APOE ε4 positivity predicts centrality of episodic memory nodes in patients with mild cognitive impairment: A cohort-based, graph theory-informed study of cognitive networks.

As network neuroscience can capture the systemic impact of APOE variability at a neuroimaging level, this study investigated the network-based cognitive endophenotypes of ε4-carriers and non-carriers across the continuum between normal ageing and Alzheimer's dementia (AD). We hypothesised that the impact of APOE-ε4 on cognitive functioning can be reliably captured by the measurement of graph-theory centrality. Cognitive networks were calculated in 8118 controls, 3482 MCI patients and 4573 AD patients, recruited in the National Alzheimer's Coordinating Center (NACC) database. Nodal centrality was selected as the neurofunctional readout of interest. ε4-carrier-vs.-non-carrier differences were tested in two independent NACC sub-cohorts assessed with either Version 1 or Version 2 of the Uniform Data Set neuropsychological battery. A significant APOE-dependent effect emerged from the analysis of the Logical-Memory nodes in MCI patients in both sub-cohorts. While non-carriers showed equal centrality in immediate and delayed recall, the latter was significantly less central among carriers (v1: bootstrapped confidence interval 0.107-0.667, p < 0.001; v2: bootstrapped confidence interval 0.018-0.432, p < 0.001). This indicates that, in carriers, delayed recall was, overall, significantly more weakly correlated with the other cognitive scores. These findings were replicated in the sub-groups of sole amnestic-MCI patients (n = 2971), were independent of differences in network communities, clinical severity or other demographic factors. No effects were found in the other two diagnostic groups. APOE-ε4 influences nodal properties of cognitive networks when patients are clinically classified as MCI. This highlights the importance of characterising the impact of risk factors on the wider cognitive network via network-neuroscience methodologies.

Verbal fluency discrepancies as a marker of the prehippocampal stages of Alzheimer's disease.

OBJECTIVE: Prior to evidence of episodic memory decline, a lengthy preclinical phase of Alzheimer's disease (AD) exists characterized by the build-up of tau pathology within extrahippocampal structures. Semantic memory, also impaired in AD, has been linked to degradation within these earliest affected areas. This study aimed to assess the utility of performance discrepancies between letter and category verbal fluency tasks to detect neuronal loss in brain regions affected very early by AD. METHOD: Whole-brain voxel-based morphometry was used to assess the neural correlates of semantic processing in three patient groups: two groups of mild cognitive impairment (MCI) patients split into mildly (n = 58) and moderately (n = 53) affected and a mild AD dementia group (n = 71). Discrepancies between the level of impairment on the semantic category fluency test and nonsemantic letter fluency test were calculated for each participant and included in regression models measuring the relationship between semantic memory and whole-brain gray matter volume. RESULTS: Patients at all disease stages demonstrated a loss of the normal semantic advantage in fluency tests, showing significantly greater impairments in category relative to letter fluency. Discrepancy scores in mild MCI correlated strongly with the structural integrity of the anterior medial temporal lobes. Correlations in more severely affected groups were weaker and more widespread. CONCLUSIONS: Semantic memory appears a useful indicator of even the earliest stages of medial temporal damage in AD. With advancing disease severity, the discrepancy index loses its focal anatomical association, reinforcing its value as an early marker of incipient decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Current Understanding of Verbal Fluency in Alzheimer's Disease: Evidence to Date.

Since their development, verbal fluency tests (VFTs) have been used extensively throughout research and in clinical settings to assess a variety of cognitive functions in diverse populations. In Alzheimer's disease (AD), these tasks have proven particularly valuable in identifying the earliest forms of cognitive decline in semantic processing and have been shown to relate specifically to brain regions associated with the initial stages of pathological change. In recent years, researchers have developed more nuanced techniques to evaluate verbal fluency performance, extracting a wide range of cognitive metrics from these simple neuropsychological tests. Such novel techniques allow for a more detailed exploration of the cognitive processes underlying successful task performance beyond the raw test score. The versatility of VFTs and the richness of data they may provide, in light of their low cost and speed of administration, therefore, highlight their potential value both in future research as outcome measures for clinical trials and in a clinical setting as a screening measure for early detection of neurodegenerative diseases.

Predicting cognitive decline using neuropsychiatric symptoms in prodromal Lewy body dementia: A longitudinal study.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Lewy body dementias (LBD) occur frequently and early in disease progression. Such symptoms are associated with worse quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the longitudinal relationship between NPS and cognitive decline in prodromal LBD. METHODS: 123 participants were derived from three cohort studies. Patients with mild cognitive impairment (MCI) relating to probable dementia with Lewy bodies (MCI-LB, n = 67) and Parkinson's disease (PD-MCI, n = 56) completed comprehensive cognitive and neuropsychiatric assessment and were followed up longitudinally. Linear regression and mixed effects models assessed the relationship between baseline NPS and cognition at baseline and over time. RESULTS: In MCI-LB, overall NPS burden was associated with declines over time in executive function (p = 0.026) and processing speed (p = 0.028) and baseline aberrant motor behaviour was associated with declines in attention (p < 0.025). Anxiety was significantly associated with poorer visuospatial functioning (p = 0.016) at baseline and poorer attention both at baseline (p = 0.017) and across time points (p = 0.024). In PD-MCI, psychosis was associated with poorer executive functioning at baseline (p = 0.008) and across time points (p = 0.002) but had no association with changes longitudinally. CONCLUSIONS: Core neuropsychiatric components of LBD are not strongly associated with cognition in prodromal disease. This may suggest that neuropathological mechanisms underlying NPS may not be the same as those underlying cognitive impairment. Non-core NPS, however, may be more directly associated with cognitive change. Future studies utilising neuroimaging techniques are needed to explore the neuropathological basis of NPS in prodromal LBD.

A Graph Theory Approach to Clarifying Aging and Disease Related Changes in Cognitive Networks.

In accordance with the physiological networks that underlie it, human cognition is characterized by both the segregation and interdependence of a number of cognitive domains. Cognition itself, therefore, can be conceptualized as a network of functions. A network approach to cognition has previously revealed topological differences in cognitive profiles between healthy and disease populations. The present study, therefore, used graph theory to determine variation in cognitive profiles across healthy aging and cognitive impairment. A comprehensive neuropsychological test battery was administered to 415 participants. This included three groups of healthy adults aged 18-39 (n = 75), 40-64 (n = 75), and 65 and over (n = 70) and three patient groups with either amnestic (n = 75) or non-amnestic (n = 60) mild cognitive impairment or Alzheimer's type dementia (n = 60). For each group, cognitive networks were created reflective of test-to-test covariance, in which nodes represented cognitive tests and edges reflected statistical inter-nodal significance (p < 0.05). Network metrics were derived using the Brain Connectivity Toolbox. Network-wide clustering, local efficiency and global efficiency of nodes showed linear differences across the stages of aging, being significantly higher among older adults when compared with younger groups. Among patients, these metrics were significantly higher again when compared with healthy older controls. Conversely, average betweenness centralities were highest in middle-aged participants and lower among older adults and patients. In particular, compared with controls, patients demonstrated a distinct lack of centrality in the domains of semantic processing and abstract reasoning. Network composition in the amnestic mild cognitive impairment group was similar to the network of Alzheimer's dementia patients. Using graph theoretical methods, this study demonstrates that the composition of cognitive networks may be measurably altered by the aging process and differentially impacted by pathological cognitive impairment. Network alterations characteristic of Alzheimer's disease in particular may occur early and be distinct from alterations associated with differing types of cognitive impairment. A shift in centrality between domains may be particularly relevant in identifying cognitive profiles indicative of underlying disease. Such techniques may contribute to the future development of more sophisticated diagnostic tools for neurodegenerative disease.

Post-tonsillectomy hemorrhage control with nebulized tranexamic acid: A retrospective cohort study.

OBJECTIVE: Evaluate nebulized tranexamic acid (TXA) as a treatment to reduce the need for an operation to control a post-tonsillectomy hemorrhage (PTH). METHODS: Based on a successful case report of a child treated with nebulized TXA for PTH in 2018, our institution began to treat PTH patients with three doses of nebulized TXA. To evaluate the outcomes of this non-invasive management, we conducted a three-year retrospective cohort study of children presenting with PTH from 2016 to 2019. Demographics, insurance, and laboratory information were collected from all pediatric tonsillectomies with and without adenoidectomy performed during the study period. Tonsillar fossae observations of bleeding and clot were documented before and after receiving TXA. RESULTS: The incidence of pediatric PTH at our institution during the study period was 5.4%. Fourteen out of 58 PTH patients received nebulized TXA. Receiving nebulized TXA had no adverse events and over 60% showed resolution of bleeding on exam. Receiving nebulized TXA compared to routine care decreased the need for an operation to restore hemostasis by 44%, p < 0.005. There was no significant difference in age, gender, body mass index, hemoglobin, platelet count, trainee presence, or Medicaid status between the children that received TXA and those that did not. CONCLUSION: Treatment of PTH with nebulized TXA may be a safe first-line therapy to decrease the need for operative control of bleeding. This data suggests that a large clinical trial is needed to determine the efficacy of nebulized TXA to mitigate this common and potentially fatal post-operative complication. LEVEL OF EVIDENCE: 4.