Putative pathological mechanisms of late-life depression and Alzheimer’s disease

Hasan, S.M. Nageeb; Clarke, Courtney; Strand, Tadhg; Bambico, Francis R.

doi:10.1016/j.brainres.2023.148423

Cited by 5 publications

(1 citation statement)

References 269 publications

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“…Depression in late life was specified as a modifiable risk factor by the Lancet Commission on dementia prevention, 3 yet depression may represent a prodrome or symptom of AD when emerging in late life. 48 In line with this, depression was more frequent in cognitively impaired individuals in our cohort, regardless of race. Depression was also uniquely associated with accelerated functional declines in AA participants with cognitive impairment.…”

Section: Discussionsupporting

confidence: 86%

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans

Lachner,

Craver,

Babulal

et al. 2024

Annals of Neurology

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ObjectiveEvaluate the frequency of modifiable dementia risk factors and association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging.MethodsModifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community‐dwelling African American (AA, n=261) and non‐Hispanic White participants (nHW, n=193) who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating® [CDR] ≥0.5) and rates of decline (CDR Sum‐of‐Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index.ResultsHypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (OR: 4.30; 95%CI: 2.13‐8.67) and nHW participants (OR: 2.79; 95%CI: 1.21‐6.44) but uniquely associated with faster decline in AA participants (β: 1.71; 95%CI: 0.69‐2.73; p=0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%; p<0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA (β: 2.65; 95%CI: 0.38‐4.91; p=0.023).InterpretationModifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants.This article is protected by copyright. All rights reserved.

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Section: Discussionsupporting

confidence: 86%

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans

Lachner,

Craver,

Babulal

et al. 2024

Annals of Neurology

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Intranasal dantrolene nanoparticles inhibit lipopolysaccharide-induced depression and anxiety behavior in mice

Liu,

Lu,

Bhuiyan

et al. 2024

Preprint

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This study investigates the therapeutic effectiveness of intranasal dantrolene nanoparticles in the Ryanodex formulation (DNRF) pretreatment to inhibit lipopolysaccharide (LPS)-induced depressive and anxiety behavior in mice.Both wild-type (WT) B6SJLF1/J and 5XFAD adult mice were pretreated with intranasal DNRF (5mg/kg), daily, Monday to Friday, 5 days per week, for 4 weeks. Then, mice were treated with intraperitoneal injection of LPS (5mg/kg) for one time. Behavioral tests for depression and anxiety were performed 24 hours after a one-time LPS injection. Biomarkers for inflammation (IL-1β and IL-18) in blood were measured using enzyme-linked immunosorbent assay (ELISA). In both types of mice, intranasal DNRF significantly inhibited LPS-induced pathological elevation of IL-1β and IL-18 in the blood. Intranasal DNRF abolished LPS-induced depression and anxiety behaviors behavior in both WT and 5XFAD mice, without obvious side effects, which was associated with its significant inhibition of pathological elevation of pyroptosis related cytokines in blood.

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Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD mice

Bhuiyan,

Zhang,

Liang

et al. 2024

Preprint

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This study compares the changes in lithium concentrations in the brain and blood following the administration of intranasal or oral lithium chloride (LiCl) dissolved in either Ryanodex Formulation Vehicle (RFV) or water, as well as the therapeutic effectiveness and side effects of intranasal versus oral lithium chloride (LiCl) in RFV, and their mechanisms for inhibiting inflammation and pyroptosis in 5xFAD Alzheimer’s Disease (AD) mice brains. In comparison to oral LiCl in RFV, intranasal LiCl in RFV decreased lithium blood concentrations but increased brain concentrations and duration, resulting in a significantly higher brain/blood lithium concentration ratio than intranasal LiCl in water or oral LiCl in RFV in young adult mice. Intranasal LiCl in RFV robustly protects both memory loss and depressive behavior in both young and old 5xFAD mice, with no side effects or thyroid/kidney toxicity. In fact, intranasal LiCl in RFV protects against age-dependent kidney function impairment in 5xFAD mice. This lithium mediated neuroprotection was associated with its potent effects on the inhibition of InsP3R-1 Ca2+channel receptor increase, ameliorating pathological inflammation and activation of the pyroptosis pathway, and the associated loss of synapse proteins. Intranasal LiCl in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and treat both dementia and depression with no or minimal side effects/organ toxicity, particular in AD

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Putative pathological mechanisms of late-life depression and Alzheimer’s disease

Cited by 5 publications

References 269 publications

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans

Intranasal dantrolene nanoparticles inhibit lipopolysaccharide-induced depression and anxiety behavior in mice

Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD mice

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