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In 2011, the UK medical research charity Cure Parkinsons set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinsons disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Background Consensus on priorities to optimize the sick leave and rehabilitation process (SRP) is lacking.Objective To explore perspectives of stakeholders in the SRP on bridging the gap between desired process scope, and actual practice, from a multi-professional, multi-organizational, and interdisciplinary approach.Design and setting Focus group interviews were conducted with various SRP frontline professionals in Region Västra Götaland, Sweden, using purposive sampling to capture a range of experiences. Participants discussed their perceptions of critical changes and priorities needed to meet patients’ SRP needs in a primary care context. All interviews were analyzed using systematic text condensation, as described by Malterud.Subjects General practitioners (n = 6), rehabilitation coordinators and licensed healthcare professionals from primary healthcare (n = 13), administrators from the Social Insurance Agency, the Employment Agency and Social Services (n = 12).Results Through data analysis, the following themes emerged: 1) The need for rules and regulations to enable coherent process governance 2) Challenges and opportunities in person-centered SRP: Professional collaboration, organizational priorities, and the need for enhanced leadership, and 3) Balancing resources and patient needs in the SRP: How to improve care quality and accessibility. In summary, participants mainly discussed how to improve process efficiency and quality of care while balancing available resources and a heavy workload. A main goal was to prevent negative spirals of suboptimal decision-making in individual cases, which could lead to increased work, unfortunate outcomes, and patient suffering.Conclusions This qualitative study indicated that gaps between a desired process scope and actual practice might be bridged by enabling coherent cross-organizational process governance, prioritizing person-centered ways of working, and balancing available resources and workload. The above changes were believed to improve process quality and overall efficiency.Trial registration The study project plan was pre-registered on September 21st, 2020, in the database FOU i VGR (researchweb.org), project number 274941.

Abstract Variants in GBA1 result in dysregulated sphingolipids. We investigated five CSF d18:1 sphingolipid species in a longitudinal multicenter cohort comprising people with Parkinson’s Disease and Dementia with Lewy bodies with and without GBA1 variants and healthy controls. We found no increase of sphingolipid species in heterozygous GBA1 variant participants and no effect on development of cognitive impairment. Thus, CSF d18:1 sphingolipids are not suitable as state markers in Parkinson’s Disease.

Abstract Background In Alzheimer’s disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience). Methods We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline. Results Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073–-0.069, pFDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099–-0.063, pFDR

Abstract The Claustrum/dorsal endopiriform cortex complex (CLA) is an enigmatic brain region with extensive glutamatergic projections to multiple cortical areas. The transcription factor Nurr1 is highly expressed in the CLA, but its role in this region is not understood. By using conditional gene-targeted mice, we show that Nurr1 is a crucial regulator of CLA neuron identity. Although CLA neurons remain intact in the absence of Nurr1, the distinctive gene expression pattern in the CLA is abolished. CLA has been hypothesized to control hallucinations, but little is known of how the CLA responds to hallucinogens. After the deletion of Nurr1 in the CLA, both hallucinogen receptor expression and signaling are lost. Furthermore, functional ultrasound and Neuropixel electrophysiological recordings revealed that the hallucinogenic-receptor agonists’ effects on functional connectivity between prefrontal and sensorimotor cortices are altered in Nurr1-ablated mice. Our findings suggest that Nurr1-targeted strategies provide additional avenues for functional studies of the CLA.

Abstract The orphan G protein-coupled receptor 37 (GPR37), widely associated with Parkinson’s disease (PD), undergoes proteolytic processing under physiological conditions. The N-terminus domain is proteolyzed by a disintegrin and metalloproteinase 10 (ADAM-10), which generates various membrane receptor forms and ectodomain shedding (ecto-GPR37) in the extracellular environment. We investigated the processing and density of GPR37 in several neurodegenerative conditions, including Lewy body disease (LBD), multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD). The presence of ecto-GPR37 peptides in the cerebrospinal fluid (CSF) of PD, MSA, CBD and PSP patients was assessed through an in-house nanoluciferase-based immunoassay. This study identified increased receptor processing in early-stage LBD within the PFC and striatum, key brain areas in neurodegeneration. In MSA only the 52 kDa form of GPR37 appeared in the striatum. This form was also significantly elevated in the striatum of AD necropsies. On the contrary, GPR37 processing remained unchanged in the brains of CBD and PSP patients. Furthermore, while CSF ecto-GPR37 increased in PD patients, its levels remained unchanged in MSA, CBD, and PSP subjects. Importantly, patients with PD with rapid progression of the disease did not have elevated ecto-GPR37 in the CSF, while those with slow progression showed a significant increase, suggesting a possible prognostic use of ecto-GPR37 in PD. This research underscores the distinctive processing and density patterns of GPR37 in neurodegenerative diseases, providing crucial insights into its potential role as an indicator of PD progression rates.

Abstract Parkinson’s disease (PD) is clinically heterogeneous, which suggests the existence of subtypes; however, there has been no consensus regarding their characteristics. This study included 633 PD individuals across distinct cohorts: unmedicated de novo PD, medicated PD, mild-moderate PD, and a cohort based on diagnostic work-up in clinical practice. Additionally, 233 controls were included. Clustering based on cortical and subcortical gray matter measures was conducted with and without adjusting for global atrophy in the entire PD sample and validated within each cohort. Subtypes were characterized using baseline and longitudinal demographic and clinical data. Unadjusted results identified three clusters showing a gradient of neurodegeneration and symptom severity across the entire sample and the individual cohorts. When adjusting for global atrophy eight clusters were identified in the entire sample, lacking consistency in individual cohorts. This study identified atrophy-based subtypes in PD, emphasizing the significant impact of global atrophy on subtype number, patterns, and interpretation in cross-sectional analyses.

Objectives To investigate whether intensified cooperation between general practitioner (GP), care manager and rehabilitation coordinator (RC) for patients sick-listed for stress-related mental disorder, combined with a person-centred dialogue meeting with employer, could reduce sick-leave days compared with usual care manager contact.Design Pragmatic cluster-randomised controlled trial, randomisation at primary care centre (PCC) level.Setting PCCs in Region Västra Götaland, Sweden, with care manager organisation.Participants Of 30 invited PCCs, 28 (93%) accepted the invitation and recruited 258 patients newly sick-listed due to stress-related mental disorder (n = 142 intervention, n = 116 control PCCs).Intervention Cooperation between GP, care manager and rehabilitation coordinator from start of illness notification plus a person-centred dialogue meeting between patient and employer within 3 months. Regular contact with care manager was continued at the control PCCs.Main outcome measures 12-months net and gross number of sick-leave days. Secondary outcomes: Symptoms of stress, depression, anxiety; work ability and health related quality of life (EQ-5D) over 12 months.Results There were no significant differences between intervention and control groups after 12 months: days on sick-leave (12-months net sick-leave days, intervention, mean = 110.7 days (95% confidence interval (CI) 82.6 − 138.8); control, mean = 99.1 days (95% CI 73.9 − 124.3)), stress, depression, or anxiety symptoms, work ability or EQ-5D. There were no significant differences between intervention and control groups concerning proportion on sick-leave after 3, 6, 12 months. At 3 months 64.8% were on sick-leave in intervention group vs 54.3% in control group; 6 months 38% vs 32.8%, and12 months 16.9% vs 15.5%.Conclusion Increased cooperation at the PCC between GP, care manager and RC for stress-related mental disorder coupled with an early workplace contact in the form of a person-centred dialogue meeting does not reduce days of sick-leave or speed up rehabilitation.Trial registration: ClinicalTrials.gov Identifier: NCT03250026 https://clinicaltrials.gov/study/NCT03250026?tab=results#publicationsCO-WORK-CAREFirst Posted: August 15, 2017. Recruitment of PCCs: September 2017. Inclusion of patients from December 2017

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

Objectives To explore the experiences of organisational support to apply best practices held by front-line employees working with patients in the sick leave and rehabilitation process (SRP).Design Qualitative study design. Data were collected with focus group interviews in Region Västra Götaland, Sweden. Participants discussed their perceptions of organisational support to apply the best SRP practice in a primary healthcare context.Participants Purposive sampling was conducted to capture a range of experiences among various professionals, including general practitioners (n=6), rehabilitation coordinators, other primary healthcare professionals (n=13) and caseworkers from the Social Insurance Agency, Employment Agency and Social Services (n=12).Results Informants perceived that their good intentions to work for the best interests of each patient were not enough to overcome inadequate organisational prerequisites. Identified themes described unequal care due to significant practice variation, conflicting messages, a situation where the patient loses control and mismatch between available support and patient needs. Perceived potential consequences for the patients included legal uncertainty of assessments, harmful passivity of the individual through misapplied sick leave and the risk of overlooking non-medical factors that could be managed in a safer and more well-adapted way.Conclusions Neither guidelines on person-centred approaches, nor laws regulating the right to coordinated individual planning, seem to have fulfilled the intended purpose. The informants depicted an SRP obstructing individualised care, thus risking worsening patients’ well-being and abilities. The opportunities to improve the quality of the processes within the SRP, and simultaneously make them more effective, appear to be extensive.

Background and objectivesThe diseases historically known as neuroacanthocytosis (NA) conditions include VPS13A disease (formerly chorea-acanthocytosis) and XK disease (formerly McLeod syndrome). Here we report a patient with a hyperkinetic syndrome associated with variants in VPS13A with a concomitant homozygous nucleotide expansion in Replication factor C, subunit 1 (RFC1) and evaluate the role of ektacytometry for the assessment of acanthocytes.MethodsInvestigations included clinical assessments, neuroimaging studies, laboratory analyses, blood smears, ektacytometry, psychometric evaluation, and genetic analyses. Using ektacytometry, an osmoscan curve is obtained yielding a diffraction pattern as a measure of average erythrocyte deformability from circular at rest to elliptical at a high shear stress. The pattern allows the derivation of several parameters (mainly EI-max, O-min and O-Hyper points). Samples from two other patients with genetically proven VPS13A disorder and XK disease and varying numbers of acanthocytes as well as from a fourth with acanthocytosis due to liver failure were also analyzed.Case presentationThe patient has impulsivity, chorea and disabling feeding dystonia refractory to treatment and 15% acanthocytes in peripheral blood. Genetic workup revealed compound heterozygous variants c.1732_1733del; p.(V578Ffs*9) and c.8282C > A, p.(S2761*) in VPS13A with absence of chorein in the blood, the latter variant is novel. In addition, he harbors a homozygous nucleotide expansion in the RFC1 gene, reported in cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). However, the patient does not display ataxia yet. Ektacytometry revealed significantly reduced erythrocyte deformability in this patient and in another man with VPS13A disease. In contrast, the patient with XK disease had 2% acanthocytes and mild abnormalities on ektacytometry. In the three cases, ektacytometry yielded a specific pattern, different from acanthocytosis due to liver failure.ConclusionPathogenicity of the VPS13A variants is confirmed by absence of chorein, long-term follow up is required to evaluate any synergistic impact of for the underlying CANVAS mutation. New generation ektacytometry provides an objective measurement of erythrocytes’ rheological properties and may serve as a complement to blood smears. Finally, ektacytometry’s ability to detect deformability of erythrocytes in NA seems to depend on the degree of acanthocytosis.

Abstract Primary care needs to find strategies to deal with today’s societal challenges and continue to deliver efficient and high-quality care. Employee-driven innovation is increasingly gaining ground as an accessible pathway to developing successful and sustainable organisations. This type of innovation is characterised by employees being engaged in the innovation process, based on a bottom-up approach. This qualitative study explores employees’ experiences of employee-driven innovation at a primary care centre in Sweden. Data are collected by focus group interviews and analysed by inductive qualitative content analysis. The result is presented with the overarching theme “Standing together at the helm” followed by three categories: “Motivating factors for practising employee-driven innovation”, “Challenges in practising employee-driven innovation” and “Benefits of employee-driven innovation”, including nine subcategories. The study found that employee-driven innovation fosters organisational innovation, empowers employees, and enhances adaptability at personal and organisational levels. This enables individual and collective learning, and facilitates the shaping, development, and adaptation of working methods to meet internal and external requirements. However, new employees encountered difficulty grasping the concept of employee-driven innovation and recognising its long-term advantages. Additionally, the demanding and task-focused environment within primary care posed challenges in sustaining efforts in innovation work. The employees also experienced a lack of external support to drive and implement some innovative ideas.

Abstract Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

TensorView for MATLAB is a GUI-based visualization tool for depicting second-rank Cartesian tensors as surfaces on three-dimensional molecular models. Both ellipsoid and ovaloid tensor display formats are supported, and the software allows for easy conversion of Euler angles from common rotation schemes (active, passive, ZXZ, and ZYZ conventions) with visual feedback. In addition, the software displays all four orientation-equivalent Euler angle solutions for the placement of a single tensor in the molecular frame and can report relative orientations of two tensors with all 16 orientation-equivalent Euler angle sets that relate them. The salient relations are derived and illustrated through several examples. TensorView for MATLAB expands and complements the earlier implementation of TensorView within the Mathematica programming environment and can be run without a MATLAB license. TensorView for MATLAB is available through github at https://github.com/LeoSvenningsson/TensorViewforMatlab, and can also be accessed directly via the NMRbox resource.

Multiple Sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system (CNS). It is characterized by a heightened activation of the immune system with ensuing inflammation, demyelination and neurodegeneration with consequences such as motor, sensory, cognitive, as well as autonomic dysfunctions. While a range of immune-modulatory drugs have shown certain efficacy in alleviating pathology and symptoms, none of the currently available therapeutics regenerates the damaged CNS to restore function. There is emerging evidence for leukotrienes and leukotriene receptors being involved in the various aspects of the MS pathology including neuroinflammation and de/remyelination. Moreover, leukotriene receptor antagonists such as the asthma drug montelukast diminish inflammation and promote regeneration/remyelination. Indeed, montelukast has successfully been tested in animal models of MS and a recent retrospective case-control study suggests that montelukast treatment reduces relapses in patients with MS. Therefore, we propose montelukast as a therapeutic adjuvant to the standard immune-modulatory drugs with the potential to reduce pathology and promote structural and functional restoration. Here, we review the current knowledge on MS, its pathology, and on the potential of leukotriene receptor antagonists as therapeutics for MS.

Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the αS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic αS phosphorylation and improved soluble αS homeostasis in cultured αS triplication PD neurons and reduced DAergic neurodegeneration in a C.elegans αS model. However, assessing LIPE as a potential therapeutic target for progressive PD motor phenotypes has not been investigated. 3K αS mice, representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation, have decreased αS T:M ratios, lipidic aggregates, and a L-DOPA responsive PD-like motor syndrome. Here, we reduced LIPE by crossings of 3K mice with LIPE null mice, which attenuated motor deficits in male LIPE+/− knockdown (LKD)-3K mice. Heterozygous LIPE reduction was associated with an improved αS T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. In female 3K-LKD mice, an increase in pS129+ and larger lipid droplets (LDs) likely decreased the benefits seen in males. Reducing LIPE decreased MUFA release from neutral lipid storage, thereby reducing MUFA in phospholipid membranes with which αS interacts. Our study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and support LIPE as a promising target in males. LIPE regulation represents a novel approach to mitigate PD and DLB risk and treat disease.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Parkinson’s disease (PD) is associated with changes in neural activity in the sensorimotor alpha and beta bands. Using magnetoencephalography (MEG), we investigated the role of spontaneous neuronal activity within the somatosensory cortex in a large cohort of early- to mid-stage PD patients (N = 78) on Parkinsonian medication and age- and sex-matched healthy controls (N = 60) using source reconstructed resting-state MEG. We quantified features of the time series data in terms of oscillatory alpha power and central alpha frequency, beta power and central beta frequency, and 1/f broadband characteristics using power spectral density. Furthermore, we characterised transient oscillatory burst events in the mu-beta band time-domain signals. We examined the relationship between these signal features and the patients’ disease state, symptom severity, age, sex, and cortical thickness. PD patients and healthy controls differed on PSD broadband characteristics, with PD patients showing a steeper 1/f exponential slope and higher 1/f offset. PD patients further showed a steeper age-related decrease in the burst rate. Out of all the signal features of the sensorimotor activity, the burst rate was associated with increased severity of bradykinesia, whereas the burst duration was associated with axial symptoms. Our study shows that general non-oscillatory features (broadband 1/f exponent and offset) of the sensorimotor signals are related to disease state and oscillatory burst rate scales with symptom severity in PD.

Abstract Mutations in the α-Synuclein (αS) gene promote αS monomer aggregation that causes neurodegeneration in familial Parkinson’s disease (fPD). However, most mouse models expressing single-mutant αS transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD αS E46K mutant mice with rationally designed triple mutations based on the α-helical repeat motif structure of αS (fPD E46K→3 K). The 3 K variant increased αS membrane association and decreased the physiological tetramer:monomer ratio, causing lipid- and vesicle-rich inclusions and robust tremor-predominant, L-DOPA responsive PD-like phenotypes. Here, we applied an analogous approach to the G51D fPD mutation and its rational amplification (G51D → 3D) to generate mutant mice. In contrast to 3 K mice, G51D and 3D mice accumulate monomers almost exclusively in the cytosol while also showing decreased αS tetramer:monomer ratios. Both 1D and 3D mutant mice gradually accumulate insoluble, higher-molecular weight αS oligomers. Round αS neuronal deposits at 12 mos immunolabel for ubiquitin and pSer129 αS, with limited proteinase K resistance. Both 1D and 3D mice undergo loss of striatal TH+ fibers and midbrain dopaminergic neurons by 12 mos and a bradykinesia responsive to L-DOPA. The 3D αS mice have decreased tetramer:monomer equilibria and recapitulate major features of PD. These fPD G51D and 3D mutant mice should be useful models to study neuronal αS-toxicity associated with bradykinetic motor phenotypes.

Abstract Parkinson’s disease (PD) is characterised by a loss of dopamine and dopaminergic cells. The consequences hereof are widespread network disturbances in brain function. It is an ongoing topic of investigation how the disease-related changes in brain function manifest in PD relate to clinical symptoms. We present The Swedish National Facility for Magnetoencephalography Parkinson’s Disease Dataset (NatMEG-PD) as an Open Science contribution to identify the functional neural signatures of Parkinson’s disease and contribute to diagnosis and treatment. The dataset contains whole-head magnetoencephalographic (MEG) recordings from 66 well-characterised PD patients on their regular dose of dopamine replacement therapy and 68 age- and sex-matched healthy controls. NatMEG-PD contains three-minute eyes-closed resting-state MEG, MEG during an active movement task, and MEG during passive movements. The data includes anonymised MRI for source analysis and clinical scores. MEG data is rich in nature and can be used to explore numerous functional features. By sharing these data, we hope other researchers will contribute to advancing our understanding of the relationship between brain activity and disease state or symptoms.

Purpose: This paper presents findings from a qualitative study of healthcare professionals' practice, where learning is taking place when a digital artefact is implemented for identification of patients' cognitive impairment. The use of digital artefacts is increasing in various workplaces, to include professionals in healthcare. This paper aims to explore the following research question: How is the professional learning unfolding in patient-based work when a digital artefact transforms the practice? Design/methodology/approach: Various data collection methods are used for this study, consisting of dialogue meetings, interviews and a reference-group meeting. Thematic analysis is used to inductively bring forth the themes of the collected data. Findings: Professionals' knowledge and experience are of vital importance in learning and changing work practices. Together with their ability to reflect on changes, their knowledge and experience constitute the prefiguration when the introduction of a digital application brings about indeterminacy in the work practice. Originality/value: This paper makes a contribution to practice-based research as it consolidates previous research and identifies professionals knowledge and learning in a healthcare context. This can be used to further explore and advance the field, as well as to establish the evidence-based importance of transforming practices based on implementation of digital artefacts.

Purpose: To meet future healthcare needs, primary care is undergoing a transformation in which innovations and new ways of working play an important role. However, successful innovations depend on joint learning and rewarding collaborations between healthcare and other stakeholders. This study aims to explore how learning develops when entrepreneurs, healthcare professionals and older people collaborate in a primary care living lab. Design/methodology/approach: The study had an action research design and was conducted at a clinically embedded living lab at a primary care centre on the west coast of Sweden. Data consisted of e-mail conversations, recordings from design meetings and three group interviews with each party (entrepreneurs, healthcare professionals and older people). Data were analysed with inductive qualitative content analysis. Findings: An overarching theme, "To share each other's worlds in an arranged space for learning", was found, followed by three categories, "Prerequisites for learning", "Strategies to achieve learning" and "To learn from and with each other". These three categories comprise eight subcategories. Originality/value: This research contributes to knowledge regarding the need for arranged spaces for learning and innovation in primary care and how collaborative learning can contribute to the development of practice.

Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of the substantia nigra compacta (SNc) in patients with Parkinson’s disease, while those in the ventral tegmental area (VTA) are relatively spared. Here, we used single nuclei RNA sequencing (snRNA-seq) of approximately 70,000 mouse midbrain cells to build a high-resolution atlas of mouse mDA neuron diversity at the molecular level. The results showed that differences between mDA neuron groups could best be understood as a continuum without sharp differences between subtypes. Thus, we assigned mDA neurons to several ‘territories’ and ‘neighborhoods’ within a shifting gene expression landscape where boundaries are gradual rather than discrete. Based on the enriched gene expression patterns of these territories and neighborhoods, we were able to localize them in the adult mouse midbrain. Moreover, because the underlying mechanisms for the variable sensitivities of diverse mDA neurons to pathological insults are not well understood, we analyzed surviving neurons after partial 6-hydroxydopamine (6-OHDA) lesions to unravel gene expression patterns that correlate with mDA neuron vulnerability and resilience. Together, this atlas provides a basis for further studies on the neurophysiological role of mDA neurons in health and disease.

Abstract A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.