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Background: Aquaporin-4 (AQP4) is crucial for brain fluid regulation and glymphatic system function. Idiopathic normal pressure hydrocephalus (INPH) is characterized by impaired CSF flow and is treated with shunt surgery. This study investigated AQP4 levels in INPH patients to explore its role in pathophysiology and as a potential biomarker for shunt response.

Methods: CSF samples from 233 INPH patients and 29 controls were analysed. AQP4 levels were compared between preoperative patients and controls, before and after shunt surgery (110 patients), and between shunt responders and non-responders (204 patients). A bead-based assay was used to measure AQP4, and outcomes were assessed by postoperative changes in maximum gait velocity.

Results: In unadjusted analyses, preoperative AQP4 levels were lower in INPH patients than in controls; however, this difference did not remain after adjustment for pre-analytical and demographic confounders (p = 0.87). Postoperative AQP4 levels were higher (median 1646 AU IQR 1347–1976) than preoperative levels (1166 AU IQR: 976–1345; p < 0.001) and the magnitude of increase showed a modest correlation with gait improvement (rₛ = 0.22, p = 0.022). Shunt responders had lower preoperative AQP4 levels median 1089 AU, IQR 971–1277) than non-responders (median 1213 AU, IQR 1074–1361; p = 0.008). Pre-analytical factors, including storage duration and sample processing, were strong determinants of measured AQP4 levels.

Conclusions: CSF AQP4 levels in INPH did not differ from those in controls and were highly sensitive to pre-analytical sample handling. CSF AQP4 levels increased following shunt surgery. A potential prognostic value of CSF AQP4 is suggested but requires further investigation.

Objective: Given the clinical heterogeneity of Parkinson’s disease (PD), identification of early -stage subgroups with shared non-motor symptom (NMS) profiles may clarify its pathophysiology. This study used latent-profile analyses (LPA) to define subgroups based on sleep disturbances, cognitive performance and neuropsychiatric symptoms, and examined dopaminergic function and brain volume differences between them.

Methods: We analyzed data from 51 cognitively normal non-PD older adults and 105 early-stage PD participants from the iPARK trial, including 19 who underwent [11C]-raclopride PET/MR. Participants completed the Hospital Anxiety and Depression Scale, the short version of the Karolinska Sleep Questionnaire and a battery of neuropsychological tests. LPA were used in PD to identify subgroups based on NMS profiles, which were then characterized and examined in relation to dopaminergic integrity and brain morphology.

Results: LPA identified a two-cluster solution as the best fit. Group 1 (N = 49) showed poorer working memory, executive function and processing speed along with greater daytime sleepiness, depression and anxiety. Group 2 (N = 56) exhibited less affected cognitive function and minimal NMS. Groups were similar in demographics, disease duration, motor symptom severity and medication, but differed on UPDRS-1 NMS. Group 1 demonstrated significantly reduced [11C]-raclopride binding potential compared to Group 2 in the left putamen at both ROI- and voxel-wise analysis.

Conclusion: These findings indicate clinically distinct subgroups in early-stage PD. Greater NMS burden is linked to impaired dopaminergic integrity, suggesting a potential neurobiological signature. Early identification of such subgroups may improve understanding of disease heterogeneity and support personalized management and interventions. Clinical trial registration: https://clinicaltrials.gov/study/NCT03680170?id=NCT03680170&rank=1, identifier (NCT03680170).

Background: People with Parkinson's (PwP) who lose independence may need care in nursing homes or similar institutions if home care is insufficient. Institutionalisation has major social and financial implications. Better understanding of which PwP are most likely to be institutionalised would improve information provision, clinical risk stratification, and healthcare planning.

Objectives: To identify risk factors for institutionalisation in PwP and develop models predicting individual institutionalisation risk.

Methods: We described institutionalisation in the Parkinson's Incidence Cohorts Collaboration, comprising 6 European incidence cohorts. We identified prognostic factors by two-stage individual-participant-data meta-analysis. Prognostic models predicting risk of institutionalisation within 7 years and 10 years were developed using the Royston-Parmar model. Heterogeneity in model performance was assessed using internal-external cross validation (IECV).

Results: In 1046 PwP, the cumulative incidence of institutionalisation by 10 years was 37.2%. The incidence rate ranged from 1.7 to 6.2 per 100 person-years. Older age, higher MDS-UPDRS part 3 and lower MMSE at baseline independently predicted higher institutionalisation risk. IECV showed good discrimination in the 10-year (C-statistics 0.73-0.81) and 7-year (0.71-0.84) models. However, calibration (agreement between predictions and observed outcomes) showed under- and over-prediction across studies. After updating model intercept and coefficients (recalibration), the calibration improved.

Conclusion: 37% of PwP entered institutional care within ten years from diagnosis. Older age, higher MDS-UPDRS part 3 and lower MMSE predicted institutionalisation. The prognostic models discriminated well, but calibration varied between cohorts. We recommend further validation before applying the models in other settings.

Background: An accurate understanding of prognosis in Parkinson's disease (PD) is important for patient information provision, personalized treatment, and clinical trial design, but most previous research has been biased towards younger, healthier patients.

Objectives: To describe key clinical outcomes longitudinally and identify baseline prognostic factors (predictors) for these outcomes using population-representative PD cohorts.

Methods: We meta-analyzed individual patient data from six incidence cohorts in Western Europe (Norway, Sweden, and UK). Each cohort aimed to recruit and follow up all newly diagnosed cases in defined population/incidence periods (between 2000 and 2011). We described postural instability (Hoehn & Yahr Stage 3), functional dependency (needing help with daily activities), dementia, and death with up to 12 years' follow-up and investigated clinical and genetic predictors using frailty Cox models.

Results: In 883 population-based incident patients, median age at motor symptom onset was 69.2 years. Median time to postural instability and functional dependency was 7.4 years. Dementia affected 49.6% by 10 years and 54.7% had died by 12 years (median survival 9.4 years). Older age, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) score, and lower Mini-Mental State Examination (MMSE) were significantly associated with all outcomes; cognitive symptoms and GBA polymorphisms with each outcome except mortality; and APOE ε4 with increased mortality and dementia.

Conclusions: This first individual patient data meta-analysis of population-based incidence cohorts provides robust prognostic data, with fewer selection biases than previous PD studies, for informing people with PD about prognosis. In incidence cohorts, overall PD prognosis is worse than previously suggested, with key outcomes often occurring early. Further work should develop validated prognostic models for objective stratification of prognostic risk and for personalized medicine. 

Meta-analyses on cognitive training (CT) for people with Parkinson’s Disease (PD) report improvements in global cognition and it is recommended as a treatment for people with PD with mild cognitive impairment. However, few studies have assessed the experience of CT. Therefore, this study explored the experience of process-based CT in people with PD and focused on how participants engaged with and made use of the training in their everyday life. In this study, semi-structured, individual interviews were conducted with 18 people with PD who had completed 6–8 weeks of process-based CT. Reflexive thematic analysis was used to analyse the data. Three overarching themes were developed that reported on the participants' (1) dedication towards CT; (2) meaning of seeing change in cognitive performance during CT; and (3) inspiration to transfer the knowledge, strategies and mindset from training into everyday life. Furthermore, a route to transfer was described including emotional and motivational experiences. In conclusion, CT was experienced in an active, reflective manner whereby emotional and cognitive challenges during training are dealt with and are seen as important ingredients to attain transfer to everyday life. Future studies are encouraged to examine the link between such qualitative findings and quantitatively measured outcomes.

Trial registration: ClinicalTrials.gov identifier: NCT03680170.

INTRODUCTION: The α-synuclein (αSyn) seed amplification assay (αSyn-SAA) is an accurate tool to detect αSyn seeds in patients with Parkinson's disease (PD). However, a minority of clinically diagnosed PD patients are negative for αSyn.

METHODS: The αSyn-SAA was performed in cerebrospinal fluid (CSF) of individuals with PD (n = 93), multiple system atrophy (MSA, n = 26), progressive supranuclear palsy (PSP, n = 18), corticobasal syndrome (n = 3), and healthy controls (n = 29).

RESULTS: The αSyn-SAA detected αSyn in 90% of PD and 81% of MSA patients, while exhibiting high specificity (97%). SAA– PD patients had a distinct phenotype compared to SAA+ PD, including a marked postural instability/gait disorder (P = 0.002), impaired episodic memory, and lower CSF amyloid beta42 (P = 0.03). SAA+ PSP also displayed distinctive traits.

DISCUSSION: A negative αSyn-SAA in PD is associated with a distinct phenotype and pathological findings suggesting that these patients may have a motor subtype of Alzheimer's disease. This could influence future clinical trials.

Highlights: The α-synuclein seed amplification assay (αSyn-SAA) is a robust assay. αSyn-SAA–negative Parkinson's disease shows a distinct motor–cognitive phenotype. Autopsy showed Alzheimer's disease (AD) pathology in parkinsonian diseases. AD stands as a major clinical confounder for the diagnosis of movement disorders.

Beta-adrenoceptor-blockers and agonists have been associated with an increased and decreased risk of Parkinson's disease (PD), respectively. We aimed to investigate whether these medications are linked to clinical heterogeneity and progression in PD. Longitudinal data from the Parkinson's Incident Cohorts Collaboration (n = 1107) were analysed. Baseline clinical status and progression to Hoehn & Yahr stage 3 (H&Y3) or dementia were compared in beta-blocker or beta-agonist users versus non-users of each drug. Baseline motor and cognitive variables were similar in beta-blocker users (n = 195) versus non-users and beta-agonist users (n = 68) versus non-users, following adjustment for relevant confounders. Beta-blocker users (n = 156) progressed faster to H&Y3 (p = 0.002), accounting for relevant confounders (Hazard Ratio (HR) = 1.538; p = 0.011), while beta-agonist users (n = 54) progressed similarly to non-users. Neither drug was associated with progression to dementia. These findings support the possibility that beta-adrenoceptor drugs may have potential in modifying aspects of PD progression. Further investigation is essential to identify any causative component in the relationship.

Background: Prediction models for dementia in Parkinson disease (PD) are needed to better identify high-risk patients, but existing risk models often lack validation in early-stage PD, when prognosis is most challenging.

Objective: This study aims to validate the Montreal Parkinson Risk of Dementia Scale (MoPaRDS) in six population-based cohorts of newly diagnosed PD and to evaluate if incorporating genetic factors (GBA1 and APOE-ε4) enhances its performance.

Methods: We calculated MoPaRDS scores for 1108 newly diagnosed PD patients, and MoPaRDS + GBA1 + APOE for the 941 patients with complete genetic data. We assessed the scores' performance in predicting dementia diagnosed over 10 years using time-dependent receiver operating characteristic (ROC) curves.

Results: Of the 1108 patients (mean age 69.5 ± 10.0 years; 61.0% men), 350 (31.6%) developed dementia. The area under the time-dependent ROC curve (AUC) was 0.79 for MoPaRDS and 0.80 for MoPaRDS + GBA1 + APOE. Subdividing patients based on their MoPaRDS scores revealed annual observed risks of PDD of 39.4% (n = 8; high risk-), 11.4% (n = 176; intermediate risk-), and 5.0% (n = 942; low risk-group). With the suggested cutoff of ≥4, MoPaRDS had a sensitivity of 21.7% and specificity of 94.9%. Including the genetic items improved the sensitivity to 36.4% while maintaining comparable performance for specificity (91.5%).

Conclusions: MoPaRDS demonstrates high specificity but limited sensitivity in early PD, highlighting that a one-size-fits-all approach is inadequate for predicting dementia risk in PD across different disease stages. Integrating genetic items increases sensitivity and identifies more newly diagnosed patients at higher risk of dementia, and may be a useful approach to assist dementia risk assessment in early-stage PD.

Variants in GBA1 are important genetic risk factors in Parkinson's disease (PD). GBA1 T369M has been linked to an ∼80 % increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the Swedish population.

Background: The early pathogenesis of Parkinson's disease (PD) and the atypical parkinsonian disorders multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) is poorly understood, but presynaptic and axonal dysfunction are hypothesized to play a prominent role. Objective: To identify synapse- and/or axonal dysfunction as indicated by cerebrospinal fluid (CSF) biomarker profiles and their clinical correlates in early-stage PD, MSA, and PSP.

Methods: Liquid chromatography mass spectrometry and enzyme-linked immunosorbent assay analyses of CSF samples from patients with early-stage PD (n = 38), MSA (n = 21), or PSP (n = 19), and age-matched, neurologically healthy controls (n = 30).

Results: Compared to controls, patients with early parkinsonian disorders had significantly reduced CSF levels of the synapse-associated proteins neuronal pentraxin-1 (NPTX1), amyloid precursor protein, and β-amyloid 42 (Aβ42), as well as the neurosecretory granin-derived proteins secretogranin-II, chromogranin-A, and secretogranin-VII. Among these, synapse-associated proteins correlated with non-motor features, while none correlated with age. CSF levels of the predominantly axonal proteins neurofilament light (NfL) and tau were elevated in patients with MSA or PSP. Reduced NPTX1 and Aβ42 distinguished PD from PSP, while elevated NfL and tau distinguished PSP and/or MSA from PD.

Conclusions: Low CSF levels of biomarkers associated with synaptic and neurosecretory function (e.g., NPTX1) implicate age-independent synaptic dysfunction as a shared, early feature in the pathogenesis of PD, MSA, and PSP. Such biomarkers may be particularly sensitive correlates of early non-motor dysfunction. Early axonal dysfunction is more pronounced in PSP and MSA than in PD.