Given the complexity of Parkinson's disease (PD), achieving acceptable diagnostic and prognostic accuracy will require the support of a panel of diverse biomarkers. We used Proximity extension assays ...to measure a panel of 92 proteins in CSF of 120 newly diagnosed PD patients and 45 control subjects without neurological disease. From 75 proteins detectable in the CSF of >90% of the subjects, regularized regression analysis identified four proteins (β-NGF, CD38, tau and NCAN) as downregulated in newly diagnosed PD patients (age at diagnosis 67.2 ± 9.4 years) compared to controls (age 65.4 ± 10.9 years). Higher tau (β −0.82 transformed MMSE points/year, 95% CI −1.37 to −0.27, P = 0.005) was also linked to faster cognitive decline over the first ten years after PD diagnosis. These findings provide insights into multiple aspects of PD pathophysiology and may serve as the foundation for identifying new biomarkers and therapeutic targets.
•Proximity extension assays enable high-throughput, multiplex analysis of proteins•PEA detected 4 neurology-related proteins dysregulated in CSF from patients with PD•β-NGF, CD38, Tau and NCAN were all downregulated in newly diagnosed PD patients•Higher Tau protein was linked to faster cognitive decline in PD•The proteins identified reflect broader biology than do the classic PD biomarkers
Abstract Background Motor complications may become major challenges in the management of patients with Parkinson's disease. In this study, we sought to determine the incidence, risk factors, ...evolution, and treatment of motor fluctuations and dyskinesias in a population-representative, incident Parkinson's disease cohort. Methods In this prospective population-based 5-year longitudinal study, we followed 189 incident and initially drug-naïve Parkinson's disease patients biannually for detailed examination of dyskinesias and motor fluctuations as defined by the Unified Parkinson's disease Rating Scale. We performed Kaplan–Meier survival and Cox regression analyses to assess cumulative incidence and risk factors of these motor complications. Results The 5-year cumulative incidence of motor complications was 52.4%. Motor fluctuations occurred in 42.9% and dyskinesias in 24.3%. Besides higher motor severity predicting both motor fluctuations (p = 0.016) and dyskinesias (p < 0.001), lower age at diagnosis predicted motor fluctuations (p = 0.001), whereas female gender predicted dyskinesias (p = 0.001). Actual levodopa dose at onset of motor fluctuations (p = 0.037) or dyskinesias (p < 0.001) rather than initial treatment with levodopa (p > 0.1) independently predicted development of motor complications. Motor fluctuations reversed in 37% and dyskinesias in 49% of patients on oral treatment and remained generally mild in those with persistent complications. No patients received device-aided therapies during the study. Conclusions More than 50% in the general Parkinson's disease population develop motor complications within 5 years of diagnosis. However, they remain mild in the vast majority and are reversible in a substantial proportion of patients.
Norsk Parkinsonregister og biobank Pedersen, Kenn Freddy; Lange, Johannes; Fiske, Eldbjørg
Norsk epidemiologi,
10/2023, Letnik:
31, Številka:
1-2
Journal Article
Recenzirano
Odprti dostop
SAMMENDRAGNorsk Parkinsonregister og biobank fikk status som nasjonalt medisinsk kvalitetsregister av Helsedirektorateti 2016 og startet datainnsamling fra pasienter med Parkinsons sykdom og atypisk ...nevrodegenerativparkinsonisme i desember 2018. Registerets hovedmål er å sikre kvalitet og enhetlig diagnostikk, behandlingog oppfølging av pasientgruppen. Dette gjøres ved å samle inn kliniske data, gjennomføre kvalitetsforbedringav behandlingstilbudet og drive forskning på årsaksforhold og sykdomsmekanismer ved å kombinereregisterdata og biobankmateriale. Registeret har i løpet av de første fire årene med datainnsamling møtt påen rekke utfordringer knyttet til koronapandemi og ressursknapphet i helsetjenesten. Flere tiltak har blittgjennomført for å løse dette og vi ser nå tydelig effekt av disse. Ved utgangen av 2022 hadde registeret endekningsgrad på nesten 22 %.ENGLISH SUMMARYThe Norwegian Parkinson’s Registry and Biobank was granted status as a National Quality Registry by theNorwegian Directorate of Health in 2016 and startet registration of patients with Parkinson’s disease andatypical neurodegenerative parkinsonism in December 2018. The main aim of the registry is to ensure qualityand uniform diagnostics, treatment and follow-up of the patient group by collecting clinical data, implementingquality offers of treatment and conducting research into causal relationships and disease mechanisms bycombining registry data and biobank material. During the first four years of data collection, the Parkinson’sRegistry has encountered a number of challenges related to coronavirus pandemic and resource scarcity inthe health service. Several measures have been implemented to solve these challenges, and we are nowstarting to see the effect of these measures. At the end of 2022, a coverage rate of nearly 22 % was achieved.
Abstract Introduction Clinical staging of Parkinson's disease (PD) is important for patient management and prognosis. The non-motor and functional features visual hallucinations, recurrent falls, ...dementia and nursing home placement are currently not included in clinical staging schemes, but have been suggested as clinical milestones with important prognostic implications in advanced PD. In this study, we sought to evaluate the potential of these four milestone events for clinical staging and prognosis during the early years of the disease. Methods We recruited 185 patients with incident PD and monitored prospectively every six months through seven years for emergence and consequences of four clinical milestones. Results One or more milestones were reached in 53.0%. Of the patients who reached the milestones, visual hallucinations appeared after a median of 3.3 (interquartile range 1.3–4.9) years from diagnosis, recurrent falls after 3.8 (2.8–5.2) years, dementia after 4.0 (2.1–4.8) years and nursing home placement after 5.4 (3.9–6.7) years. Presence of any milestone was associated with occurrence of other milestones (relative risks 1.9–6.3; all p ≤ 0.001). Experiencing two or more milestones increased the risk of death during the study (relative risk 2.7, p = 0.03). Conclusions In early PD, visual hallucinations, recurrent falls, dementia and nursing home placement appear closely interrelated, possibly reflecting a shared neuropathological disease stage. All events convey important and sinister information on PD status and prognosis and are relatively easily accessible during routine clinical consultations. Therefore, they appear highly useful as clinical PD milestones and could possibly be incorporated into a novel disease rating scale.
Abstract The objective of this study was to examine the prevalence and clinical correlates of apathy in a population-based sample of patients with Parkinson's disease (PD) and to assess whether ...apathy may present as a primary behavioural disturbance independent from depression and cognitive impairment. A total of 232 patients derived from an epidemiological study of PD in Rogaland county, Western Norway, completed a comprehensive evaluation of motor, cognitive, and depressive symptoms. Apathy was assessed with the motivation/initiative item of the Unified Parkinson's Disease Rating Scale. The majority of the population had mild to moderate PD with mean disease duration of 9.1 ± 5.7 years. Apathy was diagnosed in 38% of the 232 patients. In 11% of the total sample apathy coexisted with depression and dementia, whereas 10% had apathy and depression without dementia, 6.5% apathy and dementia without depression, and 9% were apathetic without dementia or depression (data missing in 1.5% patients). Apathy was significantly associated with higher depression scores, lower cognitive functioning, and more severe motor symptoms. When excluding patients with depression, dementia, cognitive impairment with no dementia (population-based age- and education-corrected norms for the Mini-Mental State Examination), and those using psychotropic medication, 5% of the 232 patients had apathy. In conclusion, our study shows that apathy is common in the general PD population, may present as an independent behavioural disorder, and suggests that apathy in PD may be related to dysfunction of the nigro-striatal pathway or that brain pathology underlying apathy and progression of motor symptoms develops in parallel.
Introduction: In patients with Parkinson’s disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing ...dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer’s disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods: In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results: During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions: In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.
...both the medium (β = − 1.58 transformed points; 95% confidence interval CI − 2.91 to − 0.25, P = 0.022) and the low GCase activity groups (β = − 2.26 transformed points; 95%CI − 3.59 to − 0.94, ...P = 0.001) were predicted to experience a faster annual decline in MMSE score, compared to the high activity group. Specifically, we found that the size of the effect and significance of the association of GCase activity status with the decline in cognitive function remained comparable apart from the scores for executive function, for which there was no significant difference in the annual decline between the high and the low activity groups (P = 0.086). By contrast, cognitive decline is a gradual process that starts early in a substantial subset of patients and is frequently included as an outcome in PD clinical trials. ...we performed a power calculation to estimate the predicted benefit (concerning trial size) of limiting enrolment to a clinical trial to patients in the lowest tertile of GCase activity, compared to a design in which all newly diagnosed patients are eligible for trial inclusion (an “all-comer” design) (Additional file 2: ...we found that low CSF GCase activity at the time of initial diagnosis is linked to a faster annual decline in clinical scales measuring global cognition and specific cognitive domains over the first 10 years of PD. The link between GCase dysfunction and disease progression provides insight into the pathogenesis of the disease and novel perspectives for GCase-targeted therapies to prevent neurodegeneration, and could provide a valuable biomarker to identify patients at risk of more severe disease.
Impulse control disorders (ICDs) are frequent non-motor symptoms in Parkinson's disease (PD), with potential negative effects on the quality of life and social functioning. ICDs are closely ...associated with dopaminergic therapy, and genetic polymorphisms in several neurotransmitter pathways may increase the risk of addictive behaviors in PD. However, clinical differentiation between patients at risk and patients without risk of ICDs is still troublesome. The aim of this study was to investigate if genetic polymorphisms across several neurotransmitter pathways were associated with ICD status in patients with PD.
Whole-exome sequencing data were available for 119 eligible PD patients from the Norwegian ParkWest study. All participants underwent comprehensive neurological, neuropsychiatric, and neuropsychological assessments. ICDs were assessed using the self-report short form version of the Questionnaire for Impulsive-Compulsive Disorders in PD. Single-nucleotide polymorphisms (SNPs) from 17 genes were subjected to regression with elastic net penalization to identify candidate variants associated with ICDs. The area under the curve of receiver-operating characteristic curves was used to evaluate the level of ICD prediction.
Among the 119 patients with PD included in the analysis, 29% met the criteria for ICD and 63% were using dopamine agonists (DAs). Eleven SNPs were associated with ICDs, and the four SNPs with the most robust performance significantly increased ICD predictability (AUC = 0.81, 95% CI 0.73-0.90) compared to clinical data alone (DA use and age; AUC = 0.65, 95% CI 0.59-0.78). The strongest predictive factors were rs5326 in
, which was associated with increased odds of ICDs, and rs702764 in
, which was associated with decreased odds of ICDs.
Using an advanced statistical approach, we identified SNPs in nine genes, including a novel polymorphism in
, with potential application for the identification of PD patients at risk for ICDs.
Background Although the 14-item Starkstein Apathy Scale (SAS) is recommended to screen for and measure the severity of apathetic symptoms in Parkinson disease (PD), the psychometric attributes of ...this scale have not yet been fully evaluated. Objective The authors examined the reliability, factor structure, and discriminant validity of the SAS in 194 nondemented patients with early untreated PD. Design Cross-sectional multicenter population-based study from Western and Southern Norway. Measurements Standardized rating scales for parkinsonism and neuropsychiatric symptoms. Results The SAS showed fair internal consistency (Cronbach's α = 0.69) and exploratory factor analysis identified two factors: the first factor (24.2% of the variance) represented cognitive-behavioral aspects of apathy (items 1, 2, and 4–8; Cronbach's α = 0.74) and the second factor (15.0% of the variance) a general apathy dimension (items 3 and 9–14; Cronbach's α = 0.52). The correlation between these two factors was low (Spearman's r = 0.19, N = 194, p = 0.008), indicating clinically distinct dimensions, but both factor scores were strongly related to the total SAS score (Spearman's r > 0.6, N = 194, p < 0.0005). Item 3 (insight or self-reflection) showed a negative item-total correlation, and removing this item raised the Cronbach's α of the second factor to 0.70, but did not substantially alter the other results. Both the total score and factor scores of SAS showed fair discriminant validity. Conclusions Although the SAS showed fairly good psychometric properties and the exploratory factor analysis suggested a two-factor solution, the results with this PD sample indicate that item 3 is ambiguous and should be considered removed from the scale.
OBJECTIVE:To examine the incidence, progression, and reversion of mild cognitive impairment in patients with Parkinson disease (PD-MCI) over 5 years.
METHODS:A population-based cohort of patients ...with incident PD underwent repeated neuropsychological testing of attention, executive function, memory, and visuospatial abilities at baseline (n = 178), 1 year (n = 175), 3 years (n = 163), and 5 years (n = 150). Patients were classified as PD-MCI and diagnosed with dementia according to published criteria.
RESULTS:Thirty-six patients (20.2%) fulfilled criteria for PD-MCI at baseline. Among those with normal cognition at baseline (n = 142), the cumulative incidence of PD-MCI was 9.9% after 1 year, 23.2% after 3 years, and 28.9% after 5 years of follow-up. Overall, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the 5-year study period. The conversion rate to dementia was 59.1% in patients with persistent PD-MCI at 1 year vs 7.2% in those with normal cognition during the first year (adjusted odds ratio 16.6, 95% confidence interval 5.1–54.7, p < 0.001). A total of 27.8% of patients with baseline PD-MCI and 24.2% of those with incident PD-MCI had reverted to normal cognition at study end, but the reversion rate decreased to 9.4% in those with persistent PD-MCI at 2 consecutive visits. Compared with cognitively normal patients, PD-MCI reverters within the first 3 years of follow-up were at increased risk of subsequently developing dementia (adjusted odds ratio 10.7, 95% confidence interval 1.5–78.5, p = 0.019).
CONCLUSIONS:Early PD-MCI, regardless of persistence or reversion to normal cognition, has prognostic value for predicting dementia in patients with PD.
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