Guido Alves

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.

Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial

BACKGROUND Dementia with Lewy bodies (DLB) and Parkinsons disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. METHODS We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinsons Disease Society Brain Bank clinical diagnostic criteria for Parkinsons disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. FINDINGS 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures. INTERPRETATION Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. FUNDING The Western Norway Regional Health Authority; H Lundbeck A/S.

Changes in motor subtype and risk for incident dementia in Parkinson's disease

The objective of this study was to assess the temporal relationship between changes in predominant motor symptoms and incident dementia in Parkinsons disease (PD). A community‐based sample of 171 nondemented patients with PD was followed prospectively and examined at baseline and after 4 and 8 years. The motor subtype of Parkinsonism was classified into tremor‐dominant (TD), indeterminate, or postural instability gait difficulty (PIGD) subtype at each visit, based on defined items in the Unified Parkinsons Disease Rating Scale, subscales II and III. Dementia was diagnosed according to DSM‐III‐R criteria, based on clinical interview, cognitive rating scales, and neuropsychological examination. Logistic regression was used to analyze the relationship between subtype of Parkinsonism and dementia. Transition from TD to PIGD subtype was associated with a more than threefold increase in the rate of Mini‐Mental State Examination decline. Compared to patients with persistent TD or indeterminate subtype, the odds ratio for dementia was 56.7 (95% CI: 4.0–808.4; P = 0.003) for patients changing from TD or indeterminate subtype to PIGD subtype, and 80.0 (95% CI: 4.6–1400.1; P = 0.003) for patients with persistent PIGD subtype. Patients with TD subtype at baseline did not become demented until they developed PIGD subtype, and dementia did not occur among patients with persistent TD subtype of Parkinsonism. In a substantial proportion of PD patients who develop postural instability and gait disorder during the course of the disease, this transition is associated with accelerated cognitive decline and highly increased risk for subsequent dementia. These findings raise the question whether PIGD and dementia share common or parallel neuropathology.

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.

Progression of motor impairment and disability in Parkinson disease: A population-based study

Objective: To investigate risk factors and the rate of progression of motor symptoms and disability in a population-based cohort of patients with Parkinson disease (PD). Methods: In all, 232 patients with PD, derived from a community-based prevalence study, were followed prospectively over an 8-year period. Follow-up examinations were done 4 and 8 years after baseline, and 144 patients participated in at least one follow-up examination. Information on motor function and disability was obtained using the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr staging, and the Schwab and England score. Population-averaged logistic regression models were used to describe annual disease progression and to analyze the influence of potential risk factors on functional decline. Results: We found a similar mean annual decline in the UPDRS motor score and the Hoehn and Yahr staging of 3.1% and 3.2%, respectively. Also the UPDRS Activity of Daily Living (ADL) score and the Schwab and England scale changed similarly, with 3.5% and 3.6% per year, respectively. Age, age at onset, disease duration, and excessive daytime somnolence at baseline were strong and independent predictors of greater impairment in motor function and disability. Cognitive impairment at baseline predicted higher disability and higher Hoehn and Yahr scores. Time by age-at-onset interactions were found for the UPDRS motor score and the Hoehn and Yahr staging. Conclusions: Motor function and disability worsened significantly with time, and to a similar extent. Age, age at onset and disease duration, as well as symptoms thought to be due to involvement of non-dopaminergic brain structures, are predictors of more impaired motor function and disability. However, age at disease onset was the main predictor of motor decline in our cohort, indicating a slower and more restricted pathologic disease process in patients with young-onset PD.

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.

A 12-Year Population-Based Study of Psychosis in Parkinson Disease

OBJECTIVE To investigate the prevalence, incidence, risk factors, and concomitants of Parkinson disease (PD)-associated psychosis (PDP) in a population-based prevalent cohort. DESIGN Prospective longitudinal cohort study. SETTING Community-based study in southwestern Norway. PARTICIPANTS Two hundred thirty community-based PD patients were followed up prospectively for 12 years. Reassessments were conducted at 4 and 8 years and then annually. MAIN OUTCOME MEASURES Severity of PDP was measured by the Unified Parkinson Disease Rating Scale thought disorder (UPDRS-TD) item. Patients with a UPDRS-TD score of 2 or more or those taking antipsychotic drugs owing to psychotic symptoms were categorized at each visit as having PDP. Generalized estimating equations were applied to investigate baseline risk factors for incident PDP and clinical and demographic concomitants of PDP during 12 years. RESULTS By studys end, 137 patients (60%) had developed hallucinations or delusions. The incidence rate of PDP was 79.7 per 1000 person-years. Higher age at onset, higher baseline levodopa-equivalent doses, probable rapid eye movement (REM) sleep behavior disorder at baseline, and follow-up time were independent risk factors of incident PDP. Significant concomitant features of patients with PDP during the 12-year study period were low activities of daily living function (UPDRS II), dementia, high levodopa-equivalent dose, and probable REM sleep behavior disorder. CONCLUSIONS Psychotic symptoms affect most patients with PD, with increased risk in those with higher age at onset, need for high doses of dopaminergic drugs, and probable REM sleep behavior disorder. This risk factor pattern and the observed associations with increased disability and dementia place PDP within a symptom complex signaling a malignant disease course.

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.

Is fatigue an independent and persistent symptom in patients with Parkinson disease

Objective: To evaluate if mental fatigue is a symptom that appears independently from other clinical features in patients with Parkinson disease (PD), and to study if fatigue is persistent over time in these patients. Methods: In 1993, 233 patients with PD were included in a community-based study of fatigue and followed prospectively over 8 years. Fatigue was measured by a combination of a seven-point scale and parts of the Nottingham Health Profile (NHP) at baseline and after 4 and 8 years. In addition, the Fatigue Severity Scale (FSS) was used to evaluate fatigue in 2001. Population-averaged logistic regression models for correlated data were performed to study the relationship between fatigue and various demographic and clinical variables. Results: In patients who were followed throughout the 8-year study period, fatigue increased from 35.7% in 1993 to 42.9% in 1997 and 55.7% in 2001. Fatigue was related to disease progression, depression, and excessive daytime sleepiness (EDS). However, the prevalence of fatigue in patients without depression and EDS remained high and increased from 32.1% to 38.9% during the study period. For about 44% of the patients with fatigue the presence of this symptom varied during the study period, as it was persistent in 56% of the patients with fatigue. Conclusions: The authors confirmed the high prevalence of mental fatigue in patients with Parkinson disease (PD). Fatigue is related to other non-motor features such as depression and excessive daytime sleepiness, but cannot be explained by this comorbidity alone. In more than half of the patients mental fatigue is persistent and seems to be an independent symptom that develops parallel to the progressive neurodegenerative disorder of PD.

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.