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1.
J Int Neuropsychol Soc ; 24(4): 324-334, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29284552

RESUMEN

OBJECTIVES: To evaluate prospective and retrospective memory abilities in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans with and without a self-reported history of blast-related mild traumatic brain injury (mTBI). METHODS: Sixty-one OEF/OIF/OND Veterans, including Veterans with a self-reported history of blast-related mTBI (mTBI group; n=42) and Veterans without a self-reported history of TBI (control group; n=19) completed the Memory for Intentions Test, a measure of prospective memory (PM), and two measures of retrospective memory (RM), the California Verbal Learning Test-II and the Brief Visuospatial Memory Test-Revised. RESULTS: Veterans in the mTBI group exhibited significantly lower PM performance than the control group, but the groups did not differ in their performance on RM measures. Further analysis revealed that Veterans in the mTBI group with current PTSD (mTBI/PTSD+) demonstrated significantly lower performance on the PM measure than Veterans in the control group. PM performance by Veterans in the mTBI group without current PTSD (mTBI/PTSD-) was intermediate between the mTBI/PTSD+ and control groups, and results for the mTBI/PTSD- group were not significantly different from either of the other two groups. CONCLUSIONS: Results suggest that PM performance may be a sensitive marker of cognitive dysfunction among OEF/OIF/OND Veterans with a history of self-reported blast-related mTBI and comorbid PTSD. Reduced PM may account, in part, for complaints of cognitive difficulties in this Veteran cohort, even years post-injury. (JINS, 2018, 24, 324-334).


Asunto(s)
Traumatismos por Explosión/fisiopatología , Conmoción Encefálica/fisiopatología , Disfunción Cognitiva/fisiopatología , Trastornos de la Memoria/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Veteranos , Adulto , Campaña Afgana 2001- , Traumatismos por Explosión/complicaciones , Traumatismos por Explosión/epidemiología , Conmoción Encefálica/complicaciones , Conmoción Encefálica/epidemiología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Comorbilidad , Humanos , Guerra de Irak 2003-2011 , Estudios Longitudinales , Masculino , Trastornos de la Memoria/epidemiología , Trastornos de la Memoria/etiología , Memoria Episódica , Persona de Mediana Edad , Autoinforme , Trastornos por Estrés Postraumático/epidemiología , Estados Unidos/epidemiología , Veteranos/estadística & datos numéricos
2.
Alzheimers Dement ; 14(7): 889-894, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29544979

RESUMEN

INTRODUCTION: Inheritance of the ε4 allele of apolipoprotein E (APOE) increases a person's risk of developing both Alzheimer's disease (AD) and Lewy body dementia (LBD), yet the underlying mechanisms behind this risk are incompletely understood. The recent identification of reduced APOE DNA methylation in AD postmortem brains prompted this study to investigate APOE methylation in LBD. METHODS: Genomic DNA from postmortem brain tissues (frontal lobe and cerebellum) of neuropathological pure (np) controls and npAD, LBD + AD, and npLBD subjects were bisulfite pyrosequenced. DNA methylation levels of two APOE subregions were then compared for these groups. RESULTS: APOE DNA methylation was significantly reduced in npLBD compared with np controls, and methylation levels were lowest in the LBD + AD group. DISCUSSION: Given that npLBD and npAD postmortem brains shared a similar reduction in APOE methylation, it is possible that an aberrant epigenetic change in APOE is linked to risk for both diseases.


Asunto(s)
Apolipoproteínas E/genética , Encéfalo , Metilación de ADN/genética , Lóbulo Frontal/patología , Enfermedad por Cuerpos de Lewy/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Autopsia , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Genotipo , Humanos , Enfermedad por Cuerpos de Lewy/patología , Masculino
3.
Subst Use Misuse ; 51(2): 216-29, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26800263

RESUMEN

BACKGROUND: Sexual minority women report greater alcohol misuse than heterosexual women in the general population, with more pronounced differences found among younger age groups. It is unknown whether these differences exist among women veterans. OBJECTIVE: We evaluated differences in alcohol misuse across two dimensions of sexual orientation (identity and behavior) among women veterans, and examined whether these differences were modified by age. METHODS: Women veterans were recruited via the internet to participate in an online survey. Participants provided information on their self-reported sexual identity and behavior and responded to the validated 3-item Alcohol Use Disorders Identification Test-Consumption questionnaire (AUDIT-C). Regression models were used to compare the prevalence of alcohol misuse (AUDIT-C ≥ 3) and severity (AUDIT-C scores) across sexual identity and behavior and to test effect modification by age. RESULTS: Among the 702 participants (36% lesbian/bisexual), prevalence and severity of alcohol misuse varied by both sexual identity and behavior, but there were significant interactions with age. Prevalence and severity of alcohol misuse were higher among relatively younger self-identified lesbians compared to heterosexual women. Similarly, both prevalence and severity of alcohol misuse were generally higher among younger women who had any sex with women compared to those who had sex only with men. CONCLUSIONS/IMPORTANCE: In this online study of women veterans, younger sexual minority women were more likely to screen positive for alcohol misuse, and they had more severe alcohol misuse, than their heterosexual counterparts. Prevention and treatment efforts focused specifically on sexual minority women veterans may be needed.


Asunto(s)
Alcoholismo/epidemiología , Consumo Excesivo de Bebidas Alcohólicas/epidemiología , Bisexualidad/estadística & datos numéricos , Heterosexualidad/estadística & datos numéricos , Homosexualidad Femenina/estadística & datos numéricos , Minorías Sexuales y de Género/estadística & datos numéricos , Veteranos/estadística & datos numéricos , Mujeres , Adulto , Anciano , Estudios Transversales , Femenino , Disparidades en el Estado de Salud , Humanos , Persona de Mediana Edad , Conducta Sexual/estadística & datos numéricos , Encuestas y Cuestionarios , Estados Unidos/epidemiología
4.
Genet Epidemiol ; 36(5): 488-98, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22628073

RESUMEN

Copy Number Variation (CNV) is increasingly implicated in disease pathogenesis. CNVs are often identified by statistical models applied to data from single nucleotide polymorphism panels. Family information for samples provides additional information for CNV inference. Two modes of PennCNV (the Joint-call and Posterior-call), which are some of the most well-developed family-based CNV calling methods, use a "Joint-model" as a main component. This models all family members' CNV states together with Mendelian inheritance. Methods based on the Joint-model are used to infer CNV calls of cases and controls in a pedigree, which may be compared to each other to test an association. Although benefits from the Joint-model have been shown elsewhere, equality of call rates in parents and offspring has not been evaluated previously. This can affect downstream analyses in studies that compare CNV rates in cases vs. controls in pedigrees. In this paper, we show that the Joint-model can introduce different CNV call rates among family members in the absence of a true difference. We show that the Joint-model may analytically introduce differential CNV calls because of asymmetry of the model. We demonstrate these differential call rates using single-marker simulations. We show that call rates using the two modes of PennCNV also differ between parents and offspring in one multimarker simulated dataset and two real datasets. Our results advise need for caution in use of the Joint-model calls in CNV association studies with family-based datasets.


Asunto(s)
Variaciones en el Número de Copia de ADN , Esquizofrenia/genética , Algoritmos , Bases de Datos Genéticas , Salud de la Familia , Marcadores Genéticos , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Modelos Biológicos , Modelos Genéticos , Modelos Estadísticos , Linaje , Polimorfismo de Nucleótido Simple , Probabilidad
5.
medRxiv ; 2023 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-36798376

RESUMEN

The application of machine learning (ML) tools in electronic health records (EHRs) can help reduce the underdiagnosis of dementia, but models that are not designed to reflect minority population may perpetuate that underdiagnosis. To address the underdiagnosis of dementia in both Black Americans (BAs) and white Americans (WAs), we sought to develop and validate ML models that assign race-specific risk scores. These scores were used to identify undiagnosed dementia in BA and WA Veterans in EHRs. More specifically, risk scores were generated separately for BAs (n=10K) and WAs (n=10K) in training samples of cases and controls by performing ML, equivalence mapping, topic modeling, and a support vector-machine (SVM) in structured and unstructured EHR data. Scores were validated via blinded manual chart reviews (n=1.2K) of controls from a separate sample (n=20K). AUCs and negative and positive predictive values (NPVs and PPVs) were calculated to evaluate the models. There was a strong positive relationship between SVM-generated risk scores and undiagnosed dementia. BAs were more likely than WAs to have undiagnosed dementia per chart review, both overall (15.3% vs 9.5%) and among Veterans with >90th percentile cutoff scores (25.6% vs 15.3%). With chart reviews as the reference standard and varied cutoff scores, the BA model performed slightly better than the WA model (AUC=0.86 with NPV=0.98 and PPV=0.26 at >90th percentile cutoff vs AUC=0.77 with NPV=0.98 and PPV=0.15 at >90th). The AUCs, NPVs, and PPVs suggest that race-specific ML models can assist in the identification of undiagnosed dementia, particularly in BAs. Future studies should investigate implementing EHR-based risk scores in clinics that serve both BA and WA Veterans.

6.
Behav Brain Funct ; 8: 62, 2012 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-23270420

RESUMEN

BACKGROUND: Neuropsychiatric symptoms such as psychosis are prevalent in patients with probable Alzheimer's disease (AD) and are associated with increased morbidity and mortality. Because these disabling symptoms are generally not well tolerated by caregivers, patients with these symptoms tend to be institutionalized earlier than patients without them. The identification of protective and risk factors for neuropsychiatric symptoms in AD would facilitate the development of more specific treatments for these symptoms and thereby decrease morbidity and mortality in AD. The E4 allele of the apolipoprotein E (APOE) gene is a well-documented risk factor for the development of AD. However, genetic association studies of the APOE 4 allele and BPS in AD have produced conflicting findings. METHODS: This study investigates the association between APOE and neuropsychiatric symptoms in a large sample of clinically well-characterized subjects with probable AD (n=790) who were systematically evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Behavioral Rating Scale for Dementia (BRSD). RESULTS: Our study found that hallucinations were significantly more likely to occur in subjects with no APOΕ4 alleles than in subjects with two Ε4 alleles (15% of subjects and 5% of subjects, respectively; p=.0066), whereas there was no association between the occurrence of delusions, aberrant motor behavior, or agitation and the number of Ε4 alleles. However, 94% of the subjects with hallucinations also had delusions (D+H). CONCLUSION: These findings suggest that in AD the Ε4 allele is differentially associated with D+H but not delusions alone. This is consistent with the hypothesis that distinct psychotic subphenotypes may be associated with the APOE allele.


Asunto(s)
Alelos , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Estudios de Asociación Genética , Fenotipo , Trastornos Psicóticos/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Deluciones/diagnóstico , Deluciones/epidemiología , Deluciones/genética , Femenino , Estudios de Asociación Genética/métodos , Alucinaciones/diagnóstico , Alucinaciones/epidemiología , Alucinaciones/genética , Humanos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/epidemiología
7.
Chronic Stress (Thousand Oaks) ; 5: 2470547020979780, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33623856

RESUMEN

BACKGROUND: The α1-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α1-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined. METHODS: In a post hoc reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple comparisons. RESULTS: Prazosin showed the largest effect for distressing dreams, anhedonia, difficulty falling or staying asleep, difficulty concentrating, and hypervigilance. These items were also (a) of higher baseline severity in the underlying population, and (b) more related in how they fluctuated at the level of individual subjects. Covariance analysis did not support a clear cutoff between highly prazosin responsive items and those showing a smaller, not statistically significant response. CONCLUSIONS: In this data set, twice daily prazosin substantially reduced not only nightmares and sleep disruption, but the majority of hyperarousal symptoms, with some evidence of efficacy for avoidance symptoms. The relationship of baseline symptom distribution to which symptoms showed significant response to prazosin reinforces the possibility that differences in a clinical trial's participant populations may significantly influence trial outcome. The pattern of symptom endorsement at the level of individual subjects was consistent with prazosin-responsive items sharing a common pathophysiologic mechanism.

8.
J Consult Clin Psychol ; 89(2): 134-142, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33705169

RESUMEN

OBJECTIVE: Scalable, efficiently delivered treatments are needed to address the needs of women Veterans with PTSD. This randomized clinical trial compared an online, coach-assisted cognitive behavioral intervention tailored for women Veterans with PTSD to phone monitoring only. METHOD: Women Veterans who met diagnostic criteria for PTSD were randomized to an 8-week web-based intervention, called DElivery of Self TRaining and Education for Stressful Situations (DESTRESS)-Women Veterans version (WV), or to phone monitoring only (N = 102). DESTRESS-WV consisted of online sessions and 15-min weekly phone calls from a study coach. Phone monitoring included 15-min weekly phone calls from a study coach to offer general support. PTSD symptom severity (PTSD Symptom-Checklist-Version 5 [PCL-5]) was evaluated pre and posttreatment, and at 3 and 6 months posttreatment. RESULTS: More participants completed phone monitoring than DESTRESS-WV (96% vs. 76%, p = 0.01), although treatment satisfaction was significantly greater in the DESTRESS-WV condition. We failed to confirm the superiority of DESTRESS-WV in intent-to-treat slope changes in PTSD symptom severity. Both treatments were associated with significant reductions in PTSD symptom severity over time. However, post hoc analyses of treatment completers and of those with baseline PCL ≥ 33 revealed that the DESTRESS-WV group had greater improvement in PTSD symptom severity relative to phone monitoring with significant differences at the 3-month follow-up assessment. CONCLUSIONS: Both DESTRESS-WV and phone monitoring resulted in significant improvements in women Veterans' PTSD symptoms. DESTRESS-WV may be an appropriate care model for women Veterans who can engage in the demands of the treatment and have higher baseline symptoms. Future research should explore characteristics of and the methods of reliably identifying women Veterans who are most likely to benefit. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Asunto(s)
Intervención basada en la Internet , Automanejo , Trastornos por Estrés Postraumático/terapia , Veteranos/psicología , Adulto , Femenino , Humanos , Persona de Mediana Edad , Trastornos por Estrés Postraumático/psicología , Resultado del Tratamiento
9.
J Alzheimers Dis ; 13(3): 255-66, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18430993

RESUMEN

The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.


Asunto(s)
Apolipoproteína E4/genética , Apolipoproteínas E/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Cartilla de ADN/genética , Elementos de Facilitación Genéticos , Femenino , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Pruebas Neuropsicológicas , Regiones Promotoras Genéticas , Índice de Severidad de la Enfermedad
10.
Am J Clin Pathol ; 129(4): 526-9, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18343778

RESUMEN

The therapeutic imperative for Alzheimer disease (AD) and Parkinson disease (PD) calls for discovery and validation of biomarkers. Increased cerebrospinal fluid (CSF) tau and decreased amyloid (A) beta42 have been validated as biomarkers of AD. In contrast, there is no validated CSF biomarker for PD. We validated our proteomics-discovered multianalyte profile (MAP) in CSF from 95 control subjects, 48 patients with probable AD, and 40 patients with probable PD. An optimal 8-member MAP agreed with expert diagnosis for 90 control subjects (95%), 36 patients with probable AD (75%), and 38 patients with probable PD (95%). This MAP consisted of the following (in decreasing order of contribution): tau, brain-derived neurotrophic factor, interleukin 8, Abeta42, beta2-microglobulin, vitamin D binding protein, apolipoprotein (apo) AII, and apoE. This first large-scale validation of a proteomic-discovered MAP suggests a panel of 8 CSF proteins that are highly effective at identifying PD and moderately effective at identifying AD.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Anciano , Péptidos beta-Amiloides , Apolipoproteínas/líquido cefalorraquídeo , Apolipoproteínas E/líquido cefalorraquídeo , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Líquido Cefalorraquídeo , Diagnóstico Diferencial , Femenino , Humanos , Interleucina-8/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos , Precursores de Proteínas/líquido cefalorraquídeo , Proteína de Unión a Vitamina D/líquido cefalorraquídeo , Microglobulina beta-2 , Proteínas tau/líquido cefalorraquídeo
11.
Parkinsons Dis ; 2018: 3719578, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30515290

RESUMEN

BACKGROUND: The Washington State Parkinson Disease Registry (WPDR) was created to facilitate recruitment for Parkinson's disease (PD) research studies conducted in the Pacific Northwest. The success of registries that rely on self-report is dependent on the accuracy of the information provided by participants, particularly diagnosis. OBJECTIVE AND METHODS: Our goal was to assess diagnostic accuracy within the WPDR cohort. We randomly selected and attempted to contact 168 of the 1,278 actively enrolled WPDR participants. Those who responded were invited to undergo an interview and neurological examination performed by a PD specialist. If an in-person assessment was not possible, we sought information collected during participation in prior research studies or from review of medical records. A diagnosis was considered "validated" if the individual met UK Parkinson's Disease Society Brain Bank (UKBB) clinical diagnostic criteria for PD. RESULTS: Data were ascertained for 106 participants; 77 underwent an in-person assessment, 21 had data available from a prior research study, and 8 provided access to medical records. Diagnostic accuracy within the overall sample was 93.4% (95% confidence interval (86.4%, 97.1%)). Seven patients did not fulfill UKBB criteria for the following reasons: early severe autonomic involvement (n=3), history of neuroleptic treatment (n=1), presence of the Babinski sign (n=1), or insufficient supportive criteria (n=2). CONCLUSIONS: Our results indicate that studies which use the WPDR for recruitment will rarely encounter patients who are misdiagnosed. This further supports the utility of the WPDR as an effective recruitment tool for PD research in the Pacific Northwest.

12.
Am J Psychiatry ; 175(12): 1216-1224, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30153753

RESUMEN

OBJECTIVE: Current medications for alcohol use disorder do not target brain noradrenergic pathways. Theoretical and preclinical evidence suggests that noradrenergic circuits may be involved in alcohol reinforcement and relapse. After a positive pilot study, the authors tested the α-1 adrenergic receptor antagonist prazosin to treat alcohol use disorder in a larger sample. METHOD: Ninety-two participants with alcohol use disorder but without posttraumatic stress disorder were randomly assigned to receive prazosin or placebo in a 12-week double-blind study. Medication was titrated to a target dosing schedule of 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime by the end of week 2. The behavioral platform was medical management. Participants provided daily data on alcohol consumption. Generalized linear mixed-effects models were used to examine the impact of prazosin compared with placebo on number of drinks per week, number of drinking days per week, and number of heavy drinking days per week. RESULTS: Eighty participants completed the titration period and were included in the primary analyses. There was a significant interaction between condition and week for both number of drinks and number of heavy drinking days, such that the rate of drinking and the probability of heavy drinking showed a greater decrease over time for participants in the prazosin condition compared with those in the placebo condition. Participants in the prazosin condition were more likely to report drowsiness and edema than participants in the placebo condition. CONCLUSIONS: Prazosin holds promise as a harm-reduction pharmacologic treatment for alcohol use disorder and deserves further evaluation by independent research groups.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Alcoholismo/tratamiento farmacológico , Prazosina/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/epidemiología , Método Doble Ciego , Esquema de Medicación , Etanol/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prazosina/administración & dosificación
13.
Brain Res ; 1698: 179-186, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30081037

RESUMEN

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for developing Alzheimer's disease (AD). Our recent identification of altered APOE DNA methylation in AD postmortem brain (PMB) prompted this follow-up study. Our goals were to (i) validate the AD-differential methylation of APOE in an independent PMB study cohort and (ii) determine the cellular populations (i.e., neuronal vs. non-neuronal) of AD PMB that contribute to this differential methylation. Here, we obtained an independent cohort of 57 PMB (42 AD and 15 controls) and quantified their APOE methylation levels from frontal lobe and cerebellar tissue. We also applied fluorescence-activated nuclei sorting (FANS) to separate neuronal nuclei from non-neuronal nuclei within the tissue of 15 AD and 14 control subjects. Bisulfite pyrosequencing was used to generate DNA methylation profiles of APOE from both bulk PMB and FANS nuclei. Our results provide independent validation that the APOE CGI holds lower DNA methylation levels in AD compared to control in frontal lobe but not cerebellar tissue. Our data also indicate that the non-neuronal cells of the AD brain, which are mainly composed of glia, are the main contributors to the lower APOE DNA methylation observed in AD PMB. Given that astrocytes are the primary producers of ApoE in the brain our results suggest that alteration of epigenetically regulated APOE expression in glia could be an important part of APOE's strong effect on AD risk.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/fisiopatología , Neuroglía/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Astrocitos/patología , Encéfalo/metabolismo , Islas de CpG , Metilación de ADN , Epigénesis Genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Neuroglía/metabolismo , Neuronas/patología , Regiones Promotoras Genéticas
14.
Neurobiol Stress ; 8: 103-111, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29888305

RESUMEN

BACKGROUND: Increases in the quantity or impact of noradrenergic signaling have been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). This increased signaling may result from increased norepinephrine (NE) release, from altered brain responses to NE, or from a combination of both factors. Here, we tested the hypothesis that Veterans reporting a history of trauma exposure would show an increased association between brain NE and mental health symptoms commonly observed after trauma, as compared to Veterans who did not report a history of trauma exposure, consistent with the possibility of increased brain reactivity to NE after traumatic stress. METHODS: Using a convenience sample of 69 male Veterans with a history of combat-theater deployment, we examined the relationship between trauma-related mental health symptoms and the concentration of NE in cerebrospinal fluid (CSF). CSF NE levels were measured by HPLC in CSF from morning lumbar puncture. Behavioral symptoms associated with diagnoses of PTSD, depression, insomnia, or post-concussive syndrome (PCS), which together cover a wide variety of symptoms associated with alterations in arousal systems, such as sleep, mood, concentration, and anxiety, were assessed via self-report (PTSD Checklist [PCL] for PTSD, Patient Health Questionnaire 9 [PHQ9] for depression, Pittsburgh Sleep Quality Index [PSQI] for sleep problems including insomnia, and Neurobehavioral Symptom Inventory [NSI] for PCS) and structured clinical interview (Clinician-Administered PSTD Scale [CAPS]). Individuals meeting criterion A of the DSM-IV diagnostic criteria for PTSD were considered trauma-exposed. Linear regression models were used to quantify the association between CSF NE and symptom intensity in participants with and without a history of trauma exposure, as well as in participants with a history of trauma exposure who were currently taking the noradrenergic receptor antagonist prazosin. RESULTS: Fifty-two Veterans met criteria for a history of trauma exposure; of these, 36 met criteria for PTSD. CSF NE levels were not significantly different in Veterans with a history of trauma compared to those without, nor in Veterans with PTSD as compared to those without. Veterans with a history of trauma and who were not using the medication prazosin demonstrated a significantly more positive correlation between CSF NE and behavioral symptom expression than Veterans who had not experienced traumatic stress. No relationship between CSF NE and behavioral symptom expression was found in Veterans who had experienced traumatic stress and were taking prazosin at the time of the assessments. CONCLUSIONS: These results are consistent with increased central nervous system responsiveness to noradrenergic signaling in individuals with a history of traumatic exposure, raising the possibility that there may be long-lasting physiologic effects of trauma-exposure that exist independently of whether an individual meets criteria for PTSD at any given point in time. Exploration of the mechanism by which brain responsiveness to NE is modulated following trauma holds the possibility of finding new strategies for both preventing and treating PTSD.

15.
Contemp Clin Trials ; 53: 68-79, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27940187

RESUMEN

Women Veterans are a rapidly growing population with high risk of exposure to potentially traumatizing events and PTSD diagnoses. Despite the dissemination of evidence-based treatments for PTSD in the VA, most women Veteran VA users underutilize these treatments. Web-based PTSD treatment has the potential to reach and engage women Veterans with PTSD who do not receive treatment in VA settings. Our objective is to modify and evaluate Delivery of Self Training and Education for Stressful Situations (DESTRESSS), a web-based cognitive-behavioral intervention for PTSD, to target PTSD symptoms among women Veterans. The specific aims are to: (1) obtain feedback about DESTRESS, particularly on its relevance and sensitivity to women, using semi-structured interviews with expert clinicians and women Veterans with PTSD, and make modifications based on this feedback; (2) conduct a pilot study to finalize study procedures and make further refinements to the intervention; and (3) conduct a randomized clinical trial (RCT) evaluating a revised, telephone-assisted DESTRESS compared to telephone monitoring only. We describe the results from the first two aims, and the study design and procedures for the ongoing RCT. This line of research has the potential to result in a gender-sensitive, empirically-based, online treatment option for women Veterans with PTSD.


Asunto(s)
Terapia Cognitivo-Conductual/métodos , Terapia Implosiva/métodos , Internet , Trastornos por Estrés Postraumático/terapia , Terapia Asistida por Computador/métodos , Veteranos/psicología , Mujeres/psicología , Adulto , Actitud Frente a la Salud , Femenino , Humanos , Persona de Mediana Edad , Satisfacción del Paciente , Proyectos Piloto , Investigación Cualitativa , Trastornos por Estrés Postraumático/psicología
16.
Neurology ; 89(12): 1251-1255, 2017 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-28821686

RESUMEN

OBJECTIVE: To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. METHODS: Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aß42, total tau, and p-tau181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status. RESULTS: Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aß42, total tau, and p-tau181, respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau181 (p = 0.003), where greater decreases from baseline in CSF p-tau181 concentrations were associated with higher baseline LDL level for the simvastatin group. CONCLUSIONS: Simvastatin-related reductions in CSF p-tau181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Evaluación de Resultado en la Atención de Salud , Fragmentos de Péptidos/líquido cefalorraquídeo , Simvastatina/farmacología , Proteínas tau/líquido cefalorraquídeo , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/prevención & control , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Estudios de Seguimiento , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Persona de Mediana Edad , Simvastatina/administración & dosificación
17.
Contemp Clin Trials ; 27(6): 561-70, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16875884

RESUMEN

The frequency and nature of adverse events (AEs) are important safety endpoints in clinical trials of therapies for cystic fibrosis (CF) subjects, yet published tables of background AE rates in the CF population are not readily available. Our objective in this study was to produce tables of respiratory AE rates for placebo subjects (pediatric and adult) for inhaled therapy trials in CF subjects. Respiratory AE rates in inhaled therapy trials were computed by combining data on placebo subjects from early-phase dosing studies and middle/late-phase studies, where placebo consisted of 4 or 5 mL of inhaled saline solution. AE rates were computed as number of events divided by number of placebo-subject days of observation, and 95% confidence intervals were computed based on a Poisson model. AEs were categorized as both broad (e.g., respiratory, reactive airway disease) and specific (e.g., cough, chest tightness, hemoptysis). In short-term studies, respiratory AE rates (95% confidence interval) were 1.1(0.7, 1.6)/person-week and 1.0(0.7, 1.4)/person-week in pediatric and adult subjects, respectively. In long-term studies, respiratory AE rates were 1.7(1.6, 1.8)/person-month and 2.2(2.1, 2.3)/person-month in pediatric and adult subjects, respectively. Stepwise Poisson models were fit to determine if baseline covariates were important in predicting AE rates. Forced expiratory volume in one second (FEV(1)) percent of predicted and age in short-term studies, and FEV(1) percent predicted and gender in long-term studies were statistically important in predicting respiratory AE rates. Although these variables were statistically significant, the models' predictive abilities were low, with adjusted R(2)'s of 0.06 and 0.12 in the short- and long-term studies, respectively. Combining placebo-subject AE data recorded from multiple CF clinical trials yields better estimates of true rates of occurrence in the CF population. The tables published from this study can be used to assist those charged with safety monitoring in CF clinical trials.


Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Placebos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto/efectos adversos , Enfermedades Respiratorias/etiología , Administración por Inhalación , Adolescente , Adulto , Niño , Preescolar , Comités de Monitoreo de Datos de Ensayos Clínicos , Femenino , Volumen Espiratorio Forzado , Humanos , Cuidados a Largo Plazo , Masculino , Enfermedades Respiratorias/diagnóstico , Riesgo , Tamaño de la Muestra , Estados Unidos
18.
Biol Psychiatry ; 80(10): 736-742, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27320368

RESUMEN

BACKGROUND: In a previously reported positive randomized controlled trial of the α1-adrenoreceptor (α1AR) antagonist prazosin for combat posttraumatic stress disorder (PTSD) in 67 active duty soldiers, baseline symptoms did not predict therapeutic response. If increased brain α1AR activation in PTSD is the target of prazosin treatment action, higher brain α1AR activation should predict greater prazosin efficacy. Although brain α1AR activation is not measurable, coregulated peripheral α1AR activation could provide an estimate of brain α1AR activation. Standing blood pressure (BP) is an accessible biological parameter regulated by norepinephrine activation of α1ARs on peripheral arterioles. METHODS: Effects of baseline standing systolic and other BP parameters on PTSD outcome measures from the previously reported randomized controlled trial were analyzed using linear mixed-effects models. Prazosin participants (n = 32) and placebo participants (n = 35) were analyzed separately. RESULTS: In prazosin participants, each 10-mm Hg higher baseline standing systolic BP increment resulted in an additional 14-point reduction (improvement) of Clinician-Administered PTSD Scale total score at end point (p = .002). All other combinations of baseline BP parameters and PTSD outcome measures were similarly significant or demonstrated trends in the predicted direction. In placebo participants, there was no signal for a baseline BP effect on PTSD outcome measures. CONCLUSIONS: These findings suggest that higher standing BP is a biomarker that helps identify persons with combat PTSD who are likely to benefit from prazosin. These results also are consistent with α1AR activation contributing to PTSD pathophysiology in a subgroup of patients.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Presión Sanguínea/efectos de los fármacos , Trastornos de Combate/tratamiento farmacológico , Personal Militar , Evaluación de Resultado en la Atención de Salud , Prazosina/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Adulto , Biomarcadores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prazosina/administración & dosificación , Adulto Joven
19.
Environ Toxicol Chem ; 35(5): 1201-12, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26403382

RESUMEN

For many older pharmaceuticals, chronic aquatic toxicity data are limited. To assess risk during development, scale-up, and manufacturing processes, acute data and physicochemical properties need to be leveraged to reduce potential long-term impacts to the environment. Aquatic toxicity data were pooled from daphnid, fish, and algae studies for 102 active pharmaceutical ingredients (APIs) to evaluate the relationship between predicted no-effect concentrations (PNECs) derived from acute and chronic tests. The relationships between acute and chronic aquatic toxicity and the n-octanol/water distribution coefficient (D(OW)) were also characterized. Statistically significant but weak correlations were observed between toxicity and log D(OW), indicating that D(OW) is not the only contributor to toxicity. Both acute and chronic PNEC values could be calculated for 60 of the 102 APIs. For most compounds, PNECs derived from acute data were lower than PNECs derived from chronic data, with the exception of steroid estrogens. Seven percent of the PNECs derived from acute data were below the European Union action limit of 0.01 µg/L and all were anti-infectives affecting algal species. Eight percent of available PNECs derived from chronic data were below the European Union action limit, and fish were the most sensitive species for all but 1 API. These analyses suggest that the use of acute data may be acceptable if chronic data are unavailable, unless specific mode of action concerns suggest otherwise.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Contaminantes Químicos del Agua/toxicidad , 1-Octanol/química , Animales , Chlorophyta/efectos de los fármacos , Cianobacterias/efectos de los fármacos , Daphnia/efectos de los fármacos , Peces , Medición de Riesgo , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Crónica , Agua/química
20.
Schizophr Res ; 174(1-3): 1-9, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27132484

RESUMEN

Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially.


Asunto(s)
Endofenotipos , Esquizofrenia/genética , Psicología del Esquizofrénico , Adolescente , Adulto , Anciano , Familia , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pruebas Neuropsicológicas , Curva ROC , Esquizofrenia/clasificación , Adulto Joven
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