A novel peripheral biomarker for mild cognitive impairment and Alzheimer's disease

Background: Recent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer’s disease (AD). Short-Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. A combined analysis of oculomotor responses during STMB can enhance the sensitivity of the assessment of patients with AD or at risk of AD such as those with Mild Cognitive Impairment (MCI). We investigated this hypothesis. Methods: Using eye-tracking technologies, we measured pupil dilation, fixation, and exploratory eye movement behaviours in patients with AD, MCI and in healthy controls while they performed the STMBT. The STMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding). Results: Experiment 1 involved 18 healthy older adults and 18 patients with AD dementia. We observed (1) altered pupil dilation linked to poor STMB performance in AD patients. Experiment 2 involved 42 healthy older adults and 63 patients with MCI. Impaired fixation and exploratory eye movement behaviours accompanied poor STMB abilities in MCI patients. Conclusion: Taken together, the results above suggest that eye-tracking measures combined with cognitive markers for AD (STMBT) can (1) enrich the clinical phenotype of this type of dementia, (2) unveil novel features of AD dementia unknown to date, and (2) provide more sensitive tools which can detect and trace aspects of such phenotype in people at risk, thus helping to ascertain the presence of the prodromal stages of the disease

Visual processing during short-term memory binding in mild Alzheimer's disease

Patients with Alzheimer's disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short-term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers

A novel digital cognitive biomarker for mild cognitive impairment and Alzheimer disease

Recent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer?s disease (AD). Short-Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. Viewmind is proposed as a novel ?cognitive digital biomarker? with the potential of revealing phenotypic features of AD in the pre-dementia stage of the pathology. Viewmind applies artificial intelligence to analyse eye movements and pupil responses during the performance of STMBT.Fil: Fernández Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; ArgentinaFil: Schumacher, Marcela Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages". Universidad Nacional del Sur. Departamento de Ingeniería Eléctrica y de Computadoras. Instituto de Investigaciones en Ingeniería Eléctrica "Alfredo Desages"; ArgentinaFil: Orozco, David. Clínica Privada Bahiense; ArgentinaFil: Sgrilli Gustavo. Clinica Privada Bahiense; ArgentinaFil: Echeverria Gustavo. Clinica privada Bahiense; ArgentinaFil: Linares Ramiro. Clinica Privada Bahiense; ArgentinaFil: Parra, Mario A. University of Strathclyde; Reino UnidoAlzheimer´s Association International ConferenceDenver, ColoradoEstados UnidosAlzheimer Associatio

Oculomotor responses linked to cognitive markers for Alzheimer's disease can enhance risk profiling in patients with Mild Cognitive Impairment

Background: Combining eye-tracking methodologies with a cognitive marker for Alzheimer’s disease, namely the Short-Term Memory Binding Test (STMBT), has enhanced the effectiveness of the assessment increasing its sensitivity and specificity to 100% (1). Whether such classification accuracy would help identify patients with Mild Cognitive Impairment (MCI) who may hold a higher risk of progressing to dementia remains unexplored. Methods: We measured the pupil size in 14 patients with MCI and 9 healthy controls while they performed the STMBT. The STMBT assessed the ability to temporarily hold colours presented in bicoloured objects either as individual features (baseline) or integrated within object representations (binding). Patients were also assessed with standard cognitive screening tests (MMSE, ACE-R, IFS). We applied a ROC-derived cut-off score recently obtained by (2) which achieved 100% classification between patients with AD dementia and healthy controls to our MCI patients. We aimed to identify an oculomotor profile in MCI patients compatible with that seen in patients with AD dementia. Results: Of the 14 patients with MCI, 5 fell below cut-off. They were compared with those who fell above cut-off, and with healthy controls. MCI patients above and below cut-off significantly differed from controls on all the cognitive screening tests used, but not between them. Patients above cut-off were significantly different from controls on both conditions of the STMB test (baseline and binding). However, patients below cut-off significantly differed from controls only on the binding condition. The pupil responses of above cut-off MCI patients and controls was indistinguishable (p=1.0). However, that one of below cut-off MCI patients was significantly different from both controls (p=0.007) and above cut-off MCI patients (p= 0.027). Conclusion: Pupil behaviours during performance on tests known to be markers for AD help identify MCI patients who show a profile compatible to that seen in patients with AD dementia. Such a profile was only driven by oculomotor responses as none of the neuropsychological tests used distinguished between MCI patients. Future studies are needed to explore the presence of AD pathology in those positive to the oculomotor-marker here presented or their likelihood to progress to AD dementia in longitudinal assessments

Structural and functional analyses of the shedding protease ADAM17 in HoxB8-Immortalized macrophages and dendritic-like cells

A disintegrin and metalloproteinase (ADAM) 17 has been implicated in many shedding processes. Major substrates of ADAM17 are TNF-α, IL-6R, and ligands of the epidermal growth factor receptor. The essential role of the protease is emphasized by the fact that ADAM17 deficiency is lethal in mice. To study ADAM17 function in vivo, we generated viable hypomorphic ADAM17 mice called ADAM17ex/ex mice. Recent studies indicated regulation of proteolytic ADAM17 activity by cellular processes such as cytoplasmic phosphorylation and removal of the prodomain by furin cleavage. Maturation and thus activation of ADAM17 is not fully understood. So far, studies of ADAM17 maturation have been mainly limited to mouse embryonic fibroblasts or transfected cell lines relying on nonphysiologic stimuli such as phorbol esters, thus making interpretation of the results difficult in a physiologic context. In this article, we present a robust cell system to study ADAM17 maturation and function in primary cells of the immune system. To this end, HoxB8 conditionally immortalized macrophage precursor cell lines were derived from bone marrow of wild-type and hypomorphic ADAM17ex/ex mice, which are devoid of measurable ADAM17 activity. ADAM17 mutants were stably expressed in macrophage precursor cells, differentiated to macrophages under different growth factor conditions (M-CSF versus GM-CSF), and analyzed for cellular localization, proteolytic activity, and podosome disassembly. Our study reveals maturation and activity of ADAM17 in a more physiological-immune cell system. We show that this cell system can be further exploited for genetic modifications of ADAM17 and for studying its function in immune cells

Movimientos oculares como herramienta de ayuda en el diagnóstico temprano del mal de Alzheimer

La lectura y la observación de imágenes conforman procesos cognitivos retroalimentados que requieren la integración de diferentes subsistemas (memoria, atención, acción) y por consiguiente constituyen actividades ideales para explorar las relaciones entre los movimientos oculares y los procesos neuropsicológicos involucrados en las mismas. En el presente trabajo, se describe brevemente una de las iniciativas que se llevan a cabo en el Laboratorio de Desarrollo en Neurociencias Cognitivas (LDNC) tendientes a evaluar la capacidad cognitiva y el deterioro cognitivo incipiente, a partir del registro y modelado de los movimientos oculares. La misma está especialmente orientada a colaborar en el diagnóstico en etapas tempranas de la Enfermedad de Alzheimer (EA)

Phenomenology of the nMSSM from colliders to cosmology

Low energy supersymmetric models provide a solution to the hierarchy problem and also have the necessary ingredients to solve two of the most outstanding issues in cosmology: the origin of dark matter and baryonic matter. One of the most attractive features of this framework is that the relevant physical processes are related to interactions at the weak scale and therefore may be tested in collider experiments in the near future. This is true for the Minimal Supersymmetric Standard Model (MSSM) as well as for its extension with the addition of one singlet chiral superfield, the so-called nMSSM. It has been recently shown that within the nMSSM an elegant solution to both the problem of baryogenesis and dark matter may be found, that relies mostly on the mixing of the singlet sector with the Higgs sector of the theory. In this work we review the nMSSM model constraints from cosmology and present the associated collider phenomenology at the LHC and the ILC. We show that the ILC will efficiently probe the neutralino, chargino and Higgs sectors, allowing to confront cosmological observations with computations based on collider measurements. We also investigate the prospects for a direct detection of dark matter and the constraints imposed by the current bounds of the electron electric dipole moment in this model.Comment: 44 pp, 10 figures; Fig.9 replaced; discussion on CP violation extended and references added; few minor additions in text about details of the cut

Modelos computacionales del comportamiento ocular para la evaluación del desempeño cognitivo

El seguimiento de los movimientos oculares (eye tracking) permite evaluar la información adquirida por una persona durante la lectura u observación de una imagen. Durante ambos procesos, el ojo realiza movimientos sacádicos seguidos de fijaciones en las cuales la información es adquirida para luego ser interpretada por el cerebro. El eye-tracker registra y graba tanto el lugar de fijación ocular de donde se extrae la información, y como el tiempo que necesita la persona para procesar la información. Esta técnica es utilizada en disciplinas muy diversas vinculadas a la evaluación de los procesos cognitivos que se desarrollan en un ser humano. Estos procesos constituyen un importante desafío desde el punto de vista del modelado de los mismos. Su estudio permitiría avanzar en el conocimiento sobre el manejo eficiente de la información y el control óculo-motor, que tienen implicancias en diversas áreas como la medicina, las interfaces hombre-máquina y la ingeniería de sistemas cognitivos, entre otras. Nuestro grupo de investigación tiene como objetivos el desarrollo de métodos para diagnosticar y medir el deterioro cognitivo temprano a partir del modelado del movimiento ocular.Eje: Procesamiento de Señales y Sistemas de Tiempo RealRed de Universidades con Carreras en Informática (RedUNCI

Modelos computacionales del comportamiento ocular para la evaluación del desempeño cognitivo

El seguimiento de los movimientos oculares (eye tracking) permite evaluar la información adquirida por una persona durante la lectura u observación de una imagen. Durante ambos procesos, el ojo realiza movimientos sacádicos seguidos de fijaciones en las cuales la información es adquirida para luego ser interpretada por el cerebro. El eye-tracker registra y graba tanto el lugar de fijación ocular de donde se extrae la información, y como el tiempo que necesita la persona para procesar la información. Esta técnica es utilizada en disciplinas muy diversas vinculadas a la evaluación de los procesos cognitivos que se desarrollan en un ser humano. Estos procesos constituyen un importante desafío desde el punto de vista del modelado de los mismos. Su estudio permitiría avanzar en el conocimiento sobre el manejo eficiente de la información y el control óculo-motor, que tienen implicancias en diversas áreas como la medicina, las interfaces hombre-máquina y la ingeniería de sistemas cognitivos, entre otras. Nuestro grupo de investigación tiene como objetivos el desarrollo de métodos para diagnosticar y medir el deterioro cognitivo temprano a partir del modelado del movimiento ocular.Eje: Procesamiento de Señales y Sistemas de Tiempo RealRed de Universidades con Carreras en Informática (RedUNCI

Modelos computacionales del comportamiento ocular para la evaluación del desempeño cognitivo

El seguimiento de los movimientos oculares (eye tracking) permite evaluar la información adquirida por una persona durante la lectura u observación de una imagen. Durante ambos procesos, el ojo realiza movimientos sacádicos seguidos de fijaciones en las cuales la información es adquirida para luego ser interpretada por el cerebro. El eye-tracker registra y graba tanto el lugar de fijación ocular de donde se extrae la información, y como el tiempo que necesita la persona para procesar la información. Esta técnica es utilizada en disciplinas muy diversas vinculadas a la evaluación de los procesos cognitivos que se desarrollan en un ser humano. Estos procesos constituyen un importante desafío desde el punto de vista del modelado de los mismos. Su estudio permitiría avanzar en el conocimiento sobre el manejo eficiente de la información y el control óculo-motor, que tienen implicancias en diversas áreas como la medicina, las interfaces hombre-máquina y la ingeniería de sistemas cognitivos, entre otras. Nuestro grupo de investigación tiene como objetivos el desarrollo de métodos para diagnosticar y medir el deterioro cognitivo temprano a partir del modelado del movimiento ocular.Eje: Procesamiento de Señales y Sistemas de Tiempo RealRed de Universidades con Carreras en Informática (RedUNCI