Depression and dementia: interrogating the causality of the relationship

Journal of Neurology Neurosurgery & Psychiatry, Год журнала: 2025, Номер unknown, С. jnnp - 334675

Опубликована: Янв. 11, 2025

Background Depression is often cited as a major modifiable risk factor for dementia, though the relative contributions of true causal relationship, reverse causality and confounding factors remain unclear. This study applied subset Bradford Hill criteria causation to depression dementia including strength effect, specificity, temporality, biological gradient coherence. Methods A total 491 557 participants in UK Biobank aged between 40 69 at enrolment followed up mean duration 12.4 years were studied. Diagnoses ascertained from linked health records, self-reports death certificate registration. Depressive symptoms measured using combination questions based on Patient Health Questionnaire-9 screening questionnaire. Regional grey matter volumes T1-weighted MRI 41 929 participants. Results was strong incident with an OR 1.76 (95% CI 1.63 1.90), relationship which found be specific rather than commonly proposed confounders. increased rapidly 10 prior diagnosis. The severity depressive showed dose-response risk. older ages correlated reduced volume Alzheimer’s pattern whereas younger onset associated frontal lobes cerebellum. Conclusions provides evidence that link due smaller component clear both mechanisms driving association.

Язык: Английский

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Acid sphingomyelinase modulates anxiety-like behavior likely through toll-like receptor signaling pathway

Molecular Brain, Год журнала: 2025, Номер 18(1)

Опубликована: Фев. 4, 2025

Abstract Recent studies have shown that abnormal activity of acid sphingomyelinase (Asm) has been associated with a range psychiatric disorders including schizophrenia and depression. However, the role Asm in regulation anxiety remains unclear. In present study, we employed Asm-knockout (Asm KO) mice to investigate association between using behavioral tests, RNA sequencing, q-PCR, immunohistochemical staining, other methods. The results showed KO exhibit enhanced anxiety-like behaviors, such as restricted activity, reduced cumulative times central area, diminished exploratory interest, delayed latency feed, through tests open field, novelty-suppressed feeding test, elevated plus maze ect. Transcriptional profiling combined bioinformatics analysis revealed upregulation Toll-like receptor signaling pathway related gene Tlr1/2, Ccl3, Ccl4, Ccl5 Cd86 mice, which was further confirmed by detection activated microglia astrocytes iba-1 GFAP staining. Collectively, our findings uncover for regulating behavior suggest it may be essential maintenance emotional stability, indicating its potential promising target treating disorders.

Язык: Английский

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Exploring the combined effects of serum tumor necrosis factor-alpha and serotonin on antidepressant efficacy in depression: A 12-week prospective analysis

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Год журнала: 2025, Номер unknown, С. 111328 - 111328

Опубликована: Март 1, 2025

Язык: Английский

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Donepezil for Fatigue and Psychological Symptoms in Post–COVID-19 Condition

JAMA Network Open, Год журнала: 2025, Номер 8(3), С. e250728 - e250728

Опубликована: Март 17, 2025

Importance Fatigue is the most commonly reported symptom of post–COVID-19 condition (also known as long COVID) and impairs various functions. One underlying mechanisms may be intracerebral inflammation due to decreases in acetylcholine levels. Objective To examine effects donepezil hydrochloride, an acetylcholinesterase inhibitor, on fatigue psychological symptoms. Design, Setting, Participants A multicenter, double-blind randomized clinical trial was performed Japan. Between December 14, 2022, March 31, 2024, adult patients within 52 weeks onset COVID-19 with a global binary score 4 or greater Chalder Scale were into placebo group. Exposure The intervention conducted during 3-week period, hydrochloride being administered at dosage 3 mg/d for first week then 5 2 weeks. Main Outcomes Measures primary outcome change absolute after initiation treatment. Other outcomes 8 weeks, such symptoms quality life, evaluated secondary outcomes. Results total 120 eligible enrolled 10 withdrew lost follow-up; therefore, 110 (55 each group) included efficacy analysis (64 [58%] female; mean [SD] age, 43 [12] years). No significant differences observed baseline characteristics between groups. baseline-adjusted estimating treatment effect donepezil, measured difference scores 0.34 (95% CI, −2.23 2.91), showing no ( P = .79). Scores Hospital Anxiety Depression Scale, Impact Event Scale–Revised, EuroQol 5-Dimension 5-Level Version, Patient Health Questionnaire, Daily Status similar. serious adverse events occurred either Conclusions Relevance In this treat condition, not confirmed general population. development effective therapeutics needed, more trials should future. Trial Registration Japan Registry Clinical Trials Identifier: jRCT 2031220510

Язык: Английский

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The multifaceted effects of fluoxetine treatment on cognitive functions

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Июль 16, 2024

Fluoxetine, the prototypical selective serotonin reuptake inhibitor (SSRI), is widely used to treat major depressive disorder (MDD) and a variety of other central nervous system conditions, primarily due its established clinical safety profile. Although efficacy in treating depression well-recognized, impact fluoxetine on cognitive functions remains inconsistent elusive. In this review, we first examine well-substantiated biological mechanisms underlying fluoxetine’s antidepressant effects, which include inhibition activation TrkB receptors—key brain-derived neurotrophic factor (BDNF) signaling. Subsequently, delve into side effects observed both preclinical studies, affecting domains such as memory, attention, executive functions. While certain studies indicate improvements patients with disorders, there also evidence negative influenced by variables like gender, duration treatment, age, disease pathology, specifics testing. Significantly, outcomes reported research often involve healthy, non-diseased animals. This review underscores necessity for heightened caution prescription further investigation potentially detrimental even when prophylactically.

Язык: Английский

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Unraveling the Potential Underlying Mechanisms of Mild Behavioral Impairment: Focusing on Amyloid and Tau Pathology

Cells, Год журнала: 2024, Номер 13(13), С. 1164 - 1164

Опубликована: Июль 8, 2024

The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body evidence has shown that MBI associated with alterations structural and functional neuroimaging studies, genetic predisposition clinical diagnosis Alzheimer’s disease (AD), well amyloid tau pathology assessed blood, cerebrospinal fluid, positron-emission tomography (PET) imaging neuropathological examination. These findings shed more light on MBI-related potential neurobiological mechanisms, paving way for development targeted pharmacological approaches. In this review, we aim discuss available role mechanisms. Dysregulation hypothalamic–pituitary–adrenal (HPA) axis, disruption neurotrophic factors, such brain-derived factor (BDNF), abnormal neuroinflammatory responses including kynurenine pathway, dysregulation transforming growth beta (TGF-β1), epigenetic micro-RNA (miR)-451a miR-455-3p, synaptic dysfunction, imbalance neurotransmitters acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA) norepinephrine, altered locus coeruleus (LC) integrity are some connecting pathology. elucidation neurobiology would facilitate design efficacy relative trials, especially towards amyloid- or tau-related pathways. addition, provide insights future research into our deeper understanding its pathophysiology MBI, therapeutic implications.

Язык: Английский

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The Activation of Muscarinic Acetylcholine Receptors Protects against Neuroinflammation in a Mouse Model through Attenuating Microglial Inflammation

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(19), С. 10432 - 10432

Опубликована: Сен. 27, 2024

Neuroinflammation is a critical factor that contributes to neurological impairment and closely associated with the onset progression of neurodegenerative diseases. In central nervous system (CNS), microglia play pivotal role in regulation inflammation through various signaling pathways. Therefore, mitigating microglial considered promising strategy for restraining neuroinflammation. Muscarinic acetylcholine receptors (mAChRs) are widely expressed CNS exhibit clear neuroprotective effects disease models. However, whether activation mAChRs can harness benefits neuroinflammation remains largely unexplored. this study, anti-inflammatory were found mouse model. The expression cytokines chemokines was regulated brains spinal cords after administration mAChR agonists. Microglia primary target cells which exerted their effects. results showed decreased pro-inflammatory phenotypes microglia, including inflammatory cytokines, morphological characteristics, distribution density. Such modulation further neuroprotection, be even more significant by direct neuronal mAChRs. This study elucidates dual mechanisms exert responses, providing evidence application inflammation-related disorders.

Язык: Английский

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Chronic treatment of mixture of two iridoids proportional to prescriptional dose of Yueju improves hippocampal PACAP-related neuroinflammation and neuroplasticity signaling in the LPS-induced depression model

Journal of Ethnopharmacology, Год журнала: 2024, Номер 338, С. 119031 - 119031

Опубликована: Ноя. 8, 2024

Язык: Английский

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Pharmaceutical-mediated neuroimmune modulation in psychiatric/psychological adverse events

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Год журнала: 2024, Номер 135, С. 111114 - 111114

Опубликована: Авг. 5, 2024

The therapeutic use of many pharmaceuticals, including small molecules and biological therapies, has been associated with the onset psychiatric psychological adverse events (PPAEs), posing substantial concerns to patients' health safety. These events, which encompass mood (e.g., depression, schizophrenia, suicidal ideation) cognitive changes learning memory impairment, dementia) often remain undetected until advanced stages clinical trials or pharmacovigilance, mostly because mechanisms underlying PPAEs poorly understood. In recent years, role neuroimmune modulation (comprising an intricate interplay between various cell types signaling pathways) in garnered interest. Indeed, understanding these complex interactions would substantially contribute increase ability predict potential during preclinical a new drug's R&D. This review provides comprehensive summary most advances modulation-related contributing their association specific pharmaceuticals. Reported data strongly support PPAEs. Pharmaceuticals may target molecular pathways pathway elements cholinergic serotonergic systems), turn directly indirectly impact inflammatory status homeostasis brain, regulating inflammation neuronal function. Also, peripheral immune system by pharmaceuticals that do not permeate blood-brain barrier monoclonal antibodies) alter neuroimmunomodulatory leading summary, this underscores diverse through drugs can influence brain inflammation, shedding light on targeted interventions.

Язык: Английский

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Flibanserin conquers murine depressive pseudodementia by amending HPA axis, maladaptive inflammation and AKT/GSK/STAT/BDNF trajectory: Center-staging of the serotonergic/adrenergic circuitry

European Journal of Pharmacology, Год журнала: 2024, Номер 980, С. 176869 - 176869

Опубликована: Авг. 6, 2024

Язык: Английский

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