Regional differences in the expression of corticostriatal synaptic plasticity.

Field recordings of responses to activation of corticostriatal afferents were made in coronally sectioned rat brain slices. Each recording site was categorized according to its medial to lateral and rostral to caudal position to investigate anatomical differences in synaptic plasticity. Individual responses were highly variable exhibiting extremes of tetanus induced depression and potentiation. Consequently, averaging masked the capacity of these synapses to express long-term forms of plasticity. Block of GABA(A) inhibition and elimination of dopaminergic input with 6-hydroxydopamine lesions both acted to increase the expression of potentiation, but again considerable variability was observed. Separation of recordings into medial and lateral groups revealed clear anatomical trends which contributed to the variability observed in the total sample. Paired-pulse, post-tetanic and long-term potentiation was greater in medial than in lateral groups in normal artificial cerebral spinal fluid. Similar tendencies were seen after block of GABA(A) receptors with bicuculline. 6-Hydroxydopamine lesions in combination with bicuculline treatment reduced medial to lateral differences. Factoring in medial to lateral trends revealed block of GABA(A) receptor mediated inhibition had its greatest effect on medial corticostriatal responses and 6-hydroxydopamine lesions had their greatest effect on lateral responses. From these data we suggest anatomical variation in striatal circuitry may underlie regional differences in synaptic plasticity evoked by corticostriatal activation.

The evolution of senescence in natural populations of guppies (Poecilia reticulata): a comparative approach.

Model organisms like Drosophila melanogaster or Caenorhabditis elegans have revealed genes that influence senescence and the evolvability of senescence. We are interested instead in evaluating why and how senescence evolves in natural populations. To do so, we are taking the ecological geneticist's perspective of comparing natural populations that differ in factors that are predicted to influence the evolution of senescence and are evaluating whether senescence has evolved in the predicted fashion. We are also manipulating the environment to evaluate more directly the evolution of senescence. Guppies (Poecilia reticulata) are found in streams throughout the Northern Range mountains of Trinidad. Natural populations experience large differences in mortality rate as a consequence of the predators with which they co-occur. We have already shown, both with comparative studies and manipulations of the distribution of guppies and their predators, that the early life history evolves very rapidly in response to these differences in mortality. For example, high adult mortality rates select for individuals that develop more rapidly, produce their first litter of young at an earlier age, and devote more of their available resources to reproduction for the remainder of their lives. These changes were predicted by independently derived theory. Aspects of this same theory also predict how the late life history and senescence should evolve. Specifically, theory predicts that the populations that experience low mortality rates should also experience delayed senescence and longer life spans relative to those that experience high mortality rates. We are currently evaluating these predictions with representatives from two high-predation and two low-predation environments. Our presentation will focus on our pilot study, which evaluated life span, lifetime reproduction, and the patterns of aging in our laboratory populations. We will also report on the progress in our ongoing comparative studies of senescence in natural populations.

The Satz-Mogel short form of the Wechsler Adult Intelligence Scale--revised: effects of global mental status and age on test-retest reliability.

Abbreviated versions of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) have been developed as time saving devices that provide accurate estimates of overall level of general intellectual functioning while decreasing test administration time. The Satz-Mogel short form of the WAIS-R has received substantial attention in the literature as an accurate measure of intellectual functions when compared with the Full WAIS-R. However, most studies comparing the Satz-Mogel version to the Full WAIS-R have only provided correlational analyses. Our study was an attempt to apply a more rigorous statistical methodology in determining if the Full WAIS-R and abbreviated versions are equivalent. We explored the impact of level of global mental status and age on the Satz-Mogel version. Although the two forms of the test correlated highly, repeated measures design indicated significant differences between Satz-Mogel and Full WAIS-R when participants were divided into groups based on level of global impairment and age. Our results suggest that the Satz-Mogel version of the test may not be equivalent to the full WAIS-R and is likely to misrepresent a patient's level of intellectual functioning, particularly for patients with progressive degenerative conditions. The implications of applying Satz-Mogel scoring to the Wechsler Adult Intelligence Scale-III (WAIS-III) are discussed.

Parental intrusiveness in adolescence recalled by women with a history of bulimia nervosa and comparison women.

OBJECTIVE: To learn if women with a lifetime history of bulimia nervosa (BN) report more intrusive parental behavior during adolescence than their nonclinical peers, and to provide further validation of the Parental Intrusiveness Rating Scale (PIRS). METHOD: We administered the PIRS to 86 women with a lifetime history of BN and 573 comparison subjects and examined between-group differences. RESULTS: Relative to the comparison group, lifetime BN subjects reported higher levels of parental intrusiveness, specifically maternal invasion of privacy, maternal jealousy and competition, paternal seductiveness, and maternal and paternal overconcern with the daughter's eating, weight, and shape. There were no between-group differences in paternal invasion of privacy. In exploratory analyses with the comparison sample, Caucasian women reported greater maternal jealousy and competition than Asian American/Pacific Islander women, but there were no other differences. CONCLUSION: These results support clinical observations of high levels of parental intrusiveness in the adolescent experiences of women who develop BN. Nonclinical women of diverse ethnic backgrounds report largely equivalent experiences.

Age-related change in short-term synaptic plasticity intrinsic to excitatory striatal synapses.

Aging disrupts the expression of synaptic plasticity in many central nervous system (CNS) structures including the striatum. We found age differences in paired-pulse plasticity to persist at excitatory striatal synapses following block of gamma aminobutyric acid (GABA)A and GABA(B) receptors, a property that was independent of the number of afferents activated. High Mg2+/low Ca2+ artificial cerebral spinal fluid (ACSF) reduced release probability and consequently the size of the evoked excitatory post-synaptic potential (EPSP). High Mg2+/low Ca2+ ACSF also increased the expression of paired-pulse facilitation and eliminated the age difference seen previously in normal ACSF. These data suggest that age differences in paired-pulse plasticity reflect an alteration in release probability at excitatory striatal synapses. In support of this hypothesis, we found age differences in another presynaptic form of plasticity referred to as synaptic augmentation. Examination of the synaptic depression that developed during the conditioning tetanus also revealed an age-related increase in synaptic depression. These data indicate that age-related changes in facilitation may be due in part to a reduction in the readily releasable pool of synaptic vesicles. Dendritic structure (spine density and dendritic length) was correlated with short-term synaptic plasticity, but these relationships depended upon the variance associated with age (hierarchical regression). Post-hoc within-age group regressions demonstrated relationship between spine density and paired-pulse plasticity. No other age-specific correlations were found. These findings imply an age-dependent association between altered dendritic morphology and changes in synaptic plasticity.

Microelectrode-guided posteroventral medial radiofrequency pallidotomy for Parkinson's disease.

The outcome of radiofrequency-guided posteroventral medial pallidotomy was investigated in 29 patients with recalcitrant Parkinson's disease. Extracellular recordings were obtained in the target region to differentiate the internal from the external globus pallidus, and distinct waveforms were recorded in each region. Stimulation of the target site further verified the lesion location. Of the 29 patients treated during the course of 1 year, none showed any adverse side effects (such as hemianopsia or hemiparesis) from the procedure. Significant and immediate improvement in motor involvement (dyskinesia, rigidity, dystonia, freezing, and tremor) was observed as measured by the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr scale. Patients experienced improvements in their condition as measured on a self-rating scale, and their ability to perform the activities of daily living was also significantly improved. Although the onset and duration of the effect of a single dose of levodopa did not change, the number of hours in an "off" state of dyskinesia per day was significantly decreased. These results provide further evidence, in a large group of patients, that posteroventral medial pallidotomy results in significant control of the motor symptoms of Parkinson's disease with a minimum of undesirable side effects.

Decreased duration of Ca(2+)-mediated plateau potentials in striatal neurons from aged rats.

1. The influence of age on striatal neuron Ca2+ physiology was studied through an analysis of intracellularly recorded Ca(2+)-mediated plateau potentials. In vitro brain slices from young and aged rats were treated with the K+ channel blocker tetraethylammonium (30 mM) to facilitate the expression of plateau potentials. A sample of neurons was also filled with biocytin and post hoc correlations were performed between morphology and physiology. 2. Testing of sampling parameters in neurons from young rats revealed that tetrodotoxin did not affect the amplitude or duration of plateau potentials. The membrane potential induced during plateau testing and the rate of plateau potential generation, however, had to be held constant because these variables affected plateau potential duration. 3. A significant age-related decrease was found in the duration of Ca(2+)-mediated plateau potentials that could not be explained by alterations in the activation or inactivation properties of the plateau potential. Investigation into relationships between cell morphology and plateau potential duration revealed a number of correlations. Soma size and dendritic length were correlated with plateau potential duration, independent of age (hierarchical regression), and an age-related decrease in dendritic length but not in soma size was found. Spine density and plateau potential duration were also correlated, but the significance depended on the variance associated with age. These data indicate that the extent of somadendritic membrane (including spines) affects plateau potential duration in striatal neurons and that dendrite and spine loss in aged animals may contribute to age-related decreases in plateau potential duration. 4. The response to replacement of Ca2+ with Ba2+ was age dependent, with Ba2+ causing a greater increase in the duration of plateau potentials in young neurons. These data rule out an increase in Ca(2+)-mediated inactivation of Ca2+ channels as a primary cause for the shortening of plateau potentials in aged neurons. Our morphological findings suggest that dendritic regression in aged neurons may have reduced the number of Ca2+ channels participating in plateau potential generation, but other mechanisms related to changes in the type of Ca2+ channel expressed and possible differences in their inactivation kinetics may also contribute to the age-related change in plateau potential duration.

Full-information models for multiple psychometric tests: annualized rates of change in normal aging and dementia.

The rates of change for five widely used psychometric tests were analyzed to compare how much more variance reduction can be achieved using full-information methods relative to the single-equation methods previously used in dementia research. Nondemented controls and subjects with Alzheimer disease (AD), probable/ possible vascular dementia (VD), or mixed dementia (MD) were evaluated. A cohort design was followed, with follow-up of three demented groups and one normal control group; data were analyzed in a multiple-equation regression model estimated with full-information methods. The study was conducted at Alzheimer's Disease Research Center sites at the University of California, Irvine, and at the University of Southern California. In all, 226 patients and controls who had completed initial assessment and at least one annual reassessment were included in the study. Dependent variables were annualized rates of change in the Mini-Mental State Examination (MMSE), the Short-Blessed Dementia Rating Scale (DRS), the Consortium to Establish a Registry for Alzheimer's Disease drawings test (CD), the WAIS-R Block Design test (WRB), and the Boston Naming Test (BNT). Independent variables were dementia severity, diagnosis (AD, VD, MD, or control), sex, age, marital status, education, and age at onset. Full-information methods reduced the variance in the change scores by > or = 25% compared with previous studies. The model's prediction of a test's rate of change was almost entirely due to dementia stage and diagnosis. The effects of other explanatory variables (sex, marital status, age, and education) were weak and statistically insignificant. When the effects of other independent variables were controlled, AD and MD patients were found to decline at significantly faster rates than VD patients. Full-information methods, relative to single-equation methods, substantially reduce the variance of rates of change for multiple psychometric tests. They do so by simultaneously considering the correlated error terms in the regression for each dependent psychometric change score variable. The robustness of these results to minor variations in follow-up time suggests that annualization is a reasonably valid procedure for making change scores comparable. This study's results suggest that change scores in psychometric tests provide information that can be used to aid differential diagnosis. However, the large variances of change scores preclude many other uses. Finally, since standardization of psychometric change scores translates all tests to the same scale (0-100%), standardized change scores are easier to interpret. The analysis of standardized change scores deserves further investigation.

Occupations with exposure to electromagnetic fields: a possible risk factor for Alzheimer's disease.

The authors present analyses of data from three independent clinical series and controls indicating an association between working in occupations with probable medium to high exposure to extremely low frequency (< 300 Hz) electromagnetic fields and sporadic Alzheimer's disease. Case-control analyses were carried out using data from patients examined at the following locations: the Department of Neurology, University of Helsinki, Helsinki, Finland, 1982-1985; the Koskela Hospital in Helsinki, 1977-1978; and the University of Southern California site of the Alzheimer's Disease Research Center of Los Angeles and Orange Counties, 1984-1993. The predominant occupations among medium (2-10 mG or > 10 mG intermittently) to high (> 10 mG or > 100 mG intermittently) exposed cases were seamstress, dressmaker, and tailor. The results appear to be independent of education, and the sex-combined odds ratios for the three series are quite homogeneous: 2.9, 3.1, and 3.0. The odds ratio for the three series analyzed together is 3.0 (p < 0.001), with a 95% confidence interval of 1.6-5.4. The odds ratio for women is 3.8 (p < 0.001), with a 95% confidence interval of 1.7-8.6. The most obvious, possibly etiologically relevant exposure is that of electromagnetic fields, which may have biologic plausibility because they may adversely influence calcium homeostasis and/or inappropriately activate immune system cells such as microglial cells, initiating events that result in neuronal degeneration.

The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities.

Cobalamin levels are frequently low in patients with dementia, but it is unclear if they represent definable deficiency and what the mechanisms are. Therefore, patients being evaluated for dementia who had low cobalamin levels but no obvious evidence of deficiency were studied hematologically, neurologically and with metabolic tests and were re-evaluated after cobalamin treatment. Abnormalities suggestive of or diagnostic for deficiency were documented in most of the 16 demented and nondemented patients. Metabolic results: 50% of patients tested had abnormal deoxyuridine suppression and 44% had increased serum methylmalonic acid and/or homocysteine levels; these test results correlated with each other. Neurologic results: 73% of patients had clinical abnormalities, primarily mild neuropathies, not attributable to other causes, 75% had electroencephalographic abnormalities, 77% had abnormal visual evoked potentials and 33% had abnormal somatosensory potentials. Metabolic and neurologic dysfunction were present together or absent together in all but 2 cases. Cobalamin therapy improved 50-100% of the various types of abnormalities, although it did not improve cognitive function in the 13 demented patients. Food-cobalamin malabsorption was found in 60% of the patients. Despite the absence of megaloblastic anemia and rarity of traditional malabsorption of free cobalamin, low cobalamin levels in demented patients frequently represent mild cobalamin deficiency and are often associated with food-cobalamin malabsorption. Perhaps most importantly, this is accompanied not only by metabolic changes but by evidence of mild neurologic dysfunction. Their frequent reversibility by cobalamin confirms that these defects indeed arise from cobalamin deficiency. Although the long-standing dementia does not improve, treating such patients with cobalamin has other concrete benefits.

Generalized anxiety disorder: some biochemical aspects.

Fifty-one patients who met DSM-III criteria for generalized anxiety disorder, and who were recruited to participate in a drug outcome study, filled out a variety of rating scales and had blood samples drawn for plasma norepinephrine, epinephrine, and free 3-methoxy-4-hydroxyphenylglycol (MHPG) after a 20-min rest period. This group was compared to 15 normal controls who also had their blood drawn after a 20-min rest period. While the two groups were initially found to have significantly different levels of plasma free MHPG through the use of t tests, this finding was not confirmed by subsequent discriminant analysis.