Background:Delirium is a serious condition characterized by an acute change in attention, arousal, and sleep disturbance. It is common in inpatients with Parkinson disease (PD) but is frequently missed or misidentified due to overlapping symptoms, such as cognitive impairment, hallucinations, and sleep disturbances. While clinical tools often measure only a snapshot of delirium, wearable devices could facilitate the identification and ongoing monitoring of delirium, including continuous assessment of activity and sleep patterns, which are frequently disrupted. Establishing feasibility is essential before wearable technologies can be implemented in routine clinical care. Objective:This study aimed to determine the feasibility and acceptability of using wearable devices in inpatients with PD, with and without delirium. Methods:Participants were recruited from an ongoing prospective cohort study comprising inpatients with PD. Delirium was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and assessed daily. Participants were invited to wear Axivity AX6 devices attached to their lumbar region (lower back) and/or wrist for up to 7 days. Feasibility was assessed in terms of recruitment, device placement, nonsecurement, wear time, and compliance. Acceptability, practicality, and clinical constraints were recorded and compared between groups. Results:Participants were predominantly older adults with advanced PD and high levels of frailty and cognitive impairment. The wearable device recruitment rate was 75.4% (46/61), comprising 68 admissions. Delirium was identified in 64.7% (44/68) of admissions. The wrist-worn device showed greater participant acceptability, with 98.5% (67/68) of participants wearing a device on the wrist compared to 38.2% (26/68) of participants wearing a lumbar device (25/68, 36.8%, wore both). Wrist placement was more practical, rated as "somewhat" or "very easy" to secure in 95.5% (64/67) of cases compared to 69.2% (18/26) for lumbar placement (P<.001). Clinical constraints such as injury or pain and low level of arousal were associated with lumbar nonsecurement. These findings indicate that wrist-worn devices are more practical and acceptable in acutely unwell patients. Wear time compliance for both placements tended to be lower in delirium cases but comparable overall (>83% for each location, P>.05). Conclusions:This is the first study to evaluate the feasibility of using wearable devices in inpatients with PD with and without delirium. Wearable devices were feasible, and the wrist-worn devices demonstrated greater participant acceptability and practicality, with fewer clinical constraints. These findings provide important guidance for the design and implementation of future digital health studies in this population and may ultimately support earlier recognition and management of delirium while enabling continuous, objective monitoring of delirium-related changes not captured by standard clinical assessments.

While Category Fluency (CF) is widely used to help profile semantic memory, item-level scoring (ILS) approaches to this test have been proposed to obtain indices that are less influenced by non-semantic supportive functions. We systematically reviewed the literature to test the hypotheses that (1) compared with healthy adults, individuals with a clinical diagnosis suggestive of neurodegeneration generate words of lower semantic complexity; (2) compared with young adults, older adults generate words of higher semantic complexity. We searched six databases (date of search: 8 December 2023) for studies that relied on CF and ILS methods, in normal ageing and in age-associated neurodegeneration. Thirty-four studies were shortlisted: 27 on neurodegenerative conditions; 7 on normal ageing. Risk of bias was evaluated via a published checklist. Data were presented via qualitative synthesis. Most studies reported words of lower semantic complexity in relation to at least one item-level feature in individuals with mild cognitive impairment (MCI), Alzheimer’s dementia (AD), and other neurodegenerative diseases. Post-hoc meta-analyses focussing on the MCI/AD continuum confirmed an effect on words’ frequency (385 MCI/AD individuals and 350 controls; Hedges’s G = 0.59) and age-of-acquisition (193 MCI/AD individuals and 161 controls; Hedges’s G = − 1.51). Studies on normal ageing, conversely, failed to demonstrate any overall effect. Most studies on MCI and AD have not relied on neurobiological diagnostic criteria. Moreover, only a small number of studies analysed ILS controlling for quantitative CF performance. Despite these two limitations, this study suggests that ILS can contribute to an in-depth characterisation of semantic memory in neurological ageing.

BACKGROUND:Delirium is a serious, acute neuropsychiatric condition associated with fluctuating attention and altered arousal. Delirium in Parkinson's disease (PD) is common but often missed in hospital due to shared clinical features. This study aimed to evaluate the accuracy of current tools used to identify delirium in inpatients with PD. METHODS:People with PD admitted to all hospital wards were invited to take part. Participants completed a standardised delirium assessment based on the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) criteria, in addition to standard bedside tools including the 4 As Test (4AT), arousal and cognition. This was a secondary analysis of a prospective observational study; bedside tools were not completed independently of, or blinded to, the DSM-5 criteria. Accuracy was assessed using Receiver Operating Characteristic area under the curve (AUROC). RESULTS:Participants included 115 people with PD (200 hospital admissions); 66.1% (n = 76/115) had delirium. Considering all admissions, the diagnostic accuracy of tools was good, ranging from 74% to 89% (AUROC = 0.764-0.923, P < .001 for all). The 4AT scores had the highest sensitivity (96.7%, AUROC = 0.922, P < .001). However, accuracy decreased in those with underlying cognitive impairment (AUROC = 0.499-0.886). CONCLUSIONS:Current bedside tools can accurately identify delirium in PD inpatients. Although tools were comparable, the 4AT may have greater clinical utility as it had high sensitivity, is quicker to complete and already widely used clinical. However, caution is recommended as tools did not differentiate between symptoms typical in PD and acute symptoms associated with delirium; this should be a focus for future research.

Background Inpatient prevalence of Parkinson's disease (PD) delirium varies widely across the literature. Delirium in general older populations is associated with adverse outcomes, such as increased mortality, dementia, and institutionalisation. However, to date there are no comprehensive prospective studies in PD delirium. This study aimed to determine delirium prevalence in hospitalised PD participants and the association with adverse outcomes, compared to a control group of older adults without PD. Methods Participants were hospitalised inpatients from the 'Defining Delirium and its Impact in Parkinson's Disease' and the 'Delirium and Cognitive Impact in Dementia' studies comprising 121 PD participants and 199 older adult controls. Delirium was diagnosed prospectively using the Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria. Outcomes were determined by medical note reviews and/or home visits 12 months post hospital discharge. Results Delirium was identified in 66.9% of PD participants compared to 38.7% of controls (p < 0.001). In PD participants only, delirium was associated with a significantly higher risk of mortality (HR = 3.3 (95% confidence interval [CI] = 1.3-8.6), p = 0.014) and institutionalisation (OR = 10.7 (95% CI = 2.1-54.6), p = 0.004) 12 months post-discharge, compared to older adult controls. However, delirium was associated with an increased risk of developing dementia 12 months post-discharge in both PD participants (OR = 6.1 (95% CI = 1.3-29.5), p = 0.024) and in controls (OR = 13.4 (95% CI = 2.5-72.6), p = 0.003). Conclusion Delirium is common in hospitalised PD patients, affecting two thirds of patients, and is associated with increased mortality, institutionalisation, and dementia. Further research is essential to understand how to accurately identify, prevent and manage delirium in people with PD who are in hospital.

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.

Published research reports inconsistent links between APOE-ε4 and cognition. We hypothesised that these links can be reliably captured by graph-theory analyses.Cognitive networks were calculated in 8,118 controls, 3,482 MCI patients and 4,573 Alzheimer’s dementia patients, recruited as part of the National Alzheimer’s Coordinating Center (NACC) database. Differences in nodal centrality were tested in two independent NACC sub-cohorts between ε4-carriers and non-carriers.A significant APOE-dependant 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. These findings were replicated in the sub-groups of sole amnestic-MCI patients (n = 2,971). No effects were found in the other two diagnostic groups.APOE ε4 influences nodal properties of cognitive networks at the MCI stage. This highlights the importance of characterising the impact of risk factors on the entire cognitive network.

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.

The literature based on univariate models does not lead to unequivocal conclusions on the effects of APOE variability on cognition. We thus hypothesised that the impact of APOE-ε4 on cognitive functioning can be reliably captured by graph-theory. Cognitive datasets were extracted from the National Alzheimer’s Coordinating Center’s database. After the application of stringent exclusion criteria, 16,173 participants with a known APOE ε3ε3/ε4ε3/ε4ε4 genotype were retained: 8,118 controls, 3,482 MCI patients and 4,573 AD-dementia patients. ε3ε3 individuals were classified as “non-carriers”, while ε4ε3/ε4ε4 individuals were tagged as “carriers”. Two independent sub-cohorts were defined based on the version of the battery used to characterise cognitive profiles. Pairwise Markov random-field models of cognitive functioning were constructed in “R” using the “qgraph” package, following published methodological guidelines. Nine cognitive nodes were established, and partial correlations were run to calculate the statistical strength of all node-to-node edges. This was regularised via the LASSO penalty-imposing method, to control graph sparsity. Differences in global and nodal metrics between ε4 carriers and non-carriers were tested via permutation-based Network Invariance Tests. These analyses were run separately in each sub-cohort and within each diagnostic status. “Expected Influence” was analysed as the centrality metric of interest, to assess how influential each node is within its network. A significant APOE-dependant 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. These findings were replicated in the sub-groups of sole amnestic-MCI patients (n = 2,971), were independent of differences in network communities, clinical severity or other demographic factors. No effects were found in the other diagnostic groups or in global network metrics. APOE-ε4 influences nodal properties of cognitive networks when patients are clinically classified as MCI. Our findings expand this area of knowledge by characterising the statistical effect of the ε4 allele in terms of its differential impact on immediate and delayed recall, and how this results in specific network effects. The study of the wider cognitive network can complement univariate approaches in characterising the effects of risk factors.

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.

Changes to the structural and functional integrity of brain systems are a prominent feature of both Alzheimer’s disease (AD) and the normal ageing process. Recently, research in human brain connectomics has seen many studies adopting graph theoretical methods to explore brain network topology. However, conflicting evidence surrounding disease-related alterations in structural covariance networks, leaves a gap in our understanding of how system level structural changes may distinguish healthy ageing from disease. The present study, therefore, aimed to establish differences in structural network topology between the stages of healthy ageing and in differing types and severities of cognitive decline. Structural MRI scans were collected for three groups of healthy adults, spanning the age ranges 21-39 ( n = 40), 40-64 ( n = 40) and 65 and over ( n = 40), and 3 patient groups including adults with amnestic mild cognitive impairment (aMCI, n = 40), non-amnestic MCI ( n = 30) and Alzheimer’s dementia ( n = 40). Structural brain networks were quantified using the volumes of 246 regions of interest, defined by the Brainnetome Atlas (Fan et al., 2016). Graphs were then created for each group with nodes corresponding to brain regions and edges quantified according to the strength of inter-regional partial correlations. Differences in global network parameters between healthy groups were limited. Furthermore, non-amnestic patients showed no differences in average network parameters compared with any healthy group. aMCI and dementia patients demonstrated significantly higher global efficiencies than the youngest and oldest healthy groups. aMCI patients also presented with significantly lower clustering coefficients than all other groups. Network hubs differed substantially between groups. Centrality in frontal lobes was significantly higher in older healthy adults than aMCI patients, dementia patients and both younger groups. Hubs in dementia patients instead shifted to Alzheimer-related parietal and temporal regions. Despite uncertainties surrounding the biological underpinnings of volumetric covariance within the brain, the results presented here, in agreement with previous studies, have demonstrated a utility of structural covariance networks in identifying AD specific changes in the structure of cortical networks. A non-linear progression of network alterations suggest that such changes may be best appreciated at prodromal disease stages.

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.

In accordance with the physiological networks which underlie it, human cognition is characterised by both segregation and interdependence of a number of cognitive domains. Cognition itself, therefore, constitutes a network, the organisation of which may be quantifiable using methods of graph theory. The present study aimed to exploit graph theory methods to assess changes in cognitive profiles throughout healthy ageing and further interrogate how such profiles may differ in the presence of pathology.

In the absence of disease modifying therapies, early diagnosis of Alzheimer’s disease (AD) is imperative not only for drug development but also for the timely application of pharmaceutical and behavioural treatments that may ameliorate rapid decline and improve quality of life for both patients and caregivers. The present research, therefore, applied psychological and neuroimaging approaches for the identification of cognitive markers of the earliest stages of AD physiological degradation. Specifically, the first experiments focussed on clarifying neural correlates of semantic memory decline in prodromal and dementia stages of disease. These studies not only identified a significant relationship between semantic memory performance and discrete structural alterations, within structures known to be affected at the initial stages of the AD pathological cascade, but further confirmed that a quick and simple verbal fluency test may provide a meaningful marker for very early neurodegeneration. Experiments three and four applied a more novel graph theoretical approach to the quantification of AD cognitive change. Experiment three aimed to elucidate neuropsychological profiles characteristic of the various stages of ageing and disease. The topology of networks reflecting cognitive performance were outlined and compared revealing notable differences in network structure relating to age that were further altered in the presence of disease. These findings specifically highlighted a central role for semantic processing and abstract reasoning in neuropsychological performance among healthy older adults, which appeared to be lost among patient groups. Finally, experiment four sought to investigate underlying alterations in brain structural networks that may account for the differences seen in ageing and disease at the cognitive level. Findings indicated that, even in prodromal AD, significant differences in network topology, relating to volumetric covariance, are apparent when compared with healthy age-related change, and such differences in structural relationships may account, to some extent, for the observable contrast in neuropsychological profile.