Parkinson's disease: improved function with GM1 ganglioside treatment in a randomized placebo-controlled study.

BACKGROUND/OBJECTIVE: Studies in animal models of Parkinson's disease (PD) suggest that GM1 ganglioside treatment can restore neurologic and dopaminergic function. In view of positive preclinical findings and the results of a previous open-label study demonstrating efficacy of GM1 in PD patients, this study compared effects of GM1 ganglioside and placebo on motor functions in PD patients. METHODS: Forty-five patients with mild to moderate PD were studied. The primary efficacy measure was change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. After three independent baseline assessments, patients received IV infusion of the test drug (1,000 mg GM1 or placebo) and then self-administered either GM1 or placebo twice daily (200 mg/day, subcutaneously) for 16 weeks. Patients were examined during monthly follow-up visits. RESULTS: There was a significant difference between groups in UPDRS motor scores at 16 weeks (p=0.0001). The activities of daily living portion of the UPDRS (off-period assessment) also showed a significant effect in favor of the GM1-treated patients (p=0.04). GM1-treated patients also had significantly greater mean improvements than placebo-treated patients in performance of timed motor tests including tests of arm, hand, and foot movements, and walking. GM1 was well tolerated and no serious adverse events were reported. CONCLUSIONS: This study demonstrates that GM1 ganglioside treatment enhances neurologic function significantly in PD patients. Further study is warranted to evaluate long-term effects of GM1 in PD patients and to elucidate further the mechanisms underlying patient improvements.

Differential localization of class III, beta-tubulin isotype and calbindin-D28k defines distinct neuronal types in the developing human cerebellar cortex.

This immunohistochemical study compares the localization of the neuronal class III beta-tubulin isotype (beta III) to that of calbindin-D28k in 40 human fetal and postnatal cerebella ranging from 12 weeks gestation to adulthood. In the external granule layer of the developing cerebellar cortex, beta III staining was present in the premigratory (postmitotic) zone of horizontal neurons but was absent in "epithelioid" cells of the subpial proliferative mitotic zone. In the molecular layer, intense beta III staining was associated with parallel fibers, stellate/basket neurons and migrating fusiform granule neurons. beta III staining was also present in internal granule neurons. In contrast, beta III was not detectable in fetal and neonatal Purkinje neurons and Golgi II neurons, but was evident in these neurons from juvenile and adult cerebella. Calbindin-D28k staining was present in Purkinje neurons also delineating their somatic spines ("pseudopodia"), lateralizing and apical dendrites (including dendritic spines), subpopulations of small to intermediate-sized Golgi II neurons in the internal granule layer ("synarmotic cells" of Landau), large to medium-sized subcortical Golgi II neurons and neurons of cerebellar roof nuclei, at various gestational stages and postnatally. It was absent in the external granule layer, parallel fibers, stellate/basket and internal granule neurons. Variable degrees of beta III and calbindin-D28k staining were detected in subpopulations of immature neuroepithelial cells of the ventricular matrix at the roof of the fourth ventricle. Glial (including Bergmann glia) and mesenchymal cells were not stained for either antigenic determinants. The differential expression of calbindin-D28k and beta III defines distinct populations of neurons in the developing human cerebellar cortex and supports the ontogenetic concept of Ramon y Cajal.

The clinical management of spasticity.

Spasticity remains a common and challenging problem for patient and practitioner. Understanding of the complex pathophysiology of this disorder, despite recent advances, remains incomplete. Although newer pharmacologic agents and recently introduced technologic procedures have benefited many patients with spasticity, truly safe and effective therapeutic regimens remain elusive. A balanced approach to the problem, utilizing appropriate medication in conjunction with surgical therapy for refractory cases, is warranted. Adjunctive measures, orthopedic intervention and physical therapy modalities, often combined in a multi-disciplinary setting, offer substantial opportunity for a favorable outcome.

A sensory evoked potential comparison of persons 'at risk' for Huntington's disease and hospitalized neurotic patients.

Scalp-recorded sensory evoked potentials (EPs) elicited by left and right median nerve stimulation (LSEP and RSEP), checkerboard pattern flash (VEP) and acoustic click (AEP) were obtained in 22 individuals 'at risk' (AR) for Huntington's disease and 22 hospitalized neurotic patients matched for age, gender and intelligence. EPs of AR subjects were generally similar to those of the neurotic comparison group, in terms of overall configuration; however, mean amplitudes were significantly lower for ARs. While the general amplitude reduction for ARs was seen in all three modalities, the somatosensory modality yielded the most abnormal findings.

A model clinical neuroscience curriculum.

We have attempted to identify those attitudes, skills, and competencies in the clinical neurosciences that every graduating medical student should possess. Curricular guidelines are provided that may act as a model educational outline, to be adapted and utilized as individual circumstances dictate and resources permit. A universal, although not lockstep, curriculum emerges from these considerations.

Relationship between evoked potential and neuropsychological findings in persons "at risk" for Huntington's disease.

Scalp-recorded evoked potentials (EPs) elicited by left and right median nerve stimulation (LSEP and RSEP), checkerboard pattern flash (VEP), and acoustic click (AEP) were obtained in 40 individuals "at risk" (AR) for Huntington's disease (HD) and 40 nonpatients matched for age, sex, and intelligence. EPs of AR subjects were generally similar to those of nonpatient's overall configuration; however, mean amplitudes were significantly lower for ARs. The lower amplitudes tended to occur primarily among a subgroup of ARs who manifested some degree of cognitive change, as defined by neuropsychological test criteria.

Cerebral toxoplasmosis in acquired immune deficiency syndrome.

The clinical course of and pathologic findings in a patient with cerebral toxoplasmosis and acquired immune deficiency syndrome were evaluated. The nonspecificity of CNS signs, symptoms, and laboratory features were noted. Appropriate serologic tests and a biopsy of suspicious cerebral lesions were mandatory for confirmation of the diagnosis and administration of appropriate therapy. The importance of recognizing the nature of this infectious process and of instituting vigorous therapy as promptly as possible was emphasized.

Auditory and visual evoked potentials in Huntington's disease.

Auditory and visual evoked potentials elicited by acoustic click (AEP) and checkerboard pattern flash (VEP) were recorded from 15 locations in 21 patients with Huntington's disease (HD) and 21 controls matched for age and sex. Peak latencies were approximately the same for both groups, except that AEP peak N100 appeared earlier in HDs. The main deviation in HDs consisted of generally reduced amplitude of VEP and AEP components; these deviations can be considered non-specific. Early VEP and AEP peaks contained no specific abnormalities comparable to those found in early somatosensory evoked potentials, as previously reported for the same subjects. VEP and AEP amplitudes were lower in medicated than in unmedicated HD patients, but amplitudes for both medicated and unmedicated HDs deviated from normal. Drugs may act to further diminish the already lower than normal amplitudes in HDs.

Development of neuropsychological deficits in Huntington's disease.

Patients with more recently diagnosed Huntington's disease (RHD) were compared on a neuropsychological test battery with patients who had had the disease one to eight years (moderate HD) and with asymptomatic offspring. Though the patients with HD showed deficits in motor and motor-independent abilities, the patients with RHD were less impaired on factors assessing visuospatial ability, cognitive flexibility, and motor steadiness. Of particular interest was the finding that some asymptomatic offspring showed deficits in visuospatial ability and auditory memory that resembled the deficits of patients with RHD. The findings suggest that deficits in HD do not develop at a uniform rate; deficits in cognitive flexibility occur in later stages of the disease; and visuospatial and auditory memory deficits are very early signs and are present in some asymptomatic offspring.

Cultured fibroblasts in Huntington's disease. I. Effects of L-glutamic acid.

Huntington's disease (HD) is associated with a defect in the CNS that may involve the "glutamine cycle." There is conflicting evidence that other cell types also manifest the abnormality. Thirty HD, 20 "at-risk," and 20 normal cell lines were used in studies of viability, plating efficiency, cell growth "glutamine rescue," and tritiated thymidine and tritiated leucine incorporation in the presence of O to 30mM L-glutamic acid. Cell viability, plating efficiency, and growth were decreased, with increasing glutamic acid concentrations. Tritiated thymidine and tritiated leucine incorporation was slightly affected by glutamic acid. Glutamine rescue was significantly more effective in normal cells than in HD cells. Fibroblasts in HD are a little more sensitive to L-glutamic acid than normal cells.

Cultured fibroblasts in Huntington's disease. II. Effects of glucosamine.

It has been proposed that there is a generalized membrane defect in Huntington's disease (HD) that is expressed in non-neuronal tissue. This membrane abnormality has been linked to a glucosamine dependence of HD cells that can be demonstrated in cultured skin fibroblasts. Twenty HD, "at-risk," and normal cell lines were used in studies of growth, viability, and adhesion in Eagle's Minimum Essential Medium with dialyzed serum or serum separated by a fractionating column (Sephadex G50). The effects of the supplementation of these media with serine, glutamine, glucosamine, and N-acetylglucosamine (0.1mM) on cell growth were determined. The growth of cells in the presence of glucosamine (0mM to 2mM) and N-acetylglucosamine (1mM) was monitored. The HD cells grew slightly better than normal or at-risk cells in the depleted media and attached to the culture surface better. However, the glucosamine dependence of HD cells was not demonstrated.

Somatosensory evoked potentials in Huntington's disease.

Scalp recorded somatosensory evoked potentials (SEPs) elicited by left and right median nerve stimulation were obtained in 21 patients with Huntington's disease (HD), 14 individuals at risk (AR) for HD, and 21 non-patient controls matched for age and sex. Although SEP abnormalities were not uniform in the HD group, no HD patient had SEPs that conformed fully to the normal configuration with respect to peak latencies, presence of all components and spatial distribution. The most common abnormality was non-specific in nature, consisting of amplitude reduction or virtual abscence of components after 100 msec. More specific deviations were noted in the early SEP events. In half of the HD patients, peak P30 seemed to occur at approximately 45 msec poststimulus; this peak could have been taken as the normal P45 had it not reversed in phase between the central and frontal leads. In these cases peak P45 prepared to be missing. Peak N20 latency values were longer in the HD group than in the non-patient controls, whereas the P15 latencies did not differ significantly. The conduction time between P15 and N20 was significantly longer in HD patients than the non-patient controls. SEPs of the majority of the ARs were similar to those of the non-patients controls in terms of overall configuration, although mean amplitudes were generally lower for ARs than non-patient controls and 4 ARs exhibited prolonged P15-N20 latency differences.