Lieke Bakker

Background: The tryptophan‐kynurenine pathway may play a role in cognitive decline in both neurodegenerative and cerebrovascular disorders. However, clinical studies investigating kynurenines so far have generally been small, and studies looking into prodromal disease stages are scarce. The present study used a transdiagnostic approach to investigate levels of kynurenines and B‐vitamins, as important cofactors, across diagnostic phases of dementia and healthy controls. Method: Blood plasma levels of tryptophan, seven kynurenine metabolites (kynurenine, 3‐hydroxykynurenine, kynurenic acid, xanthurenic acid, anthranilic acid, 3‐hydroxyanthranilic acid, quinolinic acid) and B‐vitamins (pyridoxal 5’‐phosphate and riboflavin) were determined in 2,452 cognitively healthy older adults (used as controls) from the population‐based The Maastricht Study, 759 patients from a memory clinic, including patients with subjective cognitive decline (SCD, n = 293), mild cognitive impairment (MCI, n = 304) or dementia ( n = 162, and in 194 patients 3 months after stroke with (PSCI, n = 127) or without post‐stroke cognitive impairment (PSNCI, n = 67). Samples were analyzed by Bevital, Bergen, Norway, by means of LC‐MS/MS. Linear regression analyses were done to assess differences between cohorts and across diagnostic phases, while adjusting for a priori defined confounders (demographics, kidney function, and lifestyle factors). Where appropriate, metabolites were log‐transformed prior to analysis and all were standardized for reasons of comparison. Result: Preliminary results showed that, in analyses comparing stroke patients to controls, plasma levels of tryptophan (‐0.36 [‐0.52, ‐0.21]), xanthurenic acid (‐0.15 [‐0.26, ‐0.00]), kynurenic acid‐to‐quinolinic acid ratio (‐0.45 [‐0.60, ‐0.29]), pyridoxal 5’‐phosphate (‐0.69 [‐0.84, ‐0.54]), and riboflavin (‐0.43 [‐0.58, ‐0.27]) were significantly lower, while levels of kynurenine (0.28 [0.15, 0.41]), 3‐hydroxykynurenine (0.70 [0.56, 0.84]), 3‐hydroxyanthranilic acid (0.45 [0.30, 0.59]), quinolinic acid (0.46 [0.33, 0.60]), and kynurenine‐to‐tryptophan ratio (0.53 [0.40, 0.66]) were higher. No difference were found in kynurenic acid (0.00 [‐0.23, 0.13]) or anthranilic acid (0.01 [‐0.14, 0.16]). Results were similar for patients with PSCI and PSNCI, with no significant differences between these groups. Analyses in the memory clinic population are currently being performed. Conclusion: These preliminary results suggest that the kynurenine pathway is dysregulated after stroke, independent of cognitive impairment. Further studies are needed to validate these findings.

Background: The kynurenine pathway (KP) is associated with pathophysiological processes underlying dementia, but results from clinical studies are contradictory. Therefore, this systematic review and meta‐analysis summarized the available evidence for differences in KP metabolites in patients with cognitive impairment compared to cognitively healthy individuals and associations between KP metabolites and cognitive functioning. Method: Studies published in English with prospective, cross‐sectional, or case‐control designs that were published in Pubmed, Embase, PsychINFO, or the Cochrane Database of Systematic Reviews up to October 2023, were included. Random‐effects meta‐analyses of standardized mean differences (SMD) were done. Heterogeneity, meta‐regression, small study bias, and study quality assessments were carried out. Result: Of 8797 studies, 98 met inclusion criteria. Meta‐analyses comparing Alzheimer's disease (AD) dementia patients to controls ( n = 27 studies) indicated lower cerebrospinal fluid (CSF) levels of tryptophan (SMD = ‐0.26 [95% CI ‐0.41, ‐0.12]), 3‐hydroxykynurenine (‐0.21 [‐0.39, ‐0.04]), anthranilic acid (‐0.28 [‐0.48, ‐0.08]), and quinolinic acid (‐0.38 [‐0.56, ‐0.21]) in AD dementia, while CSF levels of kynurenic acid were higher (0.18 [0.01, 0.35]). Blood levels of tryptophan (‐0.39 [‐0.51, ‐0.28]), kynurenic acid (‐0.31 [‐0.47, ‐0.15]), xanthurenic acid (‐0.34 [‐0.54, ‐0.15]), and 3‐hydroxyanthranilic acid (‐0.42 [‐0.61, ‐0.22]) were lower in AD dementia. For some of these metabolites, similar directions were observed in meta‐analyses comparing individuals with mild cognitive impairment with controls, although the number of included studies in these analyses was relatively small ( n = 11). Associations with cognitive test scores were inconclusive and generally non‐significant. Conclusion: These results suggest that AD dementia is associated with lower blood levels of several KP metabolites. Findings also challenge assumptions that neurotoxic quinolinic acid levels are an important contributor to dementia pathogenesis.

The long-term impact of stroke on Alzheimer’s disease (AD) progression, particularly regarding sex-specific differences, remains unknown. Using a longitudinal study design, we investigated transient middle cerebral artery occlusion in 3.5-month-old APP_swe/PS1_dE9 (APP/PS1) and wild-type mice. In vivo, we assessed behavior, cerebral blood flow (CBF), and structural integrity by neuroimaging, as well as post-mortem myelin integrity (polarized light imaging, PLI), neuroinflammation, and amyloid beta (Aβ) deposition. APP/PS1 mice exhibited cognitive decline, white matter degeneration (reduced fractional anisotropy (FA) via diffusion tensor imaging (DTI)), and decreased myelin density via PLI. Despite early hypertension, APP/PS1 mice showed only sporadic hypoperfusion. Cortical thickening and hippocampal hypertrophy likely resulted from Aβ accumulation and neuroinflammation. Stroke-operated mice retained cognition despite cortical thinning and hippocampal atrophy due to cerebrovascular adaptation, including increased CBF in the hippocampus and thalamus. Stroke did not worsen AD pathology, nor did AD exacerbate stroke outcomes. Sex differences were found: female APP/PS1 mice had more severe Aβ deposition, hyperactivity, lower body weight, and reduced CBF but less neuroinflammation, suggesting potential neuroprotection. These findings highlight white matter degeneration and Aβ pathology as key drivers of cognitive decline in AD, with stroke-related deficits mitigated by (cerebro)vascular adaptation. Sex-specific therapies are crucial for AD and stroke.

Aims/hypothesis: Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. Methods: Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders. Results: Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism. Conclusions/interpretation: Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies. Graphical