Dataset Information

Lateralized memory circuit dropout in Alzheimer's disease patients.

ABSTRACT: Altered connectivity within neuronal networks is often observed in Alzheimer's disease. However, delineating pro-cognitive compensatory changes from pathological network decline relies on characterizing network and task effects together. In this study, we interrogated the dynamics of occipito-temporo-frontal brain networks responsible for implicit and explicit memory processes using high-density EEG and dynamic causal modelling. We examined source-localized network activity from patients with Alzheimer's disease (n = 21) and healthy controls (n = 21), while they performed both visual recognition (explicit memory) and implicit priming tasks. Parametric empirical Bayes analyses identified significant reductions in temporo-frontal connectivity and in subcortical visual input in patients, specifically in the left hemisphere during the recognition task. There was also slowing in frontal left hemisphere signal transmission during the implicit priming task, with significantly more distinct dropout in connectivity during the recognition task, suggesting that these network drop-out effects are affected by task difficulty. Furthermore, during the implicit memory task, increased right frontal activity was correlated with improved task performance in patients only, suggesting that right-hemisphere compensatory mechanisms may be employed to mitigate left-lateralized network dropout in Alzheimer's disease. Taken together, these findings suggest that Alzheimer's disease is associated with lateralized memory circuit dropout and potential compensation from the right hemisphere, at least for simpler memory tasks.

SUBMITTER: Tyrer A

PROVIDER: S-EPMC7772115 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundMissing data are a notable problem in Alzheimer's disease clinical trials. One cause of missing data is participant dropout. The Research Attitudes Questionnaire is a 7-item instrument that measures an individual's attitudes toward biomedical research, with higher scores indicating more favorable attitudes. The objective of this study was to describe the performance of the Research Attitudes Questionnaire over time and to examine whether Research Attitudes Questionnaire scores predict study dropout and other participant behaviors that affect trial integrity.MethodsThe Research Attitudes Questionnaire was collected at baseline and weeks 26 and 52 from each member of 119 participant/study partner dyads enrolled in a Phase 2, randomized, double-blind, placebo-controlled mild-to-moderate Alzheimer's disease clinical trial. Within-subject longitudinal analyses examined change in Research Attitudes Questionnaire scores over time in each population. Logistic regression analyses that controlled for trial arm and clustering in trial sites were used to assess whether baseline Research Attitudes Questionnaire scores predicted trial completion, study medication compliance, and enrollment in optional substudies.ResultsParticipants and study partners endorsed statistically similar ratings on the Research Attitudes Questionnaire that were stable over time. Participants with baseline Research Attitudes Questionnaire scores above 28.5 were 4.7 (95% confidence interval = 1.01 to 21.95) times as likely to complete the trial compared to those with lower scores. Applying the same cutoff, baseline study partner Research Attitudes Questionnaire scores were similarly able to predict study completion (odds ratio = 4.2, 95% confidence interval = 1.71 to 10.32). Using a score cutoff of 27.5, higher participant Research Attitudes Questionnaire scores predicted study medication compliance (odds ratio = 5.85, 95% confidence interval = 1.34 to 25.54). No relationship was observed between Research Attitudes Questionnaire score and participation in optional substudies.ConclusionThis brief instrument that measures research attitudes may identify participants at risk for behaviors that cause missing data.

Project description:BackgroundThe degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer's disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models.MethodsNovel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively.ResultsWe found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aβ plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aβ deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased.ConclusionsThese findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit.

Project description:Network functioning during cognitive tasks is of major interest in Alzheimer's disease (AD). Cognitive functioning in AD includes variable performance in short-term memory (STM). In most studies, the verbal STM functioning in AD patients has been interpreted within the phonological loop subsystem of Baddeley's working memory model. An alternative account considers that domain-general attentional processes explain the involvement of frontoparietal networks in verbal STM beside the functioning of modality-specific subsystems. In this study, we assessed the functional integrity of the dorsal attention network (involved in task-related attention) and the ventral attention network (involved in stimulus-driven attention) by varying attentional control demands in a STM task. Thirty-five AD patients and twenty controls in the seventies performed an fMRI STM task. Variation in load (five versus two items) allowed the dorsal (DAN) and ventral attention networks (VAN) to be studied. ANOVA revealed that performance decreased with increased load in both groups. AD patients performed slightly worse than controls, but accuracy remained above 70% in all patients. Statistical analysis of fMRI brain images revealed DAN activation for high load in both groups. There was no between-group difference or common activation for low compared to high load conditions. Psychophysiological interaction showed a negative relationship between the DAN and the VAN for high versus low load conditions in patients. In conclusion, the DAN remained activated and connected to the VAN in mild AD patients who succeeded in performing an fMRI verbal STM task. DAN was necessary for the task, but not sufficient to reach normal performance. Slightly lower performance in early AD patients compared to controls might be related to maintained bottom-up attention to distractors, to decrease in executive functions, to impaired phonological processing or to reduced capacity in serial order processing.

Project description:An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

Dataset Information

Lateralized memory circuit dropout in Alzheimer's disease patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets