Kenn Freddy Pedersen

Epidemiology of Parkinson’s disease

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.

Prognosis of Mild Cognitive Impairment in Early Parkinson Disease: The Norwegian ParkWest Study

IMPORTANCE Mild cognitive impairment (MCI) is common in Parkinson disease (PD), but the prognostic value of MCI in early PD is unknown. OBJECTIVE To examine the course of MCI and its progression to dementia in an incident PD cohort. DESIGN Prospective longitudinal cohort study. SETTING The Norwegian ParkWest study, an ongoing population-based study of the incidence, neurobiology, and prognosis of PD in western and southern Norway. PARTICIPANTS A population-based cohort of 182 patients with incident PD monitored for 3 years. MAIN OUTCOMES AND MEASURES 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. RESULTS 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. CONCLUSIONS AND RELEVANCE 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 spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease

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 month period in four counties of Western and Southern Norway were included. Standardised criteria were used to diagnose PD. The Neuropsychiatric Inventory (NPI) was administered to 175 PD and 166 healthy control subjects with similar age and sex distributions. Cluster analysis was used to investigate the interrelationship of NPI items. Results: The proportion with any NPI symptoms was higher in PD (56%) than in controls (22%) (p<0.001). Depression (37%), apathy (27%), sleep disturbance (18%) and anxiety (17%) were the most common symptoms. Clinically significant symptoms occurred in 27% of the PD group compared with only 3% in the control group (p<.001). Subjects with clinically significant neuropsychiatric symptoms had more severe parkinsonism than those without. Two neuropsychiatric clusters were identified, one characterised by mood symptoms and one by apathy. Conclusions: Although the majority of patients with early untreated PD do not have clinical significant neuropsychiatric symptoms, these symptoms are more common in patients than in people without PD. Both psychological stress and brain changes associated with PD are likely to contribute to the higher frequencies.

Prevalence and clinical correlates of apathy in Parkinson's disease: a community-based study.

The objective of this study was to examine the prevalence and clinical correlates of apathy in a population-based sample of patients with Parkinsons 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 Parkinsons 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.

Occurrence and risk factors for apathy in Parkinson disease: a 4-year prospective longitudinal study

Background: Apathy is a common but under-recognised behavioural disorder associated with depression and cognitive impairment in patients with Parkinson disease (PD). However, the longitudinal course of apathy in PD has not been studied. Objective: To examine the occurrence of and risk factors for apathy over time in a representative sample of patients with PD. Methods: A sample of 139 patients was drawn from a population-based prevalence study of PD in Rogaland County, Western Norway. Apathy was measured with the Neuropsychiatric Inventory, using a composite score ⩾4 to indicate clinically significant apathy. Additional measurements included standardised rating scales for parkinsonism, depression and cognitive impairment. A follow-up evaluation was carried out in 79 patients (78.2% of the survivors) 4 years later. Results: Of the 79 patients included in this study, 29 patients (36.7%) had never had apathy, 11 (13.9%) had persistent apathy, and a further 39 (49.4%) developed apathy during follow-up. At follow-up, patients with apathy were more frequently depressed and demented than never-apathetic patients. Dementia at baseline and a more rapid decline in speech and axial impairment during follow-up were independent risk factors for incident apathy. Conclusions: Apathy is a persistent behavioural feature in PD with a high incidence and prevalence over time. Progression of motor signs predominantly mediated by non-dopaminergic systems may be a useful preclinical marker for incident apathy in PD.

CSF Aβ42 predicts early-onset dementia in Parkinson disease

Objective: To test in vivo the proposal from clinicopathologic studies that β-amyloid (Aβ) pathology shortens the time to dementia in Parkinson disease (PD), and to explore the utility of CSF Aβ and related measures as early prognostic biomarkers of dementia in an incident PD cohort. Methods: We assessed a population-based incident cohort of 104 patients with PD who underwent lumbar puncture at diagnosis. We analyzed CSF concentrations of Aβ42, Aβ40, and Aβ38 using a multiplexed immunoassay with electrochemiluminescence (ECL) detection and levels of Aβ42, total tau, and phosphorylated tau using ELISA. Patients were followed prospectively for 5 years. Dementia was diagnosed according to published criteria. Results: CSF levels of Aβ42 were significantly decreased in patients who developed dementia (n = 20, 19.2%) compared to those who did not (n = 84, 80.8%), as measured by ECL (−33%, p = 0.006) as well as ELISA (−36%, p < 0.001). No differences were observed for other markers. Low Aβ42 values predicted a substantially increased risk for subsequent dementia at high sensitivity (≥85%), with hazard ratios of 9.9 (95% confidence interval 2.3–43.5, p = 0.002) for Aβ42ECL <376 pg/mL and 7.6 (2.2–26.4, p = 0.001) for Aβ42ELISA <443 pg/mL, after adjustment for baseline age and PD–mild cognitive impairment (MCI) status. Aβ42 reductions tended to precede the onset of PD-MCI that progressed to dementia. Conclusions: These in vivo data support the role of Aβ pathology in the etiology and highlight the potential utility of CSF Aβ42 as an early prognostic biomarker of dementia associated with PD.

Apathy in drug-naïve patients with incident Parkinson’s disease: the Norwegian ParkWest study

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-naïve 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.

Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease

Background In Parkinsons 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-β (Aβ) metabolism affects the initial motor presentation in PD. Methods We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 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 Aβ42, Aβ38, Aβ42/40 and Aβ38/40 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 Aβ 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 Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.

Psychometric Properties of the Starkstein Apathy Scale in Patients With Early Untreated Parkinson Disease

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 (Cronbachs 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; Cronbachs α = 0.74) and the second factor (15.0% of the variance) a general apathy dimension (items 3 and 9-14; Cronbachs α = 0.52). The correlation between these two factors was low (Spearmans r = 0.19, N = 194, p = 0.008), indicating clinically distinct dimensions, but both factor scores were strongly related to the total SAS score (Spearmans 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 Cronbachs 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.

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.