BACKGROUND: Pain is a dynamic experience that varies over time, but it remains unknown whether trajectories of pain are associated with subsequent cognitive decline. The purpose of this study was to identify distinct trajectories of pain presence and activity-limiting pain and investigate their longitudinal associations with the rate of subsequent cognitive decline in older adults.
METHODS: A total of 5685 participants from the English Longitudinal Study of Ageing (ELSA) and 7619 participants from the Health and Retirement Study (HRS) were included. Pain presence trajectories were identified over eight years in the ELSA and 10 years in the HRS, while trajectories of activity-limiting pain were identified over 10 years in the HRS. We utilised linear mixed-effects models to investigate the long-term relationship between pain trajectories and the rate of cognitive decline across various domains, including memory, orientation, executive function and global cognition.
RESULTS: Three pain presence trajectories were identified. Moderate-increasing and high-stable groups exhibited steeper declines in global cognition than the low-stable group. Furthermore, individuals in the moderate-increasing group experienced a more rapid decline in executive function, while the high-stable group showed a faster decline in orientation function. Two trajectories of activity-limiting pain were identified, with the moderate-increasing group experiencing a faster decline in orientation function and global cognition.
CONCLUSIONS: The trajectories of both pain presence and activity-limiting pain are linked to the rate of subsequent cognitive decline among older people. Interventions for specific pain trajectories might help to delay the decline rate of cognition in specific domains.

Evidence from epidemiological studies suggests that hearing loss is associated with an accelerated decline in cognitive function, but the underlying pathophysiological mechanism remains poorly understood. Studies using auditory tasks have suggested that degraded auditory input increases the cognitive load for auditory perceptual processing and thereby reduces the resources available for other cognitive tasks. Attention-related networks are among the systems overrecruited to support degraded auditory perception, but it is unclear how they function when no excessive recruitment of cognitive resources for auditory processing is needed. Here, we implemented an EEG study using a nonauditory visual attentional selection task in 30 individuals with age-related hearing loss (ARHLs, 60-73 years) and compared them with aged (N = 30, 60-70 years) and young (N = 35, 22-29 years) normal-hearing controls. Compared with their normal-hearing peers, ARHLs demonstrated a significant amplitude reduction for the posterior contralateral N2 component, which is a well-validated index of the allocation of selective visual attention, despite the comparable behavioral performance. Furthermore, the amplitudes were observed to correlate significantly with hearing acuities (pure tone audiometry thresholds) and higher-order hearing abilities (speech-in-noise thresholds) in aged individuals. The target-elicited alpha lateralization, another mechanism of visuospatial attention, demonstrated in control groups was not observed in ARHLs. Although behavioral performance is comparable, the significant decrease in N2pc amplitude in ARHLs provides neurophysiologic evidence that may suggest a visual attentional deficit in ARHLs even without extra-recruitment of cognitive resources by auditory processing. It supports the hypothesis that constant degraded auditory input in ARHLs has an adverse impact on the function of cognitive control systems, which is a possible mechanism mediating the relationship between hearing loss and cognitive decline.

BACKGROUND: Depression has been found to be associated with cognitive decline, but whether longer depressive durations lead to more severe cognitive declines has not been investigated. We aimed to estimate the association between depressive duration and cognitive decline in middle-aged and older Americans based on a large-scale representative population study.
METHODS: We included 27,886 participants from the Health and Retirement Study (HRS) in 2010-2018. Four datasets with 2-, 4-, 6-, and 8-year consecutive interviews were further derived which involving persistent depressed and persistent depression-free individuals. Multiple linear regressions were constructed to estimate the effects of each depressive duration on the decline in global cognition, memory and mental status. Meta-regressions were performed to test the linear trends and to explore the heterogeneity between sex, age and baseline cognitive function along with subgroup analyses.
RESULTS: Depressive durations of 2, 4, 6, and 8 years were associated with reductions in global cognitive scores of 0.62 points (95 % CI: 0.51-0.73), 0.77 points (95 % CI: 0.60-0.94), 0.83 points (95 % CI: 0.55-1.10), and 1.09 points (95 % CI: 0.63-1.55), respectively, indicating a linear trend (P = 0.016). More pronounced associations were observed in middle-aged adults and females. Similar patterns were found in the associations between depressive duration and two subdomains, i.e., memory and mental health.
CONCLUSIONS: This study is essentially a cross-sectional study and therefore cannot provide causal associations.
CONCLUSIONS: Longer depressive durations were linearly related to more severe cognitive declines. Timely intervention for depression targeted middle-aged adults can more effectively alleviate cognition-related burdens.

UNASSIGNED: Synaptic dysfunction is closely associated with cognitive function in Alzheimer\'s disease (AD), and is present already in an early stage of the disease.
UNASSIGNED: Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum.
UNASSIGNED: We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n = 50 amyloid-β+ [A +], n = 50 A-) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4-2.7] years). We analyzed 17 synaptic proteins and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia.
UNASSIGNED: At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, β-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] -0.27[0.12] to -0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] -0.10[0.04] to -0.15[0.05]) and SCD/MCI-A+ (St.B[SE] -0.07[0.03] to -0.12[0.03]), but not in SCD/MCI-A- (pinteraction < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] -1.75[0.58]), but not in the other groups (pinteraction < 0.05).
UNASSIGNED: CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages.

OBJECTIVE: Hyperlipidemia and postoperative delirium (POD) significantly affect patients\' quality of life; however, the question of whether hyperlipidemia constitutes a risk factor for POD remain unclear. This study aimed to investigate whether patients with hyperlipidemia face elevated risks of developing POD and to identify potential causes for this increased risk.
METHODS: A prospective cohort study.
METHODS: Operating room.
METHODS: Patients were adults scheduled for colorectal cancer surgery in 2023.
METHODS: The exposure factor was hyperlipidemia, and the patients were divided into hyperlipidemia group and non-hyperlipidemia group.
METHODS: POD occurrence within three days post-surgery was assessed using the 3-Minute Diagnostic Interview for Confusion Assessment Method. Over one year, these patients were monitored through telephone to evaluate their survival and cognitive function. Logistic regression analysis was performed to evaluate the risk factors for POD development in patients with hyperlipidemia and to construct a clinical prediction model.
RESULTS: This study included 555 patients. POD incidence was 21.6% in the hyperlipidemia group and 12.7% in the non-hyperlipidemia group. One year following surgery, patients with hyperlipidemia and POD exhibited significantly higher rates of mortality and cognitive decline than did those without POD (p < 0.001). A multifactorial logistic clinical prediction model was constructed from seven independent risk factors for POD development in patients with hyperlipidemia, including education, preoperative total cholesterol (TC), preoperative triglyceride (TG), diet, history of hypertension, Sedation-Agitation Scale, and postoperative trimethylamine N-oxide expression level, and it had the highest predictive value for POD development in patients with hyperlipidemia.
CONCLUSIONS: Compared with those without hyperlipidemia, patients with hyperlipidemia had higher POD incidence. Elevated serum TC and TG levels are independent risk factors for POD in patients with hyperlipidemia. The study\'s findings could help develop strategies for improving POD and hyperlipidemia treatment.

BACKGROUND: Subjective cognitive decline (SCD) in amyloid-positive (Aβ+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer\'s disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies.
METHODS: Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models.
RESULTS: In the combined and stratified cohorts, Aβ+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aβ- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings.
CONCLUSIONS: Aβ+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials.
CONCLUSIONS: SCD in amyloid-positive (Aβ+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aβ+ older adults with SCD could be a target population for interventional trials.

Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer\'s disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in AD patients and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target.

OBJECTIVE: To investigate the effect of Yigong San (YGS) on learning and memory abilities of rats with lipopolysaccharide (LPS)‑induced cognitive decline and explore its possible mechanism in light of intestinal microbiota.
METHODS: Forty SD rats were randomly divided into control group, model group, donepezil (1.3 mg/kg) group, and high-dose (5.25 g/kg) and low-dose (2.63 g/kg) YGS treatment groups. After 24 days of treatment with the corresponding drugs or water by gavage, the rats in the latter 4 groups received an intraperitoneal injection of LPS (0.5 mg/kg) to establish models of Alzheimer\'s disease (AD). Water maze test and HE staining were used to evaluate the changes in learning and memory abilities and pathomorphology of the hippocampus. The changes in gut microbial species of the rats were analyzed with 16S rRNA sequencing, and the levels of IL-6, TNF-α, and IL-1β in the brain tissue and serum were detected using ELISA.
RESULTS: Compared with the AD model group, the YGS-treated rats showed significantly shortened escape latency on day 5 after modeling, reduced neuronal degeneration and necrosis in the hippocampus, lowered pathological score of cell damage, and decreased levels IL-6, TNF-α and IL-1β in the brain tissue and serum. The YGS-treated rats showed also obvious reduction of Alpha diversity indicators (ACE and Chao1) of intestinal microbiota with significantly increased abundance of Prevotellaceae species at the family level and decreased abundance of Desulfovibrionaceae, which were involved in such metabolic signaling pathways as cell community prokaryotes, membrane transport, and energy metabolism.
CONCLUSIONS: YGS improves learning and memory abilities and hippocampal pathomorphology in AD rat models possibly by regulating the abundance of intestinal microbial species such as Prevotellaceae to affect the metabolic pathways for signal transduction, cofactors, and vitamin metabolism.

BACKGROUND: Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population.
METHODS: Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer\'s disease were examined during an extended 8-year follow-up.
RESULTS: Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer\'s Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer\'s dementia (HR= 6.21, 95% CI= 3.61-10.66, p< 0.001 ).
CONCLUSIONS: APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.

Despite numerous studies have explored the association between sleep duration and cognition, the link between sleep duration trajectories and cognition remains underexplored. This systematic review aims to elucidate this correlation. We analyzed 55 studies from 14 countries, comprising 36 studies focusing on sleep duration, 20 on insomnia, and 13 on hypersomnia. A total of 10,767,085 participants were included in 49 cohort studies with a mean follow-up duration of 9.1 years. A non-linear association between sleep duration and cognitive decline was identified. Both long (risk ratio (RR):1.35, 95 % confidence intervals (CIs):1.23-1.48) and short sleep durations (RR: 1.12, 95 % CIs:1.03-1.22) were associated with an elevated risk of cognitive decline compared to moderate sleep duration. Additionally, hypersomnia (RR:1.26, 95 % CIs: 1.15-1.39) and insomnia (RR: 1.16, 95 % CIs: 1.002-1.34) were also linked to an increased risk. Moreover, prolonged sleep duration posed a higher risk of cognitive decline than stable sleep duration (RR:1.42, 95 % CIs:1.27-1.59). Importantly, transitioning from short or moderate to long sleep duration, as well as persistent long sleep duration, exhibited higher RRs for cognitive decline (RRs: 1.94, 1.40, and 1.28, respectively) compared to persistent moderate sleep duration. Our findings underscore the significance of prolonged sleep duration, alongside short and long sleep durations, with an elevated risk of cognitive decline. The association is tied to the degree of sleep duration changes. Our study highlights the importance of considering changes in sleep patterns over time, not just static sleep durations.