Mechelle M. Lewis

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

OPC-14597 {aripiprazole; 7-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)butyloxy)-3,4-dihydro-2(1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest affinity for D2L and D2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D2L receptors, although the metabolite DM-1451 behaved as a pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D2L/D2S rather than D3 or D4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D2) in distinct cellular locales.

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.

Changes in multifinger interaction and coordination in Parkinson's disease.

In this study, we tested several hypotheses related to changes in finger interaction and multifinger synergies during multifinger force production tasks in Parkinsons disease. Ten patients with Parkinsons disease, mostly early stage, and 11 healthy control subjects participated in the study. Synergies were defined as covaried adjustment of commands to fingers that stabilized the total force produced by the hand. Both Parkinsons disease patients and control subjects performed accurate isometric force production tasks with the fingers of both the dominant and nondominant hands. The Parkinsons disease patients showed significantly lower maximal finger forces and higher unintended force production (enslaving). These observations suggest that changes in supraspinal control have a major effect on finger individuation. The synergy indexes in the patients were weaker in both steady-state and cyclic force production tasks compared with the controls. These indexes also were stronger in the left (nondominant) hand in support of the dynamic-dominance hypothesis. Half of the patients could not perform the cyclic task at the highest frequency (2 Hz). Anticipatory adjustments of synergies prior to a quick force pulse production were delayed and reduced in the patients compared with the controls. Similar differences were observed between the asymptomatic hands of the patients with symptoms limited to one side of the body and matched hands of control subjects. Our study demonstrates that the elusive changes in motor coordination in Parkinsons disease can be quantified objectively, even in patients at a relatively early stage of the disease. The results suggest an important role of the basal ganglia in synergy formation and demonstrate a previously unknown component of impaired feedforward control in Parkinsons disease reflected in the reduced and delayed anticipatory synergy adjustments.

Shape (but not volume) changes in the thalami in Parkinson disease

BackgroundRecent pathological studies have suggested that thalamic degeneration may represent a site of non-dopaminergic degeneration in Parkinsons Disease (PD). Our objective was to determine if changes in the thalami could be non-invasively detected in structural MRI images obtained from subjects with Parkinson disease (PD), compared to age-matched controls.ResultsNo significant differences in volume were detected in the thalami between eighteen normal subjects and eighteen PD subjects groups. However significant (p < 0.03) shape differences were detected between the Left vs. Right thalami in PD, between the left thalami in PD and controls, and between the right thalami in PD and controls using a recently-developed, spherical harmonic-based representation.ConclusionSystematic changes in thalamic shape can be non-invasively assessed in PD in vivo. Shape changes, in addition to volume changes, may represent a new avenue to assess the progress of neurodegenerative processes. Although not directly discernable at the resolution of standard MRI, previous pathological studies would suggest that the shape changes detected in this study represent degeneration in the centre median-parafascicular (CM-Pf) complex, an area known to represent selective non-dopaminergic degeneration in PD.

Dynamic changes in cerebello-thalamo-cortical motor circuitry during progression of Parkinson's disease.

Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinsons disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI 2 years apart from 5 PD (57+/-8 yr) and five Controls (57+/-9 yr) performing either externally- (EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the mean of the dominant and non-dominant hands of Controls. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD.

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

OBJECTIVE A 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. METHODS Forearm 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. RESULTS PD 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). DISCUSSION The 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.

D1 dopamine receptors.

Publisher Summary This chapter provides an overview of the role of the Dl-like dopamine receptors in nervous system function. The goal is to provide a broader, integrated overview that relates the structure and function of these interesting receptors to how the D1 receptors may interact with human neurological and psychiatric diseases. The peripheral actions of Dl-like receptors are beginning to be understood, and the actions of drugs on Dl-like receptors in the vasculature, heart, kidney, lung, etc., are of both generic physiological interests, as well as of therapeutic importance for direct actions or as side effects of CNS targeted effects. Although many of the elegant studies have led to a greater understanding of the role of Dl-like receptors in processes such as movement, memory, and cognition, the contribution of these receptors in other functional areas is less well understood. Selective agonists and antagonists for the D 1 and D 5 receptors are extremely important research tools and have specific therapeutic niches. Some D1 agonists such as A77636 and A68390 produce rapid behavioral desensitization when administered to either animals or people. The roles of D1 like receptors in both normal nervous systems function, as well as in a variety of neurological and psychiatric disorders, yield modern molecular, cellular, and imaging approaches.