Circadian biomarkers in asymptomatic offspring of patients with late-onset Alzheimer's disease and their relationship with cognitive performance

Abstract: Introduction: Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) impact structures that regulate circadian rhythms and particularly sleep. Indeed, sleep pattern is emerging as a potential biomarker, mechanistic pathway and treatment target in LOAD. We hypothesized that circadian rhythm anomalies would already be present in asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) prior to cognitive decline. Materials and methods: We tested 35 subjects with at least one parent with LOAD (O-LOAD) and 31 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with a series of cognitive tests, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function via heart rate variability (HRV), and bodily temperature. Results: O-LOAD displayed subtle yet significant deficits in verbal episodic memory (RAVLT learning 48.32 ± 1.59 vs. 44.12 ± 1.21, p = 0.005; delayed recall 10.55 ± 0.38 vs. 8.68 ± 0.52, p = 0.005) and language (Vocabulary 50.5 ± 1.06 vs. 45.06 ± 1.48, p= 0.004) compared to CS. O-LOAD showed a more extended sleep duration (439.26 min ± 9.41 vs. 473.66 min ± 10.57, p = .018) and reduced sleep efficiency (97.07 % ± .41 vs. 95.75 % ± .48, p = .042). No significant differences were found for body temperature or HRV variables. Correlations between increased sleep duration and poorer cognition were found in CS but not in O-LOAD. Improved cognitive performance was associated to indicators of greater sympathetic activity. Conclusions: Our results support the hypothesis that sleep pattern disturbances are already present very early on in relatively young asymptomatic subjects. The unexpected reduced cognitive results found in O-LOAD suggest that cognitive decline could start earlier than anticipated in the form of subtle cognitive changes within the clinically normal range. It is widely accepted that sleep pattern disturbances would result in cognitive alterations. Taken these information together with the correlations between sleep duration and cognition present in CS but absent in O-LOAD suggest some impairment in the mechanisms underlying the sleep-cognitive relationship. Sleep pattern deserves further study as a potential biomarker in LOAD, even in healthy middle-aged individuals

Circadian biomarkers in asymptomatic offspring of patients with late-onset Alzheimer's disease and their relationship with cognitive performance

Introduction: Early neuropathological changes characteristic of late-onset Alzheimer´s disease (LOAD) impact structures that regulate circadian rhythms and particularly sleep. Indeed, sleep pattern is emerging as a potential biomarker, mechanistic pathway and treatment target in LOAD. We hypothesized that circadian rhythm anomalies would already be present in asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) prior to cognitive decline.Materials and methods: We tested 35 subjects with at least one parent with LOAD (O-LOAD) and 31 healthy individuals without family history of Alzheimer´s disease (control subjects, CS) with a series of cognitive tests, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function via heart rate variability (HRV), and bodily temperature.Results: O-LOAD displayed subtle yet significant deficits in verbal episodic memory (RAVLT learning 48.32 ± 1.59 vs. 44.12 ± 1.21, p = 0.005; delayed recall 10.55 ± 0.38 vs. 8.68 ± 0.52, p = 0.005) and language (Vocabulary 50.5 ± 1.06 vs. 45.06 ± 1.48, p= 0.004) compared to CS. O-LOAD showed a more extended sleep duration (439.26 min ± 9.41 vs. 473.66 min ± 10.57, p = .018) and reduced sleep efficiency (97.07 % ± .41 vs. 95.75 % ± .48, p = .042). No significant differences were found for body temperature or HRV variables. Correlations between increased sleep duration and poorer cognition were found in CS but not in O-LOAD. Improved cognitive performance was associated to indicators of greater sympathetic activity.Conclusions: Our results support the hypothesis that sleep pattern disturbances are already present very early on in relatively young asymptomatic subjects. The unexpected reduced cognitive results found in O-LOAD suggest that cognitive decline could start earlier than anticipated in the form of subtle cognitive changes within the clinically normal range. It is widely accepted that sleep pattern disturbances would result in cognitive alterations. Taken these information together with the correlations between sleep duration and cognition present in CS but absent in O-LOAD suggest some impairment in the mechanisms underlying the sleep-cognitive relationship. Sleep pattern deserves further study as a potential biomarker in LOAD, even in healthy middle-aged individuals.Fil: Abulafia, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Duarte Abritta, Bárbara. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Sánchez, Stella M.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Villarreal, Mirta Fabiana. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ladrón de Guevara, Maria Soledad. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sevlever, Gustavo. No especifíca;Fil: Fiorentini, Leticia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guinjoan, Salvador Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Vigo, Daniel Eduardo. Katholikie Universiteit Leuven; Bélgica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina15th World Sleep CongressCanadáWorld Sleep Societ

Hemispheric specialization of mood processing is abnormal in patients with schizophrenia

the present results offer evidence on abnormal lateralization of brain activity associated to mood processing in schizophrenia. To our knowledge, lateralized mood processing has not been previously studied in this disorder. The present observation adds to burgeoning evidence on a widespread deficit of brain lateralization in psychosis, probably underlying language-related abnormalities such as delusions and auditory hallucinations, social cognitive deficits, and motor dexterity.Fil: Drucaroff, Lucas Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires; ArgentinaFil: Costanzo, Elsa Y.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires; ArgentinaFil: Castro, Mariana Nair. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires; ArgentinaFil: Ortiz Villafañe, Manuel. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires; ArgentinaFil: Wainsztein, Agustina E.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires; ArgentinaFil: Abulafia, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Duarte Abritta, Bárbara. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Villarreal, Mirta Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Guinjoan, Salvador Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires; Argentin

Amyloid and anatomical correlates of executive functioning in middle-aged offspring of patients with late-onset Alzheimer's disease

Abstract: A traditional hallmark of cognitive impairment associated with late-onset Alzheimer´s disease (LOAD) is episodic memory impairment. However, early alterations have been identified in brain regions associated with executive function in asymptomatic, middle-age offspring of patients with LOAD (O-LOAD) compared to those with no family history. We hypothesized that executive function among O-LOAD would correlate with structural and amyloid brain imaging differently from those without a family history of LOAD (control subjects, CS). Executive function, cortical thickness, and in-vivo Aβ deposits were quantified in 30 O-LOAD and 25 CS. Associations were observed among O-LOAD only. Cortical thickness in the left lateral orbitofrontal cortex was positively associated with Design Fluency. The Stroop Color and Word Test, correlated positively with right rostral mid-frontal cortex thickness. Trails Making Test-B was inversely related to left medial orbitofrontal thickness. Tower of London total time was positively associated with β-amyloid deposition in the right precuneus. These results support previous evidence that early executive dysfunction might reflect subtle, early changes in persons at risk of LOAD and suggests that executive function alterations deserve further exploration in the LOAD literature

Relationship between cognitive and sleep–wake variables in asymptomatic offspring of patients with late-onset Alzheimer’s disease

Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.Fil: Abulafia, Carolina Andrea. Pontificia Universidad Católica Argentina ; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Duarte Abritta, Bárbara. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Villarreal, Mirta Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Ladrón de Guevara, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Garcia, Maria Celeste. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Sequeyra, Geraldine. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Sevlever, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Fiorentini, Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Bär, Karl-Jürgen. Universitat Jena; AlemaniaFil: Gustafson, Deborah. State University of New York; Estados Unidos. University Goteborg; Suecia. University of Skövde; SueciaFil: Vigo, Daniel Eduardo. Pontificia Universidad Católica Argentina ; ArgentinaFil: Guinjoan, Salvador Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Neurociencias; Argentin

White matter fiber density abnormalities in cognitively normal adults at risk for lateonset Alzheimer´s disease

Abstract: Tau accumulation affecting white matter tracts is an early neuropathological feature of late-onset Alzheimer’s disease (LOAD). There is a need to ascertain methods for the detection of early LOAD features to help with disease prevention efforts. The microstructure of these tracts and anatomical brain connectivity can be assessed by analyzing diffusion MRI (dMRI) data. Considering that family history increases the risk of developing LOAD, we explored the microstructure of white matter through dMRI in 23 cognitively normal adults who are offspring of patients with Late-Onset Alzheimer’s Disease (O-LOAD) and 22 control subjects (CS) without family history of AD. We also evaluated the relation of white matter microstructure metrics with cortical thickness, volumetry, in vivo amyloid deposition (with the help of PiB positron emission tomography -PiB-PET) and regional brain metabolism (as FDG-PET) measures. Finally we studied the association between cognitive performance and white matter microstructure metrics. O-LOAD exhibited lower fiber density and fractional anisotropy in the posterior portion of the corpus callosum and right fornix when compared to CS. Among O-LOAD, reduced fiber density was associated with lower amyloid deposition in the right hippocampus, and greater cortical thickness in the left precuneus, while higher mean diffusivity was related with greater cortical thickness of the right superior temporal gyrus. Additionally, compromised white matter microstructure was associated with poorer semantic fluency. In conclusion, white matter microstructure metrics may reveal early differences in O-LOAD by virtue of parental history of the disorder, when compared to CS without a family history of LOAD. We demonstrate that these differences are associated with lower fiber density in the posterior portion of the corpus callosum and the right fornix

Brain Structural and Amyloid Correlates of Recovery From Semantic Interference in Cognitively Normal Individuals With or Without Family History of Late-Onset Alzheimer's Disease.

Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age.status: publishe

Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease.

The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of β-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder.status: publishe

Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease

Abstract: The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of β-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder.Fil: Duarte-Abritta, Bárbara. Fundación FLENI. Servicio de Psiquiatría; ArgentinaFil: Villareal, Mirta F. Fundación FLENI. Servicio de Psiquiatría; ArgentinaFil: Villarealm, Mirta F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Abulafia, Carolina. Fundación FLENI. Servicio de Psiquiatría; ArgentinaFil: Abulafia, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Abulafia, Carolina. Universidad Católica Argentina. Facultad de Ciencas Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Loewenstein, David A. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences; Estados UnidosFil: Curiel-Cid, Rosie. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences; Estados UnidosFil: Castro, Mariana N. Fundación FLENI. Servicio de Psiquiatría; ArgentinaFil: Castro, Mariana N. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Psiquiatría y Salud Mental; ArgentinaFil: Surace, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Surace, Ezequiel. Fundacion FLENI. Departamento de Neuropatología y Biología Molecular; ArgentinaFil: Vigo, Daniel E. Consejo Nacional de Investigaciones Científicas y Tecnicas; ArgentinaFil: Vigo, Daniel E. Universidad Católica Argentina. Facultad de Ciencas Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Vázquez, Silvia. Fundación FLENI. Centro de Imágenes Moleculares; ArgentinaFil: Nemeroff, Charles B. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences; Estados UnidosFil: Sevlever, Gustavo. Fundacion FLENI. Departamento de Neuropatología y Biología Molecular; ArgentinaFil: Guinjoan, Salvador M. Fundación FLENI. Servicio de Psiquiatría; ArgentinaFil: Guinjoan, Salvador M. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de psiquiatría y salud mental; ArgentinaFil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Psicología. Neurofisiología I; Argentin

Failure to recover from proactive semantic interference and abnormal limbic connectivity in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer’s disease

Background: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of lateonset Alzheimer’s disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. Objective: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. Methods:We examined 21O-LOADand 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. Results: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. Conclusion: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.Fil: Sánchez, Stella M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Sánchez, Stella M. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sánchez, Stella M. Universidad Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Abulafia, Carolina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Abulafia, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Abulafia, Carolina. Universidad Católica Argentina. Facultad de Ciencas Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Duarte-Abritta, Bárbara. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Ladrón de Guevara, M. Soledad. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Ladrón de Guevara, M. Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, Mariana N. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Castro, Mariana N. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de psiquiatría y salud mental; ArgentinaFil: Drucaroff, Lucas J. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Drucaroff, Lucas J. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Drucaroff, Lucas J. Universidad de Buenos Aires. Facultad de Medicina. Departamento de psiquiatría y salud mental; ArgentinaFil: Sevlever, Gustavo. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Departamento de Neuropatología y Biología Molecular; ArgentinaFil: Nemeroff, Charles B. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences and Center on Aging; Estados UnidosFil: Vigo, Daniel E. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vigo, Daniel E. Universidad Católica Argentina. Facultad de Ciencas Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Loewenstein, David A. University of Miami. Miller School of Medicine. Department of Psychiatry and Behavioral Sciences and Center on Aging; Estados UnidosFil: Villarreal, Mirta F. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Villarreal, Mirta F. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Villarreal, Mirta F. Universidad Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Guinjoan, Salvador M. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Servicio de Psiquiatría; ArgentinaFil: Guinjoan, Salvador M. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de psiquiatría y salud mental; ArgentinaFil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Psicología. Neurofisiología I; Argentin