Guangwei Du

Combined R2* and Diffusion Tensor Imaging Changes in the Substantia Nigra in Parkinson's Disease†‡

Recent magnetic resonance imaging studies suggest an increased transverse relaxation rate and reduced diffusion tensor imaging fractional anisotropy values in the substantia nigra in Parkinsons disease. The transverse relaxation rate and fractional anisotropy changes may reflect different aspects of Parkinsons disease‐related pathological processes (ie, tissue iron deposition and microstructure disorganization). This study investigated the combined changes of transverse relaxation rate and fractional anisotropy in the substantia nigra in Parkinsons disease. High‐resolution magnetic resonance imaging (T2‐weighted, T2*, and diffusion tensor imaging) were obtained from 16 Parkinsons disease patients and 16 controls. Bilateral substantia nigras were delineated manually on T2‐weighted images and coregistered to transverse relaxation rate and fractional anisotropy maps. The mean transverse relaxation rate and fractional anisotropy values in each substantia nigra were then calculated and compared between Parkinsons disease subjects and controls. Logistic regression, followed by receiver operating characteristic curve analysis, was employed to investigate the sensitivity and specificity of the combined measures for differentiating Parkinsons disease subjects from controls. Compared with controls, Parkinsons disease subjects demonstrated increased transverse relaxation rate (P < .0001) and reduced fractional anisotropy (P = .0365) in the substantia nigra. There was no significant correlation between transverse relaxation rate and fractional anisotropy values. Logistic regression analyses indicated that the combined use of transverse relaxation rate and fractional anisotropy values provides excellent discrimination between Parkinsons disease subjects and controls (c‐statistic = 0.996) compared with transverse relaxation rate (c‐statistic = 0.930) or fractional anisotropy (c‐statistic = 0.742) alone. This study shows that the combined use of transverse relaxation rate and fractional anisotropy measures in the substantia nigra of Parkinsons disease enhances sensitivity and specificity in differentiating Parkinsons disease from controls. Further studies are warranted to evaluate the pathophysiological correlations of these magnetic resonance imaging measurements and their effectiveness in assisting in diagnosing Parkinsons disease and following its progression.

Differential involvement of striato- and cerebello-thalamo-cortical pathways in tremor- and akinetic/rigid-predominant Parkinson's disease

Parkinsons disease (PD) presents clinically with varying degrees of resting tremor, rigidity, and bradykinesia. For decades, striatal-thalamo-cortical (STC) dysfunction has been implied in bradykinesia and rigidity, but does not explain resting tremor in PD. To understand the roles of cerebello-thalamo-cortical (CTC) and STC circuits in the pathophysiology of the heterogeneous clinical presentation of PD, we collected functional magnetic resonance imaging (fMRI) data from 17 right-handed PD patients [nine tremor predominant (PDT) and eight akinetic-rigidity predominant (PDAR)] and 14 right-handed controls while they performed internally-guided (IG) sequential finger tapping tasks. The percentage of voxels activated in regions constituting the STC and CTC [divided as cerebellar hemisphere-thalamo-cortical (CHTC) and vermis-thalamo-cortical (CVTC)] circuits was calculated. Multivariate analysis of variance compared the activation patterns of these circuits between study groups. Compared to controls, both PDAR and PDT subjects displayed an overall increase in the percentage of voxels activated in both STC and CTC circuits. These increases reached statistical significance in contralateral STC and CTC circuits for PDT subjects, and in contralateral CTC pathways for PDAR subjects. Comparison of PDAR and PDT subjects revealed significant differences in ipsilateral STC (P=0.005) and CTC (P=0.043 for CHTC and P=0.003 for CVTC) circuits. These data support the differential involvement of STC and CTC circuits in PD subtypes, and help explain the heterogeneous presentation of PD symptoms. These findings underscore the importance of integrating CTC circuits in understanding PD and other disorders of the basal ganglia.

Imaging nigral pathology and clinical progression in Parkinson's disease

The pattern of dopamine cell loss in Parkinsons disease (PD) is known to be prominent in the ventrolateral and caudal substantia nigra (SN), but less severe in the dorsal and rostral region. Both diffusion tensor imaging (DTI) and R2* relaxometry of the SN have been reported as potential markers for PD, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. High‐resolution T2‐weighted, R2*, and DTI were obtained from 28 controls and 40 PD subjects [15 early stage [disease duration ≤1 year], 14 mid stage [duration 2–5 years], and 11 late stage [duration >5 years]). Fractional anisotropy and R2* values in both rostral and caudal SN were obtained for all subjects, and clinical measures (e.g., disease duration, levodopa‐equivalent daily dosage, and “off”‐drug UPDRS motor score) were obtained for Parkinsons subjects. There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal SN was significantly decreased in PD patients of all stages, whereas in rostral SN, it was decreased significantly only in the late‐stage group. R2* in both SN regions was significantly increased in the mid‐ and late‐stage, but not early‐stage, of PD subjects. These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal SN, whereas the changes in R2* may more closely track PDs clinical progression after symptom onset.

Quantitative susceptibility mapping of the midbrain in Parkinson's disease

Parkinsons disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD.

Both coordination and symmetry of arm swing are reduced in Parkinson's disease

OBJECTIVEnA recent study reporting significantly reduced symmetry in arm swing amplitude in early Parkinsons disease (PD), as measured during single strides in a gait laboratory, led to this investigation of arm swing symmetry and coordination over many strides using wearable accelerometers in PD.nnnMETHODSnForearm accelerations were recorded while eight early PD subjects and eight Controls performed 8-min walking trials. Arm swing asymmetry (ASA), maximal cross-correlation (MXC), and instantaneous relative phase (IRP) of bilateral arm swing were compared between PD and Controls. Correlations between arm swing measurements (ASA and MXC) and Unified PD Rating Scale (UPDRS) scores were estimated.nnnRESULTSnPD subjects demonstrated significantly higher ASA (p=0.002) and lower MXC (p<0.001) than Controls. The IRP probability distribution for PD was significantly different than Controls (p<0.001), with an angular standard deviation of 67.2° for PD and 50.6° for Controls. Among PD subjects, ASA was significantly correlated with the UPDRS score for the limbs (R(2)=0.58, p=0.049), whereas MXC was significantly correlated with the tremor subscore of the limbs (R(2)=0.64, p=0.031).nnnDISCUSSIONnThe study confirms previously reported higher arm swing asymmetry in PD but also shows there is significantly lower MXC and greater IRP variability, suggesting that reduction in bilateral arm coordination may contribute to clinically observed asymmetry in PD. The differential correlation of clinical measures of motor disability with measurements of arm swing during gait is intriguing and deserves further investigation.

Manganese accumulation in the olfactory bulbs and other brain regions of "asymptomatic" welders.

Welding-generated metallic fumes contain a substantial amount of manganese (Mn), making welders susceptible to Mn toxicity. Although overt Mn toxicity manifests as a type of parkinsonism, the consequences of chronic, low-level Mn exposure are unknown. To explore region-specific Mn accumulation and its potential functional consequences at subclinical levels of Mn exposure, we studied seven welders without obvious neurological deficits and seven age- and gender-matched controls. Mn exposure for welders was estimated by an occupational questionnaire. High-resolution brain magnetic resonance imaging (MRI), Grooved Pegboard performance of both hands, Trail making, and olfactory function tests were obtained from all subjects. Compared with controls, the welders had a significantly higher T1 relaxation rate (R1) in the olfactory bulb (OB, p = 0.02), mean T1-weighted intensity at frontal white matter (FWM; p = 0.01), bilateral globus pallidus (GP; p = 0.03), and putamen (p = 0.03). The welders scored worse than the controls on the Grooved Pegboard test for both dominant (p = 0.06) and nondominant hand (p = 0.03). The dominant hand Grooved Pegboard scores correlated best with mean MRI intensity of FWM (R² = 0.51, p = 0.004), GP (R² = 0.51, p = 0.004), putamen (R² = 0.49, p= 0.006), and frontal gray matter (R² = 0.42, p = 0.01), whereas the nondominant hand scores correlated best with intensity of FWM (R² = 0.37, p = 0.02) and GP (R² = 0.28, p = 0.05). No statistical differences were observed in either the Trail-making test or the olfactory test between the two groups. This study suggests that Mn accumulates in OB and multiple other brain regions in asymptomatic welders and that MRI abnormalities correlate with fine motor but not cognitive deficits. Further investigations of subclinical Mn exposure are warranted.

Striatal shape in Parkinson's disease

Parkinsons disease (PD) is marked pathologically by nigrostriatal dopaminergic terminal loss. Histopathological and in vivo labeling studies demonstrate that this loss occurs most extensively in the caudal putamen and caudate head. Previous structural studies have suggested reduced striatal volume and atrophy of the caudate head in PD subjects. The spatial distribution of atrophy in the putamen, however, has not been characterized. We aimed to delineate the specific locations of atrophy in both of these striatal structures. T1- and T2-weighted brain MR (3T) images were obtained from 40 PD and 40 control subjects having no dementia and similar age and gender distributions. Shape analysis was performed using doubly segmented regions of interest. Compared to controls, PD subjects had lower putamen (p = 0.0003) and caudate (p = 0.0003) volumes. Surface contraction magnitudes were greatest on the caudal putamen (p ≤ 0.005) and head and dorsal body of the caudate (p ≤ 0.005). This spatial distribution of striatal atrophy is consistent with the known pattern of dopamine depletion in PD and may reflect global consequences of known cellular remodeling phenomena.

Multi-atlas segmentation of subcortical brain structures via the AutoSeg software pipeline

Automated segmenting and labeling of individual brain anatomical regions, in MRI are challenging, due to the issue of individual structural variability. Although atlas-based segmentation has shown its potential for both tissue and structure segmentation, due to the inherent natural variability as well as disease-related changes in MR appearance, a single atlas image is often inappropriate to represent the full population of datasets processed in a given neuroimaging study. As an alternative for the case of single atlas segmentation, the use of multiple atlases alongside label fusion techniques has been introduced using a set of individual “atlases” that encompasses the expected variability in the studied population. In our study, we proposed a multi-atlas segmentation scheme with a novel graph-based atlas selection technique. We first paired and co-registered all atlases and the subject MR scans. A directed graph with edge weights based on intensity and shape similarity between all MR scans is then computed. The set of neighboring templates is selected via clustering of the graph. Finally, weighted majority voting is employed to create the final segmentation over the selected atlases. This multi-atlas segmentation scheme is used to extend a single-atlas-based segmentation toolkit entitled AutoSeg, which is an open-source, extensible C++ based software pipeline employing BatchMake for its pipeline scripting, developed at the Neuro Image Research and Analysis Laboratories of the University of North Carolina at Chapel Hill. AutoSeg performs N4 intensity inhomogeneity correction, rigid registration to a common template space, automated brain tissue classification based skull-stripping, and the multi-atlas segmentation. The multi-atlas-based AutoSeg has been evaluated on subcortical structure segmentation with a testing dataset of 20 adult brain MRI scans and 15 atlas MRI scans. The AutoSeg achieved mean Dice coefficients of 81.73% for the subcortical structures.

Early cortical gray matter loss and cognitive correlates in non-demented Parkinson's patients

BACKGROUNDnWhereas the motor dysfunction in Parkinsons disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss.nnnMETHODSnHigh-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences.nnnRESULTSnPD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients.nnnCONCLUSIONSnNon-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized frontal lobe function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD.

Higher iron in the red nucleus marks Parkinson's dyskinesia

Dopamine cell loss and increased iron in the substantia nigra (SN) characterize Parkinsons disease (PD), with cerebellar involvement increasingly recognized, particularly in motor compensation and levodopa-induced dyskinesia (LID) development. Because the red nucleus (RN) mediates cerebellar circuitry, we hypothesized that RN iron changes might reflect cerebellum-related compensation, and/or the intrinsic capacity for LID development. We acquired high resolution magnetic resonance images from 23 control and 38 PD subjects (12 with PD and history of LID [PD+DYS]) and 26 with PD and no history of LID (PD-DYS). Iron content was estimated from bilateral RN and SN transverse relaxation rates (R2*). PD subjects overall displayed higher R2* values in both the SN and RN. RN R2* values correlated with off-drug Unified Parkinsons Disease Rating Scale-motor scores, but not disease duration or drug dosage. RN R2* values were significantly higher in PD+DYS compared with control and PD-DYS subjects; control and PD-DYS subjects did not differ. The association of higher RN iron content with PD-related dyskinesia suggests increased iron content is involved in, or reflects, greater cerebellar compensatory capacity and thus increased likelihood of LID development.