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Biomedical subjects

Murray A Raskind

Publications and source records attributed to Murray A Raskind.

At least 19 recordsLinked to original sources
PubMed2006

A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder.

BACKGROUND: Excessive brain responsiveness to norepinephrine appears to contribute to post-traumatic stress disorder (PTSD), particularly at night. Prazosin, a brain active alpha-1 adrenergic receptor antagonist, significantly reduced trauma nightmares and sleep disturbance in 10 Vietnam War combat veterans in a previous placebo-controlled crossover study. The current parallel group trial in a larger sample of veterans evaluated prazosin effects on trauma nightmares, sleep quality, global clinical status, dream characteristics, and comorbid depression. METHODS: Forty veterans (mean age 56 +/- 9) with chronic PTSD and distressing trauma nightmares and sleep disturbance were randomized to evening prazosin (13.3 +/- 3 mg/day) or placebo for 8 weeks. RESULTS: In the evaluable sample (n = 34), primary outcome measures demonstrated that prazosin was significantly superior to placebo for reducing trauma nightmares and improving sleep quality and global clinical status with large effect sizes. Prazosin shifted dream characteristics from those typical of trauma-related nightmares toward those typical of normal dreams. Blood pressure changes from baseline to end study did not differ significantly between prazosin and placebo. CONCLUSIONS: Prazosin is an effective and well-tolerated treatment for trauma nightmares, sleep disturbance and global clinical status in veterans with chronic PTSD.

Adrenergic alpha-Antagonists↗
PubMed2006

Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats.

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n=11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all p<0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.

Abdominal Fat↗
PubMed2006

Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder.

BACKGROUND: Persons with posttraumatic stress disorder (PTSD) whose trauma-related nightmares improve or resolve with bedtime administration of the alpha-1 adrenergic antagonist prazosin often continue to experience PTSD symptoms during the day. This study addressed whether daytime prazosin compared to placebo would alleviate psychological distress provoked experimentally by a trauma-related word list included in the emotional Stroop (E-Stroop) paradigm. METHODS: Eleven persons with civilian trauma PTSD who continued to experience daytime PTSD symptoms despite a stable bedtime prazosin dose that suppressed trauma-related nightmares were studied. Prazosin and placebo were administered on two different occasions in the early afternoon followed two hours later by the E-Stroop. Effects of drug on psychological distress were assessed by the Profile of Mood States (POMS). RESULTS: POMS total score and an "emotional distress" POMS subscale score following trauma-related words were significantly lower in the prazosin than placebo condition. There were no treatment effects on E-Stroop completion time. In 10 subjects who continued open label daytime prazosin, there was a reduction in global PTSD illness severity at 2-week follow-up. CONCLUSIONS: Daytime prazosin pretreatment reduced psychological distress specifically to trauma cues. Adding daytime prazosin to bedtime prazosin may further reduce overall PTSD illness severity and distress.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2006

Compensatory changes in the noradrenergic nervous system in the locus ceruleus and hippocampus of postmortem subjects with Alzheimer's disease and dementia with Lewy bodies.

In Alzheimer's disease (AD), there is a significant loss of locus ceruleus (LC) noradrenergic neurons. However, functional and anatomical evidence indicates that the remaining noradrenergic neurons may be compensating for the loss. Because the noradrenergic system plays an important role in learning and memory, it is important to determine whether compensation occurs in noradrenergic neurons in the LC and hippocampus of subjects with AD or a related dementing disorder, dementia with Lewy bodies (DLB). We observed profound neuronal loss in the LC in AD and DLB subjects with three major changes in the noradrenergic system consistent with compensation: (1) an increase in tyrosine hydroxylase (TH) mRNA expression in the remaining neurons; (2) sprouting of dendrites into peri-LC dendritic zone, as determined by alpha2-adrenoreceptors (ARs) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections to the hippocampus as determined by alpha2-ARs. In AD and DLB subjects, the postsynaptic alpha1-ARs were normal to elevated. Expression of alpha1A- and alpha2A-AR mRNA in the hippocampus of AD and DLB subjects were not altered, but expression of alpha1D- and alpha2C-AR mRNA was significantly reduced in the hippocampus of AD and DLB subjects. Therefore, in AD and DLB subjects, there is compensation occurring in the remaining noradrenergic neurons, but there does appear to be a loss of specific AR in the hippocampus. Because changes in these noradrenergic markers in AD versus DLB subjects were similar (except neuronal loss and the increase in TH mRNA were somewhat greater in DLB subjects), the presence of Lewy bodies in addition to plaques and tangles in DLB subjects does not appear to further affect the noradrenergic compensatory changes.

Adrenergic alpha-Antagonists↗
PubMed2006

Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype.

BACKGROUND: The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood. OBJECTIVE: To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes. METHODS: Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using alpha-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions. RESULTS: The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP. CONCLUSION: These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.

Adult↗
PubMed2006

Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition.

BACKGROUND: Decreased cerebrospinal fluid (CSF) beta-amyloid 42 (A beta 42) concentration, but not A beta 40 concentration, is a biomarker for Alzheimer disease. This A beta 42 concentration decrease in CSF likely reflects precipitation of A beta 42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease. OBJECTIVE: To estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF A beta 42 concentration in adults with normal cognition across the life span. DESIGN: The CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF A beta 42 and A beta 40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method. Subjects One hundred eighty-four community volunteers with normal cognition aged 21 to 88 years. RESULTS: The CSF A beta 42, but not the A beta 40, concentration decreased significantly with age. There was a sharp decrease in CSF A beta 42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF A beta 42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele. CONCLUSION: These CSF A beta 42 findings are consistent with acceleration by the APOE*4 allele of pathogenic A beta 42 brain deposition starting in later middle age in persons with normal cognition.

Adult↗
PubMed2006

Chronic daily ethanol and withdrawal: 6. Effects on rat sympathoadrenal activity during "abstinence".

We have reported that repetitive daily ethanol consumption increased anxiety-like behavior in rats 4 weeks after ethanol consumption had ceased, consistent with the persistently increased anxiety exhibited by abstinent alcoholics. Increased anxiety is associated with sympathoadrenal activation, so we have now also investigated ethanol-induced persistent changes in basal and stress-induced plasma epinephrine (E) and norepinephrine (NE) levels. Male Sprague-Dawley rats received liquid diet containing ethanol versus pair-fed isocaloric control liquid diet for 9 weeks. After 5 weeks' subsequent "abstinence" (i.e., no ethanol in the diet), the control rats exhibited low basal plasma E and NE, which were both increased by 150-300% within 5 min after transfer to a novel cage in a novel room, returning toward basal levels within 15 min. "Abstinent" ethanol-treated rats exhibited elevated basal E levels (195% of controls, P<.05), which were not significantly altered by transfer to novel environment; basal NE levels tended (P<.07) to be elevated and likewise were not altered by novel environment. These results suggest that daily ethanol consumption can induce persistent increases in sympathoadrenal activation during subsequent "abstinence," which are relatively refractory to further stimulation.

Animals↗
PubMed2005

Salivary cortisol and memory function in human aging.

OBJECTIVE: To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition. METHODS: Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually. RESULTS: The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall. CONCLUSION: These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.

Aged↗
PubMed2005

Alpha1-adrenoreceptor in human hippocampus: binding and receptor subtype mRNA expression.

Alpha1-adrenoreceptors (AR), of which three subtypes exist (alpha1A-, alpha1B- and alpha1D-AR) are G-protein-coupled receptors that mediate the actions of norepinephrine and epinephrine both peripherally and centrally. In the CNS, alpha1-ARs are found in the hippocampus where animal studies have shown the ability of alpha1-AR agents to modulate long-term potentiation and memory; however, the precise distribution of alpha1-AR expression and its subtypes in the human brain is unknown making functional comparisons difficult. In the human hippocampus, 3H-prazosin (alpha1-AR antagonist) labels only the dentate gyrus (molecular, granule and polymorphic layers) and the stratum lucidum of the CA3 homogeneously. Human alpha1A-AR mRNA in the hippocampus is observed only in the dentate gyrus granule cell layer, while alpha1D-AR mRNA expression is observed only in the pyramidal cell layers of CA1, CA2 and CA3, regions where 3H-prazosin did not bind. alpha1B-AR mRNA is not expressed at detectable levels in the human hippocampus. These results confirm a difference in hippocampal alpha1-AR localization between rat and humans and further describe a difference in the localization of the alpha1A- and alpha1D-AR mRNA subtype between rats and humans.

Aged↗
PubMed2005

Gonadotrophin-releasing hormone agonist treatment of aggression in Alzheimer's disease: a case report.

No medication has received regulatory approval in the U.S.A. for the distressing agitation and aggressive behaviors that often complicate dementia. Although studies suggest that several psychotropic medications are sometimes useful for these behavioral problems, response is variable and adverse effects often limit treatment. Theoretical considerations suggest that increasing estrogenic activity or reducing androgenic activity could reduce agitation and aggression in dementia. Estrogen has been reported helpful for these symptoms, but adverse effects are problematic. Chronic administration of the synthetic gonadotropin (luteinising hormone) releasing hormone analogue, goserelin, reduces testosterone activity. Here we describe the apparently sustained elimination of previously treatment-resistant agitation and aggression with goserelin treatment in a 78-year-old male nursing-home resident with Alzheimer's disease.

Aged↗
PubMed2004

The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial.

BACKGROUND: Alzheimer disease (AD) causes progressive cognitive and functional decline over years. Although cholinesterase inhibitors have demonstrated efficacy in studies lasting 3 to 6 months, little is known about long-term therapy. OBJECTIVE: To report the long-term cognitive effects of galantamine hydrobromide given continuously for 36 months in AD patients. PARTICIPANTS: Subjects were 194 US patients with mild to moderate AD who had been randomized to continuous galantamine therapy in either of 2 double-blind placebo-controlled trials. Subjects subsequently received open-label continuous galantamine therapy for up to 36 months. MAIN OUTCOME MEASURES: Effects on cognition were analyzed as change from study enrollment baseline in scores on the Alzheimer's Disease Assessment Scale-11-item cognitive subscale. Cognitive decline in galantamine-treated subjects was compared with that in a clinically similar historical control sample of AD patients who had received placebo for 12 months and with the mathematically predicted decline of untreated patients over 36 months. The rate of cognitive decline of patients who completed the entire 36-month trial (n = 119) was compared with that of patients who withdrew for any reason during the long-term open-label extension (n = 75). An inverted responder analysis was also performed in 36-month completers. RESULTS: Patients treated continuously with galantamine for 36 months increased a mean +/- SE of 10.2 +/- 0.9 points on the Alzheimer's Disease Assessment Scale-11-item cognitive subscale-a substantially smaller cognitive decline (approximately 50%) than that predicted for untreated patients. Patients discontinuing galantamine therapy before 36 months had declined at a similar rate before discontinuation as those completing 36 months of treatment. Almost 80% of patients who received galantamine continuously for up to 36 months seemed to demonstrate cognitive benefits compared with those predicted for untreated patients. CONCLUSIONS: Cognitive decline over 36 months of continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients with mild to moderate dementia. Thus, the cognitive benefits of galantamine seemed to be sustained for at least 36 months. These findings suggest that galantamine slows the clinical progression of AD.

Aged↗
PubMed2004

Chronic cortisol exposure promotes the development of a GABAergic phenotype in the primate hippocampus.

Glucocorticoids regulate plasticity and survival of hippocampal neurons. Aberrant exposure to this steroid hormone can result in neurodegeneration, perhaps secondary to disruption of calcium homeostasis. Calbindin, a calcium-binding protein that buffers excess calcium, may protect against neurodegeneration resulting from overabundance of intracellular calcium. In this study, we examined whether chronic treatment (1 year) with cortisol enhances hippocampal calbindin expression in primates. Calbindin is a marker for inhibitory neurons and the dentate gyrus is known to adopt an inhibitory phenotype in response to extreme conditions such as seizures. Thus, we hypothesized that chronic cortisol exposure may also promote a GABAergic phenotype. Therefore, we examined the expression of the GABA-synthesizing enzyme glutamic acid decarboxylase. The expression of brain-derived neurotrophic factor, which is responsive to glucocorticoids, was also examined. Our results demonstrate significant increases in calbindin, glutamic acid decarboxylase and brain-derived neurotrophic factor in several regions of the primate hippocampus, including the dentate gyrus and CA3, in response to chronic cortisol exposure. These results suggest that chronic cortisol exposure may shift the balance towards a GABAergic phenotype, perhaps as part of a compensatory feedback mechanism to dampen the initial excitatory effects of glucocorticoids in the hippocampus.

Animals↗
PubMed2003

Update on Alzheimer drugs (galantamine).

BACKGROUND: Deficient cholinergic function contributes to the cognitive and behavioral signs and symptoms of Alzheimer disease (AD). A successful treatment approach in AD has been the enhancement of cholinergic function by cholinesterase inhibitors. REVIEW SUMMARY: Galantamine is a cholinesterase inhibitor and allosteric modulating ligand at nicotinic cholinergic receptors. Galantamine 24 mg/d has been demonstrated consistently effective compared with placebo for the cognitive, functional, and behavioral aspects of Alzheimer's disease in large multicenter trials. Cognition and function on average are preserved for 12 months in Alzheimer disease patients receiving galantamine. It is safe and very well tolerated when dosage is escalated gradually. CONCLUSIONS: Galantamine is a valuable addition to agents available for the pharmacologic treatment of AD.

Alzheimer Disease↗
PubMed2003

Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study.

OBJECTIVE: Prazosin is a centrally active alpha(1) adrenergic antagonist. The authors' goal was to evaluate prazosin efficacy for nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) in combat veterans. METHOD: Ten Vietnam combat veterans with chronic PTSD and severe trauma-related nightmares each received prazosin and placebo in a 20-week double-blind crossover protocol. RESULTS: Prazosin (mean dose=9.5 mg/day at bedtime, SD=0.5) was superior to placebo for the three primary outcome measures: scores on the 1) recurrent distressing dreams item and the 2) difficulty falling/staying asleep item of the Clinician-Administered PTSD Scale and 3) change in overall PTSD severity and functional status according to the Clinical Global Impression of change. Total score and symptom cluster scores for reexperiencing, avoidance/numbing, and hyperarousal on the Clinician-Administered PTSD Scale also were significantly more improved in the prazosin condition, and prazosin was well tolerated. CONCLUSIONS: These data support the efficacy of prazosin for nightmares, sleep disturbance, and other PTSD symptoms.

Adrenergic alpha-Antagonists↗
PubMed2003

Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder.

Trauma-related nightmares in posttraumatic stress disorder (PTSD) rarely respond to pharmacologic treatment. Neurobiologic data suggest that enhanced brain responsiveness to adrenergic stimulation may contribute to the pathophysiology of trauma-related nightmares in PTSD. Nine older men with chronic PTSD secondary to military or Holocaust trauma were prescribed the lipophilic alpha-1 adrenergic antagonist prazosin for treatment-resistant trauma-related nightmares. Prazosin 2 mg to 4 mg 1 hour before bedtime substantially reduced nightmares and moderately or markedly reduced overall PTSD severity in 8 of 9 subjects. Prazosin was well tolerated. These open-label results are consistent with demonstrated therapeutic efficacy of prazosin for PTSD nightmares and sleep disturbance in a recent placebo-controlled trial in Vietnam veterans.

Adrenergic alpha-Antagonists↗