Alzheimer's disease (AD) is a disorder of progressive memory loss and executive dysfunction. Little is known about the progression from amnestic mild cognitive impairment (aMCI; isolated memory loss) ...to AD. Studies have found impairments in mild‐stage AD and aMCI in specific tests of executive function. Here, we used objective saccade tasks to determine if they can effectively assess executive function deficits otherwise assessed by neuropsychological testing. To determine which executive function deficits the saccade tasks are most sensitive to, we also investigated the relationship between performance on saccade tasks and neuropsychological test scores. Twenty‐two aMCI patients (63–90 years), 24 mild AD patients (61–87 years) and 76 healthy controls (60–85 years) performed a battery of neuropsychological tests, and two saccade tasks designed to probe sensory, motor and cognitive function. The prosaccade task requires a fast, automatic saccade toward an eccentric visual stimulus. The antisaccade task requires additional executive processing to inhibit the automatic prosaccade toward the stimulus, so that a voluntary saccade can be initiated to a location opposite the stimulus. Antisaccade performance was impaired similarly in aMCI and AD patients relative to controls; both groups were slower to initiate correct antisaccades and they made more direction errors (erroneous prosaccades), suggesting similar brain deficits. Scores on the Stroop task were inversely correlated with the percentage of short‐latency direction errors in the antisaccade task for controls and aMCI patients, whereas other more global measures of executive function were not related to saccade measures in any subject group. Our results show that the antisaccade task is useful for detecting executive dysfunction in aMCI and AD, especially dysfunction in selective attention. Saccade tasks may therefore have potential to assess executive dysfunction when use of neuropsychological tests is not possible.
The prosaccade task (look toward a peripheral stimulus) and antisaccade task (inhibit prosaccade to peripheral stimulus and instead initiate saccade to opposite location) are used to assess cognitive impairment. Disease‐specific patterns begin to emerge. Individual antisaccade traces for a representative 75 year old elderly control, a 76 year old aMCI patient, and a 75 year old AD patient are shown here. Solid lines = correct saccades, dotted lines = direction errors. S = stimulus, FP = fixation point.
Large and complex studies are now routine, and quality assurance and quality control (QC) procedures ensure reliable results and conclusions. Standard procedures may comprise manual verification and ...double entry, but these labour-intensive methods often leave errors undetected. Outlier detection uses a data-driven approach to identify patterns exhibited by the majority of the data and highlights data points that deviate from these patterns. Univariate methods consider each variable independently, so observations that appear odd only when two or more variables are considered simultaneously remain undetected. We propose a data quality evaluation process that emphasizes the use of multivariate outlier detection for identifying errors, and show that univariate approaches alone are insufficient. Further, we establish an iterative process that uses multiple multivariate approaches, communication between teams, and visualization for other large-scale projects to follow.
We illustrate this process with preliminary neuropsychology and gait data for the vascular cognitive impairment cohort from the Ontario Neurodegenerative Disease Research Initiative, a multi-cohort observational study that aims to characterize biomarkers within and between five neurodegenerative diseases. Each dataset was evaluated four times: with and without covariate adjustment using two validated multivariate methods - Minimum Covariance Determinant (MCD) and Candès' Robust Principal Component Analysis (RPCA) - and results were assessed in relation to two univariate methods. Outlying participants identified by multiple multivariate analyses were compiled and communicated to the data teams for verification.
Of 161 and 148 participants in the neuropsychology and gait data, 44 and 43 were flagged by one or both multivariate methods and errors were identified for 8 and 5 participants, respectively. MCD identified all participants with errors, while RPCA identified 6/8 and 3/5 for the neuropsychology and gait data, respectively. Both outperformed univariate approaches. Adjusting for covariates had a minor effect on the participants identified as outliers, though did affect error detection.
Manual QC procedures are insufficient for large studies as many errors remain undetected. In these data, the MCD outperforms the RPCA for identifying errors, and both are more successful than univariate approaches. Therefore, data-driven multivariate outlier techniques are essential tools for QC as data become more complex.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As large research initiatives designed to generate big data on clinical cohorts become more common, there is an increasing need to establish standard quality assurance (QA; preventing errors) and ...quality control (QC; identifying and correcting errors) procedures for critical outcome measures. The present article describes the QA and QC approach developed and implemented for the neuropsychology data collected as part of the Ontario Neurodegenerative Disease Research Initiative study. We report on the efficacy of our approach and provide data quality metrics. Our findings demonstrate that even with a comprehensive QA protocol, the proportion of data errors still can be high. Additionally, we show that several widely used neuropsychological measures are particularly susceptible to error. These findings highlight the need for large research programs to put into place active, comprehensive, and separate QA and QC procedures before, during, and after protocol deployment. Detailed recommendations and considerations for future studies are provided.
Objective
Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared ...the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function.
Methods
We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates.
Results
Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs.
Conclusions
NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.
Neural Correlates of Predictive Saccades Lee, Stephen M.; Peltsch, Alicia; Kilmade, Maureen ...
Journal of cognitive neuroscience,
08/2016, Letnik:
28, Številka:
8
Journal Article
Recenzirano
Every day we generate motor responses that are timed with external cues. This phenomenon of sensorimotor synchronization has been simplified and studied extensively using finger tapping sequences ...that are executed in synchrony with auditory stimuli. The predictive saccade paradigm closely resembles the finger tapping task. In this paradigm, participants follow a visual target that “steps” between two fixed locations on a visual screen at predictable ISIs. Eventually, the time from target appearance to saccade initiation (i.e., saccadic RT) becomes predictive with values nearing 0 msec. Unlike the finger tapping literature, neural control of predictive behavior described within the eye movement literature has not been well established and is inconsistent, especially between neuroimaging and patient lesion studies. To resolve these discrepancies, we used fMRI to investigate the neural correlates of predictive saccades by contrasting brain areas involved with behavior generated from the predictive saccade task with behavior generated from a reactive saccade task (saccades are generated toward targets that are unpredictably timed). We observed striking differences in neural recruitment between reactive and predictive conditions: Reactive saccades recruited oculomotor structures, as predicted, whereas predictive saccades recruited brain structures that support timing in motor responses, such as the crus I of the cerebellum, and structures commonly associated with the default mode network. Therefore, our results were more consistent with those found in the finger tapping literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cognitive decline during aging includes impairments in frontal executive functions like reduced inhibitory control. However, decline is not uniform across the population, suggesting individual brain ...response variability to the aging process. Here we tested the hypothesis, within the oculomotor system, that older adults compensate for age-related neural alterations by changing neural activation levels of the oculomotor areas, or even by recruiting additional areas to assist with cognitive performance. We established that the observed changes had to be related to better cognitive performance to be considered as compensatory. To probe this hypothesis we used the antisaccade paradigm and analyzed the effect of aging on brain activations during the inhibition of prepotent responses to visual stimuli. While undergoing a fMRI scan with concurrent eye tracking, 25 young adults (21.7 y/o ± 1.9 SDM) and 25 cognitively normal older adults (66.2 y/o ± 9.8 SDM) performed an interleaved pro/antisaccade task consisting of a preparatory stage and an execution stage. Compared to young adults, older participants showed a larger increase in antisaccade reaction times, while also generating more antisaccade direction errors. BOLD signal analyses during the preparatory stage, when response inhibition processes are established to prevent an automatic response, showed decreased activations in the anterior cingulate and the supplementary eye fields in the older group. Moreover, older adults also showed additional recruitment of the frontal pole not seen in the younger group, and larger activations in the dorsolateral prefrontal cortex during antisaccade preparation. Additional analyses to address the performance variability in the older group showed distinct behavioral-BOLD signal correlations. Larger activations in the saccade network, including the frontal pole, positively correlated with faster antisaccade reaction times, suggesting a functional recruitment of this area. However, only the activation in the dorsolateral prefrontal cortex during the antisaccade events showed a negative correlation with the number of errors across older adults. These findings support the presence of two dissociable age-related plastic mechanisms that result in different behavioral outcomes. One related to the additional recruitment of neural resources within anterior pole to facilitate modulation of cognitive responses like faster antisaccade reaction times, and another related to increased activation of the dorsolateral prefrontal cortex resulting in a better inhibitory control in aging.
•Inhibitory control age-related changes can be measured within the oculomotor saccade system.•Aging results in increased reaction time that correlates negatively with BOLD signal across the saccade system.•The older group shows frontal pole recruitment whose activity also correlates with reaction time.•Dorsolateral prefrontal cortex activation in the older group negatively correlates with the number of direction errors.
83% of those diagnosed with Parkinson's Disease (PD) eventually progress to PD with mild cognitive impairment (PD-MCI) followed by dementia (PDD) - suggesting a complex spectrum of pathology ...concomitant with aging. Biomarkers sensitive and specific to this spectrum are required if useful diagnostics are to be developed that may supplement current clinical testing procedures. We used video-based eye tracking and machine learning to develop a simple, non-invasive test sensitive to PD and the stages of cognitive dysfunction.
From 121 PD (45 Cognitively Normal/45 MCI/20 Dementia/11 Other) and 106 healthy controls, we collected video-based eye tracking data on an interleaved pro/anti-saccade task. Features of saccade, pupil, and blink behavior were used to train a classifier to predict confidence scores for PD/PD-MCI/PDD diagnosis.
The Receiver Operator Characteristic Area Under the Curve (ROC-AUC) of the classifier was 0.88, with the cognitive-dysfunction subgroups showing progressively increased AUC, and the AUC of PDD being 0.95. The classifier reached a sensitivity of 83% and a specificity of 78%. The confidence scores predicted PD motor and cognitive performance scores.
Biomarkers of saccade, pupil, and blink were extracted from video-based eye tracking to create a classifier with high sensitivity to the landscape of PD cognitive and motor dysfunction. A complex landscape of PD is revealed through a quick, non-invasive eye tracking task and our model provides a framework for such a task to be used as a supplementary screening tool in the clinic.
•Structured eye-tracking produces biomarkers sensitive to PD cognitive subtypes.•Saccade, pupil, and blink reveal a complex landscape of PD spectrum.•Functional data analysis can automatically suggest features for complex signals.•ROC-AUC of 0.88 for PD classification can be achieved through machine learning.
Introduction
Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.
Methods
This multi‐site, ...longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.
Results
We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.
Discussion
Data will be shared with the global scientific community. Within‐disease and disease‐agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.
Objectives
To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI).
Methods
85 patients ...with MCI were identified, including 26 with a previous history of traumatic brain injury (MCITBI-) and 59 without (MCITBI+). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function.
Results
At baseline, the MCITBI+ group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCITBI+ group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1–2%, 90%HDI −0.01%: −0.001%, probability of direction (PD) = 90–99%). The MCITBI+ group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: 0.229%: 1.31%, PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: −5.17%: 43.2%, PD = 91.7%).
Conclusions
Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.
PDF
