Disorder Society Task Force Criteria Research Articles

The Phase 2, Randomized, Placebo-controlled PRECEDENT Trial of SAGE-718 in Patients With Parkinson's Disease Cognitive Impairment: Clinical Trial in Progress (P2-11.005)

<h3>Objective:</h3> The randomized, placebo-controlled PRECEDENT Study is designed to evaluate the efficacy, safety, and tolerability of SAGE-718 as a potential treatment for cognitive impairment due to Parkinson’s disease (PD). <h3>Background:</h3> PD is a multisystem disorder with diverse clinical features, including neuropsychiatric symptoms and non-motor manifestations alongside motor symptomatology. Cognitive impairment, a common non-motor symptom of PD, contributes to poor functional outcomes, loss of independence, and increased risk of dementia. A significant unmet need exists for effective and well-tolerated pharmacotherapies that address cognitive impairment due to PD. Positive modulation of NMDA receptors may improve cognitive deficits. SAGE-718, an investigational NMDA receptor positive allosteric modulator, has been associated with improved cognitive performance in patients with PD and other neurodegenerative diseases. <h3>Design/Methods:</h3> PRECEDENT (NCT05318937) is a Phase 2, randomized, double-blind, placebo-controlled trial that includes a 3-week screening period, a 1-week baseline period, a 6-week treatment period, and a 4-week follow-up period. Approximately 76 patients aged 50–75 years meeting Movement Disorder Society Task Force Criteria for PD Mild Cognitive Impairment with mild-to-moderate motor involvement will be randomized 1:1 to receive either SAGE-718 or placebo once daily for 42 days. The primary endpoint is change from baseline in the Wechsler Adult Intelligence Scale-IV Coding score (a measure of executive functioning) at Day 42. Secondary endpoints include the proportion of patients with treatment-emergent adverse events (TEAEs), severity of TEAEs, and number of patients who withdraw from the study due to TEAEs. Other endpoints include additional assessments of cognitive performance, safety/tolerability, motor symptoms, functioning, and pharmacokinetics. <h3>Results:</h3> PRECEDENT is currently enrolling at sites in the United States. <h3>Conclusions:</h3> PRECEDENT is designed to evaluate the efficacy, safety, and tolerability of SAGE-718 in patients with cognitive impairment due to PD. <b>Disclosure:</b> Dr. Bullock has received personal compensation for serving as an employee of Sage Therapeutics, Inc. . Dr. Bullock has stock in Sage Therapeutics, Inc. Aaron Koenig has received personal compensation for serving as an employee of Sage Therapeutics. Dr. Paumier has nothing to disclose. Ms. Freitag has nothing to disclose. Jeffrey Wald has received personal compensation for serving as an employee of Sage Therapeutics. Jeffrey Wald has received stock or an ownership interest from Sage Thereapeutics. Dr. Park has nothing to disclose. Michael Quirk has received personal compensation for serving as an employee of Sage Therapeutics. Michael Quirk has received stock or an ownership interest from Sage Therapeutics. Jennifer Petrillo, 14951 has received personal compensation for serving as an employee of Sage Therapeutics. Jennifer Petrillo, 14951 has received stock or an ownership interest from Sage Therapeutics. Dr. Doherty has received personal compensation for serving as an employee of Sage Therapeutics. Dr. Doherty has received stock or an ownership interest from Sage Therapeutics.

Mild cognitive impairment in Parkinson's disease: the Parkinson's disease cognitive study (PACOS).

Approximately 30% of Parkinson's disease (PD) patients show impaired cognitive performance, which is suggestive of Mild Cognitive Impairment (MCI), representing a predictor of dementia, especially when present at diagnosis. The objective of the study was to evaluate the frequency and clinical predictors of MCI in a large hospital-based cohort of PD patients. We collected cross-sectional data from the Parkinson's disease cognitive impairment study (PACOS), a multicenter study involving two Movement Disorder centers, which are located in south Italy. The PD subjects were diagnosed according to the UK Brain Bank criteria and they underwent an extensive neuropsychological assessment. PD-MCI was diagnosed according to the Movement Disorder Society task force criteria for MCI. PD severity was evaluated in accordance with theUnified PD Rating Scale-Motor Examination (UPDRS-ME) and the Hoehn and Yahr scales. The study included 659 PD patients (57.5% men; mean age 67.0±9.7years), with a mean disease duration of 3.8±4.6years and a mean UPRDS-ME score of 25.8±12.3. PD-MCI was diagnosed in 261 (39.6%) subjects and in 82 (31.7%) of 259 newly diagnosed patients (disease duration≤1year). An amnestic MCI multidomain phenotype was the most frequent MCI subtype (39.1% of the overall sample and 43.9% in newly diagnosed PD). A positive significant association between MCI, age and motor scores was found at multivariate logistic regression analysis, while a negative association was observed between educational level and MCI. In conclusion and in agreement with the literature data, the prevalence of MCI recorded in the PACOS sample was approximately 40 and 32% amongst newly diagnosed patients.

Progression of subcortical atrophy in mild Parkinson's disease and its impact on cognition.

Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD. Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up. Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains. Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.

The Diagnostic Accuracy of Parkinson's Disease Mild Cognitive Impairment Battery Using the Movement Disorder Society Task Force Criteria.

The aim of the present study was to provide empirical evidence regarding the classification accuracy of the International Parkinson and Movement Disorder Society (MDS) neuropsychological battery (NB) in the determination of Parkinson's disease mild cognitive impairment (PD-MCI). The present cross-sectional study included 106 PD patients subjected to PD-MCI classification at Level I and 120 healthy controls (HCs). All HC and PD subjects were then assessed with MDS-NB at Level II and matched according to age and education using different thresholds (1.5 and 2.0 standard deviations [SDs] below average). We found that Level I and II resulted in different classifications of PD-MCI status. Detection thresholds of -1.5 SD and -2.0 SDs at Level II had also a significant impact on the discriminative validity of all measures in the MDS neuropsychological battery, based on area under the curve analyses. Overall, semantic fluency showed the highest potential in all comparisons not only between PD-MCI and HC, but also between PD-MCI and PD with no deficit (PD-ND). Our results show that the battery at Level II is applicable and that some measures, such as semantic fluency, have high discriminative validity in the detection of PD-MCI versus PD-ND and HCs.

Validation of the Parkinson's Disease-Cognitive Rating Scale Applying the Movement Disorder Society Task Force Criteria for Dementia Associated with Parkinson's Disease.

The authors studied the measurement properties of the Parkinson's Disease-Cognitive Rating Scale (PD-CRS) compared with Movement Disorders Society Task Force (MDS-TF) criteria for the diagnosis of dementia in patients with Parkinson's disease. The sample consisted of 223 patients who were diagnosed in accordance with the United Kingdom Parkinson's Disease Society Brain Bank who were assessed with both the MDS-TF and the PD-CRS criteria (in addition to other instruments) without the assessors' knowledge of previous results. Internal consistency was studied (homogeneity of the items and Guttmann's λ values were obtained) in addition to convergent, divergent, and discriminative validity. The receiver operating characteristic curve was obtained, and the cutoff point at which the PD-CRS had the greatest efficiency was analyzed. The internal consistency was shown to be adequate, with a λ value of 0.821. A floor effect was observed in 4 of the items (Sustained Attention, Working Memory, Immediate Verbal Memory, and Alternating Verbal Fluency), and 1 item showed a ceiling effect (Clock Copying). The scale adequately discriminated patients with and without dementia (Kruskal-Wallis; P≤0.000). The area under the curve was 0.899. With a cutoff score of 62 (from a possible score of 134), the scale achieved 94% sensitivity and 99% specificity. The PD-CRS has adequate measurement properties and is a valid tool for studying the presence of dementia in patients with Parkinson's disease.

Mild Cognitive Impairment in Early Parkinson's Disease Using the Movement Disorder Society Task Force Criteria: Cross-Sectional Study in Hoehn and Yahr Stage 1

Background: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is common and confers a higher risk for developing dementia. Methods: In this cross-sectional study of MCI in PD conducted at a university hospital, a comprehensive neuropsychological battery covering five domains (attention/working memory, executive, verbal, and visual memory, language, and visuospatial) was administered to 111 nondemented PD patients in Hoehn and Yahr stage 1 and to 105 healthy matched control subjects (HC). MCI was diagnosed according to level 2 of the Movement Disorder Society Task Force criteria. Results: Criteria for MCI associated with PD (PD-MCI) were fulfilled by 24% of PD patients in the initial stage of the disease at the z cutoff scores of -1.5 SD in contrast to 7% of HC fulfilling criteria for MCI. Memory and visuospatial domains were the most commonly affected at -1.5 SD. PD-MCI patients mostly had a multiple-domain MCI subtype (78%). They presented a more severe bradykinesia and higher mood and apathy scores in comparison with cognitively normal PD patients. Basic motor scores predicted performance on some cognitive tests and specific cognitive-motor relationships emerged. Conclusions: MCI, predominantly of a multiple-domain subtype, was quite prevalent even in the initial stage of PD.

Baseline and longitudinal grey matter changes in newly diagnosed Parkinson's disease: ICICLE-PD study.

Mild cognitive impairment in Parkinson's disease is associated with progression to dementia (Parkinson's disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson's disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson's disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson's disease subjects into Parkinson's disease with mild cognitive impairment (n = 39) and Parkinson's disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson's disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson's disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson's disease cohort. Over 18 months, patients with Parkinson's disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson's disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson's disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson's disease with no cognitive impairment converters showed bilateral temporal cortex thinning relative to the Parkinson's disease with no cognitive impairment stable subjects. Although loss of both cortical and subcortical volume occurs in non-demented Parkinson's disease, our longitudinal analyses revealed that Parkinson's disease with mild cognitive impairment shows more extensive atrophy and greater percentage of cortical thinning compared to Parkinson's disease with no cognitive impairment. In particular, an extension of cortical thinning in the temporo-parietal regions in addition to frontal atrophy could be a biomarker in therapeutic studies of mild cognitive impairment in Parkinson's disease for progression towards dementia.

Quality of life and mild cognitive impairment in early Parkinson's disease: does subtype matter?

We evaluated the association between mild cognitive impairment (MCI) subtypes and quality of life (QoL) in 219 newly diagnosed Parkinson's disease (PD) patients without dementia. Participants completed neuropsychological tests of attention, executive function, visuospatial function, memory, and language, and reported QoL using the Parkinson's Disease Questionnaire. Impairments were most common in executive function, memory and attention. MCI subtypes were classified according to Movement Disorder Society Task Force criteria. More severe cognitive impairment was associated with poorer quality of life (p = 0.01), but subtype of impairment was not (p > 0.10), suggesting that the nature of cognitive impairment is less significant than its severity.

Addenbrooke's Cognitive Examination and Individual Domain Cut-Off Scores for Discriminating between Different Cognitive Subtypes of Parkinson's Disease.

Objective. The main aim of this study was to verify the sensitivity and specificity of Addenbrooke's Cognitive Examination-Revised (ACE-R) in discriminating between Parkinson's disease (PD) with normal cognition (PD-NC) and PD with mild cognitive impairment (PD-MCI) and between PD-MCI and PD with dementia (PD-D). We also evaluated how ACE-R correlates with neuropsychological cognitive tests in PD. Methods. We examined three age-matched groups of PD patients diagnosed according to the Movement Disorder Society Task Force criteria: PD-NC, PD-MCI, and PD-D. ROC analysis was used to establish specific cut-off scores of ACE-R and its domains. Correlation analyses were performed between ACE-R and its subtests with relevant neuropsychological tests. Results. Statistically significant differences between groups were demonstrated in global ACE-R scores and subscores, except in the language domain. ACE-R cut-off score of 88.5 points discriminated best between PD-MCI and PD-NC (sensitivity 0.68, specificity 0.91); ACE-R of 82.5 points distinguished best between PD-MCI and PD-D (sensitivity 0.70, specificity 0.73). The verbal fluency domain of ACE-R demonstrated the best discrimination between PD-NC and PD-MCI (cut-off score 11.5; sensitivity 0.70, specificity 0.73) while the orientation/attention subscore was best between PD-MCI and PD-D (cut-off score 15.5; sensitivity 0.90, specificity 0.97). ACE-R scores except for ACE-R language correlated with specific cognitive tests of interest.

Diagnosing PD-MCI by MDS Task Force criteria: how many and which neuropsychological tests?

The optimal properties of a comprehensive (level II) neuropsychological battery for determining Parkinson's disease mild cognitive impairment (PD-MCI) by Movement Disorder Society (MDS) Task Force criteria remain unresolved. Seventy-six nondemented PD patients underwent PD-MCI classification using a consensus diagnosis and level II criteria. We examined the optimal number of tests in each of the five designated cognitive domains, identified the best tests within each domain, and determined the best overall battery for PD-MCI level II diagnosis. A battery with two tests per domain provided a highly practical, robust diagnostic assessment. Level II testing with the two best tests and impairment defined as 2 standard deviations below norms was highly sensitive and specific for PD-MCI diagnosis. Our findings strongly support the MDS Task Force Level II testing recommendations, provide a framework for creating an optimal, efficient neuropsychological test battery for PD-MCI diagnosis, and offer specific test recommendations.

Defining optimal cutoff scores for cognitive impairment using Movement Disorder Society Task Force criteria for mild cognitive impairment in Parkinson's disease

ABSTRACTThe recently proposed Movement Disorder Society (MDS) Task Force diagnostic criteria for mild cognitive impairment in Parkinson's disease (PD‐MCI) represent a first step toward a uniform definition of PD‐MCI across multiple clinical and research settings. However, several questions regarding specific criteria remain unanswered, including optimal cutoff scores by which to define impairment on neuropsychological tests. Seventy‐six non‐demented PD patients underwent comprehensive neuropsychological assessment and were classified as PD‐MCI or PD with normal cognition (PD‐NC). The concordance of PD‐MCI diagnosis by MDS Task Force Level II criteria (comprehensive assessment), using a range of standard deviation (SD) cutoff scores, was compared with our consensus diagnosis of PD‐MCI or PD‐NC. Sensitivity, specificity, and positive and negative predictive values were examined for each cutoff score. PD‐MCI subtype classification and distribution of cognitive domains impaired were evaluated. Concordance for PD‐MCI diagnosis was greatest for defining impairment on neuropsychological tests using a 2 SD cutoff score below appropriate norms. This cutoff also provided the best discriminatory properties for separating PD‐MCI from PD‐NC compared with other cutoff scores. With the MDS PD‐MCI criteria, multiple domain impairment was more frequent than single domain impairment, with predominant executive function, memory, and visuospatial function deficits. Application of the MDS Task Force PD‐MCI Level II diagnostic criteria demonstrates good sensitivity and specificity at a 2 SD cutoff score. The predominance of multiple domain impairment in PD‐MCI with the Level II criteria suggests not only influences of testing abnormality requirements, but also the widespread nature of cognitive deficits within PD‐MCI. © 2013 International Parkinson and Movement Disorder Society

GREY MATTER CORRELATIONS OF COGNITIVE IMPAIRMENT IN EARLY PARKINSON'S DISEASE: THE INCIDENCE OF COGNITIVE IMPAIRMENT IN COHORTS WITH LONGITUDINAL EVALUATION–PARKINSON'S DISEASE (ICICLE–PD) STUDY

IntroductionCurrently, there are no biomarkers capable of identifiying those at greatest risk of developing Parkinson's disease dementia (PDD). In patients with PDD, magnetic resonance imaging (MRI) demonstrates diffuse grey matter...

Using the Montreal Cognitive Assessment Scale to screen for dementia in Chinese patients with Parkinson's Disease.

BackgroundDementia is one of the most distressing and burdensome health problems associated with Parkinson's Disease (PD). The Montreal Cognitive Assessment scale (MoCA) is widely used to screen for dementia in PD patients, but the appropriate diagnostic cutoff score when used with Chinese PD patients is not known.AimDetermine a diagnostic cutoff value of the Chinese version of the MoCA (MoCA-C) for Chinese PD patients and describe the characteristics of PD patients screened positive for dementia using the MoCA-C.MethodsThe presence of dementia in 616 PD patients and 85 community controls was determined using the Movement Disorder Society Task Force criteria (the gold standard diagnosis). We administered the MoCA-C to these individuals and used a receiver operating characteristic (ROC) curve to identify the cutoff score of the MoCA-C that most efficiently identified dementia in both PD patients and community controls. Demographic and clinical characteristics of PD patients who were screened positive or negative for dementia using the MoCA-C were compared.ResultsA MoCA-C score of 23 was the optimal cutoff score for dementia in both patients and controls. Using this cutoff score, the sensitivity and specificity of the MoCA-C in PD patients were 0.70 and 0.77, respectively; the positive and negative predictive values were 0.59 and 0.85, respectively; and the overall concordance (kappa [95% confidence interval]) was 0.45 (0.39-0.52). The corresponding kappa value (concordance) in community controls was only 0.25 (0.05-0.45). Compared to PD patients who screened negative for dementia, those who screened positive for dementia were significantly impaired in all cognitive domains, including visuospatial and executive functioning, naming, attention, language, abstraction, delayed recall and orientation (all p<0.001). Among the PD patients, screening positive for dementia was independently associated with old age, low educational attainment, female gender and more severe motor impairment.ConclusionsThe commonly recommended cutoff screening score for dementia of 26 on the MoCA it too high for PD patients in China; a cutoff score of 23 is more appropriate. Potential risk factors for dementia in Chinese PD patients include older age, less education, and more severe motor symptoms of PD.

Impact of Mild Cognitive Impairment on Health-Related Quality of Life in Parkinson's Disease

Background/Aims: To assess the impact of mild cognitive impairment (MCI) or cognitive decline on health-related quality of life (HR-QOL) in Parkinson's disease (PD). Methods: HR-QOL measured by the Parkinson Disease Quality of Life Questionnaire (PDQ-39), MCI according to Movement Disorder Society Task Force criteria and cognitive decline from premorbid baseline were assessed in non-demented PD patients at 6 movement disorder clinics. Results: Among 137 patients, after adjusting for education, gender, disease duration, and Movement Disorder Society Unified Parkinson's Disease Rating Scale total score, MCI was associated with worse scores within the PDQ-39 dimension of communication (p = 0.008). Subjects were divided into tertiles of cognitive decline from premorbid level. Scores in the dimension of stigma were worst in the second tertile of cognitive decline (p = 0.03). MCI was associated with worse social support scores in the second tertile of cognitive decline (p = 0.008). Conclusion: MCI and cognitive decline from premorbid baseline are associated with reduced HR-QOL in communication, stigma, and social support domains. The cognitive decline from premorbid baseline modifies the association between MCI and HR-QOL in PD and knowing both will allow a better appreciation of difficulties patients face in daily life.

Dementia associated with Parkinson’s disease: Applying the Movement Disorder Society Task Force criteria

BackgroundDiagnostic criteria and procedures for dementia in Parkinson’s disease (PDD) have been proposed by a Movement Disorders Society Task Force (MDS-TF). The objective of this study was to explore the utility of the new MDS-TF criteria and procedures in clinical practice. MethodsTwo hundred ninety nine PD patients (36.5% with PDD as per MDFS-TF criteria; 33.1% according the DSM-IV) were included in the study. A variety of standardized motor, cognitive, psychiatric, and global severity measures were administered. A multivariate logistic regression model was built to determine the variables producing discrepancy between the MDS-TF and DSM-IV criteria for PDD and the clinical features that distinguished false negative cases. ResultsAgreement between MDS-TF and DSM-IV criteria was substantial (87.3%; kappa = 0.72), but the DSM-IV criteria failed to identify 22% of patients fulfilling MDS-TF criteria. False negative cases were older and had more severe motor symptoms but less psychosis than those true non-demented PD. False positives had less severe motor symptoms than true PDD, although the difference did not reach statistical significance. ConclusionsOur findings suggest that the MDS-TF criteria are more sensitive than the DSM-IV for a diagnosis of PDD. Old age, absence of psychiatric symptoms, and severe motor impairment can hinder the diagnosis of PDD.