participation and environmental factors and improve methodological quality.

Retrograde procedural memory is impaired in people with Parkinson's disease with freezing of gait.

Background: Freezing of gait (FOG), is associated with impairment of different cognitive functions. Previous studies hypothesized that FOG may be due to a loss of automaticity. Research question: To explore whether FOG is associated with impairment in cognitive functions, focusing on retrograde procedural memory, the memory responsible for the automatic, implicit stored procedures that have been acquired in earlier life stages. Methods: In this cross-sectional, case-control study, 288 people with typical Parkinson's disease (PD) from the Luxembourg Parkinson's Study were assigned to Freezers (FOG+) and non-Freezers (FOG-) based on the MDS-UPDRS 2.13 (self-reported FOG episodes) and 3.11 (FOG evaluated by clinicians during gait assessment). Both groups were matched on age, sex and disease duration. Global cognition (MoCA), retrograde procedural memory and visuo-constructive abilities (CUPRO), psychomotor speed and mental flexibility (TMT) were assessed. Furthermore, we repeated our analyses by additionally controlling for depression (BDI-I). Results: Besides lower global cognition (MoCA; p = 0.007) and mental flexibility (TMT-B and Delta-TMT; p < 0.001), FOG+ showed a lower performance in retrograde procedural memory (CUPRO-IS1; p < 0.001) compared to FOG-. After controlling additionally for depression, our main outcome variable CUPRO-IS1 remained significantly lower in FOG+ (p = 0.010). Conclusion: Our findings demonstrated that besides lower global cognition and mental flexibility scores, FOG+ showed lower performance in retrograde procedural memory compared to matched FOG-control patients, even when accounting for factors such as age, sex, disease duration or depression. Significance: In the context of limited treatment options, especially for non-invasive therapeutic approaches, these insights on procedural memory and FOG may lead to new hypotheses on FOG etiology and consequently the development of new treatment options.

Luxembourg Parkinson's study -comprehensive baseline analysis of Parkinson's disease and atypical parkinsonism.

Background: Deep phenotyping of Parkinson's disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson's study. Objective: To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls. Methods: Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders. Results: The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003). Conclusion: Luxembourg Parkinson's study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872.

Smart Scheduling (SMASCH): multi-appointment scheduling system for longitudinal clinical research studies.

Objective: Facilitate the multi-appointment scheduling problems (MASPs) characteristic of longitudinal clinical research studies. Additional goals include: reducing management time, optimizing clinical resources, and securing personally identifiable information. Materials and methods: Following a model view controller architecture, we developed a web-based tool written in Python 3. Results: Smart Scheduling (SMASCH) system facilitates clinical research and integrated care programs in Luxembourg, providing features to better manage MASPs and speed up management tasks. It is available both as a Linux package and Docker image (https://smasch.pages.uni.lu). Discussion: The long-term requirements of longitudinal clinical research studies justify the employment of flexible and well-maintained frameworks and libraries through an iterative software life-cycle suited to respond to rapidly changing scenarios. Conclusions: SMASCH is a free and open-source scheduling system for clinical studies able to satisfy recent data regulations providing features for better data accountability. Better scheduling systems can help optimize several metrics that ultimately affect the success of clinical studies.

Retrograde Procedural Memory in Parkinson's Disease: A Cross-Sectional, Case-Control Study.

BACKGROUND: The analysis of the procedural memory is particularly relevant in neurodegenerative disorders like Parkinson's disease, due to the central role of the basal ganglia in procedural memory. It has been shown that anterograde procedural memory, the ability to learn a new skill, is impaired in Parkinson's disease. However, retrograde procedural memory, the long-term retention and execution of skills learned in earlier life stages, has not yet been systematically investigated in Parkinson's disease. OBJECTIVE: This study aims to investigate retrograde procedural memory in people with Parkinson's disease. We hypothesized that retrograde procedural memory is impaired in people with Parkinson's disease compared to an age- and gender-matched control group. METHODS: First, we developed the CUPRO evaluation system, an extended evaluation system based on the Cube Copying Test, to distinguish the cube copying procedure, representing functioning of retrograde procedural memory, and the final result, representing the visuo-constructive abilities. Development of the evaluation system included tests of discriminant validity. RESULTS: Comparing people with typical Parkinson's disease (n = 201) with age- and gender-matched control subjects (n = 201), we identified cube copying performance to be significantly impaired in people with Parkinson's disease (p = 0.008). No significant correlation was observed between retrograde procedural memory and disease duration. CONCLUSION: We demonstrated lower cube copying performance in people with Parkinson's disease compared to control subjects, which suggests an impaired functioning of retrograde procedural memory in Parkinson's disease.

Quantifying activities of daily living impairment in Parkinson's disease using the Functional Activities Questionnaire.

OBJECTIVE: Cognitive-driven activity of daily living (ADL) impairment in Parkinson's disease (PD) is increasingly discussed as prodromal marker for dementia. Diagnostic properties of assessments for this specific ADL impairment are sparsely investigated in PD. The ability of the Functional Activities Questionnaire (FAQ) for differentiating between PD patients with normal cognition and with mild cognitive impairment (PD-MCI), according to informant and self-reports, was examined. Global cognitive function in groups with and without mild ADL impairment was compared according to different cut-offs. METHODS: Multicenter data of 589 patients of an international cohort (CENTRE-PD) were analyzed. Analyses were run separately for informant-rated and self-rated FAQ. Receiver operating characteristic (ROC) analysis was conducted to define the optimal FAQ cut-off for PD-MCI (≥ 1), and groups were additionally split according to reported FAQ cut-offs for PD-MCI in the literature (≥ 3, ≥ 5). Binary logistic regressions examined the effect of the Montreal Cognitive Assessment (MoCA) score in PD patients with and without mild ADL impairment. RESULTS: Two hundred and twenty-five (38.2%) patients were classified as PD-MCI. For all three cut-off values, sensitivity was moderate to low (< 0.55), but specificity was moderately high (> 0.54) with a tendency of higher values for self-reported deficits. For the self-report, the cut-off ≥ 3 showed a significant effect of the MoCA (B = - 0.31, p = 0.003), where FAQ ≥ 3 patients had worse cognition. No effect for group differences based on informant ratings was detected. CONCLUSION: Our data argue that self-reported ADL impairments assessed by the FAQ show a relation to the severity of cognitive impairment in PD.

Determinants of Self-Stigma in People with Parkinson's Disease: A Mixed Methods Scoping Review.

BACKGROUND: Self-stigma in people with Parkinson's disease (PD) can substantially impact quality of life and possibilities for social participation. An integrative analysis of determinants of self-stigma has been lacking. OBJECTIVE: We sought to explore which complementary insights from qualitative and quantitative studies, as well as from expert consultation, could be gained. METHODS: An established mixed methods study design was employed to first conduct a mixed methods scoping review of published qualitative and quantitative literature, and then consult with experts to arrive at an exhaustive list of determinants of self-stigma after a thematic synthesis. RESULTS: A total of 87 unique determinants of self-stigma were identified. Quantitative studies and expert consultations mainly identified personal determinants of people with self-stigma (e.g., age, anxiety, or apathy). In contrast, qualitative studies identified social situations associated with self-stigma (e.g., joint meals of people with typical PD with others). Notably, self-stigma of people with PD was found to be particularly salient in unfamiliar places, at the working place or in contact with people without PD. Across methods, cognitive impairment, tremor, and abnormal walk and unsteady gait, respectively, were associated with self-stigma. CONCLUSION: The mixed method study design yielded complementary insights, but also factors commonly associated with self-stigma across methods. Future prioritization exercises may gain further insights into self-stigma of people with PD. Facilitating social encounters by both addressing needs of affected people and raising knowledge and public awareness may improve quality of life in people with PD.

The Moderating Role of Resilience in the Personality-Mental Health Relationship During the COVID-19 Pandemic.

Background: Associations between personality traits and mental health outcomes (depression, anxiety, loneliness, and stress) have rarely been assessed in a population-representative sample of a high-income country during the COVID-19 pandemic. Additionally, as far as we know, the role of health and social behaviors as well as resilience in the personality-mental health relationship has yet to be explored. Methods: A representative sample of 1,828 residents of Luxembourg filled in validated scales to assess personality traits and resilience, depressive symptoms, generalized anxiety, loneliness, and stress, indicating mental health, in mid-April 2020. Results: Approximately 21% of the participants scored above the cut-off for moderate depression and moderate loneliness. Moderate anxiety and moderate stress were present in 6.2 and 0.3% of the participants, respectively. Higher-educated respondents and those living in higher-value housing reported better mental health. Agreeableness and conscientiousness were most consistently associated with better mental health; neuroticism was most consistently associated with worse mental health. Spending more time on social media was also associated with elevated levels of all four mental health outcomes. Social and health behaviors did not change the personality-mental health relationships. Resilience moderated some of the personality-mental health associations, most consistently in neuroticism. Conclusions: Findings suggest educational and socioeconomic inequalities in mental health in a nationally representative sample during the COVID-19 confinement measures. Personality traits, particularly agreeableness, conscientiousness, and low neuroticism were associated with mental health. The moderating role of resilience in the personality-mental health relationship suggests intervention potential to improve mental health during periods of confinement.

Contributing Factors and Evolution of Impulse Control Disorder in the Luxembourg Parkinson Cohort.

Background: To establish the frequency of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Within the Luxembourg Parkinson's Study, PD patients were evaluated for ICD presence (score ≥ 1 on MDS-UPDRS I item 1.6), use of dopamine agonists (DA) and other medications. Results: 470 patients were enrolled. Among 217 patients without DA use, 6.9% scored positive for ICD, vs. 15.4% among 253 patients with DA use (p = 0.005). The regression analysis showed that age at PD diagnosis had only a minor impact on ICD occurrence, while there was no influence by gender or co-medications. The longitudinal study over 2 years in 156 patients demonstrated increasing ICD frequency in DA users (p = 0.005). Conclusion: This large and non-interventional study confirms that PD patients with DA treatment show higher frequency of ICD than patients without DA use. It newly demonstrates that ICD can develop independently from age, gender, or co-medications.

Corrigendum: Contributing Factors and Evolution of Impulse Control Disorder in the Luxembourg Parkinson Cohort.

[This corrects the article DOI: 10.3389/fneur.2020.578924.].

Unmet Needs of People With Parkinson's Disease and Their Caregivers During COVID-19-Related Confinement: An Explorative Secondary Data Analysis.

Self-perceived unmet needs in people with typical and atypical parkinsonism (PwP) and their caregivers, support network, personalized ways to address self-perceived unmet needs during confinement, as well as the prevalence of self-reported COVID-19 related symptoms, confirmed SARS-CoV-2 infection, and self-reported COVID-19 related hospitalization in Luxembourg and the Greater Region were assessed. From 18th March to 10th April 2020, 679 PwP were contacted by phone. Data was collected in the form of a semi-structured interview. The thematic synthesis identified 25 themes where PwP need to be supported in order to cope with consequences of the pandemic, and to adapt their daily and health-related activities. The present work highlights that in the context of personalized medicine, depending on the individual needs of support of the patient the identified self-perceived unmet needs were addressed in various ways ranging from one-directed information over interaction up to proactive counseling and monitoring. Family and health professionals, but also other support systems were taking care of the unmet needs of PwP (e.g., shopping, picking-up medication, etc.) during the pandemic. 7/606 PwP (1.15%) reported COVID-19 related symptoms, 4/606 (0.66%) underwent a rRT-PCR-based diagnostic test and 2/606 (0.33%) were confirmed as SARS-CoV-2 positive. None of these PwP reported being hospitalized due to COVID-19. Our results will allow health professionals to expand their services in a meaningful way i.e., personalize their support in the identified themes and thus improve the healthcare of PwP in times of crisis.

Multilingual Validation of the First French Version of Munich Dysphagia Test-Parkinson's Disease (MDT-PD) in the Luxembourg Parkinson's Study.

Introduction: The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect early oropharyngeal symptoms and aspiration risk in patients with idiopathic Parkinson's disease (iPD). In order to make this tool accessible for prevention in the French speaking populations worldwide, we performed the first French translation and provide a linguistic and psychometric validation in the unique multilingual environment of the Luxembourg Parkinson's Study. Methods: We performed the translation of the MDT-PD into French according to WHO guidelines and subsequently performed the linguistic validation including native speakers. For psychometric validation, 46 patients with parkinsonism from Luxembourg and the Greater Region without severe cognitive impairment were recruited in the frame of the Luxembourg Parkinson's Study. All patients were fluent in French and German completed the MDT-PD in both languages (three times in total). Results: Linguistic and psychometric validation of the French MDT-PD was reflected by a high test-retest (10/26 questions with K > 0.6 and 10/26 with 0.4 < K ≤ 0.6) and language reliability (12/26 K > 0.6 and 8/26 0.4 < K ≤ 0.6), with an internal consistency for the French (Cronbach's alpha 0.84) and German version (0.87); strong item collinerarity strengthens the internal consistency. No significant differences between MDT-PD score distribution and clinical parameters assessing, for example, disease progression, motor state, or cognition has been observed. Conclusion: Based on a multilingual approach in the Luxembourg Parkinson Study, we validated the translation of the first French MDT-PD as a non-invasive tool for early detection of dysphagia in patients with parkinsonism. The unexpectedly high number of positively screened patients at earlier disease stages indicate options for new prevention strategies in large French speaking populations worldwide. Diagnostic validation using clinical and endoscopic swallowing evaluation will be continued soon.

The Luxembourg Parkinson's Study: A Comprehensive Approach for Stratification and Early Diagnosis.

While genetic advances have successfully defined part of the complexity in Parkinson's disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson's study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches.