Factors associated with self-rated health in people with late-stage parkinson's and cognitive impairment.

PURPOSE: To investigate the contributors to self-rated health in people with late-stage Parkinson's disease (PD) and cognitive impairment. METHODS: A secondary analysis of baseline data from the international Care of Late-Stage Parkinsonism (CLaSP) cohort study was conducted. Participants with PD and either dementia or mild cognitive impairment or MMSE < 24/30 in the absence of major depression were included if they had completed the EQ-5D-3L assessment (n = 277). Factors associated with self-rated health (EQ-5D-3L Index and Visual Analogue Scale) were investigated through multivariable linear regression. RESULTS: More severe PD (motor and non-motor) was associated with worse self-rated health. The EQ-5D-3L dimensions of Mobility, Self-Care and Usual Activities were almost universally affected; the latter two particularly severely. Being unable to perform usual activities or having moderate to extreme anxiety or depression were significantly associated with EQ-5D-3L Visual Analogue Scale, suggesting these are particularly valued. Worse motor impairment and function and the non-motor symptom domains of mood, perception, sexual function, and miscellaneous (e.g., pain) were associated with worse self-rated health, whereas greater burden of gastrointestinal symptoms was associated with better self-rated health in multivariate analysis. Better self-rated health was associated with recent PD nurse consultation, and higher doses of dopaminergic medication. CONCLUSION: Improvement of activities of daily living, mood and anxiety should be prioritised in clinical practice, with consideration of perception and sexual function in this population. Recent nurse consultations and higher antiparkinsonian doses are associated with better self-rated health, suggesting there is no room for a therapeutic nihilism in this population of people within a complex phase of PD.

Early-phase amyloid PET reproduces metabolic signatures of cognitive decline in Parkinson's disease.

INTRODUCTION: Recent work suggests that amyloid beta (Aß) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase 18F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD. METHODS: One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aß PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion. RESULTS: Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions. DISCUSSION: EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment. Highlights: Images taken at amyloid beta (Aß) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aß burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.

Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Staging of progressive supranuclear palsy-Richardson syndrome using MRI brain charts for the human lifespan.

Brain charts for the human lifespan have been recently proposed to build dynamic models of brain anatomy in normal aging and various neurological conditions. They offer new possibilities to quantify neuroanatomical changes from preclinical stages to death, where longitudinal MRI data are not available. In this study, we used brain charts to model the progression of brain atrophy in progressive supranuclear palsy-Richardson syndrome. We combined multiple datasets (n = 8170 quality controlled MRI of healthy subjects from 22 cohorts covering the entire lifespan, and n = 62 MRI of progressive supranuclear palsy-Richardson syndrome patients from the Four Repeat Tauopathy Neuroimaging Initiative (4RTNI)) to extrapolate lifetime volumetric models of healthy and progressive supranuclear palsy-Richardson syndrome brain structures. We then mapped in time and space the sequential divergence between healthy and progressive supranuclear palsy-Richardson syndrome charts. We found six major consecutive stages of atrophy progression: (i) ventral diencephalon (including subthalamic nuclei, substantia nigra, and red nuclei), (ii) pallidum, (iii) brainstem, striatum and amygdala, (iv) thalamus, (v) frontal lobe, and (vi) occipital lobe. The three structures with the most severe atrophy over time were the thalamus, followed by the pallidum and the brainstem. These results match the neuropathological staging of tauopathy progression in progressive supranuclear palsy-Richardson syndrome, where the pathology is supposed to start in the pallido-nigro-luysian system and spreads rostrally via the striatum and the amygdala to the cerebral cortex, and caudally to the brainstem. This study supports the use of brain charts for the human lifespan to study the progression of neurodegenerative diseases, especially in the absence of specific biomarkers as in PSP.

Patient-perceived progression in multiple system atrophy: natural history of quality of life.

BACKGROUND: Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improve patient care and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients and identify informative items using a four-step statistical strategy. METHODS: We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. A four-step strategy (1) determined the subdimensions of Hr-QoL, (2) modelled the subdimension trajectories over time, (3) mapped item impairments with disease stages and (4) identified most informative items. RESULTS: Four dimensions were identified. In addition to the original motor, non-motor and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the non-motor and emotional aspects were already impaired at cohort entry and deteriorated slowly over the disease course. Impairments were associated with sex, diagnosis subtype and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items. CONCLUSION: The multidimensional Hr-QoL deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL over time using the four-step strategy can provide perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective.

Care of Late-Stage Parkinsonism: Resource Utilization of the Disease in Five European Countries.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. OBJECTIVE: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. METHODS: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. RESULTS: During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. CONCLUSION: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Recent Advances in Clinical Trials in Multiple System Atrophy.

PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.

The Care Needs of Patients With Cognitive Impairment in Late-Stage Parkinson's Disease.

BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD), but care needs and resource use for those with significant cognitive impairment are not well established. METHODS: 675 participants with PD from the international Care of Late-Stage Parkinsonism (CLaSP) study were grouped into those without (n = 333, 49%) and with cognitive impairment (MMSE < 24/30 or diagnosis of dementia or Mild Cognitive Impairment; n = 342, 51%) and their clinical features, care needs and healthcare utilisation compared. The relationship between cognition and healthcare consultations was investigated through logistic regression. RESULTS: Cognitive impairment was associated with more motor and non-motor symptoms, less antiparkinsonian but higher rates of dementia and antipsychotic medication, worse subjective health status and greater caregiver burden. A considerable proportion did not have a pre-established cognitive diagnosis. Care needs were high across the whole sample but higher in the cognitive impairment group. Home care and care home use was higher in the cognitive impairment group. However, use of healthcare consultations was similar between the groups and significantly fewer participants with cognitive impairment had had recent PD Nurse consultations. Worse cognitive impairment was associated with lower frequency of recent PD nurse and multidisciplinary therapy consultation (physiotherapy, massage, occupational therapy, speech training and general nursing). CONCLUSIONS: Those with cognitive impairment have more severe PD, higher care needs and greater social care utilisation than those with normal cognition, yet use of health care services is similar or less. Cognitive impairment appears to be a barrier to PD nurse and multidisciplinary therapy consultations. This challenges current models of care: alternative models of care may be required to serve this population. PLAIN LANGUAGE SUMMARY: Parkinson's disease is a long-term progressive health condition. Over time, many people with Parkinson's develop problems with thinking and memory, called cognitive impairment. This can negatively impact the daily lives of the person with Parkinson's and their caregiver. It is also thought to be a barrier to accessing healthcare. How people with Parkinson's who have cognitive impairment use healthcare and detail of their care needs is not well known.We analysed data from a large sample of people with advanced Parkinson's from six European countries to investigate their symptoms, care needs and healthcare use. We compared those with cognitive impairment to (342 people) to those without cognitive impairment (333 people).We found that those with cognitive impairment had more severe Parkinson's across a range of symptoms compared to those without cognitive impairment. They also had more care needs, reported their health status to be worse, and their caregivers experienced greater strain from caring. Whilst use of other healthcare services was similar between the two groups, those with cognitive impairment were less likely to have recently seen a Parkinson's nurse than those without cognitive impairment. Further analysis showed an association between cognitive impairment and not having seen a Parkinson's nurse or therapist recently, taking psychiatric symptoms, functional disability and care home residence into account. Therapists included were physiotherapy, massage, occupational therapy, speech training and general nursing. These findings highlight unmet need. We suggest that healthcare should be more targeted to help this group of people, given their higher care needs.

Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study.

OBJECTIVE: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Meaning in Life in Late-Stage Parkinson's Disease: Results from the Care of Late-Stage Parkinsonism Study (CLaSP) in Six European Countries.

The Care of Late-Stage Parkinsonism (CLaSP) study is a longitudinal, multicentre, prospective cohort study to assess the needs and provision of care for people with late-stage Parkinson's disease and their caregivers in six European countries. As a cross-sectional study within the CLaSP study, 509 people with Parkinson's disease completed the "Schedule-for-Meaning-in-Life-Evaluation" (SMiLE) questionnaire. We compared the results to those of a representative sample of healthy participants (n = 856). People with late-stage Parkinson's disease reported family, partnership and spirituality as the greatest areas of importance. Overall, they had lower SMiLE indices compared to healthy participants. People with late-stage Parkinson's disease rated the importance of core meaning in life areas (namely family, social relations and health) as significantly lower than the representative cohort and they also rated satisfaction as significantly lower in most areas. In conclusion, people with late-stage Parkinson's disease do have areas where they can find meaning, such as family, partnership and spirituality. However, they indicate a lack of fulfilment of their individual MiL, reflected by low satisfaction rates in the majority of meaning in life categories. The need for spiritual support for people with Parkinson's disease indicates the important role of chaplains to help people with Parkinson's disease maintain meaning in life.

α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis.

BACKGROUND: The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. METHODS: Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. RESULTS: The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. CONCLUSIONS: Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

Volumetric changes and clinical trajectories in Parkinson's disease: a prospective multicentric study.

BACKGROUND: Longitudinal measures of structural brain changes using MRI in relation to clinical features and progression patterns in PD have been assessed in previous studies, but few were conducted in well-defined and large cohorts, including prospective clinical assessments of both motor and non-motor symptoms. OBJECTIVE: We aimed to identify brain volumetric changes characterizing PD patients, and determine whether regional brain volumetric characteristics at baseline can predict motor, psycho-behavioral and cognitive evolution at one year in a prospective cohort of PD patients. METHODS: In this multicentric 1 year longitudinal study, PD patients and healthy controls from the MPI-R2* cohort were assessed for demographical, clinical and brain volumetric characteristics. Distinct subgroups of PD patients according to motor, cognitive and psycho-behavioral evolution were identified at the end of follow-up. RESULTS: One hundred and fifty PD patients and 73 control subjects were included in our analysis. Over one year, there was no significant difference in volume variations between PD and control subjects, regardless of the brain region considered. However, we observed a reduction in posterior cingulate cortex volume at baseline in PD patients with motor deterioration at one year (p = 0.017). We also observed a bilateral reduction of the volume of the amygdala (p = 0.015 and p = 0.041) and hippocampus (p = 0.015 and p = 0.053) at baseline in patients with psycho-behavioral deterioration, regardless of age, dopaminergic treatment and center. CONCLUSION: Brain volumetric characteristics at baseline may predict clinical trajectories at 1 year in PD as posterior cingulate cortex atrophy was associated with motor decline, while amygdala and hippocampus atrophy were associated with psycho-behavioral decline.

Describing complex disease progression using joint latent class models for multivariate longitudinal markers and clinical endpoints.

Neurodegenerative diseases are characterized by numerous markers of progression and clinical endpoints. For instance, multiple system atrophy (MSA), a rare neurodegenerative synucleinopathy, is characterized by various combinations of progressive autonomic failure and motor dysfunction, and a very poor prognosis. Describing the progression of such complex and multi-dimensional diseases is particularly difficult. One has to simultaneously account for the assessment of multivariate markers over time, the occurrence of clinical endpoints, and a highly suspected heterogeneity between patients. Yet, such description is crucial for understanding the natural history of the disease, staging patients diagnosed with the disease, unravelling subphenotypes, and predicting the prognosis. Through the example of MSA progression, we show how a latent class approach modeling multiple repeated markers and clinical endpoints can help describe complex disease progression and identify subphenotypes for exploring new pathological hypotheses. The proposed joint latent class model includes class-specific multivariate mixed models to handle multivariate repeated biomarkers possibly summarized into latent dimensions and class-and-cause-specific proportional hazard models to handle time-to-event data. Maximum likelihood estimation procedure, validated through simulations is available in the lcmm R package. In the French MSA cohort comprising data of 598 patients during up to 13 years, five subphenotypes of MSA were identified that differ by the sequence and shape of biomarkers degradation, and the associated risk of death. In posterior analyses, the five subphenotypes were used to explore the association between clinical progression and external imaging and fluid biomarkers, while properly accounting for the uncertainty in the subphenotypes membership.

UMSARS Versus Laryngoscopy-Based Assessment of Dysphagia.

Background: Multiple System Atrophy (MSA) dysphagia is routinely assessed by the Unified Multiple System Atrophy Rating Scale (UMSARS) part I-item 2. Objective: To compare the UMSARS part I-item 2 with an ear/nose/throat (ENT) expert physician assessment. Methods: We retrospectively analyzed the data of MSA patients who underwent an ENT assessment (nasofibroscopic and radioscopic exam) and an annual UMSARS assessment. Deglutition Handicap Index (DHI) and pulmonary/nutrition complications were collected. Results: Seventy-five MSA patients were included. The ENT assessment revealed more severe dysphagia compared to the UMSARS part I-item 2 score (P = 0.003). A higher proportion of patients with impaired protective mechanisms showed severe UMSARS-based dysphagia (P = 0.005). Patients with choking and oral/pharyngeal transit defects and nutritional complications were equally distributed across UMSARS part I-item 2 scores. Worse UMSARS part I-item 2 scores had worse DHI scores. Conclusions: The UMSARS-based assessment of dysphagia does not capture key aspects of pharyngo-laryngeal dysfunction reflecting swallowing efficiency.

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy.

BACKGROUND: Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling. OBJECTIVES: We tested whether lowering brain GRK2 abundance may reverse insulin-resistance. METHODS: We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA. RESULTS: Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance. CONCLUSIONS: These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease.

Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's disease pathologies and impaired brain insulin signalling. Discovering biomarkers for cognitive impairment in Parkinson's disease could help clarify the underlying pathogenic processes and improve Parkinson's disease diagnosis and prognosis. This study used plasma samples from 273 participants: 103 Parkinson's disease individuals with normal cognition, 121 Parkinson's disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia) and 49 age- and sex-matched controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting the L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-Synuclein was lower in Parkinson's disease compared to control individuals (P = 0.004) and in cognitively impaired Parkinson's disease individuals compared to Parkinson's disease with normal cognition (P < 0.001) and control (P < 0.001) individuals. Amyloid-ß42 did not differ between groups. Phosphorylated tau (T181) was higher in Parkinson's disease than control individuals (P = 0.003) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and controls (P < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson's disease compared to control individuals (P = 0.03) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and controls (P = 0.01), and also decreased with increasing motor symptom severity (P = 0.005); serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.05). The ratio of α-synuclein to phosphorylated tau181 was lower in Parkinson's disease compared to controls (P = 0.001), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and decreased with increasing motor symptom severity (P < 0.001). The ratio of insulin receptor substrate-1 phosphorylated serine312 to insulin receptor substrate-1 phosphorylated tyrosine was higher in Parkinson's disease compared to control individuals (P = 0.01), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and increased with increasing motor symptom severity (P = 0.003). α-Synuclein, phosphorylated tau181 and insulin receptor substrate-1 phosphorylated tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and tau pathologies and impaired insulin signalling underlie Parkinson's disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson's disease.