The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies

Objectives: The kynurenine (KYN) pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of studies examining KYN pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD. Methods: The PubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies published until April 2022 that assessed KYN metabolites, namely, tryptophan (TRP), KYN, kynurenic acid (KA), quinolinic acid (QA), and 3-hydroxykynurenine (3-HK), in subjects with SZ, BD, or MDD compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected for comparison of standardized mean differences (SMD) between two groups. Results: Twenty-three articles met the inclusion criteria (k = 8, k = 8, k = 11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased (SMD = 2.64, confidence interval [CI] = 1.16 to 4.13, p = 0.0005, I2 = 96%, k = 6, n=384). TRP (k = 5) and KYN (k = 4) did not differ significantly. In BD, TRP levels (k = 7) did not differ significantly. The level of KA was increased in MDD (k = 2), but the small number of studies precluded evaluation of statistical significance. Finally, in MDD, although some studies tended to show an increased level of KYN in those with remission vs. decreased levels in those with current depression, no significant difference was found in any KYN metabolite levels. Similarly, an increased level of QA was found, but the number of studies (k = 2) was small. Conclusion: KA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. Alterations in the KYN pathway may occur based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies.

INTRODUCTION: The kynurenine pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of the kynurenine pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD. METHODS: PubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies until April 2022 that assessed kynurenine metabolites, namely, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinolinic acid (QA), and 3- hydroxykynurenine (3-HK) in SZ, BD, or MDD subjects compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected when comparing the standardized mean differences (SMD) between two groups. RESULTS: There were 23 articles that met the inclusion criteria (k=8, k=8, k=11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased [SMD=2.64, confidence interval (CI) =1.16 to 4.13, p=0.0005, I2=96%, k=6, n=384 subjects]. TRP (k=5) and KYN (k=4) did not differ significantly. In BD, TRP levels (k=7) did not differ significantly. The level of KA was increased in MDD (k=2), but the small number of studies made not possible for statistical significance evaluation. Finally, in MDD, although some studies tended to have an increased level of KYN in those with remission versus decreased levels in those with current depression, no significant difference was found in any of the kynurenine metabolite levels. Similarly, there was an increased level of QA (k=2) but the number of studies (k= 2) was small. CONCLUSION: KA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. There may be alterations in this pathway based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.

The kynurenine pathway in Alzheimer's disease: a meta-analysis of central and peripheral levels.

OBJECTIVE: Changes in the kynurenine pathway are recognized in psychiatric disorders, but their role in Alzheimer's disease (AD) is less clear. We aimed to conduct a systematic review and meta-analysis to determine whether tryptophan and kynurenine pathway metabolites are altered in AD. METHODS: We performed a systematic review and random-effects meta-analyses. Inclusion criteria were studies that compared AD and cognitively normal (CN) groups and assessed tryptophan or kynurenine pathway metabolites in cerebrospinal fluid or peripheral blood. RESULTS: Twenty-two studies with a total of 1,356 participants (664 with AD and 692 CN individuals) were included. Tryptophan was decreased only in peripheral blood. The kynurenine-to-tryptophan ratio was only increased in peripheral blood of the AD group. 3-Hydroxykynurenine was decreased only in cerebrospinal fluid and showed higher variability in the CN group than the AD group. Kynurenic acid was increased in cerebrospinal fluid and decreased in peripheral blood. Finally, there were no changes in kynurenine and quinolinic acid between the groups. CONCLUSIONS: Our results suggested a shift toward the kynurenine pathway in both the brain and in the periphery, as well as a shift towards increased kynurenic acid production in the brain but decreased production in peripheral blood. In addition, our analysis indicated dissociation between the central and peripheral levels, as well as between plasma and serum for some of these metabolites. Finally, changes in the kynurenine pathway are suggested to be a core component of AD. More studies are warranted to verify and consolidate our results.

Primary balloon angioplasty of venous Sinus stenosis in idiopathic intracranial hypertension.

BACKGROUND: Venous sinus stenosis (VSS) stenting has emerged as an effective treatment for patients with Idiopathic Intracranial Hypertension (IIH). However, stenting carries risk of in-stent stenosis/thrombosis and cumulative bleeding risk from long-term dual antiplatelet (DAPT) use. Thus, we investigated the potential safety and efficacy of primary balloon angioplasty as an alternative to stenting in IIH. METHODS: A prospectively maintained single-center registry of IIH patients undergoing endovascular procedures was queried. Inclusion criteria included patients with confirmed IIH and angiographically demonstrable VSS who underwent interventions from 2012- 2021. Patients were dichotomized into primary balloon angioplasty (Group A) and primary stenting (Group S), comparing clinical outcomes using bivariate analyses. RESULTS: 62 patients were included with median age of 33 [IQR 26-37], 74% females. Group A (9/62) and Group S (53/62) had similar baseline characteristics. Papilledema improvement was higher in Group S at 6 weeks and 6 months (44 vs. 93, p = 0.002 and 44 vs. 92%, p = 0.004), with similar improvements across all symptoms. Group S had higher mean post-procedure venous pressure gradient change (8 vs. 3 mmHg, p = 0.02) and a lower CSF opening pressure at 6 months (23 vs. 36 cmH2O, p < 0.001). VPS rescue rate was higher in Group A (44 vs. 2%, p = 0.001). There was only one procedural complications; a subdural hematoma in Group A. CONCLUSIONS: Primary VSS balloon angioplasty provides a marginal and short-lived improvement of IIH symptoms compared to stenting. These findings suggest a cautious and limited role for short-term rescue angioplasty in poor shunting and stenting candidates with refractory IIH.

The kynurenine pathway in Alzheimer's disease: a meta-analysis of central and peripheral levels

Objective: Changes in the kynurenine pathway are recognized in psychiatric disorders, but their role in Alzheimer's disease (AD) is less clear. We aimed to conduct a systematic review and meta-analysis to determine whether tryptophan and kynurenine pathway metabolites are altered in AD. Methods: We performed a systematic review and random-effects meta-analyses. Inclusion criteria were studies that compared AD and cognitively normal (CN) groups and assessed tryptophan or kynurenine pathway metabolites in cerebrospinal fluid or peripheral blood. Results: Twenty-two studies with a total of 1,356 participants (664 with AD and 692 CN individuals) were included. Tryptophan was decreased only in peripheral blood. The kynurenine-to-tryptophan ratio was only increased in peripheral blood of the AD group. 3-Hydroxykynurenine was decreased only in cerebrospinal fluid and showed higher variability in the CN group than the AD group. Kynurenic acid was increased in cerebrospinal fluid and decreased in peripheral blood. Finally, there were no changes in kynurenine and quinolinic acid between the groups. Conclusions: Our results suggested a shift toward the kynurenine pathway in both the brain and in the periphery, as well as a shift towards increased kynurenic acid production in the brain but decreased production in peripheral blood. In addition, our analysis indicated dissociation between the central and peripheral levels, as well as between plasma and serum for some of these metabolites. Finally, changes in the kynurenine pathway are suggested to be a core component of AD. More studies are warranted to verify and consolidate our results.

Venous Sinus Stenting for Low Pressure Gradient Stenoses in Idiopathic Intracranial Hypertension.

BACKGROUND: Medically refractory idiopathic intracranial hypertension (IIH) is frequently treated with venous sinus stenosis stenting with high success rates. Patient selection has been driven almost exclusively by identification of supraphysiological venous pressure gradients across stenotic regions based on theoretical assessment of likelihood of response. OBJECTIVE: To explore the possibility of benefit in low venous pressure gradient patients. METHODS: Using a single-center, prospectively maintained registry of patients with IIH undergoing venous stenting, we defined treatment groups by gradient pressures of ≤4, 5 to 8, and >8 mmHg based on the most frequently previously published thresholds for stenting. Baseline demographics, clinical, and neuro-ophthalmological outcomes (including optical coherence tomography and Humphrey visual fields) were compared. RESULTS: Among 53 patients, the mean age was 32 years and 70% female with a mean body mass index was 36 kg/m 2 . Baseline characteristics were similar between groups. The mean change in lumbar puncture opening pressure at 6 months poststenting was similar between the 3 groups (≤4, 5-8, and >8 mmHg; 13.4, 12.9, and 12.4 cmH 2 O, P = .47). Papilledema improvement was observed across groups at 6 months (100, 93, and 86, P = .7) as were all clinical symptoms. The mean changes in optical coherence tomography retinal nerve fiber layer (-30, -54, and -104, P = .5) and mean deviation in Humphrey visual fields (60, 64, and 67, P = .5) at 6 weeks were not significantly different. CONCLUSION: Patients with IH with low venous pressure gradient venous sinus stenosis seem to benefit equally from venous stenting compared with their higher gradient counterparts. Re-evaluation of our restrictive criteria for this potentially vision sparing intervention is warranted. Future prospective confirmatory studies are needed.

Disparities among neurointerventionalists suggest further investigation of conscious sedation versus general anesthesia during thrombectomy for acute stroke.

INTRODUCTION: Prior retrospective and case-control studies have shown that the use of general anesthesia (GA) during endovascular therapy (EVT) for acute ischemic stroke with large vessel occlusion (AIS-LVO) was independently associated with poor clinical outcomes compared with cases performed under conscious sedation (CS). Conversely, recent small randomized clinical trials (RCT) demonstrated a trend toward better outcome in cases performed under GA. METHODS: We submitted an online survey to 193 Society of Vascular Interventional Neurology and 78 American Association of Neurological Surgeons and Congress of Neurological Surgeons - Cerebrovascular Section neuroendovascular practitioners. Questions were aimed at understanding the current state of anesthesia practice during EVT, and to determine if there is clinical equipoise for a large multicenter RCT comparing GA versus CS during EVT. RESULTS: Between March and May of 2017, we received 116 (43%) responses. Anesthesiologists were responsible for managing 96% of the GA cases as compared to only 51% of the CS cases (P < 0.0001). Notable 56% of providers reported performing less than a quarter of their cases under GA. Only 7% performed all cases under GA compared with 17% who used solely CS (P = 0.048). More than half of respondents thought a new RCT was necessary, of whom 61% were interested in participating. Among interested responders, 59% were located in centers with 3 or more neurointerventionalists. CONCLUSION: The significant variation among neuroendovascular providers, added with the lack of consensus among recent trials and meta-analyses, demonstrate clinical equipoise for further studies to explore the effects of anesthesia during EVT in AIS-LVO.

Dual Antiplatelet Therapy Duration After Venous Sinus Stenting for Idiopathic Intracranial Hypertension and Stent Survival-Is Longer Necessarily Better? A Meta-Regression.

BACKGROUND: Venous stenting (VS) for venous sinus stenosis in the setting of idiopathic intracranial hypertension has been increasing in acceptance by neurointerventionalists. Stent-adjacent stenosis (SAS) and in-stent stenosis leading to symptom recurrence and the need for retreatment are known delayed complications. However, the effect of the dual antiplatelet therapy (DAPT) duration on these complications has remained poorly characterized. METHODS: An extensive literature search was performed to identify reports of VS for patients with idiopathic intracranial hypertension from 2000 to 2020. The primary outcome was the occurrence of SAS. The secondary outcomes included the occurrence of composite stenosis (in-stent stenosis and SAS) and stent survival, defined as the need for retreatment or other surgical management. Generalized linear mixed models were used to explore the effects of DAPT duration (3 vs ≥6 months) on the primary and secondary outcomes. RESULTS: A total of 325 patients met the inclusion criteria and were included in our analysis. SAS occurred in 9% (95% confidence interval, 6%-15%) of the patients, and stent survival was 90% (95% confidence interval, 84%-93%) in the cohort. With every 1-mm Hg increase in the venous pressure gradient, an 8% decrease was found in the odds of stent survival (P = 0.043). The meta-regression revealed no association between the DAPT duration and the primary outcome or the odds of composite stenosis and stent survival. CONCLUSIONS: We found no differences between 3 and ≥6 months of DAPT in terms of the risk of stent stenosis or stent survival. However, patients with a higher venous pressure gradient before VS had a greater risk of stent failure.

Exception from informed consent in the era of social media: The SEGA stroke trial experience.

INTRODUCTION: Patients with acute ischemic stroke (AIS) and neurologic deficits are often unable to provide consent and excluded from emergency research participation. Experiences with exception from informed consent (EFIC) to facilitate research on potentially life-saving emergency interventions are limited. Here, we describe our multifaceted approach to EFIC approval for an ongoing randomized clinical trial that compares sedation versus general anesthesia (SEGA) approaches for endovascular thrombectomy during AIS. METHODS: We published a university clinical trial website with EFIC information. We initiated a social media campaign on Facebook within a 50 mile radius of Texas Medical Center. Advertisements were linked to our website, and a press release was issued with information about the trial. In-person community consultations were performed, and voluntary survey information was collected. RESULTS: A total of 193 individuals (65% female, age 46.7 ± 16.6 years) participated in seven focus group community consultations. Of the 144 (75%) that completed surveys, 88.7% agreed that they would be willing to have themselves or family enrolled in this trial under EFIC. Facebook advertisements had 134,481 (52% females; 60% ≥45 years old) views followed by 1,630 clicks to learn more. The website had 1130 views (56% regional and 44% national) with an average of 3.85 min spent. Our Institutional Review Board received zero e-mails requesting additional information or to optout. CONCLUSION: Our social media campaign and community consultation methods provide a significant outreach to potential stroke patients. We hope that our experience will inform and help future efforts for trials seeking EFIC.