RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Pioglitazona/uso terapéutico , Reproducibilidad de los Resultados , Proyectos de InvestigaciónRESUMEN
Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the "signature injury" of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast-induced mTBI. However, the underlying mechanisms are not well understood. Here we used a battlefield-relevant mouse model of blast-induced mTBI and in vivo fast-scan cyclic voltammetry (FSCV) to investigate whether the mesolimbic dopamine system contributes to the mechanisms underlying blast-induced behavioral dysfunction. In mice, blast exposure increased novelty seeking, a behavior closely associated with disinhibition and risk for subsequent maladaptive behaviors. In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans.
Asunto(s)
Traumatismos por Explosión/metabolismo , Traumatismos por Explosión/psicología , Conmoción Encefálica/metabolismo , Conmoción Encefálica/psicología , Dopamina/metabolismo , Asunción de Riesgos , Adulto , Animales , Conmoción Encefálica/etiología , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Humanos , Inhibición Psicológica , Sistema Límbico/metabolismo , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Núcleo Accumbens/metabolismo , Triazinas , Heridas Relacionadas con la Guerra/metabolismo , Heridas Relacionadas con la Guerra/psicología , Adulto JovenRESUMEN
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.
Asunto(s)
Traumatismos por Explosión/patología , Lesiones Encefálicas/patología , Macrófagos/patología , Microglía/patología , Animales , Barrera Hematoencefálica/patología , Western Blotting , Encéfalo/irrigación sanguínea , Encéfalo/patología , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Microscopía Intravital , Masculino , Ratones , Ratones Endogámicos C57BL , Microvasos/patologíaRESUMEN
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.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Subfamilia B de Transportador de Casetes de Unión a ATP , Anciano , Alelos , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido SimpleRESUMEN
The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPß or Aß42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPß, and Aß42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.
Asunto(s)
Proteínas ADAM/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Proteínas de la Membrana/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Proteína ADAM10 , Edad de Inicio , Anciano , Anciano de 80 o más Años , Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/genética , Apolipoproteína E4/genética , Biología Computacional , Análisis Mutacional de ADN/métodos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.
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Envejecimiento/inmunología , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/inmunología , Anticuerpos/inmunología , Fármacos Neuroprotectores/inmunología , Péptidos/inmunología , Envejecimiento/efectos de los fármacos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/toxicidad , Animales , Anticuerpos/sangre , Anticuerpos/líquido cefalorraquídeo , Citoprotección/efectos de los fármacos , Demencia/complicaciones , Demencia/inmunología , Progresión de la Enfermedad , Genes Dominantes , Inmunización , Inmunoglobulina G/sangre , Ratones , Peso Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Péptidos/química , Primates/inmunología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Estructura Cuaternaria de ProteínaRESUMEN
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.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Trastornos del Conocimiento/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/psicología , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Factores de RiesgoRESUMEN
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.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ovillos Neurofibrilares/efectos de los fármacos , Distribución por Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/prevención & control , Atrofia/tratamiento farmacológico , Atrofia/patología , Atrofia/prevención & control , Encéfalo/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Ovillos Neurofibrilares/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Placa Amiloide/efectos de los fármacos , Placa Amiloide/patología , Estudios Retrospectivos , Distribución por Sexo , Resultado del TratamientoAsunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/líquido cefalorraquídeo , Neuropéptidos/líquido cefalorraquídeo , Vigilia/fisiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Orexinas , Estadística como AsuntoRESUMEN
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.
Asunto(s)
Demencia/patología , Regulación de la Expresión Génica/fisiología , Corteza Prefrontal/metabolismo , Receptores Adrenérgicos/metabolismo , Antagonistas Adrenérgicos alfa/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Idazoxan/análogos & derivados , Idazoxan/farmacocinética , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Prazosina/farmacocinética , Corteza Prefrontal/patología , ARN Mensajero/metabolismo , Receptores Adrenérgicos/clasificación , Receptores Adrenérgicos/genéticaRESUMEN
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.
Asunto(s)
Memoria/efectos de los fármacos , Testosterona/análogos & derivados , Conducta Verbal/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Estradiol/sangre , Humanos , Masculino , Persona de Mediana Edad , Placebos , Testosterona/sangre , Testosterona/farmacologíaRESUMEN
OBJECTIVES: To examine the association of serum total cholesterol (TC) and high density lipoprotein (HDL) levels and subsequent incidence of dementia and Alzheimer disease (AD) in a population-based cohort study. METHODS: A cohort of cognitively intact persons, aged 65 and older, was randomly selected from Group Health Cooperative (GHC), a large health maintenance organization, and was assessed biennially for dementia. Premorbid levels of TC and HDL were obtained from a computerized clinical laboratory database at GHC. Cox proportional hazards regression was used to calculate hazard ratios (HR, 95% CI) for dementia and AD associated with quartiles of TC and HDL levels. RESULTS: Of the 2,356 eligible participants, 2,141 had at least one serum TC measure prior to the initial enrollment. Using the lowest TC quartiles as the reference group, the HR in the highest TC quartiles was not significantly elevated for dementia (1.16, 0.81 to 1.67) or for AD (1.00, 0.61 to 1.62) after adjusting for age, sex, education, baseline cognition, vascular comorbidities, body mass index, and lipid-lowering agent use. Serum HDL showed a similar lack of significant association with risk of dementia or AD. Models that included the presence of one or more APOE-epsilon4 alleles showed a typical association of epsilon4 with AD risk. This association was not materially modified by inclusion of TC level. CONCLUSION: The data do not support an association between serum total cholesterol or high density lipoprotein in late life and subsequent risk of dementia or Alzheimer disease (AD). The increased risk of AD with APOE-epsilon4 is probably not mediated by serum total cholesterol levels.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/epidemiología , Colesterol/sangre , Hiperlipidemias/sangre , Hiperlipidemias/epidemiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/fisiopatología , Causalidad , HDL-Colesterol/sangre , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Humanos , Hiperlipidemias/fisiopatología , Hipertensión/epidemiología , Hipolipemiantes/uso terapéutico , Masculino , Estudios Prospectivos , Factores de Riesgo , Factores Sexuales , Washingtón/epidemiologíaRESUMEN
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.
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Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Testosterona/farmacología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Método Doble Ciego , Humanos , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Pruebas Neuropsicológicas , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Testosterona/sangre , Testosterona/uso terapéutico , Resultado del TratamientoRESUMEN
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.
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Aromatasa/metabolismo , Estradiol/fisiología , Trastornos de la Memoria/prevención & control , Memoria/efectos de los fármacos , Conducta Espacial/efectos de los fármacos , Testosterona/análogos & derivados , Testosterona/fisiología , Aprendizaje Verbal/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Anastrozol , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/farmacología , Método Doble Ciego , Estradiol/biosíntesis , Estradiol/sangre , Humanos , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Persona de Mediana Edad , Pruebas Neuropsicológicas , Nitrilos/administración & dosificación , Nitrilos/farmacología , Antígeno Prostático Específico/sangre , Conducta Espacial/fisiología , Testosterona/administración & dosificación , Testosterona/sangre , Testosterona/farmacocinética , Testosterona/uso terapéutico , Triazoles/administración & dosificación , Triazoles/farmacología , Aprendizaje Verbal/fisiologíaRESUMEN
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.
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Antiinflamatorios/farmacología , Hidrocortisona/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Adenohipófisis/efectos de los fármacos , Adenohipófisis/fisiología , Animales , Arginina Vasopresina/genética , Hormona Liberadora de Corticotropina/genética , Femenino , Expresión Génica/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Macaca nemestrina , Masculino , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/fisiología , Receptores de Hormona Liberadora de Corticotropina/genéticaRESUMEN
BACKGROUND: Abnormal insulin metabolism may contribute to the clinical symptoms and pathophysiology of AD. In vitro studies show that insulin enhances the release of beta-amyloid protein (Abeta) or inhibits its degradation, either of which might increase amyloid burden. METHODS: On separate mornings, 16 healthy older adults (10 women, 6 men; mean age 68.7 years, SD 8.6 years) each underwent two infusions consisting of either saline (placebo) or insulin (1.0 mU x kg(-1) x min(-1)) plus dextrose to maintain euglycemia. After 120 minutes of infusion, blood, CSF, and cognitive measures were acquired. RESULTS: As expected, insulin infusion produced an increase in CSF insulin concentration. Insulin infusion also led to an increase in CSF Abeta42 levels, most notably in older subjects. As has been observed previously, insulin infusion facilitated declarative memory, but such facilitation was attenuated in the subjects with the greatest increase in CSF Abeta42 levels. CONCLUSIONS: These findings are consistent with recent in vitro studies of insulin effects on Abeta and support the notion that insulin may modulate Abeta42 levels acutely in humans.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Insulina/farmacología , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Atención/efectos de los fármacos , Cognición/efectos de los fármacos , Femenino , Humanos , Masculino , Memoria/efectos de los fármacos , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Glucose and insulin may play an important role in the pathophysiology and symptomatology of Alzheimers disease (AD), and prior studies suggest interactions among glucose, insulin, gender and apolipoprotein E genotype. We analyzed the relationship between steroid-induced glucose elevation and gender, presence of the apolipoprotein E epsilon 4 (APOE-4) allele and cognition using data from a multicenter trial of prednisone therapy in AD. The low-dose prednisone regimen (initial dose: 20 mg/day, maintenance dose: 10 mg/day) caused a moderate increase in random blood glucose (mean post-baseline glucose 115 mg/dl). There was a significant interaction between rise in glucose, gender and presence of the APOE-4 allele. There was no important relationship between glucose and cognitive function at baseline or with prednisone treatment. Meta-analysis including data from three other AD trials showed a small influence of random blood glucose on cognitive scores. These results support a relationship between gender, apolipoprotein E genotype and glucose metabolism, but do not indicate that mild changes in glucose have an important impact on cognitive function.
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Enfermedad de Alzheimer/sangre , Apolipoproteínas E/genética , Glucemia/análisis , Cognición , Prednisona/administración & dosificación , Caracteres Sexuales , Alelos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Apolipoproteína E4 , Terapia de Reemplazo de Estrógeno , Femenino , Genotipo , Humanos , Masculino , PlacebosRESUMEN
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.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteínas de Unión al Calcio/líquido cefalorraquídeo , Factores de Crecimiento Nervioso/líquido cefalorraquídeo , Proteínas S100 , Adulto , Anciano , Enfermedad de Alzheimer/psicología , Cognición , Femenino , Humanos , Masculino , Escala del Estado Mental , Escalas de Valoración Psiquiátrica , Valores de Referencia , Subunidad beta de la Proteína de Unión al Calcio S100 , Factores de TiempoRESUMEN
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.
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Hormona Adrenocorticotrópica/metabolismo , Deshidroepiandrosterona/metabolismo , Retroalimentación , Hidrocortisona/metabolismo , Metirapona/farmacología , Metirapona/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/metabolismo , Hormona Adrenocorticotrópica/sangre , Deshidroepiandrosterona/sangre , Humanos , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/fisiología , Radioinmunoensayo , Distribución Aleatoria , Sensibilidad y EspecificidadRESUMEN
Family and twin studies suggest a substantial genetic contribution to the etiology of posttraumatic stress disorder (PTSD). Identification of the nature of this genetic contribution should enhance understanding of the pathophysiology of PTSD and suggest improved therapeutic strategies for its treatment. However, a broadly defined phenotype, specific requirement for an environmental exposure and high frequency of comorbid psychiatric illness all complicate genetic studies of PTSD. It is likely that genetic heterogeneity, incomplete penetrance, pleiotropy and the involvement of more than one gene all constitute formidable obstacles to the genetic analysis of PTSD. One way to circumvent these problems is to perform genetic analysis of traits associated with PTSD, rather than PTSD itself, an approach that has been fruitful for other diseases with complex modes of inheritance. Hypothalamic-pituitary-adrenal axis hypofunction, physiologic markers of increased arousal, and increased acoustic startle response are all potential PTSD-associated traits that might be susceptible to genetic analysis. However, the capacity of these traits to distinguish PTSD from non-PTSD patients and their familial pattern must be better defined before they can be employed in genetic studies.