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Biomedical subjects

J W Newcomer

Publications and source records attributed to J W Newcomer.

At least 19 recordsLinked to original sources
PubMed2001

NMDA receptor regulation of memory and behavior in humans.

N-methyl-D-aspartate (NMDA) receptor hypofunction is associated with a range of effects on cognition and behavior in whole animal and human studies. NMDA receptor hypofunction within the brain, which can be induced experimentally in vivo using NMDA receptor antagonist drugs, produces adverse effects on memory function. The results suggest that NMDA receptor hypofunction can preferentially affect neural mechanisms regulating the efficiency of encoding and consolidation into longer-term storage. More pronounced NMDA receptor hypofunction can produce a clinical syndrome that includes core features of psychosis, as well as dissociation. Finally, sustained and severe underexcitation of NMDA receptors in the adult brain is associated with a neurotoxic process with well-characterized neuropathological features. Progressive increases in severity of NMDA receptor hypofunction within the brain can produce a range of effects on brain function, involving local and distributed circuitry, which may underlie the observed changes in behavior. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, potentially contributing to further age-related decreases in memory and learning performance. Pharmacological and genomic methods for preventing NMDA receptor hypofunction, or for preventing the upstream or downstream consequences modeled by treatment with NMDA antagonists, may be applicable to the prevention and treatment of memory and behavioral dysfunction in a variety of neuropsychiatric disease conditions.

Behavior↗
PubMed2001

Glucocorticoid effects on memory function over the human life span.

Glucocorticoids (GCs), produced by the stress-responsive hypothalamic-pituitary-adrenal axis, are well recognized for their regulatory role in peripheral metabolism. GCs are also known to regulate various brain functions, with well-described effects on human cognition. Increased GC exposure in humans-including exposure to the endogenous GC, cortisol-at levels associated with stress, decreases memory and learning function. These results extend evidence from in vitro studies of synaptic and cell function and evidence from animals indicating the GCs can regulate substrates of memory function. While considerable evidence details these effects in adult humans and animals, relatively less is know about the effect of GCs on cognitive function in children and older adults. Investigators have suggested that children, particularly preschool-aged children, may be vulnerable to adverse consequences of increased GC secretion resulting from stress and neuropsychiatric diseases such as depression. Adverse GC effects on memory substrates and memory function in the adult have also fostered concern that age-related changes, including changes in GC receptors and changes in circulating cortisol levels, could lead to age-related increases in the adverse effect of GCs on brain function. Investigators have reported an association between age-related increases in cortisol levels and age-related memory decline, but this association may or may not be due to a direct effect of cortisol on memory substrates. A number of possible treatment approaches to prevent or remediate adverse GC-induced effects are under development. In general, the use of safe and effective agents for blocking adverse GC effects on brain functions including memory may offer benefits to individuals suffering acute and chronic stressors and could prevent brain changes relevant to stress, aging, and stress-related neuropsychiatric diseases.

Adult↗
PubMed2001

Hyperglycemia and antipsychotic medications.

Type 2 diabetes mellitus and impaired glucose tolerance are associated with antipsychotic treatment. Risk factors for type 2 diabetes and impaired glucose tolerance include abdominal adiposity, age, ethnic status, and certain neuropsychiatric conditions. While impaired glucose metabolism was first described in psychotic patients prior to the introduction of antipsychotic medications, treatment with antipsychotic medications is associated with impaired glucose metabolism, exacerbation of existing type 1 and 2 diabetes, new-onset type 2 diabetes mellitus, and diabetic ketoacidosis, a severe and potentially fatal metabolic complication. The strength of the association between antipsychotics and diabetes varies across individual medications, with the largest number of reports for chlorpromazine, clozapine, and olanzapine. Recent controlled studies suggest that antipsychotics can impair glucose regulation by decreasing insulin action, although effects on insulin secretion are not ruled out. Antipsychotic medications induce weight gain, and the potential for weight gain varies across individual agents with larger effects observed again for agents like chlorpromazine, clozapine, and olanzapine. Increased abdominal adiposity may explain some treatment-related changes in glucose metabolism. However, case reports and recent controlled studies suggest that clozapine and olanzapine treatment may also be associated with adverse effects on glucose metabolism independent of adiposity. Dyslipidemia is a feature of type 2 diabetes, and antipsychotics such as clozapine and olanzapine have also been associated with hypertriglyceridemia, with agents such as haloperidol, risperidone, and ziprasidone associated with reductions in plasma triglycerides. Diabetes mellitus is associated with increased morbidity and mortality due to both acute (e.g., diabetic ketoacidosis) and long-term (e.g., cardiovascular disease) complications. A progressive relationship between plasma glucose levels and cardiovascular risk (e.g., myocardial infarction, stroke) begins at glucose levels that are well below diabetic or "impaired" thresholds. Increased adiposity and dyslipidemia are additional, independent risk factors for cardiovascular morbidity and mortality. Patients with schizophrenia suffer increased mortality due to cardiovascular disease, with presumed contributions from a number of modifiable risk factors (e.g., smoking, sedentary lifestyle, poor diet, obesity, hyperglycemia, and dyslipidemia). Patients taking antipsychotic medications should undergo regular monitoring of weight and plasma glucose and lipid levels, so that clinicians can individualize treatment decisions and reduce iatrogenic contributions to morbidity and mortality.

Antipsychotic Agents↗
PubMed2000

Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis.

BACKGROUND: Psychosis is common in patients with Alzheimer disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer disease and no psychosis. METHODS: One hundred nine subjects with Alzheimer disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. RESULTS: Psychosis occurred commonly in Alzheimer disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. CONCLUSIONS: The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.

Aged↗
PubMed1999

Age- and dose-dependent glucose-induced increases in memory and attention in schizophrenia.

Glucose is the principal energy substrate for the brain, and alterations in glucose availability can alter neuronal function, including cognitive performance. Investigators have previously demonstrated glucose-induced memory and attentional improvements in humans, including a previous report from this group in subjects with schizophrenia. However, the age- and dose-dependence of this effect in schizophrenia has not been addressed. This within-subjects, double-blind experiment evaluated the cognitive effects of placebo-controlled, multiple fixed-dose oral glucose administration (0 g, 25 g, 50 g, 75 g) in younger and older patients with schizophrenia (n = 20) and healthy age-matched controls (n = 20). Each dose condition was administered on a different morning after a 9-h fast, with cognitive testing and plasma sampling following dose administration on each day. Older patients demonstrated dose-dependent improvements in recall performance on a spatial delayed response task and reaction time on a delayed match to sample task, while younger patients had decreases in attentional performance at the 75-g dose compared to placebo. As in previous reports, patients demonstrated higher plasma glucose and insulin concentrations than controls in response to fixed glucose dosing. The results provide further evidence that glucose and/or insulin can regulate brain functions relevant to memory and attention, and suggest that systemic changes in glucose regulation in schizophrenia deserve further study.

Adult↗
PubMed1999

Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose.

BACKGROUND: Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin). METHODS: Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states. RESULTS: Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations. CONCLUSIONS: These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.

Adult↗
PubMed1999

Decreased memory performance in healthy humans induced by stress-level cortisol treatment.

BACKGROUND: Glucocorticoids (GCs) can regulate hippocampal metabolism, physiologic functions, and memory. Despite evidence of memory decreases during pharmacological GC treatment, and correlations between memory and cortisol levels in certain disease conditions, it remains unclear whether exposure to the endogenous GC cortisol at levels seen during physical and psychological stress in humans can inhibit memory performance in otherwise healthy individuals. METHODS: Randomized, double-blind, placebo-controlled comparison of 2 fixed oral doses of cortisol (40 mg/d and 160 mg/d using split doses to approximate circadian rhythm) given for 4 days to matched groups of healthy subjects (n = 51). Lower-dose treatment approximated cortisol exposure during mild stress, whereas the higher dose approximated cortisol exposure during major stress. Cognitive testing and plasma sampling were done at baseline, after 1 and 4 days of treatment, and after a 6-day washout period, hypothesizing dose-dependent decreases in verbal declarative memory. RESULTS: Cortisol treatment at the higher dose produced reversible decreases in verbal declarative memory without effects on nonverbal memory, sustained or selective attention, or executive function. A significant interaction between time and treatment condition for paragraph recall was explained by treatment-induced differences in performance after 4 treatment days, with lower immediate and delayed recall performance during higher-dose cortisol treatment compared with lower-dose treatment and placebo. CONCLUSIONS: Several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can-similar to pharmacological GC treatment-reversibly decrease specific elements of memory performance in otherwise healthy individuals.

Adult↗
PubMed1999

Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis.

N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are reported to induce schizophrenia-like symptoms in humans, including cognitive impairments. Shortcomings of most previous investigations include failure to maintain steady-state infusion conditions, test multiple doses and/or measure antagonist plasma concentrations. This double-blind, placebo-controlled, randomized, within-subjects comparison of three fixed subanesthetic, steady-state doses of intravenous ketamine in healthy males (n = 15) demonstrated dose-dependent increases in Brief Psychiatric Rating Scale positive (F[3,42] = 21.84; p < 0.0001) and negative symptoms (F[3,42] = 2.89; p = 0.047), and Scale for the Assessment of Negative Symptoms (SANS) total scores (F[3,42] = 10.55; p < 0.0001). Ketamine also produced a robust dose-dependent decrease in verbal declarative memory performance (F[3,41] = 5.11; p = 0.004), and preliminary evidence for a similar dose-dependent decrease in nonverbal declarative memory, occurring at or below plasma concentrations producing other symptoms. Increasing NMDA receptor hypofunction is associated with early occurring memory impairments followed by other schizophrenia-like symptoms.

Adult↗
PubMed1999

Glucose-induced increase in memory performance in patients with schizophrenia.

Previous investigations have found that increasing circulating glucose availability can increase memory performance in rodents, healthy humans, and individuals with dementia of the Alzheimer's type. In this study, patients with schizophrenia, healthy control subjects, and controls with bipolar affective disorder were tested using double-blind treatment with either 50 g anhydrous dextrose plus 4 mg sodium saccharin (for "taste") or 23.7 mg saccharin alone, followed by cognitive testing on a complex battery. At this glucose dose, verbal memory performance on a paragraph recall task was increased during the glucose condition relative to the saccharin condition in the patients with schizophrenia; this effect was not detected in either the psychiatric or normal controls. The results provide preliminary support for the hypothesis that memory performance can be improved in patients with schizophrenia by increasing circulating glucose availability and suggest the importance of further evaluation of therapeutic manipulations of glucose availability.

Adult↗
PubMed1998

Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans.

BACKGROUND: Leptin is a hormone that regulates fat metabolism and appetite. The secretion of leptin is regulated by adiposity and, in the rodent, by factors such as insulin, beta-adrenergic agonists, and glucocorticoids (GCs). Increased secretion of the endogenous human GC, cortisol, occurs during stress and in disorders such as major depression. Pharmacological GCs can robustly increase plasma leptin concentrations in humans, leading us to hypothesize that cortisol may serve as a physiological regulator of human leptin secretion. METHODS: A randomized double-blind placebo-controlled comparison of 2 fixed oral dosages of cortisol (40 mg/d and 160 mg/d), given for 4 days to matched groups of healthy subjects (n=47). Low-dose treatment approximated GC output during mild stress, while high-dose treatment approximated GC output during maximal stress, spanning a range of GC secretion relevant to physiological stress. RESULTS: Cortisol produced dose-dependent and time-dependent increases in plasma leptin concentrations (time x treatment condition x body mass index; F6,123=10.73; P<.001). Initial treatment-induced increases in plasma leptin concentration returned toward baseline values during 4 treatment days, suggesting tolerance to this GC effect in these healthy subjects. CONCLUSIONS: The results indicate an important role for GCs in the short-term regulation of human leptin secretion. Glucocorticoid-induced increases in leptin secretion suggest a mechanism that may contribute to anorexia and weight loss during stress and disease states such as major depression, if these conditions are associated with sustained increases in plasma leptin concentrations.

Adipose Tissue↗
PubMed1998

The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease.

Here we have described a novel excitotoxic process in which hypofunctional NMDA receptors cease driving GABA ergic neurons which cease inhibiting excitatory transmitters in the brain. These disinhibited excitatory transmitters then act in concert to slowly hyperstimulate neurons in corticolimbic brain regions. We have discussed how such an abnormality could exist in the brains of individuals with schizophrenia or AD and could account for the clinical stigmata of the two disorders. In addition, we have highlighted how other disorder-specific factors would account for the differences in the clinical presentation of AD and schizophrenia. In an animal model, pharmacological methods have been developed for preventing the overstimulation of these vulnerable corticolimbic pyramidal neurons and at least some of these methods may be applicable for treating AD and schizophrenia.

Alzheimer Disease↗
PubMed1998

Glucocorticoid interactions with memory function in schizophrenia.

Glucocorticoid (GC) exposure can affect brain function, including potential adverse effects on hippocampal physiology and on specific elements of cognitive performance. In a prior study of healthy adult humans, decreased verbal memory performance was detected during four days of double-blind, placebo-controlled dexamethasone (DEX) treatment. Using an identical experimental design and sample size (n = 19), the cognitive effect of DEX treatment was studied in 11 subjects with schizophrenia, compared with 8 receiving placebo. In contrast to the effect in healthy adults, GC treatment with DEX at this dose (cumulative 3.5 mg) and duration did not decrease verbal memory performance or other measures of cognitive function in the patients with schizophrenia. When data from this experiment was compared with data from the previous study of healthy adults, covarying differences in baseline memory performance, a significant 3-way interaction was detected between subject group, treatment condition, and the repeated measurements of verbal memory performance across baseline, treatment and washout (F[3,87] = 4.84, p = .0066), suggesting differential cognitive effects of DEX in the patients versus the previously studied healthy subjects. Baseline plasma cortisol concentrations (0800 h) prior to DEX treatment were inversely correlated with baseline delayed (rs = -0.536, p = .03) verbal recall performance, supporting a previous report. The current results await replication using a larger sample size but provide preliminary evidence for an altered behavioral response to acute GC exposure in schizophrenic versus healthy subjects, and further evidence for a relationship between chronic changes in circulating cortisol and the memory impairments found in this disorder.

Adult↗
PubMed1997

Robust leptin secretory responses to dexamethasone in obese subjects.

Although leptin reverses obesity in rodents, its function and regulation in humans are unknown. Glucocorticoids have been reported to stimulate leptin production in both rodents and humans, but data assessing the effect of obesity on dynamic leptin secretory responses are unavailable. We, therefore, studied 52 lean and obese subjects [20 men and 32 women; aged 19-84 yr; body mass index (BMI) range, 16-47 kg/m2] randomized to treatment with dexamethasone (total dose, 10 mg/4 days) or placebo. Compared with placebo, dexamethasone increased (P = 0.0001) plasma leptin levels by 64-111% above baseline values within 2-4 days. The increases occurred in all ages, showed no sexual dimorphism, and were particularly robust in obese subjects. After dexamethasone treatment, significant interactions were observed between the change in plasma leptin and BMI (P = 0.0001), baseline plasma leptin (P = 0.0006) and plasma dexamethasone levels (P = 0.04), but not age (P = 0.28); an apparent interaction with plasma insulin no longer was significant after controlling for BMI. These results confirm dexamethasone-induced hyperleptinemia in humans and further demonstrate that the response is not defective in obesity.

Adult↗
PubMed1996

The effects of chronic corticosterone on memory performance in the platform maze task.

Acquisition and reversal of a memory task dependent on hippocampal integrity were assessed in rats following chronic corticosterone treatment. Young adult male rats were injected daily with corticosterone (10 mg/kg, SC) for 8 weeks. Memory was assessed during the last week of treatment with an elevated platform maze. During acquisition trials, corticosterone-treated rats did not differ from vehicle-treated controls in either the location of first hole chosen nor in the latency to locate the escape hole. In the reversal trials, when the position of the escape hole was rotated 135 degrees, both groups successfully reversed their responses without persevering towards the previously rewarded escape hole location. These findings suggest that, despite the probability of corticosterone-induced changes in hippocampal physiology, chronic corticosterone treatment does not adversely affect performance in a memory task dependent on hippocampal integrity.

Animals↗
PubMed1996

Hippocampal MR imaging morphometry by means of general pattern matching.

PURPOSE: To determine the repeatability and validity of a pattern-matching method for the segmentation and measurement of hippocampi on magnetic resonance (MR) images. MATERIALS AND METHODS: Comparable two-dimensional MR images obtained in 18 subjects (nine healthy control subjects [six men, three women; aged 24-54 years] and nine patients with schizophrenia [six men, three women; aged 22-61 years]) were twice segmented manually and twice segmented by using pattern matching with digital atlas transformation. The atlas transformation was accomplished in two steps: global followed by local matching. Global matching was performed with use of landmarks; local matching was performed with use of a viscous fluid model. RESULTS: The mean percentage of difference between two atlas-based measurements was 1.33% +/- 1.23 (+/- standard deviation); that between two manual measurements was 4.67% +/- 4.71. The validity of the atlas transformation measurements was demonstrated by means of the high correlation (intraclass correlation coefficient = .96) with manual segmentation measurements. Schizophrenic hippocampal areas tended to be smaller; however, no differences in hippocampal shape were found between patients with schizophrenia and patients with control subjects. CONCLUSION: General pattern matching of a digital brain atlas to an individual MR image is a mathematically robust method of measurement that is reproducible and less variable than manual measurement.

Adult↗