Quantitative microbial spoilage risk assessment of Aspergillus niger in white bread reveal that retail storage temperature and mold contamination during factory cooling are the main factors to influence spoilage.

The present study developed a model for effectively assessing the risk of spoilage caused by Aspergillus niger to identify key control measures employed in bakery supply chains. A white bread supply chain comprising a processing plant and two retail stores in Taiwan was selected in this study. Time-temperature profiles were collected at each processing step in summer and winter. Visual mycelium diameter predictions were validated using a time-lapse camera. Six what-if scenarios were proposed. The mean risk of A. niger contamination per package sold by retailer A was 0.052 in summer and 0.036 in winter, and that for retailer B was 0.037 in summer and 0.022 in winter. Sensitivity analysis revealed that retail storage time, retail temperature, and mold prevalence during factory cooling were the main influencing factors. The what-if scenarios revealed that reducing the retail environmental temperature by 1 °C in summer (from 23.97 °C to 22.97 °C) and winter (from 23.28 °C to 22.28 °C) resulted in a reduction in spoilage risk of 47.0% and 34.7%, respectively. These results indicate that food companies should establish a quantitative microbial risk assessment model that uses real data to evaluate microbial spoilage in food products that can support decision-making processes.

Predictors of Cognitive Change in Parkinson Disease: A 2-year Follow-up Study.

BACKGROUND: Mild cognitive impairment is common in Parkinson disease (PD-MCI). However, instability in this clinical diagnosis and variability in rates of progression to dementia raises questions regarding its utility for longitudinal tracking and prediction of cognitive change in PD. We examined baseline neuropsychological test and cognitive diagnosis predictors of cognitive change in PD. METHODS: Persons with PD, without dementia PD (N=138) underwent comprehensive neuropsychological assessment at baseline and were followed up to 2 years. Level II Movement Disorder Society criteria for PD-MCI and PD dementia (PDD) were applied annually. Composite global and domain cognitive z -scores were calculated based on a 10-test neuropsychological battery. RESULTS: Baseline diagnosis of PD-MCI was not associated with a change in global cognitive z -scores. Lower baseline attention and higher executive domain z -scores were associated with greater global cognitive z -score worsening regardless of cognitive diagnosis. Worse baseline domain z -scores in the attention and language domains were associated with progression to MCI or PDD, whereas higher baseline scores in all cognitive domains except executive function were associated with clinical and psychometric reversion to "normal" cognition. CONCLUSIONS: Lower scores on cognitive tests of attention were predictive of worse global cognition over 2 years of follow-up in PD, and lower baseline attention and language scores were associated with progression to MCI or PDD. However, PD-MCI diagnosis per se was not predictive of cognitive decline over 2 years. The association between higher executive domain z -scores and greater global cognitive worsening is probably a spurious result.

Thalamic Segmentation and Neural Activation Modeling Based on Individual Tissue Microstructure in Deep Brain Stimulation for Essential Tremor.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is the primary surgical therapy for essential tremor (ET). Thalamic DBS traditionally uses an atlas-based targeting approach, which, although nominally accurate, may obscure individual anatomic differences from population norms. The objective of this study was to compare this traditional atlas-based approach with a novel quantitative modeling methodology grounded in individual tissue microstructure (N-of-1 approach). MATERIALS AND METHODS: The N-of-1 approach uses individual patient diffusion tensor imaging (DTI) data to perform thalamic segmentation and volume of tissue activation (VTA) modeling. For each patient, the thalamus was individually segmented into 13 nuclei using DTI-based k-means clustering. DBS-induced VTAs associated with tremor suppression and side effects were then computed for each patient with finite-element electric-field models incorporating DTI microstructural data. Results from N-of-1 and traditional atlas-based modeling were compared for a large cohort of patients with ET treated with thalamic DBS. RESULTS: The size and shape of individual N-of-1 thalamic nuclei and VTAs varied considerably across patients (N = 22). For both methods, tremor-improving therapeutic VTAs showed similar overlap with motor thalamic nuclei and greater motor than sensory nucleus overlap. For VTAs producing undesirable sustained paresthesia, 94% of VTAs overlapped with N-of-1 sensory thalamus estimates, whereas 74% of atlas-based segmentations overlapped. For VTAs producing dysarthria/motor contraction, the N-of-1 approach predicted greater spread beyond the thalamus into the internal capsule and adjacent structures than the atlas-based method. CONCLUSIONS: Thalamic segmentation and VTA modeling based on individual tissue microstructure explain therapeutic stimulation equally well and side effects better than a traditional atlas-based method in DBS for ET. The N-of-1 approach may be useful in DBS targeting and programming, particularly when patient neuroanatomy deviates from population norms.

Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Perceived social support declines after deep brain stimulation surgery in patients with Parkinson's disease.

INTRODUCTION: The Social Provisions Scale (SPS) measures a person's perceived social support. We evaluated the perceived social support in Parkinson's disease (PD) patients before and after subthalamic nucleus (STN) deep brain stimulation (DBS) and its impact on clinical outcomes following DBS. METHODS: We analyzed 55 PD patients who underwent STN DBS surgery and completed the SPS, PDQ-39, and MDS-UPDRS Parts I-IV before and 6-12 months after surgery. Some patients also completed global cognitive, mood and apathy scales. Caregivers completed the CBI at each visit. Linear regression models and linear mixed models evaluated the association between the SPS baseline score, MDS-UPDRS and PDQ-39 scores, the association between MDS-UPDRS, CBI and the SPS follow-up score, and the association between SPS, global cognition and other psychological variables. RESULTS: DBS implantation improved MDS-UPDRS I-IV and PDQ-39 scores. Perceived social support declined after DBS (baseline SPS total 82.55 ± 7.52 vs. follow-up SPS total 78.83 ± 9.02, p = 0.0001). Baseline SPS total score was not significantly associated with the MDS-UPDRS or PDQ-39 scores at follow-up. MDS-UPDRS scores and the CBI at follow-up had no significant association with SPS total score at follow-up. Measures of global cognition, mood and apathy were associated with the SPS before and after DBS, and the association was independent of STN DBS. CONCLUSION: After STN DBS, PD patients experienced a decrease in perceived social support, but baseline perceived social support did not impact clinical outcomes. It is important to further identify factors that may contribute to this perception of worsened social support.

Neural correlates of risky decision making in Parkinson's disease patients with impulse control disorders.

Some patients with Parkinson's disease (PD) experience impulse control disorders (ICDs), characterized by deficient voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of impulsive, risky decision making in PD patients with ICDs by disentangling potential dysfunctions in decision and outcome mechanisms. We collected fMRI data from 20 patients with ICDs and 28 without ICDs performing an information gathering task. Patients viewed sequences of bead colors drawn from hidden urns and were instructed to infer the majority bead color in each urn. With each new bead, they could choose to either seek more evidence by drawing another bead (draw choice) or make an urn-inference (urn choice followed by feedback). We manipulated risk via the probability of bead color splits (80/20 vs. 60/40) and potential loss following an incorrect inference ($10 vs. $0). Patients also completed the Barratt Impulsiveness Scale (BIS) to assess impulsivity. Patients with ICDs showed greater urn choice-specific activation in the right middle frontal gyrus, overlapping the dorsal premotor cortex. Across all patients, fewer draw choices (i.e., more impulsivity) were associated with greater activation during both decision making and outcome processing in a variety of frontal and parietal areas, cerebellum, and bilateral striatum. Our findings demonstrate that ICDs in PD are associated with differences in neural processing of risk-related information and outcomes, implicating both reward and sensorimotor dopaminergic pathways.

Longitudinal Change in Quality of Life in Neurological Disorders Measures Over 3 Years in Patients with Early Parkinson's Disease.

BACKGROUND: The Quality of Life in Neurological Disorders (Neuro-QoL) is a publicly available health-related quality-of-life measurement system. OBJECTIVE: The aim of this study was to evaluate the utility of Neuro-QoL item banks as outcome measures for clinical trials in Parkinson's disease. METHODS: An analysis of Neuro-QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort. RESULTS: Among 310 participants over 3 years, changes in five of eight Neuro-QoL domains were significant (P < 0.05) but very modest. The largest effect sizes were seen in the cognition and mobility domains (0.35-0.39). The largest effect size for change over the year in which levodopa was initiated was -0.19 for lower extremity function-mobility. For a similarly designed clinical trial, estimated sample size required to demonstrate a 50% reduction in worsening ranged from 420 to more than 1000 participants per group. CONCLUSIONS: More sensitive tools will be required to serve as an outcome measure in early Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

BACKGROUND: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. OBJECTIVES: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA). METHODS: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire. RESULTS: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy. CONCLUSIONS: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

HDQLIFE and neuro-QoL physical function measures: Responsiveness in persons with huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurological disorder that causes severe motor symptoms that adversely impact health-related quality of life. Patient-reported physical function outcome measures in HD have shown cross-sectional evidence of validity, but responsiveness has not yet been assessed. OBJECTIVES: This study evaluates the responsiveness of the Huntington Disease Health-Related Quality of Life (HDQLIFE) and the Quality of Life in Neurological Disorders (Neuro-QoL) physical function measures in persons with HD. METHODS: A total of 347 participants completed baseline and at least 1 follow-up (12-month and 24-month) measure (HDQLIFE Chorea, HDQLIFE Swallowing Difficulties, HDQLIFE Speech Difficulties, Neuro-QoL Upper Extremity Function, and/or Neuro-QoL Lower Extremity Function). Of the participants that completed the baseline assessment, 338 (90.9%) completed the 12-month assessment, and 293 (78.8%) completed the 24-month assessment. Standardized response means and general linear models evaluated whether the physical function measures were responsive to self-reported and clinician-rated change over time. RESULTS: Small to moderate effect sizes for the standardized response means supported 12-month and 24-month responsiveness of the HDQLIFE and Neuro-QoL measures for those with either self-reported or clinician-rated declines in function. General linear models supported 12-month and 24-month responsiveness for all HRQOL measures relative to self-reported declines in health, but generally only 24-month responsiveness was supported relative to clinician-rated declines in function. CONCLUSIONS: Longitudinal analyses indicate that the HDQLIFE and the Neuro-QoL physical function measures are sensitive to change over time in individuals with HD. Thus, these scales exhibit evidence of responsiveness and may be useful outcome measures in future clinical trials. © 2019 International Parkinson and Movement Disorder Society.

Parkinson disease with mild cognitive impairment: Domain-specific cognitive complaints predict dementia.

BACKGROUND: The presence of subjective cognitive complaints (SCC) as a predictor of cognitive impairment in Parkinson´s disease (PD) has shown conflicting results. Most previous studies only assessed complaints in the memory domain. We investigate the association of SCCs across cognitive domains with development of mild cognitive impairment (PD-MCI) and dementia (PDD) in PD and to assess agreement between SCCs and objective cognitive impairments in this population. METHODS: This is a retrospective analysis of a prospective cohort study. Participants were enrolled at six North-American movement disorders centers. They underwent neuropsychological and non-cognitive clinical evaluations, including the modified Neurobehavioral Inventory to elicit SCC (rated by each patient and independently by their close contact (CC)). Associations between SCCs and development of future cognitive impairment were assessed. Agreement between SCCs and objective impairment within the same domain was also calculated. RESULTS: Of 138 included PD patients, 42% fulfilled criteria for PD-MCI. None of the NBI items predicted development of cognitive impairment after one and two years in PD with normal cognition. In PD-MCI patients, SCCs related to attention predicted dementia at year one. CC ratings of SCCs related to memory and language problems predicted PDD in PD-MCI patients. According to CC reported patients' complaints, there was a significant agreement between SCCs and objective cognitive test scores on attention. CONCLUSIONS: Eliciting SCCs including cognitive domains other than memory is crucial for a complete evaluation, including both patient and CC report. Memory, language, and especially attention SCCs in PD-MCI may predict progression to dementia.

Psychometric properties and responsiveness of Neuro-QoL Cognitive Function in persons with Huntington disease (HD).

PURPOSE: Individuals with Huntington disease (HD) experience progressive cognitive decline that may appear years before motor manifestations of the disease. These declines have a profound effect on health-related quality of life (HRQOL) over the disease course, and thus it is important that self-report measures of cognitive function are validated for use in longitudinal studies. METHODS: 359 individuals with premanifest or manifest HD completed baseline and at least one follow-up (12- and 24-month) assessment. Neuro-QoL™ Cognitive Function was administered at each time-point. Participants completed a self-reported global rating of cognitive change, as well as performance-based cognitive changes (using the Symbol Digit Modalities Test). Standardized response means (SRMs) and general linear models evaluated whether Neuro-QoL™ Cognitive Function was responsive to change over time with respect to self-reported and performance-based anchors. Test-retest reliability and known-group validity were also examined. RESULTS: Responsiveness was supported by effect sizes that were small in magnitude, but in the expected direction relative to self-reported and performance-based change. General linear models generally supported 12- and 24-month responsiveness relative to self-reported cognitive change and 12-month responsiveness relative to performance-based change. Test-retest reliability was excellent, and the measure exhibited known-group validity. CONCLUSION: Longitudinal analyses generally indicate that the Neuro-QoL™ Cognitive Function measure is sensitive to change over time in individuals with HD. Neuro-QoL Cognitive Function changes reflect self-reported cognitive change at 12 and 24 months and performance-based change at 12 months. This measure may be useful in clinical trials or longitudinal observation studies.

Responsiveness to change over time and test-retest reliability of the PROMIS and Neuro-QoL mental health measures in persons with Huntington disease (HD).

BACKGROUND: The majority of persons with Huntington disease (HD) experience mental health symptoms. Patient-reported outcome (PRO) measures are capable of capturing unobservable behaviors and feelings relating to mental health. The current study aimed to test the reliability and responsiveness to self-reported and clinician-rated change over time of Neuro-QoL and PROMIS mental health PROs over the course of a 24-month period. METHODS: At baseline, 12-months, and 24-months, 362 participants with premanifest or manifest HD completed the Neuro-QoL Depression computer adaptive test (CAT), PROMIS Depression short form (SF), Neuro-QoL Anxiety CAT, PROMIS Anxiety SF, PROMIS Anger CAT and SF, Neuro-QoL Emotional/Behavioral Dyscontrol CAT and SF, Neuro-QoL Positive Affect and Well-Being CAT and SF, and Neuro-QoL Stigma CAT and SF. Participants completed several clinician-administered measures at each time point, as well as several global ratings of change at 12- and 24-months. Reliability (test-retest reliability and measurement error) and responsiveness (using standardized response means and general linear models) were assessed. RESULTS: Test-retest reliability and measurement error were excellent for all PROs (all ICC ≥ .90 for test-retest reliability and all SEM percentages ≤ 6.82%). In addition, 12- and 24-month responsiveness were generally supported for the Neuro-QoL and PROMIS mental health PROs; findings relative to clinician-rated anchors of change (e.g., SRMs for the group with declines ranged from .38 to .91 for 24-month change and .09 to .45, with the majority above .25 for 12-month change) were generally more robust than those relative to self-reported anchors of change (e.g., SRMs for the group with declines ranged from .02 to .75, with the majority above .39 for 24-month change and .09 to .45, with the majority above .16 for 12-month change). CONCLUSIONS: The Neuro-QoL and PROMIS mental health PROs demonstrated strong psychometric reliability, as well as responsiveness to self-reported and clinician-rated change over time in people with HD.

How different aspects of motor dysfunction influence day-to-day function in huntington's disease.

PURPOSE: This study examined the relationships between different aspects of motor dysfunction (chorea, dystonia, rigidity, incoordination, oculomotor dysfunction, dysarthria, and gait difficulties) and functional status in persons with Huntington's disease. METHODS: A total of 527 persons with Huntington's disease completed the Unified Huntington's Disease Rating Scale motor, total functional capacity, and functional assessments. RESULTS: Confirmatory factor analysis indicated that a 4-factor model provided a better model fit than the existing 5-factor model. Exploratory factor analysis identified the following 4 factors from the motor scale: dystonia, chorea, rigidity, and a general motor factor. Regression indicated that dystonia (ß = -0.47 and -0.79) and rigidity (ß = -0.28 and -0.59) had strong associations with function, whereas chorea had modest correlations (ß = -0.16 and -0.15). CONCLUSIONS: Dystonia and rigidity have stronger relationships with functional status than chorea in persons with Huntington's disease. The findings underscore the need for further research regarding the effects of dystonia and rigidity on functioning. © 2019 International Parkinson and Movement Disorder Society.

Subthalamic nucleus deep brain stimulation improves dyskinesias in Parkinson's disease beyond levodopa reduction.

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves motor fluctuations and dyskinesias in patients with Parkinson's disease (PD). Dyskinesia improvement with STN DBS is believed to result entirely from levodopa reduction. However, some studies suggest that STN DBS may also directly suppress dyskinesias. To determine whether bilateral STN DBS improves dyskinesias beyond what would be expected from levodopa reduction alone, we analyzed pre-operative and post-operative dyskinesia scores (sum of MDS-UPDRS items 4.1 and 4.2) from 61 PD patients with bilateral STN DBS. A multiple regression model (adjusted for disease severity, disease duration, active contacts above the STN, use of amantadine, high pre-operative levodopa-equivalent dose (LED), sex, and interaction between active contacts above the STN and amantadine use) was created to describe the relationship between dyskinesia scores and LED prior to DBS. Using this model, a post-operative dyskinesia score was estimated from post-operative LED and compared to the actual post-operative dyskinesia score. The regression model was statistically significant overall (p = 0.003, R2 = 0.34, adjusted R2 = 0.24). The actual post-operative dyskinesia score (1.0 ± 1.4) was significantly lower than the score predicted by the model (3.0 ± 1.1, p < 0.0001). Dyskinesias after STN DBS improved more than predicted by levodopa reduction alone. Our data support the idea that STN stimulation may directly improve dyskinesias.

Responsiveness to Change of the Montreal Cognitive Assessment, Mini-Mental State Examination, and SCOPA-Cog in Non-Demented Patients with Parkinson's Disease.

BACKGROUND: Clinical monitoring of patients with Parkinson's disease (PD) for cognitive decline is an important element of care. The Montreal Cognitive Assessment (MoCA) has been proposed to be a sensitive tool for assessing cognitive impairment in PD. The aim of our study was to compare the responsiveness of the MoCA to decline in cognition to the responsiveness of the Mini Mental State Examination (MMSE) and the Scales for Outcomes of Parkinson's disease-cognition (SCOPA-Cog). METHODS: PD patients without dementia were enrolled at 6 North American movement disorders centers between 2008 and 2011. Participants received annual evaluations including the MoCA, MMSE, and SCOPA-Cog followed by formal neuropsychological testing. The gold standard for change in cognition was defined as the change on the neuropsychological test scores over the annual assessments. The Reliable Change Method was used to provide an estimate of the probability that a given difference score would be obtained by chance. The sensitivity of the MoCA, MMSE, and SCOPA-Cog to change was quantified using receiver operating characteristics (ROC) curves. RESULTS: One hundred seventeen patients were included in the analysis. Participants were followed at mean intervals of 11 ± 2 months for a median of 2 (maximum 5) visits. According to the reliable change index, 56 intervals of cognitive testing showed a decline in global cognition. ROC analysis of change in MoCA, MMSE, and SCOPA-Cog global scores compared to gold standard testing found an area under the curve (AUC) of 0.55 (95% CI 0.48-0.62), 0.56 (0.48-0.63), and 0.63 (0.55-0.70) respectively. There were no significant differences in the AUCs across the tests. The sensitivity of the MoCA, MMSE, and SCOPA-Cog to change at various thresholds for decline in scores reached a maximum of 71% for a cut-off of 1 point change on the SCOPA-Cog. CONCLUSION: Using neuropsychological testing as a gold standard comparator, the performance of the MoCA, MMSE, and SCOPA-Cog for detecting decline in non-demented PD patients over a 1-year interval is poor. This has implications for clinical practice; stable scores may not be taken as reassurance of the absence of cognitive decline.

Atlas-Independent, Electrophysiological Mapping of the Optimal Locus of Subthalamic Deep Brain Stimulation for the Motor Symptoms of Parkinson Disease.

BACKGROUND/AIMS: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms of Parkinson disease (PD). However, motor outcomes can be variable, perhaps due to inconsistent positioning of the active contact relative to an unknown optimal locus of stimulation. Here, we determine the optimal locus of STN stimulation in a geometrically unconstrained, mathematically precise, and atlas-independent manner, using Unified Parkinson Disease Rating Scale (UPDRS) motor outcomes and an electrophysiological neuronal stimulation model. METHODS: In 20 patients with PD, we mapped motor improvement to active electrode location, relative to the individual, directly MRI-visualized STN. Our analysis included a novel, unconstrained and computational electrical-field model of neuronal activation to estimate the optimal locus of DBS. RESULTS: We mapped the optimal locus to a tightly defined ovoid region 0.49 mm lateral, 0.88 mm posterior, and 2.63 mm dorsal to the anatomical midpoint of the STN. On average, this locus is 11.75 lateral, 1.84 mm posterior, and 1.08 mm ventral to the mid-commissural point. CONCLUSION: Our novel, atlas-independent method reveals a single, ovoid optimal locus of stimulation in STN DBS for PD. The methodology, here applied to UPDRS and PD, is generalizable to atlas-independent mapping of other motor and non-motor effects of DBS.

Influence of Intracranial Air on Electrode Position and Clinical Outcomes following Deep Brain Stimulation for Parkinson's Disease.

BACKGROUND: The introduction of intracranial air during deep brain stimulation (DBS) surgery is believed to negatively impact targeting accuracy and clinical outcomes. OBJECTIVE: To quantify the relationship between intracranial air (ICA) volumes, targeting accuracy, and clinical outcomes in patients undergoing subthalamic nucleus (STN) DBS for Parkinson's disease. METHODS: ICA in 73 consecutive STN DBS cases (146 leads) was measured by high-resolution CT and correlated with proximal lead bowing, electrode displacement, targeting accuracy, and clinical outcomes at 6 and 12 months. RESULTS: There was a statistically significant correlation of ICA volume (mean ± SEM: 21.3 ± 13.7 cm3) and proximal lead bowing (2.8 ± 1.4 mm, r = 0.34, p = 0.01). There was no significant correlation of ICA with targeting error (2.0 ± 1.2 mm), distal contact deviation (1.2 ± 0.7 mm), motor Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III improvement at 6 months (42.3 ± 4.5%) or 12 months (30.3 ± 7.7%), or dopaminergic medication reduction at 6 months (44.7± 4.2%) or 12 months (32.9 ± 5.9%). Comparison of top and bottom ICA quintile extremes also revealed no differences in these measures. CONCLUSIONS: Though the proximal DBS lead bends in association with ICA, movement of the distal contact, targeting error, and clinical outcomes are not affected by ICA. This unexpected finding is maintained at ICA quintile extremes.

Parkinson's disease-related fatigue: A case definition and recommendations for clinical research.

Fatigue is one of the most common and disabling symptoms in Parkinson's disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD-related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD-related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis). © 2016 International Parkinson and Movement Disorder Society.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE: There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE: To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS: Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES: The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS: The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE: Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449865.