Frontiers in Aging Neuroscience最新文献

Background: Perioperative cognitive maintenance and protection in older adults is an important patient safety imperative. In addition to foundational care, one area of growing interest is integrating cognitive prehabilitation into the surgical trajectory. This review aimed to evaluate the effectiveness and safety of cognitive prehabilitation on cognitive functional capacity and postoperative cognitive outcomes among older adults undergoing elective surgery.

Methods: The MEDLINE, Embase, CENTRAL, CINAHL, PsycINFO, PEDro, CBM, CNKI, WANFANG, and VIP databases were systematically searched up to September 5, 2024, to identify randomized controlled trials published for English or Chinese. Two authors independently completed the study selection process, data extraction process and methodological quality assessment. The Patient, Intervention, Comparison, Outcome, Study design framework was used to construct the search strategy. The predefined primary outcomes of interest included the incidence of postoperative delirium (POD) and the incidence of delayed neurocognitive recovery (dNCR). The quality of the studies was evaluated by the PEDro scale. Owing to the small number of trials and clinical and methodological diversity, a narrative synthesis was undertaken in accordance with the Synthesis Without Meta-analysis guidelines. This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system.

Results: Six studies were analysed. These trials involved 645 total participants, with 316 in the intervention group (mean age, 66.0-73.8 years; 38.4-77.8% male) and 329 in the comparator group (mean age, 67.5-72.6 years; 31.8-88.9% male). The effects of preoperative cognitive training on reducing the incidence of dNCR, the incidence of POD, the length of hospital stay and the incidence of postsurgical complications as well as improving postoperative global cognitive function and activities of daily living are quite uncertain. The results of this study should be interpreted with caution owing to the limited number of trials and low to very low certainty of evidence.

Conclusion: Current evidence on the effectiveness and safety of cognitive prehabilitation on cognitive and noncognitive outcomes in older patients undergoing elective surgery is limited and unclear.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=277191, Identifier CRD42021277191.

Objectives: The role of trimethylamine oxide (TMAO) in patients with cognitive impairment remains controversial. This study aimed to assess the association between TMAO and its precursors and the prevalence of cognitive impairment.

Methods: PubMed, Embase, and Web of Science databases were searched for studies that met the inclusion criteria from their inception to 14 September 2024, and references were manually searched to identify any additions. Odds ratio (OR) was assessed by random-effects modeling, subgroup analyses to identify potential sources of heterogeneity, and the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality (AHRQ) Inventory for qualitative evaluation.

Results: Nine studies involving 82,246 participants were included in the analysis. Meta-analyses suggested that elevated TMAO levels were strongly associated with an increased risk of cognitive impairment (OR: 1.39, 95% confidence interval [95%CI]: 1.09-1.77, p < 0.05, I²:60%), and consistent results were obtained across all subgroups examined and sensitivity analyses. However, in the TMAO dose-response meta-analysis and TMAO precursor meta-analyses, the results were not significantly different (dietary choline: OR: 0.93, 95%CI: 0.78-1.10, p = 0.385, I²:68%, plasma choline: OR: 0.65, 95%CI: 0.41-1.02, p = 0.063, I²:76%, plasma betaine: OR: 0.74, 95%CI: 0.52-1.05, p = 0.094, I²:61%).

Conclusion: We found that high TMAO concentrations were positively associated with the risk of cognitive impairment. TMAO is expected to be a potential risk predictor and therapeutic target for cognitive impairment. However, more high-quality studies are needed to further investigate the dose relationship between circulating TMAO concentrations and cognitive impairment.

Systematic review registration: PROSPERO, identifier: CRD42023464543.

Cognitive impairment is a leading component of several neurodegenerative and neurodevelopmental diseases, profoundly impacting on the individual, the family, and society at large. Cognitive pathologies are driven by a multiplicity of factors, from genetic mutations and genetic risk factors, neurotransmitter-associated dysfunction, abnormal connectomics at the level of local neuronal circuits and broader brain networks, to environmental influences able to modulate some of the endogenous factors. Otherwise healthy older adults can be expected to experience some degree of mild cognitive impairment, some of which fall into the category of subjective cognitive deficits in clinical practice, while many neurodevelopmental and neurodegenerative diseases course with more profound alterations of cognition, particularly within the spectrum of the dementias. Our knowledge of the underlying neuropathological mechanisms at the root of this ample palette of clinical entities is far from complete. This review looks at current knowledge on synaptic modifications in the context of cognitive function along healthy ageing and cognitive dysfunction in disease, providing insight into differential diagnostic elements in the wide range of synapse alterations, from those associated with the mild cognitive changes of physiological senescence to the more profound abnormalities occurring at advanced clinical stages of dementia. I propose the term "cognitive synaptopathy" to encompass the wide spectrum of synaptic pathologies associated with higher brain function disorders.

Background: To explore the effects of different dose of aerobic exercise on motor function, balance, mobility, and quality of life in Parkinson's disease patients, aiming to provide insights into determining the optimal aerobic exercise dose for treating PD.

Methods: Searching was conducted in four databases: PubMed, Embase, Web of Science, and Cochrane. The dose of aerobic exercise intervention was evaluated based on the recommendations of the American College of Sports Medicine regarding the development and maintenance of cardiorespiratory health, muscle strength, and functional mobility in patients with PD. The exercise intervention dose of the included studies were first classified into high ACSM compliance and low ACSM compliance based on meeting 4/6 of the ACSM recommendations. The reliability of the results was then validated using the criterion of meeting 5/6 of the ACSM recommendations. Comparisons of the effects of aerobic exercise dose on Motor function, Balance, Mobility, and QOL in PD patients using standardized mean difference with 95% confidence intervals.

Results: When using the 4/6 ACSM compliance criterion, 17 studies were categorized as high ACSM compliance and 12 as low ACSM compliance. The SMD ratios for high versus low ACSM compliance were: UPDRS-III (-0.79: -0.18), BBS (0.60: 0.05), TUG (-0.60: -0.60), and QOL (-1.05: -0.15). When using the 5/6 ACSM compliance criterion, 11 studies were categorized as high ACSM compliance and 19 as low ACSM compliance. The SMD ratios for high versus low ACSM compliance were: UPDRS-III (-0.95: -0.38), BBS (0.48: 0.37), TUG (-0.71: -0.55), and QOL (-0.7: 0.04).

Conclusion: This study provides preliminary support for the potential of aerobic exercise to improve certain clinical symptoms in patients with PD. Furthermore, the results indicate that compliance to higher doses of aerobic exercise, as per ACSM standards, may contribute to improvements in motor function, balance, mobility, and quality of life for patients with PD. However, due to the heterogeneity in the studies and the influence of factors that have not yet been fully explored, these conclusions should be interpreted with caution. More high-quality randomized controlled trials are needed in the future to further verify and clarify the effects of aerobic exercise.

Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier PROSPERO: CRD42024517548.

[This corrects the article DOI: 10.3389/fnagi.2024.1393841.].

Background: The relationship of systolic blood pressure variability (SBPV) with Alzheimer's disease (AD) remains controversial. We aimed to explore the roles of SBPV in predicting AD incidence and to test the pathways that mediated the relationship of SBPV with cognitive functions.

Methods: Longitudinal data across 96 months (T₀ to T₄) were derived from the Alzheimer's disease Neuroimaging Initiative cohort. SBPV for each participant was calculated based on the four measurements of SBP across 24 months (T₀ to T₃). At T₃, logistic regression models were used to test the SBPV difference between 86 new-onset AD and 743 controls. Linear regression models were used to test the associations of SBPV with cognition and AD imaging endophenotypes for 743 non-demented participants (median age = 77.0, female = 42%). Causal mediation analyses were conducted to explore the effects of imaging endophenotypes in mediating the relationships of SBPV with cognitive function. Finally, Cox proportional hazard model was utilized to explore the association of SBPV with incident risk of AD (T₃ to T₄, mean follow-up = 3.5 years).

Results: Participants with new-onset AD at T₃ had significantly higher SBPV compared to their controls (p = 0.018). Higher SBPV was associated with lower scores of cognitive function (p = 0.005 for general cognition, p = 0.029 for memory, and p = 0.016 for executive function), higher cerebral burden of amyloid deposition by AV45 PET (p = 0.044), lower brain metabolism by FDG PET (p = 0.052), and higher burden of white matter hyperintensities (WMH) (p = 0.012). Amyloid pathology, brain metabolism, and WMH partially (ranging from 17.44% to 36.10%) mediated the associations of SBPV with cognition. Higher SBPV was significantly associated with elevated risk of developing AD (hazard ratio = 1.29, 95% confidence interval = 1.07 to 1.57, p = 0.008).

Conclusion: These findings supported that maintaining stable SBP in late life helped lower the risk of AD, partially by modulating amyloid pathology, cerebral metabolism, and cerebrovascular health.

Migraine is a chronic, recurrent neurovascular disorder characterized by episodes closely associated with neurovascular hypersensitivity. Oxidative stress can worsen the hypersensitive state of the central nervous system, which in turn can trigger pro-inflammatory factors that result in neurogenic inflammation. Topiramate is frequently used as a preventative measure for migraines, but there is currently little empirical data to support its efficacy through pathways related to neurogenic inflammation and oxidative stress. This review provides an overview of current knowledge regarding the etiology, inducements, pathophysiology, and available treatments for migraine, with a focus on the clinical and experimental evidence of neurogenic inflammation and oxidative stress in migraine. It also delves into the antioxidant and anti-inflammatory qualities of topiramate, clarifying the possible ways in which topiramate affects these pathways to lessen migraine symptoms.

Neurodegenerative diseases such as Alzheimer's disease and polyglutamine diseases are characterized by abnormal accumulation of misfolded proteins, leading to neuronal dysfunction and subsequent neuron death. However, there is a lack of studies that integrate molecular, morphological, and functional analyses in neurodegenerative models to fully characterize these time-dependent processes. In this study, we used C. elegans models expressing Aβ1-42 and polyglutamine to investigate early neuronal pathogenic features in olfactory neurons. Both models demonstrated significant reductions in odor sensitivity in AWB and AWC chemosensory neurons as early as day 1 of adulthood, while AWA chemosensory neurons showed no such decline, suggesting cell-type-specific early neuronal dysfunction. At the molecular level, Aβ1-42 or Q40 expression caused age-dependent protein aggregation and morphological changes in neurons. By day 6, both models displayed prominent protein aggregates in neuronal cell bodies and neurites. Notably, AWB neurons in both models showed significantly shortened cilia and increased instances of enlarged cilia as early as day 1 of adulthood. Furthermore, AWC neurons expressing Aβ1-42 displayed calcium signaling defects, with significantly reduced responses to odor stimuli on day 1, further supporting early behavioral dysfunction. In contrast, AWA neuron did not exhibit reduced calcium responses, consistent with the absence of detectable decreases in olfactory sensitivity in these neurons. These findings suggest that decreased calcium signaling and dysfunction in specific sensory neuron subtypes are early indicators of neurodegeneration in C. elegans, occurring prior to the formation of visible protein aggregates. We found that the ER unfolded protein response (UPR) is significantly activated in worms expressing Aβ1-42. Activation of the AMPK pathway alleviates olfactory defects and reduces fibrillar Aβ in these worms. This study underscores the use of C. elegans olfactory neurons as a model to elucidate mechanisms of proteostasis in neurodegenerative diseases and highlights the importance of integrated approaches.

Background: In Parkinson's disease (PD) brains, microglia are activated to release inflammatory factors to induce the production of reactive oxygen species (ROS) in neuron, and vice versa. Moreover, neuroinflammation and its synergistic interaction with oxidative stress contribute to the pathogenesis of PD.

Methods: In this study, we investigated whether in-house synthetic coumarin-chalcone derivatives protect human microglia HMC3 and neuroblastoma BE(2)-M17 cells against 1-methyl-4-phenyl pyridinium (MPP⁺)-induced neuroinflammation and associated neuronal damage.

Results: Treatment with MPP⁺ decreased cell viability as well as increased the release of inflammatory mediators including cytokines and nitric oxide in culture medium, and enhanced expression of microglial activation markers CD68 and MHCII in HMC3 cells. The protein levels of NLRP3, CASP1, iNOS, IL-1β, IL-6, and TNF-α were also increased in MPP⁺-stimulated HMC3 cells. Among the four tested compounds, LM-016, LM-021, and LM-036 at 10 μM counteracted the inflammatory action of MPP⁺ in HMC3 cells. In addition, LM-021 and LM-036 increased cell viability, reduced lactate dehydrogenase release, ameliorated cellular ROS production, decreased caspase-1, caspase-3 and caspase-6 activities, and promoted neurite outgrowth in MPP⁺-treated BE(2)-M17 cells. These protective effects were mediated by down-regulating inflammatory NLRP1, IL-1β, IL-6, and TNF-α, as well as up-regulating antioxidative NRF2, NQO1, GCLC, and PGC-1α, and neuroprotective CREB, BDNF, and BCL2.

Conclusion: The study results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenic mechanisms, and indicate the potential use of LM-021 and LM-036 as dual inflammasome inhibitors in treating both NLRP1- and NLRP3-associated PD.

Postoperative cognitive dysfunction (POCD) poses a significant threat to patients undergoing anesthesia and surgery, particularly elderly patients. It is characterized by diminished cognitive functions post surgery, such as impaired memory and decreased concentration. The potential risk factors for POCD include age, surgical trauma, anesthetic type, and overall health condition; however, the precise mechanisms underlying POCD remain elusive. Recent studies suggest that neuroinflammation might be a primary pathogenic factor. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes are implicated in exacerbating POCD by promoting the release of inflammatory factors and proteins that initiate pyroptosis, further influencing the disease process. The regulation of NLRP3 inflammasome activity, including its activation and degradation, is tightly controlled through multiple pathways and mechanisms. In addition, autophagy, a protective mechanism, regulates the NLRP3 inflammasome to control the progression of POCD. This review reviews recent findings on the role of the NLRP3 inflammasome in POCD pathogenesis and discusses therapeutic strategies aimed at reducing NLRP3 sources, inhibiting cellular pyroptosis, and enhancing autophagy.