Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence of compensatory changes.

In Alzheimer's disease (AD) there is a significant loss of locus coeruleus (LC) noradrenergic neurons. However, recent work has shown the surviving noradrenergic neurons to display many compensatory changes, including axonal sprouting to the hippocampus. The prefrontal cortex (PFC) is a forebrain region that is affected in dementia, and receives innervation from the LC noradrenergic neurons. Reduced PFC function can reduce cognition and disrupt behavior. Because the PFC is an important area in AD, we determined if noradrenergic innervation from the LC noradrenergic neurons is maintained and if adrenoreceptors are altered postsynaptically. Presynaptic PFC alpha2-adrenoreceptor (AR) binding site density, as determined by 3H-RX821002, suggests that axons from surviving noradrenergic neurons in the LC are sprouting to the PFC of subjects with dementia. Changes in postsynaptic alpha1-AR in the PFC of subjects with dementia indicate normal to elevated levels of binding sites. Expression of alpha1-AR subtypes (alpha1A- and alpha1D-AR) and alpha2C-AR subtype mRNA in the PFC of subjects with dementia is similar to what was observed in the hippocampus with one exception, the expression of alpha1A-AR mRNA. The expression of the alpha1A-AR mRNA subtype is significantly reduced in specific layers of the PFC in subjects with dementia. The loss of alpha1A-, alpha1D- and alpha2C-AR mRNA subtype expression in the PFC may be attributed to neuronal loss observed in dementia. These changes in postsynaptic AR would suggest a reduced function of the PFC. Consequence of this reduced function of the PFC in dementia is still unknown but it may affect memory and behavior.

Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men.

BACKGROUND: It has been suggested that cognitive changes in response to T supplementation may occur within an ideal range. The objective of this study was to compare the cognitive responses of older, eugonadal men in whom moderate or large increases in serum testosterone levels was induced by exogenous testosterone supplementation. DESIGN: Randomized, double-blind, placebo-controlled study with subsequent grouping of participants according to average increase in circulating T from baseline. SETTING: Community dwelling participants. PARTICIPANTS: Fifty-seven healthy, eugonadal, community dwelling male volunteers, mean age 67 years (+/-11 years). INTERVENTIONS: Participants were randomized to receive weekly intramuscular (i.m.) injections of either 50, 100 or 300 mg T enanthate or placebo (saline) injection for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, weeks 3 and 6 of treatment and after 6 weeks of wash-out. MAIN OUTCOME MEASURES: Performance on cognitive tests of verbal and spatial memory. RESULTS: Men with moderate increases in serum T and/or its metabolites demonstrated significant improvements in verbal and spatial memory. In contrast, men with large or low increases in circulating T levels, failed to demonstrate significant changes in memory. CONCLUSION: These results suggest that in healthy older men, beneficial changes in cognitive function induced by T supplementation are most evident with moderate changes in cognition from moderate to high T supplementation increases in T levels. Large or no to low increases in T levels do not appear to appreciably effect cognition.

Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction.

Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased ameboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3×) blast exposure. Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.

Cerebrospinal fluid vasopressin, oxytocin, somatostatin, and beta-endorphin in Alzheimer's disease.

As a first step toward assessing the status of brain neuropeptide systems that may be involved in Alzheimer's disease (AD), the cerebrospinal fluid (CSF) concentrations of the neuropeptides arginine vasopressin, somatostatin, oxytocin, and beta-endorphin were measured in patients with AD, normal elderly subjects, and normal young subjects. The plasma arginine vasopressin level was also measured in the three groups. The CSF arginine vasopressin level was significantly lower in patients with AD than in either elderly or young normal subjects, but oxytocin and beta-endorphin levels did not differ between groups. The CSF osmolarity also did not differ between groups. The plasma arginine vasopressin level did not significantly differ between groups, but high plasma arginine vasopressin values were absent in the patients with AD. The CSF somatostatin level was significantly lower in patients with AD than in normal elderly persons, but it did not differ in young normal subjects. These results suggest that central vasopressinergic activity may be decreased in AD and confirm reports of low CSF somatostatin levels in AD.

Norepinephrine and MHPG levels in CSF and plasma in Alzheimer's disease.

Postmortem findings of decreased brain norepinephrine (NE) content and decreased locus ceruleus neuronal density have suggested a possible noradrenergic deficit in Alzheimer's disease (AD). We assessed CNS and peripheral noradrenergic function in patients with advanced AD, moderate AD, and age-matched normals by measuring NE and the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in CSF and plasma. Subjects were drug free for at least two weeks. Plasma and CSF NE and MHPG levels were significantly higher in patients with advanced AD than in either patients with moderate AD or normal controls, while values in the patients with moderate AD did not differ from those in normal controls. These findings do not support either a central or peripheral noradrenergic deficit in AD. Rather, they suggest increased CNS and peripheral noradrenergic activity in advanced stages of the disease.

Effects of Alzheimer's disease and normal aging on cerebrospinal fluid norepinephrine responses to yohimbine and clonidine.

BACKGROUND: The resting cerebrospinal fluid (CSF) norepinephrine concentration is unchanged or even increased in patients with Alzheimer's disease (AD). These in vivo findings appear to be inconsistent with the post-mortem locus ceruleus neuronal loss that is reported in patients with AD. METHODS: The effects of AD and advanced age on central nervous system noradrenergic status were estimated by comparing CSF norepinephrine concentrations following the administration of yohimbine hydrochloride, clonidine hydrochloride, and placebo in outpatients with AD and older and young normal subjects. Levels of yohimbine, its metabolite 11-hydroxy-yohimbine, and clonidine were measured in CSF and plasma samples. Behavioral responses were quantified by rating the Tension, Excitement, and Anxiety items on the Brief Psychiatric Rating Scale. RESULTS: Yohimbine-induced increases of CSF norepinephrine concentrations were greater in both patients with AD and normal older subjects than in normal young subjects. Clonidine-induced decreases of CSF norepinephrine concentrations did not differ among groups. Behavioral arousal following the administration of yohimbine was greater in patients with AD than in the other groups. CONCLUSIONS: Central nervous system noradrenergic responsiveness is enhanced in normal older subjects, and this age effect is retained in patients with AD. Behavioral sensitivity to increased central nervous system noradrenergic activity is enhanced in patients with AD.

Neuroendocrine responses to physostigmine in Alzheimer's disease.

To assess central nervous system cholinergic neuroendocrine regulation in Alzheimer's disease (AD), we measured plasma arginine vasopressin, beta-endorphin, and epinephrine responses to a cholinergic challenge elicited by intravenous administration of the acetylcholinesterase inhibitor physostigmine (0.0125 mg/kg) in male patients with AD (n = 12) and compared their responses with those of age-matched normal control subjects (n = 12). Physostigmine promptly increased plasma arginine vasopressin (tenfold), beta-endorphin (twofold to threefold) and epinephrine (threefold) levels in elderly control subjects. In contrast, patients with AD showed attenuated responses to physostigmine. When controls and patients with AD who experienced nausea (n = 2 and n = 6, respectively) were excluded, the arginine vasopressin, beta-endorphin, and epinephrine responses of patients with AD were significantly less than those of control subjects. These data suggest that the central nervous system cholinergic deterioration of AD results in decreased responsiveness of neuroendocrine systems that are regulated by central cholinergic mechanisms.

Sympathetic nervous system activity in major depression. Basal and desipramine-induced alterations in plasma norepinephrine kinetics.

BACKGROUND: To determine whether elevations of plasma norepinephrine (NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function. METHODS: SNS activity was assessed in depressed patients and controls by an isotope-dilution, plasma NE kinetic technique using mathematical modeling and compartmental analysis. This approach provided estimates of the rate of NE appearance into an extravascular compartment, which is the site of endogenous NE release from SNS nerves, the corresponding rate of NE appearance into plasma, and the rate of NE clearance from plasma. RESULTS: Norepinephrine appearance into the extravascular and vascular compartments was significantly elevated in 17 depressed patients compared with that in 36 controls. The rate of NE clearance from plasma was similar in both groups. This is compatible with increased SNS activity in major depression. Desipramine, given for 2 days, significantly reduced the concentration of NE in plasma of patients and controls by markedly suppressing the rates of extravascular and vascular NE appearance, compatible with a short-term reduction in SNS activity. Desipramine prolonged the rate of NE clearance from plasma, consistent with a blockade of NE re-uptake into SNS nerve terminals. The initial suppression of SNS activity by desipramine was reversed by long-term (28 days) treatment of patients, with extravascular and vascular NE appearance rates returning to approximately basal levels. An associated rise in plasma NE concentrations compared with the baseline was attributable to a progressive reduction in plasma NE clearance. CONCLUSION: Sympathetic nervous system activity is elevated in major depression and is suppressed by short-term desipramine administration. The demonstration of SNS reactivation occurring with prolonged desipramine treatment is compatible with the theory that long-term treatment desensitizes CNS alpha 2-adrenergic receptors and emphasizes the value of examining the temporal course of responses to pharmacological challenges of neuroendocrine systems. Previously reported elevations of plasma NE during prolonged administration of tricyclic antidepressants are probably the result of a reduction in plasma NE clearance, not an increase in SNS activity.

Estrogen receptor and neurotensin/neuromedin-N gene expression in the preoptic area are unaltered with age in Fischer 344 female rats.

The sensitivity of hypothalamic centers to estrogenic regulation may be impaired with age and contribute to the loss of reproductive function in female rats. Here, we have tested the hypothesis that aging is associated with alterations in the level of expression of the estrogen receptor (ER) gene and/or the neurotensin/neuromedin-N (NT/N) gene in the preoptic area (POA) of female rats. We have used in situ hybridization histochemistry and quantitative autoradiography to compare ER gene expression and NT/N gene expression in the POA of ovariectomized and ovariectomized/estradiol-treated female rats at 3, 11, and 20 months of age. We found no evidence for an age-related impairment of either ER or NT/N gene expression in two subdivisions of the POA: the anterior medial preoptic nucleus and the medial preoptic nucleus. Likewise, estrogenic regulation of both ER messenger RNA levels and NT/N messenger RNA levels did not differ across age groups. These results indicate that transcription of the ER gene within the POA is not reduced with age and suggest that the receptor translated within the POA functions normally in old female rats. Our observations do not support a role for impaired expression of the ER gene or impaired estrogenic induction of NT/N gene expression by preoptic neurons in the development of reproductive acyclicity with aging.

Galanin in the bed nucleus of the stria terminalis and medial amygdala of the rat: lack of sexual dimorphism despite regulation of gene expression across puberty.

Neurons in the bed nucleus of the stria terminalis (BNST) and the medial amygdala (AMe) coexpress vasopressin and galanin (GAL) in the adult male rat. Here, we have asked whether GAL gene expression, like vasopressin gene expression in these same neurons, exhibits sexual dimorphism and whether GAL pathways in the BNST and AMe are activated with puberty in female rats as we have previously observed in male rats. In Exp 1, in situ hybridization histochemistry and quantitative autoradiography were used to compare GAL gene expression in the BNST and AMe of prepubertal (24-day-old) and adult (90-day-old) male and female rats. In the BNST, both the number of GAL mRNA-expressing neurons (F = 41.98; P < or = 0.0001; males, P < or = 0.007; females, P < or = 0.001) and the intensity of labeling (F = 40.35; P < or = 0.0001; males, P < or = 0.004; females, P < or = 0.002) were significantly increased in adult compared to prepubertal animals of both sexes. In the AMe of both males (P < or = 0.001) and females (P < or = 0.001), the intensity of labeling was significantly enhanced across puberty (F = 66.29; P < or = 0.0001); however, the number of GAL mRNA-expressing neurons in this region did not change. We found no evidence for sexual dimorphism of GAL gene expression in either brain region. In Exp 2, we replicated our observations of a lack of sexual dimorphism of GAL gene expression in the BNST of adult male and female rats. These findings are consistent with the hypothesis that GAL neurons in the BNST and AMe are steroid sensitive in both sexes. However, our failure to detect any differences in either the number of GAL mRNA-expressing neurons or the level of expression between male and female rats at either age indicates that these pathways do not exhibit sexual dimorphism.

Sex difference in coexpression by galanin neurons accounts for sexual dimorphism of vasopressin in the bed nucleus of the stria terminalis.

Vasopressin (VP) neurons in the bed nucleus of the stria terminalis (BNST) are steroid sensitive and sexually dimorphic. The number of VP messenger RNA (mRNA)-expressing neurons is larger in male than in female rats. This initial observation suggested that sexual dimorphism resulted from enhanced proliferation and/or survival of VP neurons after gonadal hormone exposure during the critical perinatal period. However, galanin (GAL) and VP mRNAs were recently reported to be coexpressed in the BNST of adult male rats, and GAL gene expression, unlike VP gene expression, is not sexually dimorphic. These findings are consistent with the hypothesis that the sex difference in VP cell number in the BNST results from a sex difference in the number of GAL neurons dedicated to express the VP gene. To test this hypothesis, double in situ hybridization histochemistry was performed for GAL and VP mRNAs in the BNST of adult male and female rats. For quantification, the posterior BNST was divided into its two anatomical regions: medial (BSTM) and lateral (BSTL) divisions. Extending previous results for the whole BNST, the number of GAL-expressing cells in either the BSTM or the BSTL was not sexually dimorphic. A significant sex difference was found in the number of GAL cells coexpressing VP in the BSTM (mean +/- SE, male, 124 +/- 8; female, 56 +/- 6; P < or = 0.0001), but not in the BSTL (male, 80 +/- 9; female, 83 +/- 15). Accordingly, the number of cells expressing GAL mRNA only was significantly lower (P < or = 0.002) in the BSTM of male (43 +/- 5) than in female (85 +/- 9) rats. Evidence is provided that the reduced incidence of coexpression of VP by GAL neurons in the BSTM of female rats may account for the reported sex difference in VP cell number in the entire BNST. The results suggest that gonadal hormones in the perinatal period may not influence the proliferation and/or survival of VP neurons in the BNST per se but influence, instead, the capacity of GAL neurons to synthesize VP.

Evidence for two differentially regulated populations of peripheral beta-endorphin-releasing cells in humans.

In the current study we tested the hypothesis that human plasma beta-endorphin (beta E) is derived from at least two subpopulations of beta E-releasing cells: one sensitive to glucocorticoids as well as to dopamine (DA; regulated analogously to the corticotrophs of the rat pituitary), and one insensitive to glucocorticoids but sensitive to DA (regulated analogously to the melanotrophs of the rat pituitary). To test this hypothesis, human plasma levels of ACTH, cortisol, and beta E-like immunoreactivity were measured at baseline and after haloperidol treatment (0.05 mg/kg, i.v.) in two experimental groups, one pretreated with dexamethasone (1.5 mg) and one pretreated with placebo. Plasma PRL levels were also measured in both groups as an indicator of DA receptor blockade. Dexamethasone partially suppressed both baseline and haloperidol-stimulated levels of human plasma beta E-like immunoreactivity, whereas it completely suppressed both basal and haloperidol-stimulated levels of ACTH and cortisol and had no statistically significant effect on either basal or haloperidol-stimulated PRL levels. These data support a negative feedback effect of glucocorticoids on one DA-sensitive cell population that releases both ACTH and beta E (corticotroph like), but not on a second cell population that releases beta E but not ACTH.

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.

Differential effects of aging on neuroendocrine responses to physostigmine in normal men.

We assessed the effects of age on cholinergic regulation of the hypothalamic-pituitary-adrenal axis and other neuroendocrine systems by measuring the plasma cortisol and beta-endorphin responses to an infusion of the centrally active cholinesterase inhibitor physostigmine (0.0125 mg/kg) in 12 healthy older men (68 +/- 1.7 yr) and 9 healthy young men (25 +/- 1.4 yr). We also measured the responses to physostigmine of plasma GH, arginine vasopressin, epinephrine, and norepinephrine (NE). As estimated by comparing calculated areas under the curve, older subjects had greater cortisol (P = 0.02) and beta-endorphin (P less than 0.01) secretory responses, but a reduced GH (P less than 0.01) secretory response. The arginine vasopressin response did not differ between groups. By analysis of variance, older subjects also had a greater epinephrine response (P = 0.01). Older subjects had higher basal NE concentrations (P less than 0.05), but NE responses to physostigmine did not differ between groups. These findings suggest age-related enhancement of the cholinergic stimulatory regulation of the hypothalamic-pituitary-adrenal axis and adrenal medulla. They also confirm previous reports of reduced GH secretory response with aging in normal men.

Increased plasma and cerebrospinal fluid norepinephrine in older men: differential suppression by clonidine.

To evaluate the effect of advanced age on central nervous system noradrenergic activity, cerebrospinal fluid (CSF) and plasma norepinephrine (NE) concentrations were measured concurrently in 14 older [mean, 65 +/- 9 (+/- SD) yr] and 33 younger (25 +/- 2 yr) normal men. CSF NE was significantly higher in older men than in young men [214 +/- 75 (+/- SD) vs. 164 +/- 56 pg/mL (1.26 +/- 0.44 vs. 0.97 +/- 0.33 nmol/L); P less than 0.02] as was plasma NE [282 +/- 103 vs. 211 +/- 63 pg/mL (1.67 +/- 0.61 vs. 1.25 +/- 0.37 nmol/L); P less than 0.02]. Subgroups of young and older men underwent two lumbar punctures, one of which was performed 100 min after the administration of 5 micrograms/kg oral clonidine. The young (n = 7) and older (n = 7) men had similar plasma clonidine levels [1.0 +/- 0.1 vs. 0.8 +/- 0.1 ng/mL (4.35 +/- 0.43 vs. 3.48 +/- 0.78 nmol/L)] and CSF clonidine levels [0.18 +/- 0.02 vs. 0.22 +/- 0.03 ng/mL (0.78 +/- 0.09 vs. 0.96 +/- 0.13 nmol/L)]. The suppression of CSF NE by clonidine was significantly greater (P less than 0.015) in young men [189 +/- 44 to 104 +/- 26 pg/mL (1.12 +/- 0.26 to 0.62 +/- 0.15 nmol/L)] than in older men [190 +/- 49 to 164 +/- 58 pg/mL (1.12 +/- 0.29 to 0.97 +/- 0.34 nmol/L)]. In contrast, the suppression of plasma NE by clonidine did not significantly differ between young [242 +/- 72 to 93 +/- 24 pg/mL (1.43 +/- 0.43 to 0.55 +/- 0.14)] and older men [285 +/- 102 to 167 +/- 84 pg/mL (1.68 +/- 0.60 to 0.99 +/- 0.50 nmol/L)]. These data suggest that decreased sensitivity of alpha 2-adrenergic mechanisms regulating CNS noradrenergic activity may contribute to increased CNS noradrenergic activity with aging.

Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease.

BACKGROUND: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. METHODS: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied. RESULTS: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. CONCLUSIONS: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.

The effect of apolipoprotein E genotype on expression of an autosomal dominant schizophreniform disorder with progressive dementia and neurofibrillary tangles.

The apolipoprotein E (APOE) epsilon 4 allele is associated with an increased and the epsilon 2 allele a decreased risk for Alzheimer's disease (AD). It has been hypothesized that these risks are mediated by differential effects of the APOE alleles on the cytoskeletal degeneration, which results in neurofibrillary tangle (NFT) formation. It has also been suggested that APOE alleles differentially affect the beta amyloid accumulation. We examined APOE genotypes and their effects on age of onset in a family with an autosomal dominant "neurofibrillary tangle only" dementia. This disorder is manifested by schizophreniform psychosis followed by progressive dementia and neuropathologically by prominent AD-like neurofibrillary tangles without neuritic plaques. The only affected epsilon 4 heterozygote in this family did not demonstrate accelerated disease onset. In contrast, the affected epsilon 2 heterozygote had the latest age of onset of any affected family member. The two other epsilon 2 heterozygotes remained unaffected at an age much greater than the mean age of onset for the disease. These results are consistent with a protective effect of the epsilon 2 allele in a hereditary neuropsychiatric disorder with prominent NFT formation.

Is antidiuretic hormone elevated in psychosis? A pilot study.

Plasma antidiuretic hormone (ADH) measured by radioimmunoassay was higher in acutely psychotic subjects than in acutely anxious nonpsychotic subjects or normal subjects. ADH was not elevated in acutely anxious nonpsychotic subjects. ADH was positively correlated with degree of psychosis. Normal osmolar and volume regulatory mechanisms did not seem responsible for the ADH elevations in the psychotic subjects. Because ADH is both produced in the hypothalamus and can be accurately measured in blood, this substance may prove particularly valuable in the study of psychiatric disorders.

Laboratory evaluation for Cushing's syndrome in psychiatric patients with cortisol nonsuppression following the overnight dexamethasone suppression test.

Laboratory tests used for the differential diagnosis of Cushing's syndrome have infrequently been employed in investigations of psychiatric patients who demonstrate hypothalamic-pituitary-adrenal (HPA) overactivity, and these laboratory procedures have not previously been applied for the specific purpose of further evaluating the endocrine function of psychiatric patients with serum cortisol nonsuppression following the standard 1-mg overnight Dexamethasone Suppression Test (DST). Low-dose (4 mg/48 hr) and high-dose (16 mg/48 hr) DSTs were administered to 10 psychiatric patients who exhibited cortisol nonsuppression after the overnight DST. Patients all had normal suppression to both the low-dose and high-dose tests. HPA overactivity in these patients was thus not sufficient to meet laboratory criteria for the diagnosis of Cushing's syndrome. Study results suggest that psychiatric patients with abnormal cortisol suppression following the 1-mg overnight DST are likely to have normal responses when assessed by standard laboratory protocols used for the diagnosis of Cushing's syndrome.