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Background and ObjectivesVariations in the glucocerebrosidase gene (GBA) are common risk factors for Parkinson disease (PD) and dementia in PD (PDD) and cause a reduction in the activity of the lysosomal enzyme glucocerebrosidase (GCase). It is anticipated that GCase dysfunction might contribute to a more malignant disease course and predict cognitive impairment in PD, although evidence is lacking. We aimed to discover whether CSF GCase activity is altered in newly diagnosed patients with PD and associated with future development of dementia.MethodsPatients with PD were participants of the ongoing population-based longitudinal ParkWest study in Southwestern Norway and were followed prospectively for up to 10 years. CSF was collected at diagnosis, andGBAcarrier status was obtained. Control samples were from persons without neurodegenerative disorders. GCase activity was measured using a validated assay. PD dementia diagnosis was set according to the Movement Disorder Society criteria, and parametric accelerated failure time models were applied to analyze the association of GCase activity with dementia-free survival.ResultsThis study enrolled 117 patients with PD (mean age 67.2 years, including 12GBAnon‐synonymous variant carriers) and 50 control participants (mean age 64 years). At the time of diagnosis, GCase activity was reduced in patients with PD with (mean ± SD, 0.92 ± 0.40 mU/mg, n = 12) or withoutGBAvariations (1.00 ± 0.37 mU/mg, n = 105) compared with controls (1.20 ± 0.35, n = 50). GCase activity at the time of diagnosis was lower in patients with PD who developed dementia within 10 years (0.85 ± 0.27 mU/mg, n = 41) than in those who did not (1.07 ± 0.40 mU/mg, n = 76,p= 0.001). A 0.1-unit reduction in baseline GCase activity was associated with a faster development of PDD (hazard ratio 1.15, 95% CI 1.03–1.28,p= 0.014).DiscussionThe association of early CSF GCase activity with long-term progression to PD dementia will have important implications for the design of clinical trials for GCase targeting therapies and patient management.Classification of EvidenceThis study provides Class III evidence that reduced CSF GCase activity at the time of PD diagnosis is associated with an increased risk for later development of PDD.

Functional dependency in basic activities of daily living (ADLs) is a key outcome in Parkinson's disease (PD). We aimed to define dependency in PD, using the original and MDS versions of the Unified Parkinson's Disease Rating Scale (UPDRS).We developed two algorithms to define dependency from items of UPDRS Part 2 and MDS-UPDRS Part 2 relating to basic ADLs (feeding, dressing, hygiene and walking, and getting out of a chair). We validated both algorithms using data from 1110 patients from six community-based PD incidence cohorts, testing concurrent validity, convergent validity, and predictive validity.Our optimal algorithm showed high specificity and moderate to high sensitivity versus SchwabEngland80% (specificity 95% [95% confidence interval (CI) 93-97] and sensitivity 65% [95% CI 55-73] at baseline; 88% [95% CI 85-91] and 85% [95% CI 79-97] respectively at five-years follow-up). Convergent validity was demonstrated by strong associations between dependency defined by the algorithm and cognition (MMSE), quality of life (PDQ39), and impairment (UPDRS part 3) (all p 0.001). Algorithm-defined dependency status also predicted mortality: HR for mortality in those dependent vs independent at baseline was 1.6 (95%CI 1.2-2.1) and in those dependent vs independent at five-years' follow-up was 2.2 (1.6-3.0).We have demonstrated the concurrent validity, convergent validity, and predictive validity of a UPDRS-/MDS-UPDRS-based algorithm to define functional dependency in PD. This can be used for studying dependency in any study where UPDRS or MDS-UPDRS part 2 data have been collected.

Background: The criteria for PD-MCI allow the use of global cognitive tests. Their predictive value for conversion from PD-MCI to PDD, especially compared to comprehensive neuropsychological assessment, is unknown. Methods: The MDS PD-MCI Study Group combined four datasets containing global cognitive tests as well as a comprehensive neuropsychological assessment to define PD-MCI (n = 467). Risk for developing PDD was examined using a Cox model. Global cognitive tests were compared to neuropsychological test batteries (Level I&II) in determining risk for PDD. Results: PD-MCI based on a global cognitive test (MMSE or MoCA) increases the hazard for developing PDD (respectively HR = 2.57, P = 0.001; HR = 4.14, P =

Introduction Cognitive impairment is a common feature of Parkinson’s disease and is a significant determinant of patients’ quality of life and dependence. The pattern and progression of cognitive symptoms vary greatly between individuals, and genetic biomarkers may help to predict the severity and trajectory of cognitive impairment in groups of patients. Methods The study included 171 patients from a longitudinal population-based incident Parkinson’s disease study from South Western Norway. All participants were followed from the time of diagnosis for up to seven years, undertaking repeated batteries of clinical and neuropsychological tests, measuring global cognitive impairment, executive function, attention, verbal learning and memory, and visuospatial skills. We used linear mixed regression analyses to explore associations between the function in specific cognitive domains over time and common genetic variants in APOE, MAPT, COMT and BDNF. Results The COMT158Val/Val allele was associated with faster decline in executive function (p = 0.028), verbal learning and memory (p = 0.029), and visuospatial skills (p = 0.027). The BDNF, MAPT and APOE genotypes were not significantly associated with longitudinal changes in individual cognitive domains, however carriers of the APOE-e4 allele were shown to be at increased risk of mild cognitive impairment and dementia within the study period (OR 3.03; p = 0.006). Conclusions This population-based study of newly diagnosed patients provides new evidence that COMT Val158Met effects cognitive outcomes limited to discrete domains and APOE-e4 status predicts a poor overall cognitive prognosis. Together, these data contribute to our understanding of the biology underlying the heterogeneity observed in the progression of PD.

The longitudinal course of ICBs in patients with Parkinson’s disease (PwP) relative to controls has not been explored as of yet. The aim of this study is to determine the frequency, evolution and associated cognitive and clinical features of impulsive and compulsive behaviors (ICBs) over 4 years of prospective follow-up in a population-based cohort with early Parkinson’s disease (PD). We recruited 124 cognitively intact participants with early PD and 156 matched controls from the Norwegian ParkWest study. ICBs were assessed using the self-report short form version of the Questionnaire for Impulsive–Compulsive Disorders in PD. Cognitive changes were examined in PwP with and without ICBs who completed the 4-year follow-up. Generalized linear mixed modelling and mixed linear regression were used to analyze clinical factors and cognitive changes associated with ICBs in PwP over time. ICBs were more common in PwP than controls at all visits, with an age-adjusted odds ratio (OR) varying between 2.5 (95% CI 1.1–5.6; p = 0.022) and 5.1 (95% CI 2.4–11.0; p

Introduction To disentangle the association between impulsive and compulsive behaviors (ICBs), health-related quality of life (HRQOL), satisfaction with life (SwL), and caregiver distress in dyads of people with Parkinson's disease (PwP) and caregivers. Methods Data used in this study were obtained from the ongoing Norwegian ParkWest study, a population-based longitudinal cohort study of the incidence, neurobiology and prognosis of PD in Western Norway. One hundred and one dyads of PwP free of dementia and their caregivers were included 5 years after PD diagnosis and inclusion in the ParkWest study. Standardized clinical rating scales were used to evaluate ICBs, HRQOL, SwL and caregiver distress. Results Of 101 PwP-caregiver dyads, self-reported ICBs were seen in 33% of PwP and only caregiver-reported ICBs in 12% of PwP. PwP-reported ICBs were associated with poorer HRQOL and SwL, whereas ICBs reported by caregivers only were associated with increased caregiver distress, but not poorer HRQOL or SwL in PwP. Conclusions ICBs have adverse effects on HRQOL, SwL and caregiver distress. These findings underpin the need for proper identification and management of ICBs in PwP.

Background and purpose: Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are three of the most common neurodegenerative disorders. Up to 20% of these patients have the wrong diagnosis, due to overlapping symptoms and shared pathologies. A cerebrospinal fluid (CSF) biomarker panel for AD is making its way into the clinic, but an equivalent panel for PD and DLB and for improved differential diagnoses is still lacking. Using well‐defined, community‐based cohorts and validated analytical methods, the diagnostic value of CSF total‐α‐synuclein (t‐α‐syn) alone and in combination with total tau (t‐tau) in newly diagnosed patients with PD, DLB and AD was determined. Methods: Cerebrospinal fluid concentrations of t‐α‐syn were assessed using our validated in‐house enzyme‐linked immunosorbent assay in 78 PD patients, 20 AD patients, 19 DLB patients and 32 controls. t‐tau was measured using a commercial assay. Diagnostic performance was assessed by receiver operating characteristic curve analysis. Results: Compared to controls (mean 517 pg/ml), significantly lower levels of CSF t‐α‐syn in patients with PD (434 pg/ml, 16% reduction, P = 0.036), DLB (398 pg/ml, 23% reduction, P = 0.009) and AD (383 pg/ml, 26% reduction, P = 0.014) were found. t‐α‐syn levels did not differ significantly between PD, DLB and AD. The t‐tau/t‐α‐syn ratio showed an improved performance compared to the single markers. Conclusion: This is the first study to compare patients with PD, DLB and AD at the time of diagnosis. It was found that t‐α‐syn can contribute as a teammate with tau in a CSF biomarker panel for PD and DLB, and strengthen the existing biomarker panel for AD. publishedVersion

Background Numerous neuropsychological tests and test versions are used in Parkinson's disease research, but their relative capacity to detect mild cognitive deficits and their comparability across studies are unknown. The objective of this study was to identify neuropsychological tests that consistently detect cognitive decline in PD across studies. Methods Data from 30 normed neuropsychological tests across 20 international studies in up to 2908 nondemented PD patients were analyzed. A subset of 17 tests was administered to up to 1247 healthy controls. A 2-step meta-analytic approach using standardized scores compared performance in PD with normative data. Results Pooled estimates of the differences between PD and site-specific healthy controls identified significant cognitive deficits in PD patients on 14 test scores across 5 commonly assessed cognitive domains (attention or working memory, executive, language, memory, and visuospatial abilities), but healthy control performance was statistically above average on 7 of these tests. Analyses based on published norms only, as opposed to direct assessment of healthy controls, showed high between-study variability that could not be accounted for and led to inconclusive results. Conclusions Normed neuropsychological tests across multiple cognitive domains consistently detect cognitive deficits in PD when compared with site-specific healthy control performance, but relative PD performance was significantly affected by the inclusion and type of healthy controls versus the use of published norms only. Additional research is needed to identify a cognitive battery that can be administered in multisite international studies and that is sensitive to cognitive decline, responsive to therapeutic interventions, and superior to individual cognitive tests. © 2018 International Parkinson and Movement Disorder Society.

Introduction Both polymorphisms and mutations in glucocerebrosidase ( GBA ) may influence the development of dementia in patients with Parkinson's disease. Methods Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis. Results A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers. Discussion GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Objective Dementia in Parkinson disease (PD) is a common occurrence, and shows a marked overlap at a clinical and pathological level with Alzheimer’s disease (AD), suggesting they share underlying disease mechanisms. Genetic variants in SORL1 have been identified in patients with AD, but a possible role in other dementias is unknown. The aim of this study was to investigate whether common polymorphisms in SORL1 affect the risk of developing dementia in a population-based cohort of patients with incident PD. Methods One common, nonsynonymous SORL1 variant (rs2298813; A528T) was identified in whole exome sequencing data from 185 patients with PD from the Norwegian ParkWest study, who had been followed up to the 7-year visit after diagnosis. A528T was tested for association with PD risk, the development of dementia, and in a subset of patients (n = 103) for associations with established AD cerebrospinal fluid (CSF) biomarkers measured at the time of PD diagnosis. Results We found an association of A528T carrier status with increased risk of developing PD dementia (HR 2.31; 95% CI 1.09–4.90; p = 0.03) compared to non-carriers. Additionally, A528T carrier status was associated with a reduced ratio of CSF β-amyloid 42 to p-Tau (p = 0.014) but no alterations in absolute AD marker levels (all p > 0.05) at the time of PD diagnosis. Conclusion Our results show the first association of the AD risk factor SORL1 with incident dementia in PD, providing new evidence that AD related disease mechanisms may contribute to dementia in a subset of patients with PD. Finding support for a shared etiology for AD and PD dementia provides new directions for research into treatments for these diseases.

Depression is common in patients with Parkinson disease and causes suffering and increased caregiver burden. A better understanding of depressive symptoms in Parkinson disease, their progression, and risk factors may, therefore, benefit management of these patients. The present study included 187 drug-naïve patients with incident PD and 166 controls from the population-based Norwegian ParkWest project. Depressive symptoms were examined with the Montgomery and Aasberg Depression Rating Scale (MADRS) at time of diagnosis and inclusion in the study and after 1, 3, 5, and 7 years of follow-up. Associations between MADRS scores and risk factors were assessed using generalized estimating equations (GEE). The mean MADRS score from all 823 examinations during the study period was 4.2 in patients and 1.3 in 732 examinations among controls. Among controls, the occurrence of depressive symptoms was also lower and rather stable during follow-up, while in patients, we observed a decrease from time of diagnosis and until the 1-year visit, followed by a steady increase in these symptoms over time. Factors associated with higher MADRS score in the multivariable model were female sex, being dependent, higher pain score, higher Unified PD Rating Scale (UPDRS) motor score, and lower Mini-Mental State Examination (MMSE) score. The results from this study underscore the importance and frequency of depressive symptoms in patients with early PD. Furthermore, risk factors that may be considered PD-nonspecific are associated with depressive symptoms as are factors that reflect the progression of PD.

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.

Background Impulsive and compulsive behaviors (ICBs) are frequent in Parkinson's disease (PD), but data from population-based cohorts is lacking. Objectives To determine the frequency and associated demographic, clinical, neuropsychiatric and cognitive features of ICBs in a population-based PD cohort. Methods This cross-sectional study included 125 patients with PD and 159 age- and gender-matched normal controls recruited from the Norwegian ParkWest study. Participants underwent comprehensive neurological, neuropsychiatric and neuropsychological assessments. ICBs were assessed using the Questionnaire for Impulsive-Compulsive Disorders in PD short form. Multiple logistic regression analyses were performed to compare the odds of ICBs between groups and to identify independent correlates of ICBs in PD. Results 30.4% of patients reported at least one ICB, with an odds ratio (OR) of 3.2 (95% confidence interval [CI] 1.8-5.9) compared with controls. Multiple ICBs were experienced by 8.8% of patients vs 1.3% of controls (OR 7.6, 95% CI 1.7-34.8). Compared to controls, the ORs of having an ICB were 7.4 (95% CI 2.6-20.9) in patients taking DA without levodopa, 4.6 (95% CI 2.3-9.3) in those treated with both DA and levodopa, and 1.2 (95% CI 0.5-3.2) in patients using levodopa but not DA. In multivariate models, ICB status in patients was independently associated with DA treatment and depressive symptoms, but not with other dopaminergic medications, motor function, or cognitive performance. Conclusions Patients with PD treated with DA, but not other dopaminergic medications, have increased odds of having ICBs compared with age- and gender-matched controls. This has implications for individualized patient management and follow-up.

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.

The objective of this study is to examine the frequency, development, concomitants, and risk factors of falls in a population-based incident Parkinson’s disease (PD) cohort. One hundred eighty-one drug-naive patients with incident PD and 173 normal controls recruited from the Norwegian ParkWest study were prospectively monitored over 7 years. Information on falls was obtained biannually from patients, and at baseline and after 1, 3, 5, and 7 years of follow-up in control subjects. Generalized estimating equation models for correlated data were applied to investigate concomitant features of falls and risk factors for incident falls during 7 years of follow-up in PD. Overall, 64.1% of patients reported falling during the study period. The 7-year cumulative incidence of falls in non-falling patients at baseline (n = 153) was 57.5%, with a relative risk to controls of at least 3.1 (95% confidence interval 1.5–6.3; p

ObjectiveTo determine the frequency, evolution, and associated features of orthostatic hypotension (OH) over 7 years of prospective follow-up in a population-based, initially drug-naive Parkinson disease (PD) cohort.MethodsWe performed repeated lying and standing blood pressure measurements in 185 patients with newly diagnosed PD and 172 matched normal controls to determine the occurrence of (1) OH using consensus-based criteria and (2) clinically significant OH (mean arterial pressure in standing position ≤75 mm Hg). We applied generalized estimating equations models for correlated data to investigate associated features of these 2 outcomes in patients with PD.ResultsOH was more common in patients with PD than controls at all visits, with the relative risk increasing from 3.0 (95% confidence interval [CI] 1.6–5.8; p < 0.001) at baseline to 4.9 (95% CI 2.4–10.1; p < 0.001) after 7 years. Despite a high cumulative prevalence of OH (65.4%) and clinically significant OH (29.2%), use of antihypotensive drugs was very rare (0.5%). OH was independently associated with older age (odds ratio [OR] 1.06 per year; 95% CI 1.03–1.10), lower Mini-Mental State Examination score (OR 0.91 [0.85–0.97] per unit), and longer follow-up time (OR 1.12 [1.03–1.23] per year). Clinically significant OH was associated with the same characteristics, in addition to higher levodopa equivalent dosage (OR 1.16 [1.07–1.25] per 100 mg).ConclusionsIn this population-based study, we found OH to be a very frequent but undertreated complication in early PD, with associations to both disease-specific symptoms and drug treatment. Our findings suggest that clinicians should more actively assess and manage OH abnormalities in PD.

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.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.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 (p0.001), 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 (p0.001) rather than initial treatment with levodopa (p0.1) 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.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.

Author(s): Hoogland, Jeroen; Boel, Judith A; de Bie, Rob MA; Schmand, Ben A; Geskus, Ronald B; Dalrymple-Alford, John C; Marras, Connie; Adler, Charles H; Weintraub, Daniel; Junque, Carmen; Pedersen, Kenn F; Mollenhauer, Brit; Goldman, Jennifer G; Troster, Alexander I; Burn, David J; Litvan, Irene; Geurtsen, Gert J; MDS Study Group “Validation of Mild Cognitive Impairment in Parkinson Disease” | Abstract: BackgroundThe International Parkinson and Movement Disorders Society criteria for mild cognitive impairment in PD need validation. The objectives of this present study were to evaluate prognostic validity of level I (abbreviated) International Parkinson and Movement Disorders Society mild cognitive impairment in PD criteria for development of PD dementia and compared them with level II (comprehensive) criteria.MethodsWe analyzed data from 8 international studies (1045 patients) from our consortium that included baseline data on demographics, motor signs, depression, detailed neuropsychological testing, and longitudinal follow-up for conversion to Parkinson's disease dementia. Survival analysis evaluated their contribution to the hazard of Parkinson's disease dementia.ResultsLevel I mild cognitive impairment in PD, increasing age, male sex, and severity of PD motor signs independently increased the hazard of Parkinson's disease dementia. Level I and level II mild cognitive impairment in PD classification had similar discriminative ability with respect to the time to Parkinson's disease dementia.ConclusionsLevel I mild cognitive impairment in PD classification independently contributes to the hazard of Parkinson's disease dementia. This finding supports the prognostic validity of the abbreviated mild cognitive impairment in PD criteria. © 2019 International Parkinson and Movement Disorder Society.

Introduction Cerebrospinal fluid (CSF) total α-synuclein is considered a potential biomarker for Parkinson's disease (PD), but little is known about the evolution of this marker during the course of the disease. Our objective was to investigate whether CSF total α-synuclein concentrations change over time and are associated with motor and cognitive function in PD. Methods CSF total α-synuclein concentrations were quantified in 56 longitudinally followed PD patients, 27 of whom provided CSF repeatedly 2 and/or 4 years later. Another 18 subjects were included as controls. The samples were analyzed using two independent, validated ELISA methods: our recently developed and validated in-house ELISA and a commercial kit from BioLegend. Results CSF total α-synuclein levels did not distinguish PD patients from controls, displayed no substantial changes during a period of up to 4 years, and did not predict subsequent motor or cognitive decline. These findings were consistent for both analytical methods. Conclusion Our findings do not support the clinical utility of total α-synuclein as a single diagnostic or prognostic biomarker in PD.

Introduction This registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care. Methods Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of “On” and “Off” time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39. Results Overall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in “Off” time (hours/day) (mean ± SD = −4.1 ± 3.5, P < 0.001), “On” time with dyskinesia (hours/day) (−1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (−16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (−7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%). Conclusions LCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Prospective long-term studies of falls in Parkinson's disease (PD) are scarce. Objective To examine the development of falls over 8 years in a population-based cohort of ambulatory patients with PD, and to investigate predictors of future falls in non-fallers at baseline. Methods All patients were examined at baseline and after 4 and 8 years, including the UPDRS, MMSE, Montgomery and Aaberg Depression Rating Scale, Functional Comorbidity Index, and a clinical dementia interview. Logistic regression models were applied to investigate baseline risk factors for future falls. A total of 211 patients were included at baseline, whereas 121 and 64 were re-examined at 4 and 8 years, respectively. Results The prevalence of falls increased from 41% (87 of 211) at baseline to 72% (46 of 64) after 8 years of prospective follow-up (disease duration 16.2 ± 4.8 years). Forty-seven non-falling patients at baseline completed all study visits, of these 68% (n = 32) changed fall status during follow-up. Predictive variables for current falling after 4 years were rare or occasional freezing of gait (OR 6.6, 95% CI 1.2–36.9), higher levodopa equivalent doses and more severe speech and axial impairment (both OR 1.3, 95% CI 1.0–1.7) in non-fallers at baseline. Higher baseline age was the only risk factor for current falling after 8 years. Conclusions Nearly ¾ of the PD cohort reported falling after 8 years of follow-up. Disease-specific gait and axial impairments were the major risk factors for future falls in non-fallers at baseline. This has implications for patient education and management.

Introduction Fatigue is a common and disabling symptom which may be seen in early Parkinson's disease (PD). Our understanding of the phenomenology and etiology of fatigue in PD is limited. The objective of this study was to determine whether fatigue was related to cognition in early PD patients. Methods The study is part of the Norwegian ParkWest project, a population-based cohort study, comprising 184 de novo, drug-naive patients with PD. PD was diagnosed according to the Gelb criteria. Fatigue was assessed by the Fatigue Severity Scale (FSS). Cognition was assessed by a battery of tests evaluating functions in the domains of verbal memory, processing speed, executive function and visuospatial abilities. Results 107 of the cohort had moderate to severe fatigue (FSS ≥ 4). In univariate correlation analyses high fatigue score was correlated to disease severity, presence of sleep problems, depressive symptoms, apathy, reduced processing speed and reduced visuospatial abilities. In a multiple regression analysis only disease severity (measured by the UPDRS part 3), sleep problems, depressive symptoms and reduced visuospatial abilities contributed to the model. Conclusion Fatigue is associated with visuospatial function in early PD patients. Further studies are needed to determine the pathophysiologic relevance of this association.

BACKGROUND: A complex relationship exists between motor impairment, physical activity (sedentary behavior, standing and ambulatory activity) and falls in people with Parkinson's disease (PD). OBJECTIVE: To explore associations between recent fall history and the ability to retain an active lifestyle as determined by the volume, pattern and variability of physical activity in people with PD. METHODS: Forty-eight participants with PD were recruited from the Norwegian ParkWest study. Body posture and ambulatory activity were monitored objectively over 7 days using the activPAL3 TM accelerometer. Clinical assessments included the Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale motor section and Falls Efficacy Scale-International. Structured interviews were performed to obtain information about demographics, fall history last 6 months, mobility and dementia. RESULTS: Participants with a fall history (n = 20) spent more time sedentary and less time standing than non-falling participants (n = 28). There were no significant differences regarding pattern or variability of sedentary behavior, standing or ambulatory activity in falling versus non-falling participants. Confidence in being able to get up from floor contributed significantly to time spent in sedentary behavior and ambulatory activity in participants with fall history, whereas motor impairment was significantly associated with time spent in all facets of physical activity for non-falling participants. CONCLUSIONS: Fall history in our PD cohort was associated with a more sedentary lifestyle, but not less ambulatory activity. More emphasis on improving the capacity to safely complete activities of daily living and increase confidence in getting up from floor may reduce sedentary behavior in people with PD. Language: en

Epidemiological research aims to provide information on the development, prevalence and progression of diseases, and their associated risk factors. Epidemiological research is thus the basis of increasing our understanding on the aetiology of diseases and as a consequence the starting point for identifying at risk groups in the population, development for novel prevention and treatment strategies, and health care planning. This review provides an overview of the epidemiology of Parkinson's disease, the second most common neurodegenerative disorder, with special emphasis on population-based data on the clinical progression of motor and non-motor features of the disease.

Item does not contain fulltext BACKGROUND: In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. OBJECTIVE: To explore in vivo whether variability in brain amyloid-beta (Abeta) metabolism affects the initial motor presentation in PD. METHODS: We quantified cerebrospinal fluid (CSF) concentrations and ratios of Abeta42, Abeta40 and Abeta38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. RESULTS: Patients with PD with the PIGD phenotype had significantly reduced CSF Abeta42, Abeta38, Abeta42/40 and Abeta38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Abeta markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. CONCLUSIONS: Motor heterogeneity in de novo PD independently relates to CSF Abeta markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Abeta metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.

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.: The authors examined the reliability, factor structure, and discriminant validity of the SAS in 194 nondemented patients with early untreated PD.: Cross-sectional multicenter population-based study from Western and Southern Norway.: Standardized rating scales for parkinsonism and neuropsychiatric symptoms.: 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 r0.6, N = 194, p0.0005). 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.: 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.

International audience; Background: Neuropsychiatric symptoms are common in Parkinson's disease (PD), and have important clinical consequences for patients, caregivers and society. Few studies of neuropsychiatric symptoms in early, untreated PD exist. Objective: To explore the range, clustering and correlates of neuropsychiatric symptoms in an incidence-cohort of untreated subjects with PD. Methods: All cases with incident PD identified during a 22-months period in four counties of Western and Southern Norway were included. Standardized criteria were employed to diagnose PD. The Neuropsychiatric Inventory (NPI) was administered to 175 PD and 166 healthy control subjects with similar age and sex distribution. Cluster analysis was used to investigate the inter-relationship of NPI items. Results: The proportion with any symptom and severity of NPI symptoms was higher in PD (56%) than in controls (22%) (p

Apathy is a common behavioural problem in Parkinson’s disease (PD), with important clinical consequences for patients and their families. However, little is known about apathy in early PD. We examined the frequency and clinical characteristics of apathy in 175 nondemented, drug-naive patients with newly diagnosed PD and 165 control subjects matched for age, sex and education level in Western and Southern Norway. All participants underwent a comprehensive neurological, psychiatric and neuropsychological evaluation. Apathy was diagnosed based on Neuropsychiatric Inventory assessment and recently proposed consensus criteria. Apathy was found in 22.9% of the PD patients, of whom 37.5% had significant depressive symptoms, whereas none of the control subjects were apathetic. Apathy was significantly associated with male gender, higher depression scores and more severe motor symptoms, but was not associated with greater cognitive impairment. When excluding patients with significant depressive symptoms, apathy remained significantly associated with motor severity. Approximately 50% of the caregivers of patients with apathy reported the apathetic behaviour to be at least moderately distressing. The association between apathy and motor severity in our PD cohort suggests a common underlying pathophysiological mechanism. Future studies should explore the longitudinal effect of dopamine replacement therapy on apathetic behaviour in early PD. The relationship between apathy and male gender needs further study to be fully evaluated.

A variety of neuropsychiatric symptoms commonly occur in Parkinson's disease. Extensive research the last 10 years has provided new knowledge in the field.This review is based on literature retrieved from a Medline search and own research and clinical experience.Neuropsychiatric symptoms occur in the majority of patients with Parkinson's disease, and are associated with impaired quality of life for patients and relatives, additional deterioration of function and increased use of health resources. Medical and surgical therapies can induce or worsen such symptoms. Cognitive impairment and dementia are among the most common and severe complications to Parkinson's disease. No disease-modifying treatment is available, but rivastigmine was effective in one large randomised trial. Visual hallucinations are common and often persistent, but can be treated with klozapin if reducing the number and dose of antiparkinson agents are not helpful. Depression occurs frequently, usually mild, but there is little evidence of treatment efficacy. Apathy, anxiety and sleep disturbances are additional commonly occurring neuropsychiatric symptoms. Neuropsychiatric symptoms are so frequent in Parkinson's disease that they should be considered an integral part of the disease; it is important that clinicians are aware of these symptoms.

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.

We examined the validity of the motivation/initiative item of the Unified Parkinson's Disease Rating Scale (UPDRS) section I as a screening and diagnostic measure for apathy in Parkinson's disease (PD). Fifty-eight patients with PD were evaluated with the UPDRS, the 14-item Apathy Scale (AS), and standardized rating scales of depression and cognitive impairment. Apathy was diagnosed using specific items of the AS together with proposed criteria for apathy. A score of 2 or more on the motivation/initiative item was adequate to screen for apathy, whereas a score of 4 had high diagnostic accuracy at the cost of unacceptable low sensitivity.

Mild cognitive impairment (MCI) is common in Parkinson disease (PD), but the prognostic value of MCI in early PD is unknown.To examine the course of MCI and its progression to dementia in an incident PD cohort.Prospective longitudinal cohort study.The Norwegian ParkWest study, an ongoing population-based study of the incidence, neurobiology, and prognosis of PD in western and southern Norway.A population-based cohort of 182 patients with incident PD monitored for 3 years.Serial neuropsychological tests of attention, executive function, verbal memory, and visuospatial skills were administered at baseline, 1 year, and 3 years. Patients were classified as having MCI and received a diagnosis of dementia according to published consensus criteria.Significantly more patients with MCI than without MCI at baseline (10 of 37 [27.0%] vs 1 of 145 [0.7%]; relative risk, 39.2 [95% CI, 5.2-296.5]; P.001) progressed to dementia during follow-up. Of those with MCI at baseline, 8 of 37 (21.6%) had MCI that reverted to normal cognition during follow-up. Mild cognitive impairment at the 1-year visit was associated with a similar progression rate to dementia (10 of 36 patients [27.8%]) and reversion rate to normal cognition (7 of 36 [19.4%]). However, among the 22 patients with persistent MCI at baseline and the 1-year visit, 10 (45.5%) developed dementia and only 2 (9.1%) had MCI that reverted to normal cognition by the end of study.Mild cognitive impairment at PD diagnosis predicts a highly increased risk for early dementia. Repeated neuropsychological testing increases the prognostic accuracy of MCI with respect to early dementia development in PD.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess Depression, Anxiety and Apathy in prHD and early HD individuals.