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Biomedical subjects

M A Raskind

Publications and source records attributed to M A Raskind.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effect of chronic high-dose exogenous cortisol on hippocampal neuronal number in aged nonhuman primates.

Chronic exposure to increased glucocorticoid concentrations appears to lower the threshold for hippocampal neuronal degeneration in the old rat. It has been proposed that increased brain exposure to glucocorticoids may lower the threshold for hippocampal neuronal degeneration in human aging and Alzheimer's disease. Here, we asked whether chronic administration of high-dose cortisol to older nonhuman primates decreases hippocampal neuronal number as assessed by unbiased stereological counting methodology. Sixteen Macaca nemestrina (pigtailed macaques) from 18 to 29 years of age were age-, sex-, and weight-matched into pairs and randomized to receive either high-dose oral hydrocortisone (cortisol) acetate (4-6 mg/kg/d) or placebo in twice daily palatable treats for 12 months. Hypothalamic-pituitary-adrenal activity was monitored by measuring plasma adrenocorticotropin and cortisol, 24 hr urinary cortisol, and CSF cortisol. Urinary, plasma, and CSF cortisol were elevated, and plasma adrenocorticotropin was reduced in the active treatment group. Total hippocampal volume, subfield volumes, subfield neuronal density, and subfield total neuronal number did not differ between the experimental groups. These findings suggest that chronically elevated cortisol concentrations, in the absence of stress, do not produce hippocampal neuronal loss in nonhuman primates.

Aging↗
PubMed1999

The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series.

CONTEXT: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community. OBJECTIVE: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area. DESIGN: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein. CONCLUSIONS: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.

Aged↗
PubMed1999

Effects of Alzheimer's disease and gender on the hypothalamic-pituitary-adrenal axis response to lumbar puncture stress.

Differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to lumbar puncture (LP) stress were studied in normal elderly subjects and Alzheimer's disease (AD) patients of both genders. Elderly normal subjects had larger peak cortisol and ACTH responses than AD patients. These results contrast with some previous reports of increased HPA-axis responsivity associated with AD and suggest that AD-related changes in HPA responsiveness depend on the type of stressor involved and are mediated 'upstream' to the final common pathway to ACTH secretion. HPA-axis responsiveness also differed by gender, with higher peaks and prolonged elevations in elderly female subjects than in elderly males.

Adrenal Glands↗
PubMed1999

Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: results of a placebo-controlled, double-blind, pilot study.

Preliminary evidence from clinical studies indicates that treatment with estrogen augments cognitive function for women with Alzheimer's disease (AD). The neurobiology of estrogen, particularly its neuromodulatory and neuroprotective actions, provide a viable basis to support such cognition-enhancing effects. We conducted a placebo-controlled, double-blind, parallel-group design pilot clinical study to evaluate the cognitive and neuroendocrine response to estrogen administration for postmenopausal women with AD. Twelve women with probably AD of mild-moderate severity completed the study. During an eight week treatment period, six women received 0.05 mg/day dosage of 17 beta-estradiol via a skin patch and the remaining six wore a placebo skin patch. Subjects were randomized to equal distribution, and evaluated at baseline, at weeks 1, 3, 5, and 8 on treatment, and at weeks 9, 10, 11, and 13 off treatment. On each day of evaluation, cognition was assessed using a battery of neuropsychological tests, and blood samples were collected to measure plasma concentrations of estradiol and estrone. In addition, several neuroendocrine markers were measured in plasma to evaluate the relationship between estrogen-induced cognitive effects and fluctuations in the catecholaminergic and insulin-like growth factor systems. Significant effects of estrogen treatment were observed on attention (i.e. Stroop: number of self-corrections in the Interference condition, F[1,8] = 8.22, P < 0.03) and verbal memory (i.e., Buschke: delayed cued recall, F[3,30] = 4.31, P < 0.02). The salutary effects of estrogen on cognition were observed after the first week of treatment, and started to diminish when treatment was terminated. For women treated with estrogen, enhancement in verbal memory was positively correlated with plasma levels of estradiol (r = 0.96, P < 0.02) and negatively correlated with concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) in plasma (r = -0.92, P < 0.03). Furthermore, a trend in the data was evident to suggest a negative relationship between plasma levels of insulin-like growth factor-1 (IGF-1) and verbal memory (r = -0.86, P = 0.06). Estrogen administration suppressed peripheral markers of the IGF system, as evidenced by a negative correlation between plasma concentration of estradiol and IGF-1 (r = -0.93, P < 0.03), and a trend for a similar relationship between plasma levels of estradiol and IGFBP-3 (r = -0.86, P = 0.06). With respect to the catecholamines assayed, norepinephrine was positively correlated with verbal memory (r = 0.95, P < 0.02) for women who were treated with estrogen. Furthermore, there was a trend to suggest a negative relationship between plasma epinephrine levels and the number of errors committed on a test of attention (r = -0.84, P = 0.07). In the placebo group, no significant effects of estrogen replacement were evident either on measures of cognition or on any of the neuroendocrine markers. The results of this study suggest that estrogen replacement may enhance cognition for postmenopausal women with AD. Furthermore, several markers of neuroendocrine activity may serve to index the magnitude of estrogen-induced facilitation on cognition. In addition, research findings from the present study will provide important information for the design of larger prospective clinical studies that are essential to definitively establish the therapeutic role of estrogen replacement for postmenopausal women with AD.

Administration, Cutaneous↗
PubMed1999

The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's disease patients. Metrifonate Study Group.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of metrifonate, a long-acting acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease of mild-to-moderate severity. METHOD: This was a prospective, multicenter, 26-week, double-blind, parallel group study. The 264 randomized patients met diagnostic criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association for probable Alzheimer's disease. Patients had Mini-Mental State Examination (MMSE) scores of 10-26 and ischemic scores (Rosen modification) of <4. Metrifonate-treated patients received a single 50-mg dose once daily. The efficacy of metrifonate was investigated with respect to 3 symptom domains. Cognitive performance was analyzed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the MMSE. Psychiatric and behavioral disturbances were analyzed using the Neuropsychiatric Inventory (NPI) and the ADAS-Noncognitive subscale (ADAS-Noncog). The ability to perform instrumental and basic activities of daily living was evaluated using the Disability Assessment for Dementia (DAD) scale. Additionally, global state was assessed using the Clinician Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus) scale. RESULTS: After 26 weeks of metrifonate therapy, a statistically significant benefit of metrifonate was observed in the cognitive performance of Alzheimer's disease patients (ADAS-Cog, t = 2.55, df = 237, p = .012; MMSE, t = 4.60, df = 237, p = .0001). Metrifonate also significantly attenuated the deterioration in activities of daily living of the patients (DAD total score, t = -2.11, df = 233, p = .036) and relieved patients' psychiatric and behavioral disturbances (NPI total score, t = 2.51, df = 233, p = .013). In addition, metrifonate significantly improved the scores for the global state of the patients (CIBIC-Plus, t = 2.07, df = 232, p = .039). Metrifonate was well tolerated; adverse events were predominantly mild in intensity, and no hepatotoxicity was observed. CONCLUSION: In this study, metrifonate was safe and well tolerated. It benefited the cognitive decline, psychiatric and behavioral disturbances, impaired ability to perform instrumental and basic activities of daily living, and global state of patients diagnosed with mild-to-moderate Alzheimer's disease.

Activities of Daily Living↗
PubMed1999

Evaluation and management of aggressive behavior in the elderly demented patient.

Aggression is common in elderly patients with dementia and often leads to placement of these patients in long-term care facilities. Unfortunately, identification and evaluation of aggression is sometimes hindered by disagreement as to how aggression is distinguished from agitation. Aggression in elderly patients with dementia is best understood as a product of the interaction of neurobiological, cognitive, and environmental factors. Such a complex etiology calls for an approach to treatment that considers pharmacologic therapy as well as environmental manipulation; however, further research is needed to clarify the causes of aggression in elderly patients with dementia and thus allow the refinement of approaches to treatment.

Age Factors↗
PubMed1999

Preservation of noradrenergic neurons in the locus ceruleus that coexpress galanin mRNA in Alzheimer's disease.

Galanin (GAL) innervation is hypertrophied in the basal forebrain and cortex of patients with Alzheimer's disease (AD). Increased GAL could exacerbate the cognitive and behavioral deficits of AD because GAL acts as an inhibitory modulator of cholinergic and noradren-ergic neurotransmission. The locus ceruleus (LC) may be a source of increased GAL in AD because (a) GAL is coexpressed in a subset of LC neurons, (b) GAL expression is up-regulated with neuronal injury, and (c) the LC undergoes extensive degeneration in AD. Therefore, we have used in situ hybridization histochemistry to measure GAL gene expression in the LC of AD patients and sex- and age-matched nondemented controls. Despite the extensive loss of norepinephrine neurons with AD, GAL mRNA-expressing neurons in the LC did not differ between groups. This resulted in a significant increase in the percentage of neuromelanin-pigmented cells that coexpressed GAL in AD patients compared with controls. These findings raise the possibility that the increased incidence of GAL expression among remaining LC neurons contributes to the hyperinnervation of GAL fibers in AD. Furthermore, GAL may be neuroprotective in the LC.

Aged↗
PubMed1998

Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder.

BACKGROUND: Although experimental induction of panic by infusion of 0.5 mol/L sodium lactate in persons with panic disorder was described three decades ago, the mechanism underlying this observation remains unclear. Here we asked if the rapid administration of the large sodium load contained in the 0.5-mol/L sodium lactate infusion might be involved in panic induction. METHODS: We compared in panic disorder and healthy subjects behavioral, electrolyte, endocrine, and acid-base responses to three double-blind randomly ordered equal volume 20-min infusions: 0.5 mol/L sodium lactate, hypertonic saline (3% sodium chloride), and normal saline placebo. RESULTS: Sodium lactate (0.5 mol/L) and hypertonic saline produced the same high incidence of panic and equivalent increases in panic symptoms, serum sodium, and plasma vasopressin in the panic disorder subjects. Neither hypertonic infusion increased cortisol or adrenocorticotropin. No normal subject experienced panic in any condition. The 0.5-mol/L sodium lactate infusion induced alkalosis, whereas hypertonic saline and normal saline induced a mild acidosis. CONCLUSIONS: Hypertonic sodium solution containing either chloride or lactate anion induces panic in panic disorder. The large sodium loads delivered by hypertonic saline and 0.5 mol/L sodium lactate may be involved in the mechanism of panic induction.

Acidosis↗
PubMed1998

Few cholinergic neurons in the rat basal forebrain coexpress galanin messenger RNA.

The concept that galanin (GAL) is cosecreted with acetylcholine (ACh) into the ventral hippocampus is a major component of the current model delineating GAL regulation of the cholinergic memory pathways in the rat. Although GAL-immunoreactivity coexists in 50-70% of cholinergic neurons in the basal forebrain (BF) of colchicine-treated rats, the actual coexistence of these neurotransmitters in the basal state may be lower, because colchicine treatment was recently shown to both induce GAL gene expression and inhibit choline acetyltransferase (ChAT) gene expression in this brain region. We have used single and double in situ hybridization histochemistry to examine the distribution and coexistence of GAL and ChAT mRNAs in the BF of male and female rats. Compared with other forebrain regions, few GAL mRNA-expressing neurons are present within the cholinergic fields of the BF. The greatest number of GAL mRNA-expressing cells in this region are located within the nucleus of the horizontal limb of the diagonal band; but, even in this region, they represent only a small percentage (<20%) of ChAT mRNA-expressing cells. Our results indicate that few cholinergic neurons in the rat BF coexpress GAL mRNA and suggest that, in the basal state, GAL is not widely cosecreted with ACh into hippocampal memory centers.

Acetylcholine↗
PubMed1998

Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis.

The presence of the neuropathological alterations of Alzheimer's disease (AD) in essentially all older Down syndrome (DS) patients suggests that the examination of younger DS patients may clarify the early pathological progression of AD. We examined the hippocampus and parahippocampal-inferior temporal gyri of 42 DS patients (ages 4 days to 38 years) for the deposition of amyloid beta protein (Abeta) using both a modified Bielschowsky stain and immunohistochemistry for Abeta protein. The parahippocampal and inferior temporal gyri demonstrated Abeta staining in cases as young as 8 years of age. As age and degree of Abeta deposition increased, staining included the CA-1/subiculum and dentate molecular layer followed then by the remainder of the CA hippocampal regions. The first neuritic plaques were observed in the CA-1/subiculum, despite this being a later region of Abeta deposition. Although Abeta staining increased with age, there was substantial variability in the severity of Abeta deposition within age groups. These results suggest that within the hippocampal/parahippocampal region there is a progressive stereotypic deposition of Abeta. The variable severity of Abeta deposition within age groups suggests that other factors, besides DS, may be contributing to the timing and severity of Abeta deposition.

Adolescent↗
PubMed1998

Cerebrospinal fluid epinephrine in Alzheimer's disease and normal aging.

Central nervous system (CNS) adrenergic systems are involved in regulation of behavior and blood pressure. The effects of Alzheimer's disease (AD) and normal aging on resting CNS adrenergic activity were estimated by measuring cerebrospinal fluid (CSF) epinephrine (EPI) concentrations in 74 persons with AD, 42 cognitively normal healthy older persons, and 54 healthy young persons. The responsiveness of CSF EPI to the alpha-2 adrenergic antagonist yohimbine and the alpha-2 adrenergic agonist clonidine was measured in smaller subject groups. Resting CSF EPI was higher in AD than in older or young subjects, and increased with dementia severity in AD subjects. There was no relationship between resting CSF EPI and blood pressure. CSF EPI increased following yohimbine in AD and older subjects but not in young subjects. CSF EPI was unaffected by clonidine in all subject groups. The agitation increase following yohimbine was substantially greater in AD subjects than in older or young subjects. CNS adrenergic activity seems increased in AD, may further increase as AD progresses, and may be involved in the pathophysiology of agitation.

Adrenergic alpha-Agonists↗
PubMed1998

The clinical interface of depression and dementia.

The interface between depression and dementia is complex and has been studied primarily in Alzheimer's disease. This article discusses several aspects of this intriguing area of clinical research, including depressive pseudodementia and the possibility that depression may be a risk factor for the expression of Alzheimer's disease in later life and that depression may occur as a prodrome for this most common dementing disorder. In addition, the treatment challenges faced by clinicians when depression complicates the course of Alzheimer's disease are addressed. It is likely that a combination of behavioral treatment and use of antidepressant medication will provide the optimal management of depression in Alzheimer's disease.

Alzheimer Disease↗
PubMed1998

Psychopharmacology of noncognitive abnormal behaviors in Alzheimer's disease.

Disruptive agitation and psychotic symptoms are important problems in the management of Alzheimer's disease and are major determinants of nursing home placement. This article reviews interpretable, placebo-controlled studies of psychopharmacologic approaches to the treatment of these "noncognitive" psychiatric and behavioral problems. Clinical trials of antipsychotic drugs demonstrate modest efficacy for psychosis and agitation, but adverse effects are common. Trials of serotonin selective reuptake inhibitors suggest they may be effective for emotional disturbances complicating Alzheimer's disease. Trials of drugs that enhance central cholinergic activity (certain cholinesterase inhibitors and selective M1 muscarinic cholinergic agonists) demonstrate positive effects on both cognitive deficits and noncognitive psychiatric and behavioral problems. Further clinical studies are needed to provide guidelines for the management of noncognitive psychiatric and behavioral problems in Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

GALR1 galanin receptor mRNA is co-expressed by galanin neurons but not cholinergic neurons in the rat basal forebrain.

The neuropeptide galanin (GAL) has been proposed to be an inhibitory modulator of cholinergic transmission in the hippocampus and may impair memory by directly affecting the activity of basal forebrain (BF) cholinergic neurons. Alternatively, GAL may act indirectly and modulate the activity of other neurotransmitter systems which, in turn, influence cholinergic transmission. We have used double in situ hybridization histochemistry to evaluate the co-expression of the GAL receptor subtype, GALR1, within cholinergic neurons in the medial septum/diagonal band of adult male rats. In alternate brain sections, we assessed the co-expression of GALR1 mRNA within another forebrain cell group implicated in memory functions, the neurons of the bed nucleus of the stria terminalis (BNST) and medial amygdala (AMe) which co-express vasopressin (VP) and GAL and project to septo-hippocampus. Despite the abundance of GALR1 mRNA-expressing neurons in the cholinergic BF, we found no evidence for the co-expression of this receptor subtype within cholinergic neurons in the medial septum/diagonal band. In contrast, we detected an extensive co-expression (95%) of GALR1 mRNA within extrahypothalamic VP/GAL neurons. These results do not support the idea that GAL, acting via the GALR1 receptor, directly impairs BF cholinergic neurons but suggest, instead, that non-cholinergic neurons in the BF may play a role in mediating the inhibitory actions of GAL on cholinergic function. However, our findings provide anatomical evidence that GAL could directly modulate the activity and/or secretion pattern of extrahypothalmic VP/GAL neurons into septo-hippocampal regions.

Acetylcholine↗
PubMed1997

Estrogen regulates galanin but not tyrosine hydroxylase gene expression in the rat locus ceruleus.

The neuropeptide galanin (GAL) is coexpressed by the majority of noradrenergic neurons in the rat locus ceruleus (LC) and may function as an inhibitory modulator of noradrenergic transmission. Because estrogen has been shown to induce GAL expression in other brain regions and modulate noradrenergic transmission, we used in situ hybridization histochemistry to assess the effects of chronic estrogen treatment on GAL and tyrosine hydroxylase (TH) gene expression in the LC of ovariectomized female rats. We found that GAL mRNA levels were significantly elevated in rats implanted with a Silastic capsule containing estradiol compared to sham-implanted controls. Both the average optical density (P < or = 0.05) and the labelling area (P < or = 0.007) differed significantly between the groups. In contrast, TH gene expression measured in alternate brain sections did not differ between the groups. If GAL functions as an inhibitory modulator of noradrenergic transmission as postulated, these findings suggest that chronic estrogen treatment could reduce the noradrenergic tone of the brain in the absence of significant alterations in TH expression by enhancing the level of cosecreted GAL.

Analysis of Variance↗