Ole-Bjørn Tysnes

Cognitive impairment in incident, untreated Parkinson disease The Norwegian ParkWest Study

Background: Little is known regarding the cognitive impairment in subjects with early, drug-naïve Parkinson disease (PD). The aim of this study was to explore the proportion with mild cognitive impairment (MCI) and subtypes in an incidence cohort of untreated PD in Southern and Western Norway. Methods: A total of 196 non-demented, drug-naive patients who were recruited after an extensive search of all new cases of PD in the area and 201 healthy control subjects completed a battery of neuropsychological tests of verbal memory, visuospatial, and attentional-executive functioning. Subjects were classified as MCI if the age- and education-corrected z-score was falling 1.5 standard deviations below the mean for at least one of the cognitive domains. Results: The PD group was more impaired on all neuropsychological tests than controls, but the effect sizes were small. The largest effect size was found for verbal memory. A total of 18.9% of the patients with PD were classified as MCI, with a relative risk of 2.1 (1.2–3.6) in PD compared to the control group. Patients with PD with and without MCI did not differ significantly regarding demographic and motor features. Among PD-MCI patients, nearly two-thirds had a non-amnestic MCI subtype, and one third had an amnestic MCI subtype. Conclusions: The findings demonstrate a twofold increase in the proportion with cognitive impairment in subjects with early, untreated Parkinson disease (PD) compared to controls. This has implications for diagnosis and management of PD. AD = Alzheimer disease; aMCI-MD = amnestic multiple-domain MCI; aMCI-SD = amnestic single-domain MCI; CVLT-2 = California Verbal Learning Test II; IQCode = Informant Questionnaire on Cognitive decline in the elderly; MADRS = Montgomery and Aasberg Depression Rating Scale; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; naMCI-MD = non-amnestic multiple-domain MCI; naMCI-SD = non-amnestic single-domain MCI; PD = Parkinson disease; RR = relative risks; UPDRS = Unified Parkinson’s Disease Rating Scale; VOSP = Visual Object and Space Perception Battery.

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.

Incidence of Parkinson's disease in Norway: the Norwegian ParkWest study.

Objective: To present the incidence of Parkinson’s disease (PD) in Norway and to explore gender influences on incidence and age at onset, as well as severity and pattern of parkinsonism at the time of diagnosis in a representative drug naïve cohort with newly diagnosed PD. Methods: In four Norwegian counties comprising a base population of 1 052 075 inhabitants, multiple sources of case ascertainment and a four step diagnostic procedure were used to establish a representative cohort of patients with incident PD at a high level of diagnostic accuracy. Of a total of 604 subjects referred to the study, 265 individuals fulfilled the clinical research criteria of PD at their latest clinical visit, at a mean 28 months after identification. Results: The incidence of PD in the study area, age standardised to the 1991 European standard population, was 12.6/105yr-1 (95% CI 11.1 to 14.2). The overall age standardised male to female ratio was 1.58 (95% CI 1.22 to 2.06), with a consistent male preponderance throughout all age groups. Clinical onset of PD was later in women than in men (68.6 vs 66.3 years; p = 0.062) whereas severity and pattern of parkinsonism in drug naïve patients was not different between genders at the time of diagnosis. Conclusion: Incidence rates of PD in Norway are similar to those in other Western European and American countries. Female gender was associated with a considerably lower risk of PD and slightly delayed motor onset but had no impact on severity of parkinsonism or clinical phenotype in incident drug naïve PD, suggesting that the female gender influences on the nigrostriatal system are most pronounced in the preclinical phase of the disease.

CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's Disease: the Norwegian ParkWest study

Background Alzheimers disease (AD) pathology is found in a considerable portion of patients with Parkinsons disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid (CSF) levels of amyloid-β (Aβ) and tau proteins have been found in PDD, with intermediate changes for Aβ42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD. Methods CSF concentrations of Aβ42, Aβ40 and Aβ38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD. Results PD patients displayed significant reductions in Aβ42 (19%; p=0.009), Aβ40 (15.5%; p=0.008) and Aβ38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Aβ42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Aβ42 (β=0.205; p=0.019), Aβ40 (β=0.378; p<0.001) and Aβ38 (β=0.288; p=0.001) and memory impairment, but not executive-attentional or visuospatial dysfunction. Tau protein levels did not correlate with cognitive measures. Conclusion CSF Aβ levels are altered in a subset of patients with early PD and relate to memory impairment. Our study suggests that alterations in Aβ protein metabolism may contribute to the heterogeneity in pattern and course of cognitive decline associated with PD. Longitudinal studies are needed to clarify the clinical significance of CSF Aβ peptides as prognostic biomarkers in PD.

Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson's disease

BACKGROUND The relative impact of motor- and non-motor symptoms on health-related quality of life in early Parkinsons disease is poorly documented. METHODS 188 patients with incident Parkinsons disease from a population-based study were examined at the time of diagnosis, before initiation of dopaminergic treatment, with follow-up of 166 patients three years later. Health-related quality of life was assessed by the 36-item Short-form Health Survey (SF-36). Motor and non-motor variables were derived from the Unified Parkinsons disease rating scale and other established scales. RESULTS Multiple regression analyses showed that the non-motor symptoms strongest associated with reduced SF-36 scores at diagnosis and three years later were depression, fatigue and sensory complaints. The motor symptoms most related to impaired SF-36 scores were problems with gait and activities of daily living that cover personal needs. The variance of SF-36 mental summary scores was much better explained by non-motor vs. motor symptoms, both at baseline (R(2) = 0.384 vs. 0.095) and 3 years later (R(2) = 0.441 vs. 0.195). Also SF-36 physical summary scores were better explained by non-motor vs. motor symptoms with R(2) = 0.372 vs. 0.322 at baseline and R(2) = 0.468 vs. 0.315 after 3 years. CONCLUSION In early PD, including the phase before dopaminergic treatment is initiated, non-motor symptoms are more important for reduced health-related quality of life than motor symptoms. Fatigue, depression, sensory complaints and gait disturbances emerge as the most relevant symptoms and should be given corresponding attention in the management of patients with early 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.

Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinsons disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimers disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta‐analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total‐tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10−25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF‐total‐tau (P = .0110) but not Aβ42 suggesting that TREM2s role in AD may involve tau dysfunction.