Orthostatic Hypotension and Risk of Mild Cognitive Impairment and Dementia in Parkinson's Disease.

BACKGROUND: Orthostatic hypotension (OH) is a common condition in Parkinson's disease (PD) with a possible link to cognitive decline. OBJECTIVE: The aim was to explore the association between OH and PD-associated mild cognitive impairment (PD-MCI) and dementia (PDD) over 9 years in a population-based incident PD cohort. METHODS: We prospectively followed up patients from PD diagnosis with serial blood pressure measurements, clinical examinations, and neuropsychological assessments. We defined OH using (1) consensus-based criteria and (2) clinically significant OH by mean arterial pressure (MAP) in standing position ≤75 mmHg. PD-MCI and PDD were diagnosed according to acknowledged criteria. We applied generalized estimating equations models to investigate associations between OH measurements and cognitive impairment over time. Weibull accelerated failure time regression models were used to study if early OH (≤3 years of PD diagnosis) accelerates the time to incident PD-MCI and PDD. RESULTS: Of 186 enrolled patients, consensus-based OH affected 68.8%, clinically significant OH 33.9%, PD-MCI 60.8%, and PDD 31.2%. Consensus-based OH was associated with PD-MCI (odds ratio [OR]: 2.04, 95% confidence interval: 1.44-2.90, P < 0.001), whereas clinically significant OH was associated with both PD-MCI (OR: 1.95, 1.11-3.43, P = 0.020) and PDD (OR: 3.66, 1.95-6.86, P < 0.001). Early clinically significant OH, but not early consensus-based OH, reduced time to incident PD-MCI by 54% (P = 0.021) and time to PDD by 44% (P = 0.003) independently of potential confounders, including supine hypertension and cardiovascular disease. CONCLUSIONS: MAP in standing position emerged as a stronger predictor of cognitive decline than OH determined using consensus-based criteria. These findings have implications for both research and clinical practice.

Cognitive Profile in Parkinson's Disease Dementia Patients with Low versus Normal Cerebrospinal Fluid Amyloid Beta.

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.

Identification of diagnostic and prognostic biomarkers of PD using a multiplex proteomics approach.

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 (ß-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 (ß -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.

Association of CSF Glucocerebrosidase Activity With the Risk of Incident Dementia in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Variations 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. METHODS: Patients 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, and GBA carrier 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. RESULTS: This study enrolled 117 patients with PD (mean age 67.2 years, including 12 GBA non-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 without GBA variations (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). DISCUSSION: The 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 EVIDENCE: This 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.

GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10-Year Population-Based Study.

BACKGROUND: Common genetic variance in apolipoprotein E (APOE), ß-glucocerebrosidase (GBA), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. OBJECTIVES: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non-selective, population-based cohorts of newly diagnosed PD patients. METHODS: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE-ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini-Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini-Hochberg corrections. RESULTS: Carriers of APOE-ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE-ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non-carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. CONCLUSIONS: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The impact of common genetic variants in cognitive decline in the first seven years of Parkinson's disease: A longitudinal observational study.

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 wasassociatedwith 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-ε4 allele were shown to be at increased risk of mild cognitive impairment and dementia within the study period (OR3.03; p = 0.006). CONCLUSIONS: This population-based study of newly diagnosed patients provides new evidence that COMTVal158Met effects cognitive outcomes limited to discrete domains and APOE-ε4 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.

Impulsive and compulsive behaviors in Parkinson's disease: Impact on quality of and satisfaction with life, and caregiver burden.

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.

Evolution of impulsive-compulsive behaviors and cognition in Parkinson's disease.

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 < 0.001). The 4-year cumulative frequency of ICBs in PwP was 46.8% and 23.3% developed incident ICBs during the study period, but the presence of ICBs was non-persistent in nearly 30%. ICBs were independently associated with younger age (OR 0.95, 95% CI 0.91-0.99: p = 0.008) and use of dopamine agonist (OR 4.1, 95% CI 1.56-10.69). Cognitive changes over time did not differ between patients with and without ICBs. In conclusion, ICBs are common in PwP, but are often non-persistent and not associated with greater cognitive impairment over time.

Orthostatic hypotension in Parkinson disease: A 7-year prospective population-based study.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: OH 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). CONCLUSIONS: In 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.

Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease.

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.

Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease.

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 ß-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.

Dopaminergic and Opioid Pathways Associated with Impulse Control Disorders in Parkinson's Disease.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 DRD1, which was associated with increased odds of ICDs, and rs702764 in OPRK1, which was associated with decreased odds of ICDs. CONCLUSION: Using an advanced statistical approach, we identified SNPs in nine genes, including a novel polymorphism in DRD1, with potential application for the identification of PD patients at risk for ICDs.

Evolution of cerebrospinal fluid total α-synuclein in Parkinson's disease.

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.

The natural history of depressive symptoms in patients with incident Parkinson's disease: a prospective cohort study.

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.

Clinical milestones in Parkinson's disease: A 7-year population-based incident cohort study.

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.

Is fatigue associated with cognitive dysfunction in early Parkinson's disease?

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-naïve 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.

Natural course of mild cognitive impairment in Parkinson disease: A 5-year population-based study.

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.

Long-term risk of falls in an incident Parkinson's disease cohort: the Norwegian ParkWest study.

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-naïve 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 < 0.002). Significant concomitants of falls in patients during the study period were higher age, Unified PD Rating Scale motor score, postural instability and gait difficulties (PIGD) phenotype, dementia, and follow-up time. Higher age at baseline, PIGD phenotype at 1-year visit, and follow-up time were independent risk factors for incident falls during follow-up. Nearly two-thirds of patients in the general PD population experience falls within 7 years of diagnosis, representing a more than threefold increased risk compared to age- and gender-matched controls. Patients with higher age at baseline and early PIGD have the greatest risk of falling and may, therefore, be the prime target of specialized assessment and treatment interventions.