ABCB1 genotype and CSF beta-amyloid in Alzheimer disease.

The ABCB1 gene, coding for the efflux transporter P-glycoprotein (PGP), is a candidate gene for Alzheimer disease (AD). P-glycoprotein is heavily expressed at the blood-brain barrier, where it mediates the efflux of ß-amyloid (Aß) from the brain. In this study, we investigated a possible association between 2 common ABCB1 polymorphisms, G2677T/A (Ala893Ser/Thr) and C3435T, AD, and cerebrospinal fluid (CSF) levels of Aß. No strong evidence for association was found.

Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease.

BACKGROUND: Treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors ("statins") has been associated in some epidemiologic studies with reduced risk of Alzheimer disease (AD). However, direct evidence of statin effects on neuropathologic markers of AD is lacking. We investigated whether antecedent statin exposure is associated with neuritic plaque (NP) or neurofibrillary tangle (NFT) burden in a population-based sample of human subjects. METHODS: Brain autopsies were performed on 110 subjects, ages 65 to 79 years, who were cognitively normal at enrollment into the Adult Changes in Thought Study. Neuropathologic findings were compared between statin users with > or =3 prescriptions of > or =15 pills of simvastatin, pravastatin, lovastatin, or atorvastatin vs nonusers, based on pharmacy dispensing records. RESULTS: After controlling for age at death, gender, cognitive function at study entry, brain weight, and presence of cerebral microvascular lesions, the odds ratio (OR) for each unit increase in Braak NFT stage in statin users vs nonusers was 0.44 (95% CI: 0.20 to 0.95). The OR for each unit increase in Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging of NPs did not deviate significantly from unity (OR 0.69; 95% CI: 0.32 to 1.52). However, the risk for typical AD pathology (Braak stage > or = IV and CERAD rating > or = moderate) was reduced in statin users (OR 0.20; 95% CI: 0.05 to 0.86). CONCLUSIONS: These findings demonstrate an association between antecedent statin use and neurofibrillary tangle burden at autopsy. Additional study is needed to examine whether statin use may be causally related to decreased development of Alzheimer disease-related neuropathologic changes.

Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.

BACKGROUND: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. METHODS: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). RESULTS: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. CONCLUSIONS: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.

Increased CSF cortisol in AD is a function of APOE genotype.

BACKGROUND: Increased hypothalamic-pituitary-adrenal (HPA) axis activity manifested by elevated cortisol levels is observed in AD and may contribute to AD by lowering the threshold for neuronal degeneration. Presence of the APOE-epsilon4 allele increases risk for AD. Increased cortisol concentrations in apoE-deficient mice suggest that APOE genotype may influence cortisol concentrations in AD. METHODS: The authors measured cortisol levels in CSF and determined APOE genotypes for 64 subjects with AD and 34 nondemented older control subjects. RESULTS: CSF cortisol was significantly higher in AD than in control subjects. CSF cortisol concentrations differed with respect to APOE genotype in both subjects with AD (epsilon4/epsilon4 > epsilon3/4epsilon > epsilon3/epsilon3) and normal older control subjects (epsilon3/epsilon4 > epsilon3/epsilon3 > epsilon2/epsilon3). Comparison of CSF cortisol concentrations within the epsilon3/epsilon4 and epsilon3/epsilon3 genotypes revealed no differences between AD and control subject groups. CONCLUSIONS: Higher CSF cortisol concentrations were associated with increased frequency of the APOE-epsilon4 allele and decreased frequency of the APOE-epsilon2 allele in AD subjects relative to control subjects. This effect of APOE genotype on HPA axis activity may be related to the increased risk for AD in persons carrying the APOE-epsilon4 allele and decreased risk for AD in persons carrying the APOE-epsilon2 allele.

Human glucocorticoid feedback inhibition is reduced in older individuals: evening study.

We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20-35 yr, n = 22) and old (>65 yr, n = 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids.

Plasma catecholamine and cardiovascular responses to physostigmine in Alzheimer's disease and aging.

Stimulation of brain cholinergic systems increases activity of both the sympathoneural (SN) and sympathoadrenomedullary (SAM) components of the peripheral sympathetic nervous system. Because presynaptic cholinergic neuron numbers are substantially reduced in Alzheimer's disease (AD), we predicted decreased responsiveness in AD of plasma norepinephrine (NE), an estimate of SN activity, and of epinephrine (EPI), an estimate of SAM activity, to central cholinergic stimulation by the cholinesterase inhibitor physostigmine (0.0125 mg/kg i.v.). Because previous studies have demonstrated that normal human aging increases SN activity but not SAM activity, we specifically hypothesized: (1) a smaller NE response to physostigmine in subjects with mild to moderate AD (n=11; age 72+/-2 yrs; mini-mental state exam [MMSE] scores of 19+/-2) than in healthy older subjects (n=20; age 71+/-1 yrs); and (2) a smaller EPI response in AD subjects than in either healthy older or healthy young subjects (n=9; age 27+/-2 yrs). Unexpectedly, the plasma NE increase following physostigmine only achieved significance in AD subjects and plasma EPI responses were greater in both AD and older subjects than in young subjects. Blood pressure responses to physostigmine were consistent with the catecholamine responses. These data suggest that the presence of mild to moderate AD increases the SN response to cholinergic stimulation and that both AD and normal aging increase the SAM response to cholinergic stimulation. As a result, plasma catecholamine responses to physostigmine do not appear to be useful peripheral neuroendocrine estimates of the severity of brain cholinergic deficits in mild to moderate AD.

Hypothalamic pituitary adrenocortical and sympathetic nervous system responses to the cold pressor test in Alzheimer's disease.

BACKGROUND: Increased basal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been repeatedly demonstrated in Alzheimer's disease (AD), and some studies suggest increased basal activity of the sympathetic nervous system (SNS) in this disorder; however, the effects of AD on HPA axis or SNS responses to a standardized aversive stressor have not been examined. The neuroendocrine response to aversive stress may be relevant to the pathophysiology of AD. METHODS: Plasma adrenocorticotropic hormone (ACTH), cortisol, norepinephrine (NE), and epinephrine responses to a 1-min cold pressor test (CPT) were measured in nine medically healthy AD outpatients (age 76 +/- 2 years) and nine age- and gender-matched medically healthy cognitively normal older subjects (age 76 +/- 1 year). RESULTS: The cortisol response to CPT was increased in the AD group but the ACTH response did not differ between groups. Basal NE concentrations were higher in the AD group. Although NE responses to CPT did not differ between groups, the blood pressure response to CPT was higher in the AD subjects. CONCLUSIONS: These results suggest increased HPA axis responsiveness to CPT at the level of the adrenal cortex in AD. The results also suggest increased basal sympathoneural activity and increased cardiovascular responsiveness to sympathoneural stimulation in AD under the conditions of this experimental protocol. Increased SNS stimulatory modulation of the adrenal cortex is a possible mechanism contributing to the observed enhanced cortisol response to CPT in these AD subjects.

Increased plasma norepinephrine response to yohimbine in elderly men.

BACKGROUND: The effects of aging on sympathetic nervous system and adrenomedullary outflow were estimated by the measurement of plasma norepinephrine (NE) and epinephrine (EPI) responses to yohimbine and clonidine in healthy young and healthy older subjects. METHODS: Yohimbine (0.65 mg/kg), clonidine (5 microg/kg), and placebo were administered on separate days in random order to 5 healthy older men (age 74 +/- 1 years) and 18 healthy young men (age 26 +/- 1 years). NE and EPI were measured by radioenzymatic assay in plasma samples obtained before and 30, 60, and 90 minutes after drug administration. RESULTS: Plasma NE increases after yohimbine were greater in older men than in young men. but plasma NE decreases following clonidine did not differ between groups. Plasma NE and systolic blood pressure were higher in older men than in young men at baseline but no longer differed 90 minutes after clonidine. Plasma EPI increases after yohimbine and decreases after clonidine did not differ between groups. CONCLUSIONS: These results suggest increased sympathetic nervous system outflow in human aging that is not a function of reduced responsiveness of alpha-2 adrenoreceptor-mediated feedback inhibition.

The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases.

BACKGROUND: Central nervous system (CNS) adrenergic hyperresponsiveness may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). Two Vietnam combat veterans with PTSD prescribed the centrally active alpha1-adrenergic antagonist prazosin for symptoms of benign prostatic hypertrophy unexpectedly reported elimination of combat trauma nightmares. This observation prompted an open-label feasibility trial of prazosin for combat trauma nightmares in chronic combat-induced PTSD. METHOD: Four consecutively identified combat veterans with chronic DSM-IV PTSD and severe intractable combat trauma nightmares participated in an 8-week open trial of escalating-dose prazosin. Nightmare severity response was rated using the nightmare item of the Clinician Administered PTSD Scale and the Clinical Global Impressions-Change scale. RESULTS: The 2 patients who achieved a daily prazosin dose of at least 5 mg were markedly improved, with complete elimination of trauma nightmares and resumption of normal dreaming. The 2 subjects limited to 2 mg of prazosin to avoid excessive blood pressure reduction were moderately improved with at least 50% reduction in nightmare severity. CONCLUSION: These clinical observations, together with neurobiological evidence for alpha1-adrenergic regulation of CNS neurobiological systems relevant to PTSD, provide rationale for placebo-controlled trials of prazosin for PTSD combat trauma nightmares.

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.

Effects of advanced aging on plasma catecholamine responses to the cold pressor test.

Increased basal norepinephrine (NE) concentrations have been demonstrated repeatedly in human aging, but these studies have included almost exclusively "early aging" subjects younger than age 75. We asked if "advanced aging" (over age 80) enhanced the effects of early aging on plasma NE and epinephrine (EPI) concentrations at rest and in response to the cold pressor test (CPT). Eight medically well, cognitively intact advanced aging subjects (84.4+/-0.9 years), 28 medically well cognitively intact early aging subjects (70.3+/-1.3 years), and 19 medically well young subjects (25.4+/-0.9 years) were studied. Both basal NE and the acute NE increase after CPT were significantly higher in advanced aging than in either early aging or young subjects. Plasma EPI concentrations were higher in the advanced aging group than in the other groups and an acute plasma EPI increase after CPT occurred only in the advanced aging group. These results suggest specific effects of advanced aging on both the sympathoneural and sympathoadrenomedullary components of the sympathetic nervous system.

Bupropion and desipramine increase dopamine transporter mRNA expression in the ventral tegmental area/substantia nigra of rat brain.

1. Regulation of dopamine transporter (DAT) mRNA was studied in rats treated with the DAT blocker bupropion (BUP; 15 or 30 mg/kg tid x 2d), the norepinephrine transporter blocker desipramine (DMI; 10 mg/kg/d x 2d), or saline. 2. mRNA expression was assessed via in situ hybridization histochemistry. 3. BUP and DMI both increased DAT mRNA expression in the ventral tegmental area/substantia nigra. 4. These findings suggest that DAT mRNA expression in the brain may be regulated by both noradrenergic and dopaminergic mechanisms.

A microassay for measuring synaptosomal 3H-dopamine and 3H-metabolite release.

A modified synaptosomal superfusion apparatus is described which uses less than 10 micrograms of tissue per replicate sample and facilitates the routine separation of 3H-DA, 3H-DOPAC, and 3H-HVA. A flow rate of 1.5 ml/min allows superfusion without the use of reuptake or monoamine oxidase inhibitors. Superfusate samples are collected directly onto alumina columns for the separation of 3H-DA and its acid metabolites. Total recovery of authentic 3H-DA applied via superfusion was 87.63(1.10) percent [Mean(SEM)]. Contamination of the acetic acid eluate fraction, containing 80.98(1.15)% of the total DA, by DOPAC and HVA was less than 0.1%. To illustrate the utility of this technique, the relative proportions of 3H-DA and 3H-metabolites released from synaptosomes by 6 mM potassium and 1 microM reserpine were compared.

Correlates of rapid neuroleptic response in male patients with schizophrenia.

Correlates of neuroleptic response latency were assessed in 16 male schizophrenic inpatients during 4 weeks of fixed dose (20 mg/day) haloperidol treatment. Rapid responders showed a mean 40% reduction in Brief Psychiatric Rating Scale (BPRS) positive symptom scores by day 10 of treatment. Rapid responders had significantly lower plasma homovanillic acid (pHVA) concentrations compared to non-rapid responders during week 4 of haloperidol treatment. However, rapid versus non-rapid responders did not differ with respect to demographics, baseline positive or negative BPRS symptom scores, performance on tests of neuropsychological function, or mean plasma haloperidol concentrations.

Modulation of luteinizing hormone pulse amplitude by the frequency of luteinizing hormone-releasing hormone stimulation and by testosterone in castrated, hypothalamic-lesioned male rats.

The frequency of spontaneous luteinizing hormone (LH) pulses is thought to be a direct result of the frequency of luteinizing hormone-releasing hormone (LHRH) pulses from the hypothalamus. By contrast, the amplitude of spontaneous LH pulses may be controlled by several factors other than the amplitude of LHRH pulses. We tested two hypotheses: 1) that LH pulse amplitude is determined in part by the frequency of LHRH pulses of constant magnitude, and 2) that testosterone (T) exerts a direct feedback effect on the pituitary gland to regulate LH pulse amplitude. Gonadal feedback was eliminated by castrating adult male rats (n = 20). Endogenous LHRH secretion was eliminated by lesioning the medial basal hypothalamus. Serum LH levels (0.19 +/- 0.04 ng/ml RP-2, mean +/- SEM) and T levels (0.15 +/- 0.02 ng/ml), measured several weeks after hypothalamic lesioning, confirmed the hypogonadotropic hypogonadal state of the animals. During a 8-h period, unanesthetized, unrestrained animals were injected with 40-ng pulses of LHRH via catheters into the jugular vein, and blood samples for LH measurement were drawn at 10-min intervals. The LHRH pulse interval was 20 min during the first 4 h in all animals. The pulse interval was doubled to 40 min in half of the animals (n = 10) during the next 4 hours; in the other 10 animals, the pulse interval was maintained constant at 20 min throughout the study. Within both of these groups, one-half of the animals (n = 5) were infused with T to achieve a physiological level of T in serum (2.46 +/- 0.36 ng/ml at 4 h), while the other half received vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Conditioned morphine tolerance in the rat: absence of a compensatory response and cross-tolerance with stress.

In four separate experiments with rats as subjects, strong evidence was obtained that tolerance development to morphine analgesia occurs most rapidly when morphine delivery is paired with salient contextual cues. However, contextual cues previously paired with morphine did not elicit conditioned drug-compensatory responses when presented to nondrugged animals. These results were obtained by different analgesia assessments, with different drug-administration--analgesia-test latencies, and in environments differing with respect to stress level. Stress level did influence nociceptive response, as it was found that the combination of bright illumination, white noise, and a strong odor resulted in antinociception in the absence of drug. Moreover, rats that had a history of receiving morphine in this stressful context were tolerant to this stress-induced antinociception, but only when morphine was present in their systems. In the final two studies, this antinociception, which was cross-tolerant with morphine, was characterized with respect to naloxone reversibility and brain levels of met- and leu-enkephalin as determined by radioimmunoassay.

Drug signals enhance morphine tolerance development in hypophysectomized rats.

Hypophysectomized and sham-operated (normal) rats were given morphine (5 mg/kg) either paired or unpaired with distinctive environmental cues. Both hypophysectomized and normal animals developed analgesic tolerance when drug effects were signaled, but little tolerance was evident in either surgery group when drug was unsignaled. Results suggest that the pituitary is not critical to associational tolerance development.

Dynorphin (1-13): analgesia, hypothermia, cross-tolerance with morphine and beta-endorphin.

Intracerebroventricular administration of 20, 40 and 60 nmol of dynorphin (1-13) produced analgesia, as assessed by flinch/jump response to footshock, and hypothermia in the rat. Rats developed tolerance to both the analgesic and thermic effects of the 20 nmol dose of dynorphin. Dynorphin and beta-endorphin showed cross-tolerance with respect to their analgesic but not their thermic effects. Dynorphin and morphine also produced cross-tolerant analgesic effects. Naloxone (10 mg/kg, IP) completely blocked the barrel rolling produced by 20 nmol dynorphin but did not alter its analgesic or thermic effects.