Biomedical subjects

G T Stebbins

Publications and source records attributed to G T Stebbins.

At least 19 recordsLinked to original sources

PubMed2004

Altered cortical visual processing in PD with hallucinations: an fMRI study.

OBJECTIVE: To compare fMRI activation during two visual stimulation paradigms in Parkinson disease (PD) subjects with chronic visual hallucinations vs PD patients who had never hallucinated. METHODS: Twelve pairs of PD subjects, matched for age, PD duration, and dopaminergic drug exposure duration, participated in this study. The authors examined group differences in activation during stroboscopic (flashing) vs no visual stimulation and kinematic (apparent motion) vs stationary visual stimulation. RESULTS: During stroboscopic stimulation, non-hallucinating PD subjects showed significantly greater activation in the parietal lobe and cingulate gyrus compared to hallucinating PD subjects. In contrast, the hallucinating subjects showed significantly greater activation in the inferior frontal gyrus and the caudate nucleus. During kinematic stimulation, non-hallucinating PD subjects showed significantly greater activation in area V5/MT, parietal lobe, and cingulate gyrus compared to hallucinating PD subjects. Hallucinating PD subjects showed significantly greater activation in the superior frontal gyrus. CONCLUSIONS: PD patients with chronic visual hallucinations respond to visual stimuli with greater frontal and subcortical activation and less visual cortical activation than non-hallucinating PD subjects. Shifting visual circuitry from posterior to anterior regions associated primarily with attention processes suggests altered network organization may play a role in the pathophysiology of visual hallucinations in PD.

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PubMed2001

Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys.

Systemic administration of immunophilin ligands provides trophic influences to dopaminergic neurons in rodent models of Parkinson's disease (PD) resulting in the initiation of clinical trials in patients with Parkinson's disease. We believe that prior to clinical trials, novel therapeutic strategies should show safety and efficacy in nonhuman models of PD. The present study assessed whether oral administration of the immunophilin 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrollidinecarboxylate (GPI 1046) could prevent the structural and functional consequences of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in nonhuman primates. Twenty-five rhesus monkeys received daily oral administration of vehicle (n = 5) or one of four doses of GPI 1046 (0.3 mg/kg, n = 5; 1.0 mg/kg, n = 5; 3.0 mg/kg, n = 5; 10.0 mg/kg, n = 5). Two weeks after starting the drug treatment, all monkeys received a unilateral intracarotid injection of MPTP-HCl (3 mg). Daily drug administration continue for 6 weeks postlesion after which time the monkeys were sacrificed. Monkeys were assessed for performance on a hand reach task, general activity, and clinical dysfunction based on a clinical rating scale. All groups of monkeys displayed similar deficits on each behavioral measure as well as similar losses of tyrosine hydroxylase (TH)-immunoreactive (ir) nigral neurons, TH-mRNA, and TH-ir striatal optical density indicating that in general treatment failed to have neuroprotective effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment.

Layer II of the entorhinal cortex contains the cells of origin for the perforant path, plays a critical role in memory processing, and consistently degenerates in end-stage Alzheimer's disease. The extent to which neuron loss in layer II of entorhinal cortex is related to mild cognitive impairment without dementia has not been extensively investigated. We analyzed 29 participants who came to autopsy from our ongoing longitudinal study of aging and dementia composed of religious clergy (Religious Orders Study). All individuals underwent detailed clinical evaluation within 12 months of death and were categorized as having no cognitive impairment (n = 8), mild cognitive impairment (n = 10), or mild or moderate Alzheimer's disease (n = 11). Sections through the entorhinal cortex were immunoreacted with an antibody directed against a neuron-specific nuclear protein (NeuN). Stereological counts of NeuN-immunoreactive stellate cells, their volume, and the volume of layer II entorhinal cortex were estimated. Cases exhibiting no cognitive impairment averaged 639,625 +/- 184,600 layer II stellate neurons in the right entorhinal cortex. Individuals with mild cognitive impairment (63.5%; p < 0.0003) and mild or moderate Alzheimer's disease (46.06%; p < 0.0017) displayed significant losses of layer II entorhinal cortex neurons relative to those with no cognitive impairment but not relative to each other (p > 0.33). There was also significant atrophy of layer II entorhinal cortex neurons in individuals with mild cognitive impairment (24.1%) and Alzheimer's disease (25.1%). The volume of layer II was also reduced in individuals with mild cognitive impairment (26.5%), with a further reduction in those with Alzheimer's disease (46.4%). The loss and atrophy of layer II entorhinal cortex neurons significantly correlated with performance on clinical tests of declarative memory. Atrophy of layer II entorhinal cortex and the neurons within this layer significantly correlated with performance on the Mini Mental Status Examination. These data indicate that atrophy and loss of layer II entorhinal cortex neurons occur in elderly subjects with mild cognitive impairment prior to the onset of dementia and suggests that these changes are not exacerbated in early Alzheimer's disease.

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PubMed2000

Objective changes in motor function during placebo treatment in PD.

OBJECTIVE: To examine the frequency, temporal development, and stability of objectively derived motor changes during placebo treatment in PD and to define the clinical domains and demographic groups most affected. BACKGROUND: Placebo effects are documented in neurology, but the timing and specific disabilities most susceptible to changes during placebo treatment in PD have not been examined. METHODS: The authors examined the placebo-treated group from a randomized, multicenter, placebo-controlled clinical trial of monotherapy ropinerole in PD patients without motor fluctuations. In 105 patients, they evaluated placebo-associated effects on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS), dividing the motor examination into four categories: tremor, bradykinesia, rigidity, and gait/balance/midline functions. The motor UPDRS and its subscales were compared over time (at baseline and at 4, 12, and 24 weeks) using Wilcoxon's signed rank test. They applied a rigorous definition of placebo-associated improvement as an improvement over baseline score in motor UPDRS of at least 50% or a change in at least two motor items at any one visit by > or =2 points. RESULTS: During the 6-month study, 16% of subjects improved on placebo treatment. The prevalence of response was steady (8 to 9%) at any one visit without a predominance of an early effect. No patient showed a placebo-associated improvement on all visits. All domains of parkinsonian disability were subject to placebo-associated improvement, with a trend toward more response in bradykinesia and rigidity than in tremor or gait/balance/midline function. Gender, age, disease duration, and baseline disability score did not influence the likelihood of improvement in association with placebo treatment. CONCLUSION: Based on a rigorous definition of placebo-associated improvement, prominent improvements in objective measures of PD disability occur during clinical trials. Because placebo-associated improvements occur throughout a 6-month trial, placebo-controlled studies in PD should be at least 6 months to capture early as well as late improvements.

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PubMed2000

Application of the Unified Parkinson's Disease Rating Scale in progressive supranuclear palsy: factor analysis of the motor scale.

An important criterion in scale validation is the demonstration of a stable factor structure. The Unified Parkinson's Disease Rating Scale (UPDRS) is widely used to assess Parkinson's disease (PD). The reliability and applicability of the motor subscale of the UPDRS (UPDRSm) when applied to patients diagnosed with progressive supranuclear palsy (PSP) is unknown. In a sample of 175 patients with PSP, factor analysis revealed five clinically distinct factors: two independent bradykinesia factors (axial/gait and extremities), one rigidity factor, and two independent tremor factors (rest and action). Two items (posture and rest head tremor) did not reach criteria for factor loadings. There was a high degree of internal consistency. These results suggest that UPDRSm is a reliable and applicable scale for assessing most aspects of PSP function as well as severity measures of five clinical disability domains.

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PubMed2000

Differential progression of motor impairment in levodopa-treated Parkinson's disease.

OBJECTIVE: To monitor comparative progression of clinical impairment over 4 years in patients with Parkinson's disease (PD) who present on levodopa at two different levels of Hoehn and Yahr (HY) stages, II and III. BACKGROUND: The rate of clinical impairment progression in patients with PD being treated with levodopa has not been studied in detail using current, standardized assessment tools. Sample size estimates for all levodopa adjunctive treatment studies and proper definition of study groups require a solid estimate of longitudinal motor impairment progression. DESIGN/METHODS: From our computer database, we identified two groups of patients with PD being treated with levodopa based on their initial HY stage at presentation to our center (II or III). Fifty randomly selected subjects in each stage were monitored in the ON state with annual Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, dyskinesia ratings, and antiparkinsonian medication doses using a repeated measures analysis of variance. RESULTS: The stage II and stage III subjects had similar disease duration. In stage II subjects, parkinsonian impairment was maintained without progression over 4 years, but in association with significantly higher dyskinesia scores and dopaminergic medication doses. In stage III subjects, UPDRS motor scores deteriorated despite more medication and increased dyskinesias. Of the established six factors comprising the UPDRS motor scale, bradykinesia accounted for the increased impairment. Initial UPDRS motor score and disease duration did not influence progression of motor impairment. CONCLUSION: In subjects with similar disease duration, progression of PD motor impairment differs significantly between stage II and stage III subjects over 4 years. Whereas in stage II subjects, parkinsonian impairment can be stabilized at the expense of increased dyskinesia and dopaminergic drugs, once subjects reach stage III, motor impairment progresses. Power estimates and sample size calculations for these groups of patients should be calculated separately.

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PubMed2000

Impaired frontostriatal cognitive functioning following posteroventral pallidotomy in advanced Parkinson's disease.

We investigated the long-term effects of posteroventral pallidotomy on tests sensitive to the functional integrity of frontostriatal neural systems in a sample of 11 patients with advanced Parkinson's disease (PD). Patients were assessed within 1 month prior to surgery and at 12 months following pallidotomy. Changes in outcome measures were compared to a control sample of equally performing PD patients receiving nonsurgical medical management assessed over a 12-month period. Measures of cognitive abilities sensitive to frontostriatal functional integrity tested psychomotor processing speed, executive components of working memory, and reasoning. Additional tests of general mental status and semantic memory ability were utilized to assess the specificity of the effect of pallidotomy on cognitive function. Significant declines in performance on all measures sensitive to frontostriatal integrity were found for the surgery group but not the PD control group. No significant changes in performance were found on the measures of general mental status or semantic memory for either the surgery or PD control samples. These results suggest that the posteroventral pallidotomy selectively impairs performance on tests of frontostriatal cognitive abilities.

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PubMed1999

Switching dopamine agonists in advanced Parkinson's disease: is rapid titration preferable to slow?

BACKGROUND: New dopamine agonists are available, but no study has examined safe and effective ways to switch from one agonist to another. OBJECTIVE: To compare rapid- versus slow-titration schedules for starting a new dopamine agonist in patients already on chronic agonist therapy for Parkinson's disease. METHODS: Sixteen patients on stable carbidopa/levodopa and a dopamine agonist (bromocriptine or pergolide) switched to pramipexole using a conversion calculation of 1:1 for pergolide dose and 10:1 for bromocriptine dose. Patients were randomized to two titration schedules-either slow titration, following the package insert and taking up to 8 weeks to reach their equivalent dosage (8 patients), or rapid titration, receiving the full converted dose the day after stopping the former agonist (8 patients) with subsequent weekly dose adjustments. Using a blinded observer, the primary outcome variable was the time required to a Unified Parkinson's Disease Rating Scale (UPDRS) motor score superior to baseline without increased adverse effects. RESULTS: Both groups showed equivalent and statistically significant improvement after switching to the new agonist. The mean time to reach a UPDRS score that was superior to baseline without increased adverse effects was significantly shorter in the rapid-titration group (mean 2.1 weeks versus 5.3 weeks). Furthermore, with slow titration two patients experienced enhanced parkinsonian serious adverse effects requiring hospitalization (two falls with fractures). CONCLUSION: The switchover from one agonist to another can be safely and successfully accomplished with a rapid titration based on an equivalency dose calculation.

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PubMed1999

Factor analysis of the motor section of the unified Parkinson's disease rating scale during the off-state.

Determination of a scale's factor structure requires a two-part process: (1) an initial examination of the factor structure using a sample of individuals with the condition of interest, and (2) repeated examinations of the factor structure using the same analytic methods but applied to independent samples of individuals with the condition of interest who contribute unique variability to the scale measurement. In a previous study, we performed an initial investigation of the factor structure of the Motor Examination section of the Unified Parkinson's Disease Rating Scale (UPDRS). We used a sample of 294 consecutive patients with idiopathic Parkinson's disease (PD) assessed while in the on-state and identified six clinically distinct factors. In the present study, we performed a confirmatory investigation of the factor structure and analysis of the internal consistency of the UPDRS in a new sample of 200 consecutive PD patients who were assessed while in the off-state. Factor analysis again revealed six factors with identical item loadings as those obtained from examinations of patients in the on-state. Estimates of internal consistency were comparable in the off- and on-state examinations. These results indicate that the Motor Examination section of the UPDRS has a stable factor structure and high internal consistency across off- and on-state examinations.

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PubMed1999

Delayed recognition memory in Parkinson's disease: a role for working memory?

Immediate and delayed recognition memory for words was examined in a sample of 16 non-demented patients with Parkinson's disease and 16 normal control participants of equivalent age and educational attainment. The patients, relative to control participants, had intact immediate but impaired delayed recognition memory performance. Patients were also impaired on tests of free and cued recall, working memory and a measure of psychomotor processing speed. Processing speed was a significant covariate for delayed recognition, free and cued recall and working memory performance, but not for immediate recognition performance. These results suggest that the same cognitive processes which support performance on tests of recall and working memory also support performance on tests of delayed recognition.

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PubMed1998

5-Hydroxytryptophan-induced myoclonus in guinea pigs: mediation through 5-HT1/2 receptor subtypes.

In guinea pigs, myoclonus can be induced by 5-hydroxytryptamine (5-HT, serotonin) precursors and synthetic 5-HT receptor agonists, yet the receptor subtype specificity of this behavior is not fully delineated. Guinea pigs were pre-treated with carbidopa (50 mg) followed by one of eight 5-HT antagonists: (-)-N-tert-butyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenyl propionamide ((-)-WAY 100135) (5-HT1A), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridyl)-cy clohexancarboxamide (WAY 100635) (5-HT1A), methiothepin mesylate (5-HT1/2), mesulergine hydrochloride (5-HT2A/2C), N[4-methoxy-3-(4-methyl-L-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadizol-3-yl) (GR 127935) (5-HT1D), trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorop hen yl) propen-1-yl]phenol, hemifumarate (SR 46349) (5-HT2), ondansetron hydrochloride (5-HT3), and [1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-5-fluoro-2-meth oxy-1H-indole-3-carboxylate (GR 125487) (5-HT4). Thirty minutes later, they received 5-hydroxytryptophan (5-HTP) (75 mg/kg, sc) and myoclonic jumping rates were assessed every 10 min for 200 min by a blinded observer. Repeated measures analysis of variance of drug-induced antagonism of 5-HTP-induced myoclonus revealed a significant effect for the 5-HT receptor antagonists methiothepin mesylate, GR127935, and mesulergine hydrochloride compared to placebo, and each of these drugs inhibited 5-HTP-induced myoclonus in a dose-dependent fashion. Based on the receptor profiles of the three effective antagonists, 5-HTP-induced myoclonus is influenced by the 5-HT1/2 receptor systems. The absence of a significant change with any other receptor subtype antagonist suggests that myoclonus is not related to diffuse activation of central serotonergic mechanisms.

Animals↗

PubMed1998

The effect of changes in head posture on the patterns of muscle activity in cervical dystonia (CD).

Twelve patients with cervical dystonia (CD) and predominant rotation were studied to determine the effects of changes in head posture on the specific patterns of cervical muscle activity. Turns analysis was used to quantify muscle activity underlying head rotation, recorded simultaneously from the agonist and antagonist muscle pairs bilaterally (sternocleidomastoid [SCM] and splenius [SPL]). Muscle activity was compared between the uncompensated dystonic posture and during the maintenance of midposition. In addition, patients were separated into two groups (geste = 6; no geste = 6) based on whether they had a clinically efficacious geste to determine the effect of geste on patterns of cervical muscle activity. Muscle activity was measured during the maintenance of midposition with and without a clinical or simulated geste. Differences in muscle activity between the groups and postures were compared using repeated measure analysis of variance (ANOVA) analyses. The four muscles tested showed a significant difference in muscle activity in the uncompensated dystonic posture as a result of the increased activity in the agonist muscle pair (SCM and SPL responsible for the dystonic posture) (EMG amplitude: F[1,11] = 18.81, p = 0.0012; EMG frequency: F[1,11] = 32.07, p = 0.0001). Maintaining the head in the midposition was associated with a significant reduction in muscle activity compared with the uncompensated dystonic posture (EMG amplitude: F[1,9] = 6.36, p < 0.033; EMG frequency: F[1,9] = 10.96, p < 0.0091). This reduction in midposition muscle activity was significantly greater in the agonist muscle pair (EMG amplitude: F[1,10] = 19.70, p = 0.0013; EMG frequency: F[1,10] = 44.67, p < 0.0001). In the patients with clinically effective geste, there was no additional reduction in muscle activity observed in the midposition when they performed their geste (EMG amplitude: F[1,9] = 4.63, p = 0.060; EMG frequency: F[1,9] = 1.22, p = 0.298). These findings suggest that CD with rotation is characterized by predominantly increased agonist muscle activation. Patients with CD retain the ability to modulate this involuntary agonist muscle activity to maintain the head in the midposition. The maintenance of the midposition does not seem to be facilitated by geste.

Adult↗

PubMed1998

Factor structure of the Unified Parkinson's Disease Rating Scale: Motor Examination section.

The Unified Parkinson's Disease Rating Scale (UPDRS) is widely used to assess Parkinson's disease (PD) disability but its metric properties have not been extensively studied. We investigated the factor structure and internal consistency of the Motor Examination section of the UPDRS in a sample of 294 consecutive patients with idiopathic PD who were assessed while in the "on" state. There was a high degree of internal consistency. Factor analysis revealed six clinically distinct factors, three bradykinesia measures (axial/gait, right and left), one rigidity measure, and two tremor measures (rest and postural). These factors accounted for 78% of the variance. Total Motor Examination scores and selected factors correlated well with other examiner-determined global ratings of PD disability (Hoehn and Yahr stage and Schwab-England Activities of Daily Living score). These results suggest that the Motor Examination section of the UPDRS provides a useful measure of PD function as well as severity measures of six clinical disability domains.

Activities of Daily Living↗

PubMed1998

Neuropsychological dissociation between recognition familiarity and perceptual priming in visual long-term memory.

The present study examined whether the same brain region mediates visual-perceptual repetition priming and a familiarity component of visual recognition memory. In two experiments, familiarity-based recognition was measured in an individual (M.S.) with impaired visual repetition priming due to a lesion of right occipital cortex. In both experiments, M.S. demonstrated intact recognition familiarity despite his visual nondeclarative memory impairment. These results converge with other behavioral results to indicate that recognition familiarity does not depend on the same memory system that mediates perceptual priming.

Adult↗

PubMed1998

Working and strategic memory deficits in schizophrenia.

Working memory and its contribution to performance on strategic memory tests in schizophrenia were studied. Patients (n = 18) and control participants (n = 15), all men, received tests of immediate memory (forward digit span), working memory (listening, computation, and backward digit span), and long-term strategic (free recall, temporal order, and self-ordered pointing) and nonstrategic (recognition) memory. Schizophrenia patients performed worse on all tests. Education, verbal intelligence, and immediate memory capacity did not account for deficits in working memory in schizophrenia patients. Reduced working memory capacity accounted for group differences in strategic memory but not in recognition memory. Working memory impairment may be central to the profile of impaired cognitive performance in schizophrenia and is consistent with hypothesized frontal lobe dysfunction associated with this disease. Additional medial-temporal dysfunction may account for the recognition memory deficit.

Adult↗

PubMed1998

Intravenous levodopa in hallucinating Parkinson's disease patients: high-dose challenge does not precipitate hallucinations.

In five nondemented Parkinson's disease patients with daily visual hallucinations, we tested whether high-dose IV levodopa (LD) infusions precipitated hallucinations. Two infusion paradigms were studied, each with 1.5-mg/kg hourly dose for 4 hours--steady infusion and pulse infusion of the full hour dose over 5 minutes each hour. In both protocols, plasma LD levels changed significantly during the infusion protocol. The cumulative area under the curve was equivalent for the two infusions. All patients remained alert, and none developed visual hallucinations. The two patients with peak-dose dyskinesias on oral LD developed prominent dyskinesias during the infusion. Visual hallucinations do not relate simply to high levels of LD or to sudden changes in plasma levels.

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PubMed1998

Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson's disease.

OBJECTIVE: To determine the occurrence of REM sleep behavior disorder (RBD) and sleep-related injury (SRI) in an outpatient PD practice. BACKGROUND: RBD is a frequent cause of SRI in older individuals. Although RBD is seen in PD, the association of SRI and RBD in PD has not been previously assessed. DESIGN/METHODS: Consecutive patients with PD and their caregivers were interviewed using a structured questionnaire assessing the presence of RBD and SRI. Patients fulfilling the International Classification of Sleep Disorders (ICSD) criteria for RBD were compared with non-RBD patients. In a separate analysis, patients with a prior SRI were compared to those without. RESULTS: Of the 61 patient/caregiver pairs, 15% (7 men and 2 women) met the clinical criteria for RBD. There were more episodes of SRI in the RBD group, with 33% causing injury to themselves or to their caregivers compared with 6% of the non-RBD group (chi(2) = 13, p = 0.005). In the second analysis, 15% (all men) patient/caregiver pairs reported SRI. Of these, 66% of the patients had behaviors resembling those seen in RBD, and 33% had recalled dream content. There is a significant association between SRI and RBD for dream-enacting sleep behaviors (Fisher's exact test, p = 0.0001). CONCLUSION: PD patients with SRI frequently have behavioral features of RBD. If RBD underlies most SRI, treatment with appropriate pharmacologic agents, such as clonazepam, may prevent future occurrences of SRI.

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PubMed1998

Early dopaminergic drug-induced hallucinations in parkinsonian patients.

OBJECTIVE: To characterize patients who develop hallucinations early in the course of dopaminergic therapy for Parkinson's disease (PD) and contrast them with patients developing hallucinations after chronic drug treatment. METHODS: Parkinsonian patients who met diagnostic criteria for PD, experienced hallucinations, had a detailed hallucination interview at the onset time of their first hallucination, and had a 5-year clinical follow-up or an autopsy in those 5 years were identified and divided into two groups for comparison: 12 patients who developed early hallucinations within 3 months of starting levodopa therapy and 58 PD patients who developed hallucinations after 1 year of dopaminergic therapy. We contrasted the quality, content, diurnal nature, and emotional elements of the hallucinations, as well as the 5-year follow-up data on diagnosis, disease course, community home or nursing home outcome, and mortality. RESULTS: Both groups experienced a predominance of visual hallucinations, visions of people and animals, and vivid colors and definition. Features distinctive to the early onset hallucinating patients included visions that persisted in daytime as well as nighttime, frightening content with paranoia, and accompanying nonvisual hallucinations, either auditory, olfactory, tactile, or combinations thereof. At the 5-year follow-up, none of the early onset hallucinators had PD as their sole disorder. Four of the 12 had an underlying psychiatric illness that included hallucinations or psychosis preceding their parkinsonism by several years. In the other eight patients at the 5-year follow-up, their parkinsonism evolved to include additional signs that were no longer consistent with PD. The primary diagnoses were diffuse Lewy body disease and Alzheimer's disease (AD) with extrapyramidal signs. Patients with early drug-induced hallucinations had significantly greater placement to nursing homes and greater mortality. CONCLUSIONS: Early onset drug-related hallucinations are not typical of PD. Their presence should signal an investigation of two alternative diagnoses, either a comorbid psychotic illness (often unrevealed by the patient initially) or an evolving parkinsonism-plus syndrome.

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