Daniel J. Myall

The influence of motor and cognitive impairment upon visually-guided saccades in Parkinson's disease

Studies of saccades in Parkinsons disease (PD) have seldom examined the influence of cognitive status, ranging from normal cognition, through mild cognitive impairment, to dementia. In a large and heterogeneous sample, we examined how motor and cognitive impairment was reflected in the performance of reflexive, visually-guided saccades. We examined 163 people with PD and 47 similar-aged controls. Ninety three of the PD group had normal cognition (PDN), 48 had mild cognitive impairment (PD-MCI), and 22 had dementia (PDD). Pseudo-random targets (amplitudes of 5, 10, 15 and 20 deg and inter-stimulus-intervals ranging from 550 to 1800 ms) were shown in 108 mixed randomised trials, incorporating gap, step, and overlap onset conditions. Analyses were conducted using multi-level regression modeling. Participants were first assessed by continuous measures (Unified PD Rating Scale motor score and the Montreal Cognitive Assessment). Prolonged latency was significantly related to both motor and cognitive impairment, with the cognitive effect being compounded by increasing age. Decreased saccade amplitude, meanwhile, was primarily related to motor impairment. When assessed by discrete cognitive categories, all of the PD groups showed reduced saccadic amplitude relative to controls. Saccadic latencies, meanwhile, were abnormally prolonged only in the PD-MCI and PDD groups (the control and PDN groups were similar to each other). Latency in the overlap task was particularly sensitive to increasing motor and cognitive impairment. We conclude that reflexive saccades in PD are subtly decreased in amplitude even early in the disease process. Prolonged saccade latency, meanwhile, tends to occur later in the disease process, in the presence of more substantial motor and cognitive impairment, and greater age. The progressive impairment of reflexive saccades, and the differential onset of amplitude and latency impairments, may make them a useful objective tool for assessing disease status.

Comparing cerebral perfusion in Alzheimer's disease and Parkinson's disease dementia: an ASL-MRI study

Emerging evidence suggests that Alzheimers disease (AD) and Parkinsons disease dementia (PDD) share neurodegenerative mechanisms. We sought to directly compare cerebral perfusion in these two conditions using arterial spin labeling magnetic resonance imaging (ASL-MRI). In total, 17 AD, 20 PDD, and 37 matched healthy controls completed ASL and structural MRI, and comprehensive neuropsychological testing. Alzheimers disease and PDD perfusion was analyzed by whole-brain voxel-based analysis (to assess absolute blood flow), a priori specified region of interest analysis, and principal component analysis (to generate a network differentiating the two groups). Corrections were made for cerebral atrophy, age, sex, education, and MRI scanner software version. Analysis of absolute blood flow showed no significant differences between AD and PDD. Comparing each group with controls revealed an overlapping, posterior pattern of hypoperfusion, including posterior cingulate gyrus, precuneus, and occipital regions. The perfusion network that differentiated AD and PDD groups identified relative differences in medial temporal lobes (AD < PDD) and right frontal cortex (PDD < AD). In conclusion, the pattern of cerebral hypoperfusion is very similar in AD and PDD. This suggests closely linked mechanisms of neurodegeneration mediating the evolution of dementia in both conditions.

Fractal Dimension of the EEG for Detection of Behavioural Microsleeps

The fractal dimension (FD) of EEG has been shown to be of value in the detection of epileptic seizures. In this paper, we assess its usefulness in detecting behavioural microsleeps. Fifteen non-sleep-deprived normal subjects performed two 1-hour sessions of a continuous tracking task while EEG, EOG and facial video were recorded. Higuchis algorithm was used to calculate the FD of the EEG. Video lapses were scored independently from tracking performance by a human rater. A subset of data was rated independently by three human raters observing both tracking performance and the video rating to identify behavioural microsleep events. The mean point-biserial correlation between FD and the mean human rating was -0.213 indicating modest agreement. Cross-validated detection performance of the FD was poor with a mean correlation (phi = -0.099). This suggests that, on its own, FD of the EEG is unlikely to be useful for detecting microsleeps

A perceptual discrimination task abnormally facilitates reflexive saccades in Parkinson’s disease

Numerous studies have shown that Parkinson’s disease (PD) affects the ability to generate voluntary saccades and the ability to suppress reflexive saccades. The effects of PD on the generation of reflexive saccades, however, are not clear. Some studies report impairments, but there are also reports of abnormal facilitation or hyper‐reflexivity of the saccade system in PD. Meanwhile, it has been reported that the concurrent performance of a perceptual discrimination task facilitates saccade initiation and reduces saccade latencies in healthy subjects [ A. Montagnini & L. Chelazzi (2005)Vis. Res., 45, 3391–3401; L. Trottier & J. Pratt (2005)Vis. Res., 45, 1349–1354]. To investigate the circumstances under which the saccade system may appear hyper‐reflexive in PD, we compared reflexive saccades with and without a concurrent perceptual discrimination task in 20 PD patients and 20 controls. Without the discrimination task, the PD group produced reflexive saccades at normal latencies. The discrimination task reduced saccade latencies more in the PD group than in the control group, resulting in abnormally short mean reflexive saccade latencies in the PD group. The discrimination task increased saccade gain in both groups, but saccades in the PD group remained hypometric as compared with saccades in the control group. We conclude that the attentional demands of this paradigm revealed a hypersensitivity to visual inputs in the PD group.

Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study

The Movement Disorder Society Task Force (MDS-TF) has proposed diagnostic criteria for mild cognitive impairment in Parkinson’s disease (PD-MCI). We hypothesized that the risk of dementia (PDD) varies across the different cutoff schemes allowed. A longitudinal study followed 121 non-demented PD patients for up to 4.5 years. In Part One, unique groups of patients were identified as PD-MCI at baseline using the MDS-TF requirement of two impaired cognitive test scores, with both scores classified as impaired at either (i) 2 s.d., (ii) 1.5 s.d. or (iii) 1 s.d. below normative data; relative risk (RR) of PDD was assessed at each criterion. In Part Two, the whole sample was reassessed and (i) RR of PDD determined when two impairments at 1.5 s.d. existed within a single cognitive domain, followed by (ii) RR of PDD in the unique group whose two impairments at 1.5 s.d. did not exist within a single domain (i.e., only across two domains). Twenty-one percent of patients converted to PDD. Part One showed that the 1.5 s.d. criterion at baseline is optimal to maximize progression to PDD over 4 years. Part Two, however, showed that the 1.5 s.d. cutoff produced a high RR of PDD only when two impairments were identified within a single cognitive domain (7.2, 95% confidence interval (CI)=3.4–16.6, P<0.0001; 51% converted). The RR when the 1.5 s.d. impairments occurred only across two different domains, was nonsignificant (1.7, CI=0.5–7.4, P=0.13; 11% converted) and similar to using a 1 s.d. criterion (1.9, CI=0.3–4.3, P=0.13; 8% converted). If the intent of a PD-MCI diagnosis is to detect increased risk of PDD in the next 4 years, optimal criteria should identify at least two impairments at 1.5 s.d. within a single cognitive domain.

Metabolite ratios in the posterior cingulate cortex do not track cognitive decline in Parkinson's disease in a clinical setting

INTRODUCTION Parkinsons Disease (PD) is classified as a motor disorder, but most patients develop cognitive impairment, and eventual dementia (PDD). Predictive neurobiomarkers may be useful in the identification of those patients at imminent risk of PDD. Given the compromised cerebral integrity in PDD, we investigated whether brain metabolites track disease progression over time. METHODS Proton Magnetic Resonance Spectroscopy (MRS) was used to identify brain metabolic changes associated with cognitive impairment and dementia in PD. Forty-nine healthy participants and 130 PD patients underwent serial single voxel proton MRS and neuropsychological testing. At baseline patients were classified as either having normal cognitive status (PDN, n = 77), mild cognitive impairment (PDMCI, n = 33), or dementia (PDD, n = 20). Posterior cingulate cortex (PCC) was examined to quantify N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI). A hierarchical Bayesian model was used to assess whether cognitive ability and other covariates were related to baseline MRS values and changes in MRS over time. RESULTS At baseline, relative to controls, PDD had significantly decreased NAA/Cr and increased Cho/Cr. However, these differences did not remain significant after accounting for age, sex, and MDS-UPDRS III. At follow-up, no significant changes in MRS metabolite ratios were detected, with no relationship found between MRS measures and change in cognitive status. CONCLUSIONS Unlike Alzheimers disease, single voxel MR spectroscopy of the PCC failed to show any significant association with cognitive status at baseline or over time. This suggests that MRS of PCC is not a clinically useful biomarker for tracking or predicting cognitive impairment in Parkinsons disease.

Design of a Modular and Low-Latency Virtual-Environment Platform for Applications in Motor Adaptation Research, Neurological Disorders, and Neurorehabilitation

We have developed a modular virtual environment platform for movement research and rehabilitation. The system uses several networked computers running Linux to share computation. An electromagnetic tracker is the primary position tracker and both a head-mounted display and stereo goggles are used for visual display. System software is written in a combination of C++, JAVA, and Python and makes considerable use of the open-source toolkits VR Juggler and OpenSceneGraph. These are integrated with additional toolkits and custom modules written specifically for the study of motor control and rehabilitation. The system performs well with low latency, accurate calibration, and a consistently high graphics update rate. Preliminary applications have confirmed that the system is a powerful tool for sensory-motor investigation and has considerable potential as a tool for neurorehabilitation. Its primary advantage over other systems is its ability to utilize different display and input devices, and run a range of experiments simply by changing XML configuration files. Additionally, the use of powerful open-source libraries provides a feature-rich foundation for advanced features and low-cost duplication. Further work and experiments are needed to extend, further validate, and fully utilize this platform.

Tracking Parkinson's Disease Over One Year with Multimodal Magnetic Resonance Imaging in a Group of Older Patients with Moderate Disease

Background & Objectives Cross-sectional magnetic resonance imaging (MRI) suggests that Parkinson’s disease (PD) is associated with changes in cerebral tissue volume, diffusion tensor imaging metrics, and perfusion values. Here, we performed a longitudinal multimodal MRI study—including structural, diffusion tensor imaging (DTI), and perfusion MRI—to investigate progressive brain changes over one year in a group of older PD patients at a moderate stage of disease. Methods Twenty-three non-demented PD (mean age (SD) = 69.5 (6.4) years, disease duration (SD) = 5.6 (4.3) years) and 23 matched control participants (mean age: 70.6 (6.8)) completed extensive neuropsychological and clinical assessment, and multimodal 3T MRI scanning at baseline and one year later. We used a voxel-based approach to assess change over time and group-by-time interactions for cerebral structural and perfusion metrics. Results Compared to controls, in PD participants there was localized grey matter atrophy over time in bilateral inferior and right middle temporal, and left orbito-frontal cortices. Using a voxel-based approach that focused on the centers of principal white matter tracts, the PD and control cohorts exhibited similar levels of change in DTI metrics. There was no significant change in perfusion, cognitive, or motor severity measures. Conclusions In a cohort of older, non-demented PD participants, macrostructural MRI detected atrophy in the PD group compared with the control group in temporal and orbito-frontal cortices. Changes in diffusion MRI along principal white matter tracts over one year were found, but this was not differentially affected by PD.

A perceptual discrimination task results in greater facilitation of voluntary saccades in Parkinson's disease patients

Many studies have shown that Parkinsons disease (PD) affects not only the ability to generate voluntary saccades but also the ability to suppress reflexive saccades (hyper‐reflexivity). To further investigate these apparently contradictory effects of PD on the saccade system we adapted a well‐known dual‐task paradigm (Deubel, 2008) to measure saccades with and without a peripheral discrimination task. Previously we reported that the concurrent performance of a perceptual discrimination task abnormally reduced the latencies of reflexive saccades in PD. Here we report the effects of the concurrent discrimination task on the generation of voluntary saccades in a PD and a control group. As expected, when saccades were performed without the discrimination task the PD group made voluntary saccades with longer latencies and smaller gain than the control group. The concurrent performance of the perceptual discrimination task facilitated the initiation of voluntary saccades in both groups, but, surprisingly, this facilitatory effect was stronger in the PD group than in the control group. In addition, in the PD group voluntary saccades were abnormally facilitated by the peripheral symbol‐changes that occur during saccade planning in this paradigm. The results of this study may help to clarify apparently contradictory oculomotor abnormalities observed in PD.

Construction of joint confidence regions for the optimal true class fractions of Receiver Operating Characteristic (ROC) surfaces and manifolds.

The three-class approach is used for progressive disorders when clinicians and researchers want to diagnose or classify subjects as members of one of three ordered categories based on a continuous diagnostic marker. The decision thresholds or optimal cut-off points required for this classification are often chosen to maximize the generalized Youden index (Nakas et al., Stat Med 2013; 32: 995–1003). The effectiveness of these chosen cut-off points can be evaluated by estimating their corresponding true class fractions and their associated confidence regions. Recently, in the two-class case, parametric and non-parametric methods were investigated for the construction of confidence regions for the pair of the Youden-index-based optimal sensitivity and specificity fractions that can take into account the correlation introduced between sensitivity and specificity when the optimal cut-off point is estimated from the data (Bantis et al., Biomet 2014; 70: 212–223). A parametric approach based on the Box–Cox transformation to normality often works well while for markers having more complex distributions a non-parametric procedure using logspline density estimation can be used instead. The true class fractions that correspond to the optimal cut-off points estimated by the generalized Youden index are correlated similarly to the two-class case. In this article, we generalize these methods to the three- and to the general k-class case which involves the classification of subjects into three or more ordered categories, where ROC surface or ROC manifold methodology, respectively, is typically employed for the evaluation of the discriminatory capacity of a diagnostic marker. We obtain three- and multi-dimensional joint confidence regions for the optimal true class fractions. We illustrate this with an application to the Trail Making Test Part A that has been used to characterize cognitive impairment in patients with Parkinson’s disease.