Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria

Herpes simplex virus (HSV) type 1 encephalitis (HSE) is a viral infectious disease with commonly occurring neurodegeneration and neurological/cognitive long-term sequelae. Kynurenic acid (KYNA) is a neuroactive tryptophan metabolite, which is elevated in the cerebrospinal fluid (CSF) during viral infection as a result of immune activation. The aim of the study was to investigate the role of endogenous brain KYNA for the long-term outcome of the disease. CSF KYNA concentration was analyzed in 25 HSE patients along the course of the disease and compared with that of 25 age-matched healthy volunteers. Within 3 weeks of admission CSF KYNA of HSE patients was markedly elevated (median 33.6 nM) compared to healthy volunteers (median 1.45 nM). Following a decline observed after 1–2 months, levels of CSF KYNA were elevated more than 1 year after admission (median 3.4 nM range: 1–9 years). A negative correlation was found between initial CSF KYNA concentrations and severity of the long-term sequelae. This study show a marked elevation in CSF KYNA from patients with HSE, most pronounced during the acute phase of the disease and slowly declining along the recovery. We propose that brain KYNA might potentially protect against neurodegeneration while causing a long-lasting loss in cognitive function associated with the disease.

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Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia

JAMA Network Open ◽

10.1001/jamanetworkopen.2021.38515 ◽

2021 ◽

Vol 4 (12) ◽

pp. e2138515

Author(s):

Dibyadyuti Datta ◽

Paul Bangirana ◽

Robert O. Opoka ◽

Andrea L. Conroy ◽

Katrina Co ◽

...

Keyword(s):

Cerebral Malaria ◽

Neurocognitive Impairment ◽

Severe Malarial Anemia ◽

Malarial Anemia

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Elevated Cerebrospinal Fluid Tau Protein Concentrations on Admission Are Associated With Long-term Neurologic and Cognitive Impairment in Ugandan Children With Cerebral Malaria

Clinical Infectious Diseases ◽

10.1093/cid/ciz325 ◽

2019 ◽

Vol 70 (6) ◽

pp. 1161-1168 ◽

Cited By ~ 5

Author(s):

Dibyadyuti Datta ◽

Andrea L Conroy ◽

Peter F Castelluccio ◽

John M Ssenkusu ◽

Gregory S Park ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Cerebral Malaria ◽

Axonal Injury ◽

Kidney Injury ◽

Cognitive Outcomes ◽

Cognitive Outcome ◽

Neurologic Deficits ◽

Lower Glucose

Abstract Background Elevated concentrations of cerebrospinal fluid (CSF) tau, a marker of axonal injury, have been associated with coma in severe malaria (cerebral malaria [CM]). However, it is unknown whether axonal injury is related to long-term neurologic deficits and cognitive impairment in children with CM. Methods Admission CSF tau concentrations were measured in 145 Ugandan children with CM and compared to clinical and laboratory factors and acute and chronic neurologic and cognitive outcomes. Results Elevated CSF tau concentrations were associated with younger age, increased disease severity (lower glucose and hemoglobin concentrations, malaria retinopathy, acute kidney injury, and prolonged coma duration, all P < .05), and an increased CSF:plasma albumin ratio, a marker of blood–brain barrier breakdown (P < .001). Admission CSF tau concentrations were associated with the presence of neurologic deficits at hospital discharge, and at 6, 12, and 24 months postdischarge (all P ≤ .02). After adjustment for potential confounding factors, elevated log10-transformed CSF tau concentrations correlated with worse cognitive outcome z scores over 2-year follow-up for associative memory (β coefficient, –0.31 [95% confidence interval [CI], –.53 to –.10]) in children <5 years of age, and for overall cognition (–0.69 [95% CI, –1.19 to –.21]), attention (–0.78 [95% CI, –1.34 to –.23]), and working memory (–1.0 [95% CI, –1.68 to –.31]) in children ≥5 years of age (all P < .006). Conclusions Acute axonal injury in children with CM is associated with long-term neurologic deficits and cognitive impairment. CSF tau concentrations at the time of the CM episode may identify children at high risk of long-term neurocognitive impairment.

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Persistent cognitive impairment associated with cerebrospinal fluid anti-SARS-CoV-2 antibodies six months after mild COVID-19

Neurological Research and Practice ◽

10.1186/s42466-021-00135-y ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Max Borsche ◽

Dirk Reichel ◽

Anja Fellbrich ◽

Anne S. Lixenfeld ◽

Johann Rahmöller ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Cognitive Impairment ◽

Female Patient ◽

Acute Phase ◽

Neuropsychological Testing ◽

Important Challenge ◽

Central Nervous System Invasion

AbstractNeurological long-term sequelae are increasingly considered an important challenge in the recent COVID-19 pandemic. However, most evidence for neurological symptoms after SARS-CoV-2 infection and central nervous system invasion of the virus stems from individuals severely affected in the acute phase of the disease. Here, we report long-lasting cognitive impairment along with persistent cerebrospinal fluid anti-SARS-CoV-2 antibodies in a female patient with unremarkable standard examination 6 months after mild COVID-19, supporting the implementation of neuropsychological testing and specific cerebrospinal fluid investigation also in patients with a relatively mild acute disease phase.

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The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy

International Journal of Molecular Sciences ◽

10.3390/ijms22094822 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4822

Author(s):

Viktória Kovács ◽

Gábor Remzső ◽

Tímea Körmöczi ◽

Róbert Berkecz ◽

Valéria Tóth-Szűki ◽

...

Keyword(s):

Neuronal Activity ◽

Kynurenic Acid ◽

Neuronal Damage ◽

Brain Regions ◽

Hypoxic Ischemic Encephalopathy ◽

Hippocampal Field ◽

Power Spectral ◽

Density Values ◽

Ischemic Encephalopathy

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.

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Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria

BMC Medicine ◽

10.1186/s12916-021-02033-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Andrea L. Conroy ◽

Robert O. Opoka ◽

Paul Bangirana ◽

Ruth Namazzi ◽

Allen E. Okullo ◽

...

Keyword(s):

Executive Function ◽

Hospital Mortality ◽

Cerebral Malaria ◽

Severe Malaria ◽

Behavioral Outcomes ◽

Artemisinin Derivatives ◽

Neurologic Deficits ◽

Adjusted Scores

Abstract Background In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM. Methods From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up. Results 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07–0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine. Conclusions Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

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A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria

Molecular Neurobiology ◽

10.1007/s12035-016-0226-3 ◽

2016 ◽

Vol 54 (9) ◽

pp. 7063-7082 ◽

Cited By ~ 6

Author(s):

Aline Silva de Miranda ◽

Fátima Brant ◽

Luciene Bruno Vieira ◽

Natália Pessoa Rocha ◽

Érica Leandro Marciano Vieira ◽

...

Keyword(s):

Receptor Antagonist ◽

Cerebral Malaria ◽

Glutamate Receptor ◽

Neuroprotective Effect ◽

Behavioral Outcomes ◽

Glutamate Receptor Antagonist ◽

Experimental Cerebral Malaria

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Effect of Long-Term Fluvoxamine Treatment on Endogenous Serotonin Uptake Inhibitor-Like Substance in Monkey Cerebrospinal Fluid

The Japanese Journal of Pharmacology ◽

10.1254/jjp.67.177 ◽

1995 ◽

Vol 67 (2) ◽

pp. 177-180

Author(s):

Toru Egashira ◽

Shinichiro Goto ◽

Yuji Wada ◽

Fusako Takayama ◽

Yasumitu Yamanaka

Keyword(s):

Cerebrospinal Fluid ◽

Serotonin Uptake ◽

Uptake Inhibitor ◽

Serotonin Uptake Inhibitor

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Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/617420 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Peter Wostyn ◽

Debby Van Dam ◽

Kurt Audenaert ◽

Peter Paul De Deyn

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Senile Plaques ◽

Protective Effects ◽

Caffeine Consumption ◽

Neuroprotective Effects ◽

Csf Production

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na+-K+ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

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