BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. ...Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTSIn delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 1.78, 2.87, P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (β 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 2.93, 6.45 for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSIONOur data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDINGNorwegian Health Association and South-Eastern Norway Regional Health Authorities.
Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and ...neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.
Background Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, ...dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. Methods Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. Results We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. Discussion In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women. Keywords: Alzheimer disease, Biomarkers, Cerebrospinal fluid, Kynurenic acid, Kynurenine pathway, Longitudinal case control study, Quinolinic acid, Sex differences, Tryptophan, Mitophagy
•Amino acids’ (AAs) neuroactivity are linked to dementia.•Effect of circulating AAs on cognitive prognosis in dementia subgroups is unknown.•Longitudinal follow-up and linear-mixed effects model ...stratified by diagnosis.•Tyrosine associated with cognition in Lewy body dementia but not Alzheimer's.•Tyrosine availability and catecholamine synthesis may effect cognitive performance.
Amino acids’ neuroactivity, and roles in excitotoxity and oxidative stress are linked to dementia. We aimed to investigate whether circulating amino acid concentrations were associated with cognitive decline in patients with mild Alzheimer’s disease (AD) and Lewy body dementia (LBD). Baseline serum amino acid concentrations were measured in 89 patients with AD and 65 with LBD (13 with Parkinson’s disease dementia and 52 with dementia with Lewy bodies). The Mini-Mental State Examination (MMSE) was administered at baseline and annually for five years. Associations between baseline amino acid concentrations and longitudinal MMSE score were assessed using a linear-mixed effects model stratified by diagnosis with adjustment for multiple comparisons. The results of the study indicated that serum tyrosine was positively associated with MMSE performance during the five-year follow-up period in patients with LBD (q-value = 0.012), but not AD. In conclusion, higher baseline serum concentrations of tyrosine, the precursor amino acid in dopamine and norepinephrine synthesis, was associated with better cognitive performance in patients with LBD, but not AD, throughout the 5-year follow-up period.
The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. ...Reports further indicate that COVID‐19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS‐CoV‐2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID‐19 patients in a cohort of 231 individuals, of which 161 were COVID‐19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID‐19 infection. Autoantibody levels often accompanied anti‐SARS‐CoV‐2 antibody concentrations while stratifying COVID‐19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID‐19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID‐19. This work maps the intersection of COVID‐19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS‐CoV‐2 infection. Thus, this cross‐sectional study suggests that SARS‐CoV‐2 infection induces autoantibody signatures associated with COVID‐19 severity and several autoantibodies that can be used as biomarkers of COVID‐19 severity, indicating autoantibodies as potential therapeutical targets for these patients.
BACKGROUND/OBJECTIVES
Functional status is one of the most important markers of well‐being in older adults, but the drivers of functional decline in dementia are not well known. The aim of our work ...was to study the association of neuropsychiatric symptoms (NPSs) with functional decline over 5 years in newly diagnosed people with Alzheimer´s disease (AD) and Lewy body dementia (LBD).
DESIGN
Secondary analysis of the Dementia Study of Western Norway longitudinal cohort study.
SETTING
Multicenter study conducted in memory clinics in western Norway.
PARTICIPANTS
We included a total of 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed up annually for 5 years.
MAIN OUTCOMES AND MEASURES
The outcome was the rapid disability rating scale (items 1–13). Linear mixed‐effects models were used for analysis with the total score of the Norwegian Neuropsychiatric Inventory (NPI) as a predictor measured either at baseline or longitudinally, adjusted for potential confounders, including cognition. Effect modification was checked by introducing interactions with NPI score and stratifying by diagnosis.
RESULTS
The total NPI score longitudinal course was associated with functional decline in both AD and LBD. At baseline, the total NPI score predicted functional decline in AD.
CONCLUSION
NPSs were associated with the rate of functional decline in people with AD and LBD, independent of cognitive impairment. These results highlight the relevance of early detection and intervention of NPSs, which may also reduce functional decline. J Am Geriatr Soc 68:2257–2263, 2020.
Introduction:
The amygdala is implicated in psychiatric illness. Even as the amygdala undergoes significant atrophy in mild dementia, amygdala volume is underexplored as a risk factor for ...neuropsychiatric symptoms (NPS).
Objective:
To analyze the association between baseline amygdala volume and the longitudinal trajectories of NPS and cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) over 5 years.
Methods:
Eighty-nine patients with mild dementia were included (AD = 55; DLB = 34). Amygdala volume was segmented from structural magnetic resonance images (sMRI) using a semi-automatic method (Freesurfer 6.0) and normalized by intracranial volumes. The intracranial volume-normalized amygdala was used as a predictor of the Neuropsychiatric Inventory (NPI) total score, ordinal NPI item scores (0 = absence of symptoms, 1–3 = mild symptoms, ≥4 = clinically relevant symptoms), and Mini-Mental State Examination (MMSE) as measured annually over 5 years using gamma, ordinal, and linear mixed-effects models, respectively. The models were adjusted for demographic variables, diagnosis, center of sMRI acquisition, and cognitive performance. Multiple testing-corrected
p
-values (
q
-values) are reported.
Results:
Larger intracranial volume-normalized amygdala was associated with less agitation/aggression (odds ratio (OR) = 0.62 0.43, 0.90,
p
= 0.011,
q
= 0.038) and less MMSE decline per year (fixed effect = 0.70, 0.29, 1.03,
p
= 0.001,
q
= 0.010) but more depression (OR = 1.49 1.09, 2.04,
p
= 0.013,
q
= 0.040).
Conclusions:
Greater amygdala volume in mild dementia is associated with lower odds of developing agitation/aggression, but higher odds of developing depression symptoms during the 5-year study period.
Abstract
Background
In-hospital delirium is associated with adverse outcomes and is underdiagnosed, limiting research and clinical follow-up.
Objective
To compare the incidence of in-hospital ...delirium determined by chart-based review of electronic medical records (D-CBR) with delirium discharge diagnoses (D-DD). Furthermore, to identify differences in symptoms, treatments and delirium triggers between D-CBR and D-DD.
Method
The community-based cohort included 2,115 participants in the Hordaland Health Study born between 1925 and 1927. Between 2018 and 2022, we retrospectively reviewed hospital electronic medical records from baseline (1997–99) until death prior to 2023. D-DD and D-CBR were validated using The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for delirium.
Results
Of the 2,115 participants, 638 had in-hospital delirium. The incidence rate (IR) of D-CBR was 29.8 95% confidence interval 28, 32 per 1,000 person-years, whereas the IR by D-DD was 3.4 2.8, 4.2. The IR ratio was 9.14 (P < 0.001). Patients who received pharmacological treatment for delirium (n = 121, odds ratio (OR) 3.4, 2.1, 5.4, P < 0.001), who were affected by acute memory impairment (n = 149, OR 2.8, 1.8, 4.5, P < 0.001), or change in perception (n = 137, OR 2.9, 1.8, 4.6 P < 0.001) had higher odds for D-DD. In contrast, post-operative cases (OR 0.2, 0.1, 0.4, P < 0.001) had lower odds for D-DD.
Conclusion
Underdiagnosis of in-hospital delirium was a major issue in our study, especially in less severe delirium cases. Our findings emphasise the need for integrating systematic delirium diagnostics and documentation into hospital admission and discharge routines.
One-carbon metabolism (OCM) refers to the transfer of methyl groups central to DNA methylation and histone modification. Insufficient access to methyl donors and B-vitamin cofactors affects ...epigenetic maintenance and stability, and when occurring in early life may impact future health and neurodevelopment.
The objective of this study was to examine the relative associations between one-carbon metabolites in Nepalese mother–infant pairs and child cognition measured at 5 y of age.
This is a cross-sectional study from Bhaktapur, Nepal, in a population at high risk of subclinical B-vitamin deficiencies and cumulative infection burden. Venous blood samples from 500 mother–infant pairs were collected when the infants were 2 to 12 mo old, and metabolite concentrations measured by microbiological assays and GC–tandem MS. We re-enrolled 321 of these children at 5 y and assessed cognition by the Ages and Stages Questionnaire, 3rd edition, and subtests from the Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). The associations of the independent metabolites or unobserved metabolic phenotypes (identified by latent class analysis) with the cognitive outcomes were estimated by seemingly unrelated regression. We explored direct and indirect relations between the OCM pathway and the cognitive outcomes using path analysis.
Infant cystathionine concentration was inversely associated with 4 cognitive outcomes (standardized βs ranging from −0.22 to −0.11, P values from <0.001 to 0.034). Infants with a metabolic phenotype indicating impaired OCM and low vitamin B-12 status had poorer cognitive outcomes compared with infants with normal OCM activity and adequate vitamin B-12 status (standardized βs ranging from −0.80 to −0.40, P < 0.001 and 0.05). In the path analysis, we found several OCM biomarkers were associated with affect recognition through infant plasma cystathionine.
Elevated plasma cystathionine during infancy reflects a metabolic phenotype of impaired OCM and low vitamin B-12 status and is associated with poorer cognitive function when the children are 5 y old.
Dengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue ...vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs).
We analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response.
This work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g.,
and
) for anti-dengue-specific therapies and effective vaccination development.
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