Effect of anticholinergics on memory in Parkinson's disease.
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Biomedical subjects
Publications and source records attributed to K Syndulko.
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We studied auditory event-related potentials elicited in a target detection paradigm (P300) and pattern shift visual evoked potentials (PVEPs) in 22 patients with chronic renal failure and no clinical evidence of cognitive or visual impairment. Thirteen patients were maintained on chronic hemodialysis, and 9 patients were receiving a low-protein diet. Thirty-three percent of patients receiving the low-protein diet and 58% of the dialysis patients had abnormal P300 latencies. Most patients tested had abnormal PVEP. Four hemodialysis patients had elevated serum parathyroid hormone (PTH) levels, and 9 had normal or slightly elevated values. P300 and PVEP latencies were abnormal in both groups. These observations indicate that elevated PTH levels are not solely responsible for the abnormalities in all patients. P300 and PVEP may be valuable in evaluating neuronal dysfunction in the patient with chronic renal failure.
Auditory event-related potentials (ERP) elicited in a target detection stimulus paradigm and pattern-shift visual ERPs were studied in 20 male patients with idiopathic Parkinson disease (PD) and 20 age-matched normal controls. Patients showed significantly increased latencies for both the P200 and P300 components of the auditory ERP. Patients and controls showed no significant differences in latency of the visual ERP but patients showed significantly decreased amplitude. Only one of five neuropsychological measures, the Symbol Digit Modalities test (SDMT), showed a significant negative correlation with P300 latency. The significant association between the two measures that showed impairments in the PD patients (P300 latency and SDMT scores) suggested that these measures reflect a common, disrupted aspect of cognitive function in PD.
1. A randomized, placebo controlled, double-blind cross-over study was conducted to evaluate the clinical efficacy of the anticholinergic agent, benztropine mesylate (CogentinR) in 29 patients with mild to moderate, idiopathic Parkinson disease. 2. Patients were maintained on a stable, therapeutically optimal dosage and schedule of levadopa-carbidopa (Sinemet) throughout the study. 3. Both the neurologist's and the patient's global assessments of treatment efficacy indicated that Sinemet plus benztropine mesylate resulted in significantly greater improvement than Sinemet plus placebo. 4. Qualitative and quantitative evaluations of relevant neurologic functions showed small, but statistically significant improvements for rigidity, finger tapping speed and activities of daily living in patients during the Sinemet plus benztropine mesylate treatment period. 5. At the completion of the study 16 patients chose to continue taking benztropine mesylate as an adjuvant to Sinemet. 6. No important adverse side effects occurred during the study.
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The primary neurologic application of event-related potentials (ERP) to date has been of relatively short-latency (less than 100-200 ms), stimulus-dependent components. These so-called exogenous components are used to evaluate the structural, and to a lesser extent, the functional integrity of primary afferent pathways. Another class of ERP, termed endogenous, and involving longer-latency (greater than 100 ms) stimulus-independent components has been utilized by psychologists and cognitive psychophysiologists in the measuring of neurocognitive processes. Although the experimental specification of these neurocognitial processes is still in its infancy, the empirical applications of endogenous ERP's offers considerable promise for objective non-invasive evaluations of cognitive functions now conducted only behaviorally. Initial neurocognitive ERP applications have focused on global mental status in dementia. A brief review is presented of experimental studies of some endogenous ERPs (mainly P300), their hypothesized underlying neurocognitive processes, and initial and potential clinical applications.
Neurological applications of visual evoked potentials (VEP) have been expanding over the last decade. Stimulation techniques and waveform interpretation are reviewed. Physiologic variables including age, sex, habituation, refraction, cooperation, and factors influencing the amount of light reaching the retina will effect the VEP. Technical variables including luminance, check size, field size and color of check will also have an effect on the VEP. When properly performed, VEP can contribute important information on the visual pathways in patients with optic neuritis, multiple sclerosis, optic nerve and chiasm compressive lesions, non-compressive lesions affecting the visual pathways and neurodegenerative diseases not primarily involving the visual pathways. VEP has been shown to be a very sensitive though non-specific diagnostic tool.
Visual evoked potentials (VEP), brain stem auditory evoked potentials (BAEP), somatosensory evoked potential (SEP), and long latency event related potentials (ERP) have been used to assess various aspects of the central nervous system. Multimodality evoked potential (MEP) testing uses a combination of these tests in the same clinical setting. In the diagnosis of multiple sclerosis and in the diagnosis of brain death, MEP testing has been shown to be more effective than any one evoked potential test used alone. In head trauma, MEP testing is an effective means of localization and prognostication. There are potential uses for MEP testing in Parkinson's Disease and uremia.
The effects of chronic administration of the anticholinergic agent, benztropine mesylate (CogentinTM), on specific verbal memory were investigated as part of a placebo-controlled randomized double-blind crossover study to determine the clinical efficiency of CogentinTM as an adjuvant therapy with SinemetTM in Parkinson's disease. Twenty-nine males with clinically definite idiopathic Parkinson's disease participated in the trial. They were tested for acquisition of new word lists, and on four other cognitive tests before, during, between, and after two 10-week trial periods when they received either increasing doses of CogentinTM (maximum 2 mg) or placebo while on a maintenance dose of SinemetTM. Patients showed a statistically significant decrease (5--10%) in word list acquisition while on CogentinTM. The anticholinergic memory effect was unrelated to the degree of improved clinical efficacy of CogentinTM for the Parkinsonism, and to initial word list acquisition ability. Verbal memory findings indicate that chronic administration of an anticholinergic in even low therapeutic dosage may play an important role in memory function.
Traditionally, neurologists have emphasized qualitative techniques for assessing results of clinical trials. However, in recent years qualitative evaluations have been increasingly augmented by quantitative tests for measuring neurologic functions pertaining to mental state, strength, steadiness, reactions, speed, coordination, sensation, fatigue, gait, station, and simulated activities of daily living. Quantitative tests have long been used by psychologists for evaluating asymptomatic function, assessing human information processing, and predicting proficiency in skilled tasks; however, their methodology has never been directly assessed for validity in a clinical environment. In this report, relevant contributions from the literature on asymptomatic human performance and that on clinical quantitative neurologic function are reviewed and assessed. While emphasis is focused on tests appropriate for evaluating clinical neurologic trials, evaluations of tests for reproducibility, reliability, validity, and examiner training procedures, and for effects of motivation, learning, handedness, age, and sex are also reported and interpreted. Examples of statistical strategies for data analysis, scoring systems, data reduction methods, and data display concepts are presented. Although investigative work still remains to be done, it appears that carefully selected and evaluated tests of sensory and motor function should be an essential factor for evaluating clinical trials in an objective manner.
Slow shifts in brain potential (commonly called the contingent negative variation), obtained during a warned reaction-time task with a foreperiod of 1 second, were compared with waveforms synthesized by the addition of separately obtained potentials associated with individual (nonpaired) sensory stimuli and self-initiated motor movements. The synthesized waveforms match closely the actual contingent negative variation, suggesting that it is constituted largely of separate, noncontingent elements related to sensory and motor processes.
Patients with known or suspected multiple sclerosis (MS) were tested for abnormalities in visual evoked potentials. We compared the critical frequency of photic driving (CFPD) with pattern reversal visual evoked potentials (PVER). We found the CFPD to be somewhat more sensitive than PVER for detecting abnormalities in the visual pathways of patients with MS. When used together, the two were complementary, each fining abnormalities that the other missed. When evaluating patients with MS with evoked potentials, both PVER and CFPD should be tested.
Megavoltage CNS irradiation was given to 20 patients with clinically definite multiple sclerosis (MS) to determine if de novo CNS IgG synthesis could be eradicated. In all five patients given 1,200 rads, a transient reduction in the de novo CNS IgG synthesis rate was noted. In ten patients given 1,800 rads, the following occurred: a reduction in synthesis rate in three patients, a reduction followed by enhancement in two, only enhancement in four, and no change in one. In all five additional patients, a therapy of adrenocorticotropic hormone (ACTH) followed by prednisone in combination with 1,800 rads produced greater and more persistent decreases in CNS IgG synthesis, but did not block the enhancement effect. Only two of 19 patients who had abnormal CNS IgG synthesis rates had reductions to normal; no patients showed changes in the number or pattern CSF IgG oligoclones. Hence, no treatment eradicated de novo CNS IgG synthesis. A persistent decrease in CSF leukocytes occurred in all 20 patients due to the reduction of small lymphocytes (not dose related). The blood-brain-barrier to albumin concentration was transiently damaged in 11 of 15 patients given irradiation, but when patients were premedicated with ACTH/prednisone therapy, no damage was found. None of the patients demonstrated neurological improvement, change in the activity of their disease, or persistent adverse effects.
A randomized, double-blind clinical trial was designed to compare two ratios of carbidopa to levodopa (10 mg of carbidopa to 100 mg of levodopa [Sinemet 10/100] and 20 mg of carbidopa to 100 mg of levodopa [Sinemet 20/100]) with levodopa (100 mg) alone. Twenty-nine male patients (46 to 78 years of age) with clinically definite idiopathic Parkinson's disease of mild to moderate severity were selected and hospitalized for the three-week period of the study. Medications being taken at time of entry were phased out during week 1. Fixed daily increments of medications were given during week 2, and adjusted during week 3 to achieve best clinical response with fewest side effects. Qualitative and quantitative examinations of neurologic function showed that upper extremity measurements of resting tremor, rigidity, and finger-tapping speed, and lower extremity measurements of foot coordination and tandem gait (both types of speed tests) showed significantly more improvement in patients receiving the 20:100 combination than in those receiving the 10:100 combination or levodopa alone. Adverse effects were similar and minimal in each of the three groups. Results indicate that increasing the amount of carbidopa from 10 to 20 mg per 100-mg dose of levodopa gives a greater therapeutic response in Parkinson's disease than does a 10:100 carbidopa-levodopa ratio or levodopa alone.
To study the nature of the multiple sclerosis (MS) central nervous system (CNS) immune reaction, cytarabine (ara-C) was administered intravenously to three patients and intrathecally to another seven. Although intravenous administration severely suppressed circulating leukocytes derived fom the bone marrow, there was no change in de novo CNS IgG synthesis (rate or presence of CSF IgG oligoclones). Therefore, the MS CNS immune reaction can persist in the presence of severe granulocytopenia and severe monocytopenia of one to two weeks' duration. In four patients who were given ara-C intrathecally, cytotoxic levels (> 10 micrograms/ml) were present for a least 24 hours. A brief elevation in CSF albumin indicated transient damage to the blood-brain barrier. Leukopenia did not result in the seven patients treated intrathecally, and de novo CNS IgG synthesis did not change or was transiently increased. Assuming that cytotoxic levels in CSF diffused to the CNS sites responsible for synthesizing IgG, results indicate that CNS IgG synthesis does not depend on in situ rapid turnover of immune cells. None of the ten patients demonstrated neurological improvement or persistent adverse effects.