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Objective: Parkinson's disease with mild cognitive impairment (PD-MCI) is a risk factor for progression to PD dementia (PDD) at a later stage of the disease. The consensus criteria of PD-MCI use a traditional test-by-test normative comparison. The aim of this study was to investigate whether a new multivariate statistical method provides a more sensitive tool for predicting dementia status at 3- and 5-year follow-ups. This method allows a formal evaluation of a patient's profile of test scores given a large aggregated database with regression-based norms., Method: The cognitive test results of 123 newly diagnosed PD patients from a previously published longitudinal study were analyzed with three different methods. First, the PD-MCI criteria were applied in the traditional way. Second, the PD-MCI criteria were applied using the large aggregated normative database. Last, multivariate normative comparisons (MNCs) were made using the same aggregated normative database. The outcome variable was progression to dementia within 3 and 5 years., Results: The MNC was characterized by higher sensitivity and higher specificity in predicting progression to PDD at follow-up than the two PD-MCI criteria methods, although the difference in classification accuracy did not reach statistical significance., Conclusion: We conclude that MNCs could allow for a more accurate prediction of PDD than the traditional PD-MCI criteria, because there are encouraging trends in both increased sensitivity and increased specificity. (JINS, 2019, 25, 678-687).

Background: Cognitive impairment is a common nonmotor manifestation of Parkinson's disease, with deficits ranging from mild cognitive difficulties in 1 or more of the cognitive domains to severe dementia. The International Parkinson and Movement Disorder Society commissioned the assessment of the clinimetric properties of cognitive rating scales measuring global cognitive performance in PD to make recommendations regarding their use., Methods: A systematic literature search was conducted to identify the scales used to assess global cognitive performance in PD, and the identified scales were reviewed and rated as "recommended," "recommended with caveats," "suggested," or "listed" by the panel using previously established criteria., Results: A total of 12 cognitive scales were included in this review. Three scales, the Montreal Cognitive Assessment, the Mattis Dementia Rating Scale Second Edition, and the Parkinson's Disease-Cognitive Rating Scale, were classified as "recommended." Two scales were classified as "recommended with caveats": the Mini-Mental Parkinson, because of limited coverage of executive abilities, and the Scales for Outcomes in Parkinson's Disease-Cognition, which has limited data on sensitivity to change. Six other scales were classified as "suggested" and 1 scale as "listed.", Conclusions: Because of the existence of "recommended" scales for assessment of global cognitive performance in PD, this task force suggests that the development of a new scale for this purpose is not needed at this time. However, global cognitive scales are not a substitute for comprehensive neuropsychological testing. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Objective: To develop a prognostic model to predict disease outcomes in individual patients with Parkinson disease (PD) and perform an external validation study in an independent cohort., Methods: Model development was done in the Comorbidity and Aging in Rehabilitation Patients: The Influence on Activities (CARPA) cohort (Netherlands). External validation was performed using the Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort (UK). Both are longitudinal incident cohort studies that prospectively followed up patients with PD from the time of diagnosis. A composite outcome measure was made in which patients were classified as having an unfavorable prognosis when they had postural instability or dementia at the 5-year assessment (or at the last assessment before loss to follow-up), or had died before this time. The final model was derived with a backward selection strategy from candidate predictor variables that were measured at baseline., Results: In the resulting model, higher patient age, higher Unified Parkinson's Disease Rating Scale motor examination axial score, and a lower animal fluency score were all associated with a higher probability of an unfavorable outcome. External validation confirmed good discriminative ability between favorable and unfavorable outcomes with an area under the receiver operating characteristic curve of 0.85 (95% confidence interval 0.77-0.93) and a well-calibrated model with a calibration slope of 1.13 and no significant lack of fit (Hosmer-Lemeshow test: p = 0.39)., Conclusion: We constructed a model that allows individual patient prognostication at 5 years from diagnosis, using a small set of predictor variables that can easily be obtained by clinicians or research nurses., (© 2016 American Academy of Neurology.)

Objective: We examined the development of Parkinson disease (PD)-mild cognitive impairment (MCI) in patients with newly diagnosed PD over 5 years using recently proposed consensus criteria, and we assessed the reliability of the criteria., Methods: Patients with PD (n = 123) underwent extensive neuropsychological testing at baseline and after 3 (n = 93) and 5 years (n = 59). Two neuropsychologists independently applied the PD-MCI criteria to examine the interrater and intrarater reliability., Results: At baseline, 35% of patients had PD-MCI. Three years later, 53% of the patients had PD-MCI. At 5-year follow-up, 20 patients who had PD-MCI at an earlier assessment had converted to PD dementia and 50% of the remaining patients without dementia had MCI. The interrater reliability (kappa) was 0.91. The intrarater reliabilities were 0.85 and 0.96., Conclusion: Approximately one-third of patients with newly diagnosed PD fulfill the consensus criteria for PD-MCI; after 5 years, this proportion is approximately 50% of patients without dementia. The criteria have good interrater and intrarater reliability.

Cognitive change is frequently observed in patients with Parkinson's disease (PD). However, the exact profile and extent of cognitive impairments remain unclear due to the clinical heterogeneity of PD and methodological issues in many previous studies. In this study, we aimed to examine the severity, frequency, and profile of cognitive changes in newly diagnosed PD patients over 5 years. At baseline and after 3 and 5 years, a hospital-based sample of PD patients (n = 59) and healthy controls (n = 40) were given neuropsychological tests covering six cognitive domains. Patients showed greater decline over time than healthy controls on all cognitive domains, except for attention. The profile of decline showed that psychomotor speed and memory were most affected. At the individual level 53% of the patients showed more cognitive decline than controls. Age at onset and memory impairment at baseline predicted cognitive decline. Cognitive functions in PD patients show greater decline in most domains than in healthy elderly over the course of 5 years. Due to selection bias as a result of attrition, the actual degree of decline may be greater than reported here.

Objective: In Parkinson disease (PD), the rate of clinical progression is highly variable. To date, there are conflicting findings concerning the prognostic factors influencing the rate of progression. Methodologic issues such as the use of selected patients from therapeutic trials, and short durations of follow-up probably underlie this problem. We therefore designed a prospective follow-up study of a cohort of newly diagnosed patients with PD., Methods: A cohort of 129 patients with newly diagnosed PD was assessed at baseline, and 1, 2, 3, and 5 years later. The rate of progression and its prognostic factors on the level of motor impairments, disability, and quality of life were investigated using linear mixed-model analysis., Results: Annual increase of motor impairments measured with the Unified Parkinson's Disease Rating Scale-Motor Examination was estimated to be 2.46 points (95% confidence interval: 2.05-2.88). The main determinants of faster increase of motor impairments were male sex and cognitive dysfunction at the time of diagnosis. The main determinants of faster increase of disability were higher age at onset, cognitive dysfunction, and the presence of levodopa-nonresponsive motor symptoms at the time of diagnosis. No clinically relevant determinants were found for the decrease in quality of life., Conclusion: This study shows the importance of nondopaminergic symptoms at the time of diagnosis, because these symptoms are the main determinants of increased disability in the first 5 years of the disease.

Objective: To find predictors of cognitive decline and quality of life 1 year after bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD)., Methods: A total of 105 patients were evaluated with a comprehensive neuropsychological assessment before and 12 months after surgery. A control group of 40 PD patients was included to control for effects of repeated testing and disease progression. The authors determined individual changes in cognition, mood and quality of life using a statistical method that controls for multiple comparisons, and performed logistic regression analyses to assess predictors of cognitive changes and quality of life., Results: 12 months after surgery, the improvement in motor function was 41% (Unified Parkinson's Disease Rating Scale Part 3 score in off). The STN group showed a large improvement in quality of life compared with the control group (Cohen d=0.9). At the individual level, 32% (95% CI 22 to 40) of the STN group showed a substantial improvement in quality of life. 36% (95% CI 27 to 46) of the STN patients showed a profile of cognitive decline compared with the control group. Mood improved in 16 STN patients and declined in 16 subjects. Impaired attention, advanced age and a low l-dopa response at baseline predicted cognitive decline, whereas a high l-dopa response at baseline predicted an improvement in quality of life. Postoperative decrease in dopaminergic medication was not related to cognitive decline., Conclusions: STN DBS improves quality of life. However, a profile of cognitive decline can be found in a significant number of patients. l-dopa response, age and attention at baseline are predictors of cognitive and psychosocial outcome.

Objective: To determine progression and prognostic factors of progression rate of motor impairment, disability, and quality of life (QoL) in patients with newly diagnosed Parkinson's disease., Methods: A group of 126 patients with newly diagnosed PD recruited from outpatient clinics participated in this 3-year prospective cohort study. Motor impairment was rated with the Unified Parkinson Disease Rating Scale Motor-Examination. Disability was rated using the Schwab and England Activities of Daily Living Scale, the AMC Linear Disability Score. QoL was assessed with the Parkinson's Disease Quality of Life questionnaire. Linear mixed model analyses were conducted to identify determinants of progression rate of motor impairment, disability, and poor QoL., Results: Motor impairment progressed with 3 points per year. There was a slight progression of disability and QoL during 3 years of follow-up. Female sex was a prognostic factor for slower progression of motor impairment and QoL. Older age at onset showed to prognosticate faster progression of disability and impaired QoL. Furthermore, independent of follow-up time, older age at onset was associated with worse motor impairment; nondopaminergic reactive symptoms (Axial impairment) were associated with more disability and poorer QoL; comorbidity showed relation with disability and QoL but to a lesser extent; self-reported mood symptoms were associated with poorer QoL; and disease duration correlated with motor impairment., Conclusions: Motor impairment, disability, and QoL of newly diagnosed Parkinson patients show progression in the first 3 years. Older age at onset predicts worse progression rate of disability and impaired QoL over time. Female sex predicts slower progression of motor impairment and less decline of QoL., (Copyright © 2011 Movement Disorder Society.)

Cognitive dysfunction is one of the most incapacitating non-motor symptoms of Parkinson's disease (PD). Some cognitive deficits are thought to be related to abnormal dopamine homeostasis. The latter is influenced by catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine. Previous research suggests a relationship between the COMT val158met functional polymorphism (SNP) and measures of executive function. We evaluated this hypothesis in a cohort of PD patients with an extensive neuropsychological test battery. Cognitive assessment and COMT genotyping were performed in 153 early PD patients from outpatient clinics general hospitals in the Netherlands. Our results do not support a direct effect of COMT val158met genotype on performance on neuropsychological measures of attention and executive function, but they suggest that genotype may interact with dopaminergic medication use to influence cognitive ability., (© 2010 Movement Disorder Society.)

This controlled prospective study examined the evolution and predictors of cognitive decline in Parkinson's disease (PD). Consecutive patients diagnosed at baseline with PD (n = 89), established PD (EPD) patients (n = 52) with a mean disease duration of 6.5 years, and healthy control subjects (n = 64) underwent extensive neuropsychological assessment twice, approximately 3 years apart. A standardized regression-based method, normative data, and multivariate normative comparisons were used to assess the cognitive course of PD. Cognitive performance of newly diagnosed patients decreased significantly over time, particularly on measures of psychomotor speed and attention and to a lesser extent on tests of memory, visuospatial skills, and executive functions. About 50% of the patients showed cognitive decline and 9% developed dementia. Similar results were observed in EPD patients. None of the baseline features predicted cognitive change in newly diagnosed patients, whereas age at disease onset and axial impairment (postural and gait disorders) contributed to decline in established patients. We conclude that within few years after diagnosis, PD patients show faster rate of cognitive decline than matched healthy subjects, particularly in domains of attention and psychomotor speed. Selection bias probably led to underestimation of the true extent of cognitive decline in established patients.

Objective: To identify factors that independently contribute to disability and quality of life (QoL) in patients with mild to moderate Parkinson disease (PD)., Methods: A group of 190 patients with PD recruited from outpatient clinics and the Dutch Parkinson's Disease Association participated in this cross-sectional study. Data on demographic and clinical factors, motor symptoms, cognitive functions, affective symptoms, comorbidity, and social support were collected during neurologic and neuropsychological examinations. Disability was rated using the Schwab and England Activities of Daily Living Scale (SE-ADL), the AMC Linear Disability Score (ALDS), and the Functional Independence Measure (FIM). QoL was assessed with the Parkinson's Disease Quality of Life questionnaire (PDQL) and the Medical Outcome Study Short Form (SF-36). Multiple linear regression analyses were conducted to identify determinants of disability and poor QoL., Results: Axial impairment (postural instability and gait difficulty) explained the largest proportion of variance in disability. Bradykinesia and comorbidity contributed to disability, but to a lesser extent. Self-reported mood symptoms and axial impairment were the two factors most closely associated with poorer QoL, but comorbidity and bradykinesia additionally contributed to the explanatory power. Semantic fluency and psychomotor skills were the only cognitive variables related to some aspects of functional outcome., Conclusion: Axial impairment is strongly associated with disability in patients with mild to moderate Parkinson disease (PD). Self-report indices of mood status and axial impairment are identified as the main determinants of poor quality of life (QoL). The results of this study may help to identify patients with PD at risk for functional dependence and reduced QoL.

A meta-analysis was conducted on 25 longitudinal studies involving 901 initially non-demented Parkinson's disease (PD) patients to examine the magnitude of decline across multiple cognitive domains associated with disease progression. Pooled effect sizes reflecting the standardized difference between baseline and follow-up neuropsychological performance were calculated for 8 cognitive domains using a random-effects model. Relatively small effect sizes were found across all cognitive domains (d = .00 - .40). During a mean follow-up interval of 29 months, significant declines were detected in global cognitive ability (d = .40), visuoconstructive skills (d = .32), and memory (d = .29). Age showed a significant relation with decline in global cognitive ability and memory. Lower educational level was associated with greater decline in all cognitive domains. Studies with longer follow-up intervals yielded larger effect sizes for global cognitive ability. In non-demented PD patients, changes in cognitive functions over time appear to be modest. Educational level, age, and length of the follow-up interval are likely to affect the magnitude of decline in several domains. Methodological flaws, such as selection bias and uncontrolled practice effects, may have caused underestimation of the true extent of decline.

Functional neuroimaging research has repeatedly implicated the striatum in motor procedural learning, but attempts to explore this relation in patients with Parkinson's disease (PD) have yielded inconsistent results. Furthermore, the functional impact of procedural learning impairment is unknown. The present study sought to examine the effects of PD on procedural learning and to determine whether impaired procedural learning affects functional status. The performance of 95 non-demented PD patients on the serial reaction time task (SRTT) was compared with that of 44 demographically matched control subjects. The SRTT is a four-choice reaction time task in which visual stimuli are presented in six blocks of 100 trials either in a repeating sequence of 10 stimuli or randomly. Learning was inferred from the reduction of response times over five successive blocks of repeating sequence trials and from the increase in response times in the sixth random block. In addition, neuropsychological tests of declarative memory, executive and visuospatial functions were administered to all participants. Patients also received quantitative ratings of functional outcome. The two groups did not differ in the learning rate across blocks of repeating sequence trials. However, PD patients were significantly less efficient than controls in acquiring sequence-specific knowledge, although this impairment was relatively small (d = 0.38). Patients with more advanced clinical symptoms tended to show worse performance. Separate analyses of a subgroup of 24 non-medicated patients in the early stages of PD revealed no differences in SRTT performance relative to controls. Neuropsychological testing showed impairments in attention and executive functions, immediate and delayed explicit memory and visuospatial skills in the PD group, but none of the cognitive measures were related to procedural learning. Reduced motor sequence learning in PD patients did not influence their functional status. These findings indicate that procedural learning impairment is not an early feature of PD, but is likely to emerge with progression of the disease, independently of cognitive dysfunction or dopaminergic medication.

In neuropsychological evaluations and single case research generally a number of tests are administered, since the interest is not in a single, but in multiple characteristics of a patient. The typical problem is to decide whether or not a patient is different from normal controls with respect to one or more of these characteristics. Consideration of each characteristic separately entails an increased risk of a false positive decision (a wrongful decision that the patient is abnormal, or a type 1 error). From a statistical point of view this calls for a multivariate analysis. In this paper, we propose two approaches to perform normative comparisons for such multivariate data: Bonferroni corrected univariate comparisons and a multivariate comparison. Both approaches allow for the testing of unidirectional (two-sided) as well as directional (one-sided) hypothesis, i.e. the hypothesis that a patient deviates in a negative sense from the norm. Monte Carlo simulations were performed to check if the type I error of both approaches is adequately controlled, and to investigate the power of both approaches to detect deviation from the norm. The results indicate that the type I error rate of both approaches is correct, even in small samples. The results also indicate that the power is higher for the univariate approach if the normative sample size is very small (i.e. just exceeds the number of tests administered). In larger samples, the multivariate comparison has in general increased power. We illustrate both approaches with a clinical example of patients with Parkinson disease, who received deep brain stimulation to alleviate motor symptoms, and who were neuropsychologically evaluated to detect possible cognitive side effects.

We describe a patient with advanced Parkinson's disease who developed pathological gambling within a month after successful bilateral subthalamic nucleus (STN) stimulation. There was no history of gambling. On neuropsychological testing, slight cognitive decline was evident 1 year after surgery. Stimulation of the most dorsal contact with and without medication induced worse performances on decision making tests compared with the more ventral contact. Pathological gambling disappeared after discontinuation of pergolide and changing the stimulation parameters. Pathological gambling does not seem to be associated with decision making but appears to be related to a combination of bilateral STN stimulation and treatment with dopamine agonists.

Objective: To evaluate the cognitive and behavioral effects of bilateral subthalamic nucleus (STN) stimulation in patients with Parkinson disease (PD)., Methods: The authors included 103 patients; 99 patients were evaluated 6 months after surgery. A control group of 39 patients with PD was formed and 36 patients were evaluated 6 months later. At baseline and at follow-up we administered neuropsychological tests of language, memory, visuospatial function, mental speed, and executive functions. A depression rating scale, a quality of life scale, self and proxy ratings of memory and dysexecutive symptoms, and a neuropsychiatric interview were also administered., Results: Six months after surgery, the STN group showed a larger decline than the control group on measures of verbal fluency, color naming, selective attention, and verbal memory. Moreover, the STN group showed a decrease in positive affect, and an increase in emotional lability and cognitive complaints. On the other hand, the STN group showed an increase in quality of life and a slight decrease in depressive symptoms. Nine percent of the STN patients had psychiatric complications (vs 3% of controls)., Conclusions: Bilateral subthalamic nucleus stimulation has an adverse effect on executive functions with implications for daily life of the patients and their relatives.

Objective: To determine the frequency and pattern of cognitive dysfunction in patients with newly diagnosed Parkinson disease (PD) and to identify its demographic and clinical correlates., Methods: A cohort of 115 consecutive patients with newly diagnosed PD and 70 healthy controls underwent a comprehensive neuropsychological assessment including tests of psychomotor speed, attention, language, memory, executive and visuospatial functions, as well as measures of affective status. Patients also received quantitative ratings of motor symptom severity and functional status. Neuropsychological performance of PD patients was compared with that of healthy controls and with available normative data. Independent demographic and clinical predictors of cognitive impairment were identified with multiple logistic regression analysis., Results: Relative to controls, PD patients performed significantly worse on most cognitive measures. However, further analysis revealed that group differences in cognitive performance could mainly be explained by measures of immediate memory and executive function. Comparison with normative data showed that impairments were most frequent on measures of executive function, memory and psychomotor speed. In all, 24% of PD patients (4% of controls) displayed defective performance on at least three neuropsychological tests and were classified as cognitively impaired. Late onset of disease was an independent predictor of cognitive dysfunction in PD., Conclusion: Cognitive impairments are common even in newly diagnosed Parkinson disease patients, with deficits being most prominent in the domains of memory and executive functions. Older age at disease onset is likely to be an important determinant of cognitive dysfunction in Parkinson disease.

Objective: To compare the cognitive and behavioural effects of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation., Methods: After baseline examination 34 patients were randomly assigned to unilateral pallidotomy (4 left-sided, 10 right-sided) or bilateral STN stimulation (n = 20). At baseline and six and twelve months after surgery we administered neuropsychological tests of language, memory, visuospatial function, mental speed and executive functions. Also a depression rating scale, and self and proxy ratings of memory and dysexecutive symptoms were administered., Results: Six months after surgery, the STN group and the pallidotomy group differed significantly in change from baseline in number of errors on two tests of executive functioning. After 12 months the STN group reported less positive affect compared with baseline than the pallidotomy group. One patient in the STN group showed an overall cognitive deterioration due to complications., Conclusions: Although we need larger groups to draw firm conclusions, our results suggest that bilateral STN stimulation has slightly more negative effects on executive functioning than unilateral pallidotomy.

Objectives: In a randomised trial to study the efficacy of unilateral pallidotomy in patients with advanced Parkinson's disease, patients having pallidotomy within 1 month after randomisation were compared with patients having pallidotomy 6 months after the primary outcome assessment. Of the 37 patients enrolled 32 had a unilateral pallidotomy. The follow up study of these patients is presented to report (1) clinical outcome; (2) adverse effects; (3) cognitive and behavioural effects; (4) relation between lesion location and outcome; and (5) preoperative patient characteristics predictive for good outcome., Methods: Outcome measures were the motor section of the unified Parkinson's disease rating scale (UPDRS), levodopa induced dyskinesias, disability, quality of life, and a comprehensive neuropsychological assessment. Multivariate logistic regression was used to identify preoperative patient characteristics independently associated with good outcome., Results: Off phase assessment showed a reduction in parkinsonism from 49 to 36.5 points on the UPDRS 6 months after surgery. Improvements were also demonstrated for activities of daily living and quality of life. In the on phase dyskinesias were reduced. All effects lasted up to 12 months after surgery. Three patients had major permanent adverse effects. Besides worsening of verbal fluency after left sided surgery, systematic cognitive deterioration was not detected. Patients taking less than 1000 levodopa equivalent units (LEU)/day were more likely to improve., Conclusions: The positive effects of unilateral pallidotomy are stable up to 1 year after surgery. Patients taking less than 1000 LEU per day were most likely to improve.

Objective: To investigate whether unilateral pallidotomy affects cognitive and behavioral functioning., Methods: At baseline and after 6 months we assessed neuropsychological functioning in 35 patients with advanced PD. After baseline examination, patients were randomized to pallidotomy within 1 month (6 left-sided, 13 right-sided) or to pallidotomy after follow-up assessment 6 months later (n = 16; control group). We performed neuropsychological tests of language, visuospatial function, memory, attention, and executive functions. Self ratings and proxy ratings of memory problems and dysexecutive symptoms were also collected., Results: No significant differences over time were found between pallidotomy and control groups, with the exception of a decrease of verbal fluency in the left-sided pallidotomy group., Conclusions: Unilateral pallidotomy is relatively safe with respect to cognition and behavior. Left-sided pallidotomy may lead to minor deterioration in verbal fluency. The sample size of this study is too small, however, to rule out the possibility of infrequent but clinically important side effects.

Background: The results of several cohort studies suggest that patients with advanced Parkinson's disease would benefit from unilateral pallidotomy. We have assessed the efficacy of unilateral pallidotomy in a randomised, single-blind, multicentre trial., Methods: We enrolled 37 patients with advanced Parkinson's disease who had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. Patients were randomly assigned to unilateral pallidotomy within 1 month or to pallidotomy after the primary outcome assessment (6 months later). The primary outcome was the difference between the groups in median changes on the motor examination section of the unified Parkinson's disease rating scale (UPDRS 3) score done in the off phase. Secondary outcome measures included levodopa-induced dyskinesias (dyskinesia rating scale [DRS]) and extent of disability (UPDRS 2)., Findings: The median UPDRS 3 off score of the pallidotomy patients improved from 47 to 32.5, whereas that of control patients slightly worsened from 52.5 to 56.5 (p<0.001). In the on phase the median DRS score improved 50% in pallidotomy patients compared with no change in controls. The UPDRS 2 off score improved with a median of 7 in the pallidotomy group. Two treated patients had major adverse effects., Interpretation: Unilateral pallidotomy is an effective treatment in patients with advanced Parkinson's disease, who have an unsatisfactory response to pharmacological treatment.