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.

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.

Lesioning noradrenergic neurons of the locus coeruleus in C57Bl/6 mice with unilateral 6-hydroxydopamine injection, to assess molecular, electrophysiological and biochemical changes in noradrenergic signaling.

The locus coeruleus (LC) is the major loci of noradrenergic innervation to the forebrain. Due to the extensive central nervous system innervation of the LC noradrenergic system, a reduction in the number of LC neurons could result in significant changes in noradrenergic function in many forebrain regions. LC noradrenergic neurons were lesioned in adult male C57Bl/6 mice with the unilateral administration of 6-hydroxydopamine (6OHDA) (vehicle on the alternate side). Noradrenergic markers were measured 3 weeks later to determine the consequence of LC loss in the forebrain. Direct administration of 6OHDA into the LC results in the specific reduction of noradrenergic neurons in the LC (as measured by electrophysiology, immunoreactivity and in situ hybridization), the lateral tegmental neurons and dopaminergic neurons in the substantia nigra (SN) and ventral tegmental region were unaffected. The loss of LC noradrenergic neurons did not result in compensatory changes in the expression of mRNA for norepinephrine (NE)-synthesizing enzymes. The loss of LC noradrenergic neurons is associated with reduced NE tissue concentration and NE transporter (NET) binding sites in the frontal cortex and hippocampus, as well as other forebrain regions such as the amygdala and SN. Adrenoreceptor (AR) binding sites (α(1)- and α(2)-AR) were not significantly affected on the 6OHDA-treated side compared to the vehicle-treated side, although there is a reduction of AR binding sites on both the vehicle- and 6OHDA-treated side in specific forebrain regions. These studies indicate that unilateral stereotaxic injection of 6OHDA into mice reduces noradrenergic LC neurons and reduces noradrenergic innervation to many forebrain regions, including the contralateral side.

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat.

Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha(1)-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in alpha(2)-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a loss of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.

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.

CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study.

BACKGROUND: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Abeta(42) as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. METHODS: We determined the ratio of CSF tau/Abeta(42) (T/Abeta) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). RESULTS: We identified 16% of the control group with abnormally elevated CSF T/Abeta; all were 53 years or older. Using age-matched controls with normal CSF T/Abeta we showed that the high CSF T/Abeta subgroup of controls had significantly increased frequency of the epsilon4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. CONCLUSIONS: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.

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.

Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment.

OBJECTIVE: To determine the efficacy of testosterone (T) supplementation on cognition in a sample of men with Alzheimer disease (AD) or mild cognitive impairment (MCI). METHODS: Fifteen patients with AD and 17 patients with MCI aged 63 to 85 years completed a randomized, double-blind, placebo-controlled study. Nineteen participants received weekly intramuscular (IM) injections of 100 mg T enanthate and 13 participants received weekly injections of placebo (saline) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3, and week 6 of treatment and again after 6 weeks of washout. RESULTS: Peak serum total T levels were raised from baseline an average of 295% in the active treatment group. Improvements in spatial memory (p < 0.05) and constructional abilities (p < 0.05) and verbal memory were evident in the T group. No changes were noted for selective and divided attention or language. Prostate specific antigen did not significantly change during this brief treatment. CONCLUSION: Testosterone supplementation may benefit selective cognitive functions in men with Alzheimer disease and mild cognitive impairment.

The role of aromatization in testosterone supplementation: effects on cognition in older men.

OBJECTIVE: To determine the contribution of conversion of testosterone (T) to estradiol on cognitive processing in a population of healthy older men who received T supplementation. METHODS: Sixty healthy, community-dwelling volunteers aged 50 to 90 years completed a randomized, double-blind, placebo-controlled study. Participants were randomized to receive weekly IM injections of 100 mg T enanthate plus daily oral placebo pill (T group, n = 20), 100 mg testosterone enanthate plus 1 mg daily of anastrozole, an aromatase inhibitor (oral pill), to block the conversion of T to estradiol (AT group, n = 19), or saline injection and placebo pill (placebo group, n = 21) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3 and week 6 of treatment, and after 6 weeks of washout. RESULTS: Circulating total T was increased from baseline an average of 238% in the T and AT treatment groups. Estradiol increased an average of 81% in the T group and decreased 50% in the AT group during treatment. Significant improvements in spatial memory were evident in the AT and T treatment groups. However, only the group with elevated estradiol levels (T group) demonstrated significant verbal memory improvement. CONCLUSION: In healthy older men, improvement in verbal memory induced by testosterone administration depends on aromatization of testosterone to estradiol, whereas improvement in spatial memory occurs in the absence of increases in estradiol.

Chronic cortisol suppresses pituitary and hypothalamic peptide message expression in pigtailed macaques.

The effects of chronic elevations in circulating glucocorticoids on the expression of peptides and peptide receptors of the hypothalamic-pituitary-adrenal (HPA) axis have been studied extensively in rodents, but they have not been examined in primates. To determine the responses of the HPA axis in primates to elevated cortisol, hypothalamic and pituitary tissue from normal older pigtailed macaques (Macaca nemestrina) that had received daily oral administration of cortisol or placebo for 1 year were studied. Pro-opiomelanocortin in the anterior pituitary and corticotropin-releasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN) were significantly reduced in cortisol-treated monkeys in comparison with controls. CRF receptor 1 (CRF-R1) expression in the anterior pituitary and arginine vasopressin mRNA expression in the PVN were unchanged by chronic cortisol administration. Sustained elevation of circulating glucocorticoids results in suppression of HPA peptide and peptide receptor expression in the PVN and anterior pituitary similar to those found in rodents. Chronic therapeutic administration of glucocorticoids in humans may have unintended consequences for hypothalamic and pituitary function.

Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer's disease.

Postmortem demonstration of increased expression of biologically active S100B in Alzheimer's disease (AD) and its relation to progression of neuropathological changes across the cortical regions suggests involvement of this astrocytic cytokine in the pathophysiology of AD. The hypothesis that the overexpression of S100B in Alzheimer brain is related to the progression of clinical symptoms was addressed in living persons by measuring S100B concentrations in cerebrospinal fluid (CSF) from AD patients with a broad range of clinical dementia severity and from healthy older persons. The effect of normal aging on CSF S100B concentrations also was estimated. CSF S100B did not differ between all 68 AD subjects (0.98+/-0.09 ng/ml (mean+/-S.E.M.)) and 25 healthy older subjects (0.81+/-0.13 ng/ml). When AD subjects were divided into mild/moderate stage and advanced stage clinical dementia severity by the established Clinical Dementia Rating Scale (CDR) criteria, S100B was significantly higher in the 46 mild/moderate stage AD subjects (1.17+/-0.11 ng/ml) than in either the 22 advanced stage AD subjects (0.60+/-0.12 ng/ml) or the healthy older subjects. Consistent with higher CSF S100B in mild to moderate AD, there was a significant correlation among all AD subjects between CSF S100B and cognitive status as measured by the Mini Mental State Exam (MMSE) score. CSF S100B did not differ between healthy older subjects and healthy young subjects. These results suggest increased CNS expression of S100B in the earlier stages of AD, and are consistent with a role for S100B in the initiation and/or facilitation of neuritic plaque formation in AD brain.

High-dose estradiol improves cognition for women with AD: results of a randomized study.

OBJECTIVE: To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. METHODS: Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17 beta-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. RESULTS: Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. CONCLUSIONS: Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

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 alpha 2-adrenergic receptor binding in locus coeruleus projection areas in dementia with Lewy bodies.

Clinical studies suggest involvement of brain noradrenergic systems in the pathophysiology of disruptive agitation in Alzheimer's disease (AD). This behavioral problem is even more prevalent in dementia with Lewy bodies (DLB). Here we used receptor autoradiography with [(125)I]para-iodoclonidine to estimate alpha-2 adrenergic receptor (A2R) density in locus coeruleus (LC) projection areas in postmortem brain tissue from age and gender comparable groups of DLB (n = 6), AD (n = 5) and normal (n = 7) subjects. LC neuronal loss was substantial and equivalent in DLB and AD. A2R density was greater in DLB than in normals in the deep layers of the frontal cortex. A2R density was greater in DLB than in AD in hippocampus (CA-1, CA-3 and dentate hilus) and in the granule layer of the cerebellum. Increased A2R binding in DLB is consistent with expression of presynaptic A2R on fibers from surviving LC neurons involved in reinnervation of LC projection areas. These areas develop compensatory noradrenergic hyperinnervation in a rat model of partial LC ablation. It is also consistent with upregulation of post-synaptic A2R in response to loss of LC noradrenergic innervation. Either mechanism could lower the threshold for increased agitation in response to noradrenergic outflow in these dementing disorders.

Testosterone supplementation improves spatial and verbal memory in healthy older men.

OBJECTIVE: To determine the relationship between exogenous testosterone administration and cognitive abilities in a population of healthy older men. BACKGROUND: Serum levels of total and bioavailable testosterone gradually decrease with age in men and are associated with reductions in muscle mass, osteoporosis, decreased sexual activity, and changes in cognition. METHODS: Twenty-five healthy, community-dwelling volunteers, aged 50 to 80 years, completed a randomized, double-blind, placebo-controlled study. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Cognitive evaluations were conducted at baseline, week 3, and week 6 of treatment by use of a battery of neuropsychologic tests. RESULTS: Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Because of aromatization of testosterone, estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. Significant improvements in cognition were observed for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) in older men treated with testosterone compared with baseline and the placebo group, although improvements were not evident for all measures. CONCLUSIONS: The results suggest that short-term testosterone administration enhances cognitive function in healthy older men. However, it remains unclear whether these improvements in cognition are attributable to increased testosterone or estradiol levels, or both. The potential role of testosterone vs its metabolites on cognition requires further research.

Alzheimer's disease and related disorders.

The cholinesterase inhibitors provide the first clearly effective treatments for the cognitive deficits of AD and appear to have a beneficial effect on activities of daily living function and noncognitive behavior. There is increasing support for starting donepezil, rivastigmine, or galantamine early in the disease course and maintaining treatment at least during the early and middle stages of AD. Depressive signs and symptoms complicating AD are treated best with SSRIs. Placebo-controlled trials support the use of citalopram and sertraline in AD complicated by depression. The atypical antipsychotics are the first choice for managing psychosis and disruptive agitation in AD and particularly in the Lewy body variant of AD. Studies suggest that low-dose treatment with risperidone, 1 mg/d, or olanzapine, 5 mg/d, offers the optimal ratio of therapeutic to adverse effects.

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.