Edward Ofori

Longitudinal changes in free-water within the substantia nigra of Parkinson’s disease

There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinsons disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinsons disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinsons disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinsons disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinsons disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinsons disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinsons disease, increases with progression of Parkinsons disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra.

Age-related differences in force variability and visual display

It is well established that older adults are more variable in their force output and that this age-related decrement is mediated by visuomotor processing. The purpose of this investigation was to examine whether the type of visual display impacts age-related differences in the control of force output. In order to address this question, young and old participants produced constant isometric force via index finger abduction to 3 force levels [5, 10, and 20% of their maximal voluntary contraction (MVC)]. Visual feedback was presented with either a compensatory or a pursuit display. A compensatory display provides visual feedback about force amplitude in relation to the criterion target whereas a pursuit display provides visual feedback about the force trajectory in relation to the criterion target and preview of the target path of the force trajectory. The magnitude of force variability was indexed with standard deviation and coefficient of variation. The structure of force output was indexed with spectral slope and approximate entropy. As expected, older adults were more variable and had more structured force output compared to younger adults. Moreover, this age-related difference in force control was paramount in pursuit displays. Overall, the findings suggest that age-related differences in force control are centrally mediated. It is proposed that older adults have deficits in visuomotor processing and this may be partly related to age-related decrements in the control of eye movements.

Free-water imaging in Parkinson’s disease and atypical parkinsonism

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinsons disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinsons disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinsons disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinsons disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinsons disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Comparison of Tests To Detect Oxacillin Resistance in Staphylococcus intermedius, Staphylococcus schleiferi, and Staphylococcus aureus Isolates from Canine Hosts

ABSTRACT Multiple tests were compared to the reference standard PBP2a latex agglutination test for detection of mecA-mediated oxacillin resistance in canine staphylococci. Cefoxitin disk diffusion, using breakpoints for human isolates of coagulase-negative Staphylococcus spp., had low sensitivity for detection of oxacillin resistance in members of the Staphylococcus intermedius group.

Increased free water in the substantia nigra of Parkinson's disease: a single-site and multi-site study

Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinsons disease. It is the case, however, that partial volume effects from free water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free water is elevated in the substantia nigra for Parkinsons disease compared with control subjects. This hypothesis was tested between large cohorts of Parkinsons disease and control participants in a single-site study and validated against a multisite study using multiple scanners. The fractional volume of free water was increased in the posterior region of the substantia nigra in Parkinsons disease compared with control subjects in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water-corrected fractional anisotropy or free-water-corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinsons disease, and this was evidenced across both single-site and multi-site cohorts.

Complexity of force output during static exercise in individuals with Down syndrome

Force variability is greater in individuals with Down syndrome (DS) compared with persons without DS and is similar to that seen with normal aging. The purpose of this study was to examine the structure (in both time and frequency domains) of force output variability in persons with DS to determine whether deficits in force control are similar between individuals with DS and older adults. An isometric handgrip task at a constant force (30% of maximal voluntary contraction) was completed by individuals with DS (n = 29, age 26 yr), and healthy young (n = 26, age 27 yr) and older (n = 33, age 70 yr) individuals. Mean, standard deviation (SD), and coefficient of variation (CV) were used to analyze the magnitude of force output variability. Spectral analysis and approximate entropy (ApEn) were used to analyze the structure of force output variability. Mean force output for DS was lower than in young controls (P < 0.05) but no different from old controls. Individuals with DS had greater SD and CV than young and old controls (P < 0.05). The DS group had a significantly greater proportion of spectral power within the 0-to 4-Hz bandwidth than the young and older controls (P < 0.05). The DS group had significantly lower ApEn values than the young controls (P < 0.05), but there were no differences in ApEn between the DS group and the old controls (P > 0.05). In conclusion, young persons with DS demonstrate enhanced temporal structure and greater amplitude of low-frequency oscillations in the force output signal than age-matched non-DS peers. Interestingly, young persons with DS and older persons without DS have similar time-dependent structure of force output variability. This would suggest a possible link between premature aging and less complex force output in persons with DS.

Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease

The basal ganglia‐thalamo‐cortical and cerebello‐thalamo‐cortical circuits are important for motor control. Whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinsons disease (PD) is not clear. A functional magnetic resonance imaging (fMRI) force production paradigm and voxel‐based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age‐matched controls. We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared with controls and PD. Furthermore, lobules I through IV, V, and VI of the cerebellum are hypoactive in PSP and PD, whereas Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. These patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD.

Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes

Objective: To explore longitudinal changes in brain activity in patients with Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) using task-based functional MRI (fMRI). Methods: A total of 112 individuals were scanned 1 year apart while performing a unimanual grip force task: 46 PD, 13 MSA, 19 PSP, and 34 healthy controls. The outcome measure was percent signal change in prespecified regions of interest: putamen, primary motor cortex (M1), supplementary motor area (SMA), and superior motor regions of the cerebellum (lobules V–VI). Results: Patients with PD showed a decline in functional activity over the course of 1 year in the putamen and M1 compared to controls. Changes after 1 year in MSA were exclusively extrastriatal, and included a reduction in functional activity in M1, SMA, and superior cerebellum. In PSP, all regions of interest were less active at 1 year compared to baseline. The functional activity of these regions did not change in the control group. Conclusions: We provide evidence using task-based fMRI for cortical and striatal functional deterioration in PD over a 1-year period of time. Results also describe more widespread and unique patterns of functional changes in MSA and PSP compared to PD, suggesting distinct rates of disease progression in parkinsonian disorders that may assist in future clinical studies testing the potential efficacy of disease-modifying therapies.

3D Cortical electrophysiology of ballistic upper limb movement in humans

Precise motor control requires the ability to scale the parameters of movement. Theta oscillations across the cortex have been associated with changes in memory, attention, and sensorimotor processing. What has proven more elusive is pinpointing the region-specific frequency band oscillations that are associated with specific parameters of movement during the acceleration and deceleration phases. We report a study using 3D analytic techniques for high density electroencephalography that examines electrocortical dynamics while participants produce upper limb movements to different distances at varying rates. During fast ballistic movements, we observed increased theta band activity in the left motor area contralateral to the moving limb during the acceleration phase of the movement, and theta power correlated with the acceleration of movement. In contrast, beta band activity scaled with the type of movement during the deceleration phase near the end of the movement and correlated with movement time. In the ipsilateral motor and somatosensory area, alpha band activity decreased with the type of movement near the end of the movement, and gamma band activity in visual cortex increased with the type of movement near the end of the movement. Our results suggest that humans use distinct lateralized cortical activity for distance and speed dependent arm movements. We provide new evidence that a temporary increase in theta band power relates to movement acceleration and is important during movement execution. Further, the theta power increase is coupled with desychronization of beta band power and alpha band power which are modulated by the task near the end of movement.

Progression marker of Parkinson's disease: a 4-year multi-site imaging study.

Progression markers of Parkinson’s disease are crucial for therapeutic development. Burciu et al. validate free-water in the substantia nigra as a progression marker at one- and four-year follow-up, in an international cohort of de novo Parkinson’s disease. One-year changes in free-water predict the progression of motor symptoms over four years.