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1.
Nat Commun ; 11(1): 6075, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247100

RESUMO

Our memories enable us to form expectations for our future experiences, yet the precise neural mechanisms underlying how we compare any experience to our memory remain unknown. Here, using intracranial EEG recordings, we show that episodic memories formed after a single visual experience establish expectations for future experience within neocortical-medial temporal lobe circuits. When subsequent experiences violate these expectations, we find a 80-120 Hz prediction error signal that emerges in both visual association areas and the medial temporal lobe. Critically, this error signal emerges in visual association areas first and then propagates to the medial temporal lobe. This error signal is accompanied by alpha coherence between the two regions. Our data therefore suggest that internal models formed from episodic memories are generated throughout the visual hierarchy after just a single exposure, and that these internal models are then used for comparison with future experiences.

2.
Clin Proteomics ; 17: 19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32514259

RESUMO

Introduction: Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline. Protein biomarkers of AD brain pathology, including ß-amyloid and Tau, are reflected in cerebrospinal fluid (CSF), yet the identification of additional biomarkers linked to other brain pathophysiologies remains elusive. We recently reported a multiplex tandem-mass tag (TMT) CSF proteomic analysis of nearly 3000 proteins, following depletion of highly abundant proteins and off-line fractionation, across control and AD cases. Of these, over 500 proteins were significantly increased or decreased in AD, including markers reflecting diverse biological functions in brain. Here, we use a targeted mass spectrometry (MS) approach, termed parallel reaction monitoring (PRM), to quantify select CSF biomarkers without pre-depletion or fractionation to assess the reproducibility of our findings and the specificity of changes for AD versus other causes of cognitive impairment. Method: We nominated 41 proteins (94 peptides) from the TMT CSF discovery dataset, representing a variety of brain cell-types and biological functions, for label-free PRM analysis in a replication cohort of 88 individuals that included 20 normal controls, 37 clinically diagnosed AD cases and 31 cases with non-AD cognitive impairment. To control for technical variables, isotopically labeled synthetic heavy peptide standards were added into each of the 88 CSF tryptic digests. Furthermore, a peptide pool, representing an equivalent amount of peptide from all samples, was analyzed (n = 10) across each batch. Together, this approach enabled us to assess both the intra- and inter-sample differences in peptide signal response and retention time. Results: Despite differences in sample preparation, quantitative MS approaches and patient samples, 25 proteins, including Tau, had a consistent and significant change in AD in both the discovery and replication cohorts. Validated CSF markers with low coefficient of variation included the protein products for neuronal/synaptic (GDA, GAP43, SYN1, BASP1, YWHAB, YWHAZ, UCHL1, STMN1 and MAP1B), glial/inflammation (SMOC1, ITGAM, CHI3L1, SPP1, and CHIT1) and metabolic (PKM, ALDOA and FABP3) related genes. Logistical regression analyses revealed several proteins with high sensitivity and specificity for classifying AD cases from controls and other non-AD dementias. SMOC1, YWHAZ, ALDOA and MAP1B emerged as biomarker candidates that could best discriminate between individuals with AD and non-AD cognitive impairment as well as Tau/ß-amyloid ratio. Notably, SMOC1 levels in postmortem brain are highly correlated with AD pathology even in the preclinical stage of disease, indicating that CSF SMOC1 levels reflect underlying brain pathology specific for AD. Conclusion: Collectively these findings highlight the utility of targeted MS approaches to quantify biomarkers associated with AD that could be used for monitoring disease progression, stratifying patients for clinical trials and measuring therapeutic response.

3.
IEEE Trans Biomed Eng ; PP2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32340935

RESUMO

OBJECTIVE: Alzheimer's disease is a neurodegenerative disorder that initially presents with memory loss in the presence of underlying neurofibrillary tangle and amyloid plaque pathology. This period offers an early window for detecting subtle cognitive impairment prior to progressive decline and dementia. We recently developed the Visuospatial Memory Eye-Tracking Test (VisMET), a passive task capable of predicting cognitive impairment in AD in under five minutes. Here we describe the development of a mobile version of VisMET to enable efficient and widespread administration of the task. METHODS: We delivered VisMET on iPad devices and used a transfer learning approach to train a deep neural network to track eyegaze. Eye movements were used to extract memory features to assess cognitive status in a population of 250 individuals. RESULTS: Mild to severe cognitive impairment was identifiable with a test accuracy of 70%. By enforcing a minimal eye tracking calibration error of 2cm, we achieved an accuracy of 76% which is equivalent to the accuracy obtained using commercial hardware for eye-tracking. CONCLUSION: This work demonstrates a mobile version of VisMET capable of predicting the severity of cognitive impairment. SIGNIFICANCE: Given the ubiquity of tablet devices, our approach has the potential to scale globally.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31871211

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of death and the most common cause of dementia worldwide. Over the last few decades, significant advancements have been made in our understanding of AD by investigating the molecular mechanisms underlying amyloid-ß and tau pathology. Despite this progress, no disease-modifying treatments exist for AD, an issue that will exacerbated by the rising costs and prevalence of the disorder. Moreover, effective therapies to address the devastating cognitive and behavioral symptoms are also urgently needed. This perspective focuses on the value of nonhuman primate (NHP) models in bridging the molecular, circuit, and behavioral levels of analysis to better understand the complex genetic and environmental/lifestyle factors that contribute to AD pathogenesis. These investigations could provide an opportunity for translating our understanding of the pathogenesis and physiological mechanisms underlying AD and related disorders into new diagnostic approaches and disease-modifying therapies to prevent disease or restore brain function for symptomatic individuals.

5.
Learn Mem ; 26(3): 93-100, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30770466

RESUMO

The entorhinal-hippocampal circuit is one of the earliest sites of cortical pathology in Alzheimer's disease (AD). Visuospatial memory paradigms that are mediated by the entorhinal-hippocampal circuit may offer a means to detect memory impairment during the early stages of AD. In this study, we developed a 4-min visuospatial memory paradigm called VisMET (Visuospatial Memory Eye-Tracking Task) that passively assesses memory using eye movements rather than explicit memory judgements. We had 296 control or memory-impaired participants view a set of images followed by a modified version of the images with either an object removed, or a new object added. Healthy controls spent significantly more time viewing these manipulations compared to subjects with mild cognitive impairment and AD. Using a logistic regression model, the amount of time that individuals viewed these manipulations could predict cognitive impairment and disease status with an out of sample area under the receiver-operator characteristic curve of 0.85. Based on these results, VisMET offers a passive, sensitive, and efficient memory paradigm capable of detecting objective memory impairment and predicting cognitive and disease status.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Envelhecimento Saudável/psicologia , Memória Espacial , Processamento Espacial , Idoso , Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Medições dos Movimentos Oculares , Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Psicológicos , Desempenho Psicomotor , Sensibilidade e Especificidade
6.
J Neurosci ; 35(40): 13577-86, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26446212

RESUMO

UNLABELLED: Neural activity preceding an event can influence subsequent memory formation, yet the precise cortical dynamics underlying this activity and the associated cognitive states remain unknown. We investigate these questions here by examining intracranial EEG recordings as 28 participants with electrodes placed for seizure monitoring participated in a verbal paired-associates memory task. We found that, preceding successfully remembered word pairs, an orientation cue triggered a low-frequency 2-4 Hz phase reset in the right temporoparietal junction with concurrent increases in low-frequency power across cortical regions that included the prefrontal cortex and left temporal lobe. Regions that exhibited a significant increase in 2-4 Hz power were functionally bound together through progressive low-frequency 2-4 Hz phase synchrony. Our data suggest that the interaction between power and phase synchrony reflects the engagement of attentional networks that in large part determine the extent to which memories are successfully encoded. SIGNIFICANCE STATEMENT: Here we investigate the spatiotemporal cortical dynamics that precede successful memory encoding. Using intracranial EEG, we observed significant changes in oscillatory power, intertrial phase consistency, and pairwise phase synchrony that predict successful encoding. Our data suggest that the interaction between power and phase synchrony reflects the engagement of attentional networks that in large part determine the extent to which memories are successfully encoded.


Assuntos
Mapeamento Encefálico , Ondas Encefálicas/fisiologia , Córtex Cerebral/fisiologia , Sincronização de Fases em Eletroencefalografia/fisiologia , Memória/fisiologia , Adulto , Biofísica , Estimulação Elétrica , Epilepsia/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Dinâmica não Linear , Análise Espectral , Fatores de Tempo
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