Background: Older adults frequently experience persistent cognitive impairment after COVID-19, yet the mechanisms underlying impaired recovery and resilience remain poorly understood. Integrating longitudinal clinical trajectories with molecular signatures may clarify why cognitive function fails to recover in this population. Methods: We conducted a longitudinal study of adults aged ≥60 years hospitalized with COVID- 19, integrating comprehensive geriatric assessments across premorbid, morbid, and postmorbid states with transcriptomic analyses from three independent public cohorts (GSE152641, GSE196822, and GSE157103). Clinical resilience was classified as complete, partial, or absent across geriatric domains. Differential expression analyses, cross-cohort gene integration, and transcriptomic score analyses were performed to identify biological pathways associated with COVID-19 in older adults. Results: Forty-nine older adults contributed 147 longitudinal observations. Cognitive performance (MoCA) declined significantly during acute COVID-19 compared with the premorbid state (p < 0.001) and remained persistently impaired during follow-up, with no improvement from the morbid state (p = 0.549), indicating absence of cognitive resilience. Depressive symptoms and mobility showed similar patterns of persistent impairment, whereas functional status and nutritional measures demonstrated partial recovery. Age was the only independent predictor of poorer outcomes across multiple geriatric domains (all p < 0.05). Transcriptomic analyses identified 66 genes consistently upregulated across all cohorts, including CDC6, RRM2, CDCA2, DTL, MCM10, and CLSPN. The most reproducible molecular finding was activation of interferon-responsive pathways. The Interferon Response Score was significantly elevated in the pooled meta-analysis (Hedges’ g = 1.00, 95% CI 0.14–1.87, p = 0.022), whereas Neuroinflammation and Synaptic Function scores were not significantly altered. Discussion: Persistent cognitive impairment after COVID-19 was accompanied by a reproducible interferon-associated transcriptional signature across independent cohorts of older adults. The absence of recovery in cognition, together with sustained activation of interferon-responsive pathways, suggests that aging-related immune dysregulation may contribute to impaired resilience following COVID-19. In contrast, broader neuroinflammatory and synaptic transcriptional signatures showed limited reproducibility, highlighting interferon signaling as the most consistent biological correlate of post-COVID vulnerability. Conclusion: COVID-19 in older adults induces a state of persistent vulnerability characterized by incomplete cognitive recovery and sustained activation of interferon-associated transcriptional programs. The dominant influence of age and the absence of both clinical and molecular resilience suggest that recovery is constrained by aging-related biological processes. These findings identify interferon signaling as a potential therapeutic target for improving long-term outcomes in older COVID-19 survivors.
The ubiquitin-proteasome system (UPS) is crucial for maintaining protein homeostasis in the central nervous system. Dysfunction of the UPS leads to the accumulation of neurotoxic aggregates, including amyloid, tau, alpha-synuclein, SOD1, and TDP-43, which are hallmark features of various neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. Agerelated decline in the UPS and autophagy-lysosomal pathways results in compromised proteostasis and progressive neuronal damage. Current literature from diverse databases provides insights emphasizing the clinical relevance of UPS-targeted interventions. Strategies such as targeted degradation of misfolded proteins, modulation of PINK1/Parkin-mediated mitophagy, and the use of enzyme activators or allosteric modulators show potential in restoring brain homeostasis. This review discusses UPS-mediated proteolytic mechanisms, molecular disruptions associated with disease progression, and emerging therapeutic approaches aimed at enhancing protein clearance.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including amyloid-beta plaques, tau tangles, and neuronal loss. The glymphatic system, a recently discovered network responsible for brain waste clearance, plays a crucial role in maintaining cerebral homeostasis by facilitating the removal of neurotoxic metabolites, including amyloid-beta. Disruption of glymphatic function has emerged as a key factor in AD pathophysiology, contributing to the accumulation of toxic proteins and accelerating neurodegenerative processes. This narrative review explores the complex interplay between glymphatic dysfunction and AD. We discuss the mechanisms of the glymphatic system, emphasizing its reliance on cerebrospinal fluid (CSF) and interstitial fluid flow to clear metabolic waste, and how this process is closely linked to sleep cycles. In AD, impaired glymphatic function, exacerbated by aging and sleep disturbances, accelerates the buildup of amyloid-beta and tau, driving neurodegeneration. Furthermore, sleep disturbances commonly observed in AD patients further hinder glymphatic activity, creating a vicious cycle that exacerbates cognitive decline. Emerging therapeutic approaches aimed at enhancing glymphatic function—including sleep regulation, pharmacological agents, and lifestyle interventions—are promising, but most findings remain preliminary and largely based on animal studies or early clinical observations. These strategies should therefore be considered exploratory until validated in large-scale human trials. By restoring efficient waste clearance, such interventions may offer novel avenues for slowing or preventing AD progression.
Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and cognitive impairments associated with oxidative stress, mitochondrial dysfunction, neuroinflammation, and degeneration of dopaminergic neurons. Celastrus paniculatus (CP), Jyothshmati, possesses antioxidant and neuroprotective properties. This study evaluated the neuroprotective effects of CP in a rotenone-induced rat model of PD and explored its mechanisms using network pharmacology. Materials and Methodology: PD-like neurotoxicity was induced in male Wistar rats (180-200g) by subcutaneous administration of rotenone (1.5 mg/kg) on alternate days for 28 days. CP was administered intraperitoneally at doses of 200 and 400 mg/kg throughout the study period. Behavioural assessments evaluating locomotor activity, exploratory behaviour, motor coordination, muscle strength, balance, anhedonia, and recognition memory were performed between days 15 and 28. On day 29, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine levels were estimated using ELISA. Oxidative stress markers, including superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and malondialdehyde (MDA), were assessed in the hippocampus and striatum. Network pharmacology analysis was also conducted. Results: Rotenone administration produced significant motor and cognitive deficits, increased lipid peroxidation, reduced antioxidant enzyme activity, and decreased hippocampal BDNF and striatal dopamine levels. CP treatment significantly improved behavioural performance, restored antioxidant defences, reduced oxidative stress, and enhanced neurochemical parameters in a dose-dependent manner. Network pharmacology analysis demonstrated that Celastrus paniculatus modulates multiple targets and signalling pathways related to oxidative stress, neuroprotection, and dopaminergic neurotransmission. Discussion: The neuroprotective effects of CP may be attributed to its antioxidant, neurotrophic, and dopaminergic regulatory actions. Restoration of antioxidant status and dopamine levels contributed to improvements in motor and cognitive functions. Conclusion: Celastrus paniculatus exhibited significant neuroprotective activity against rotenone- induced Parkinsonian alterations, suggesting its potential as a complementary prophylactic neuroprotective strategy for Parkinson’s disease.
Introduction: This study aims to explore the quality of life (QoL) of family caregivers for patients with neurocognitive disorders in Oman. Understanding the experiences of these caregivers is crucial for developing effective support programs and interventions. The research aims to identify factors influencing caregiver well-being and to propose strategies to enhance their caregiving experience. Methods: A descriptive cross-sectional study was conducted between February and May 2022 among 117 primary family caregivers recruited from the memory clinic at Sultan Qaboos University Hospital. To assess caregiver QoL and depression levels, the validated Caregiver of People with Dementia Quality of Life and Patient Health Questionnaire-9 instruments were administered, respectively. Dementia severity was evaluated using the Clinical Dementia Rating scale. SPSS was used for data analysis, including comparisons of sociodemographic and clinical characteristics. Results: The study found that the overall QoL of dementia family caregivers was high, with an overall relative importance index of 71%. Among the various dimensions assessed, "caregiverpatient relationship" emerged as the most significant, while "feeling supported" received the lowest score. Regarding sociodemographic variables, male caregivers, those who are married, employed, and have monthly incomes exceeding 600 OMR (1558$) exhibited significantly higher QoL scores. A significant negative correlation was found between caregiver depression and QoL. Conclusion: The study concludes that dementia caregivers in Oman experience a high QoL. The study highlights a concerning link between caregiver depression and QoL, emphasizing the need for targeted interventions to improve support for caregivers.
