Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

Hydrocephalus is a neurological condition due to the aberrant circulation and/or obstruction of cerebrospinal fluid (CSF) flow with consequent enlargement of cerebral ventricular cavities. However, it is noticed that a lot of patients may still go through symptomatic progression despite standard shunting procedures, suggesting that hydrocephalus is far more complicated than a simple CSF circulative/obstructive disorder. Growing evidence indicates that genetic factors play a fundamental role in the pathogenesis of some hydrocephalus. Although the genetic research of hydrocephalus in humans is limited, many genetic loci of hydrocephalus have been defined in animal models. In general, the molecular abnormalities involved in the pathogenesis of hydrocephalus include brain development and ependymal cell dysfunction, apoptosis, inflammation, free radical generation, blood flow, and cerebral metabolism. Moreover, recent studies have indicated that the molecular abnormalities relevant to aberrant cerebral glymphatic drainage turn into an attractive subject in the CSF circulation disorder. Furthermore, the prevalent risk factors could facilitate the development of hydrocephalus. In this review, we elicited some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus, and aimed to widen the diagnosis and therapeutic strategies for hydrocephalus management. Such knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.

Characterising the dynamics of cerebral metabolic dysfunction following traumatic brain injury: A microdialysis study in 619 patients

Traumatic brain injury (TBI) is a major cause of death and disability, particularly amongst young people. Current intensive care management of TBI patients is targeted at maintaining normal brain physiology and preventing secondary injury. Microdialysis is an invasive monitor that permits real-time assessment of derangements in cerebral metabolism and responses to treatment. We examined the prognostic value of microdialysis parameters, and the inter-relationships with other neuromonitoring modalities to identify interventions that improve metabolism. This was an analysis of prospective data in 619 adult TBI patients requiring intensive care treatment and invasive neuromonitoring at a tertiary UK neurosciences unit. Patients had continuous measurement of intracranial pressure (ICP), arterial blood pressure (ABP), brain tissue oxygenation (PbtO2), and cerebral metabolism and were managed according to a standardized therapeutic protocol. Microdialysate was assayed hourly for metabolites including glucose, pyruvate, and lactate. Cerebral perfusion pressure (CPP) and cerebral autoregulation (PRx) were derived from the ICP and ABP. Outcome was assessed with the Glasgow Outcome Score (GOS) at 6 months. Relationships between monitoring variables was examined with generalized additive mixed models (GAMM). Lactate/Pyruvate Ratio (LPR) over the first 3 to 7 days following injury was elevated amongst patients with poor outcome and was an independent predictor of ordinal GOS (p<0.05). Significant non-linear associations were observed between LPR and cerebral glucose, CPP, and PRx (p<0.001 to p<0.05). GAMM models suggested improved cerebral metabolism (i.e. reduced LPR with CPP >70mmHg, PRx <0.1, PbtO2 >18mmHg, and brain glucose >1mM. Deranged cerebral metabolism is an important determinant of patient outcome following TBI. Variations in cerebral perfusion, oxygenation and glucose supply are associated with changes in cerebral LPR and suggest therapeutic interventions to improve cerebral metabolism. Future prospective studies are required to determine the efficacy of these strategies.

Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine

It has been well established in epidemiological studies and randomized controlled trials that habitual exercise is beneficial for brain health, such as cognition and mental health. Generally, it may be reasonable to say that the physiological benefits of acute exercise can prevent brain disorders in late life if such exercise is habitually/chronically conducted. However, the mechanisms of improvement in brain function via chronic exercise remain incompletely understood because such mechanisms are assumed to be multifactorial, such as the adaptation of repeated acute exercise. This review postulates that cerebral metabolism may be an important physiological factor that determines brain function. Among metabolites, the provision of lactate to meet elevated neural activity and regulate the cerebrovascular system and redox states in response to exercise may be responsible for exercise-enhanced brain health. Here, we summarize the current knowledge regarding the influence of exercise on brain health, particularly cognitive performance, with the underlying mechanisms by means of lactate. Regarding the influence of chronic exercise on brain function, the relevance of exercise intensity and modality, particularly high-intensity interval exercise, is acknowledged to induce “metabolic myokine” (i.e., lactate) for brain health.

Biomarkers of Cerebral Glucose Metabolism and Neurodegeneration in Parkinson’s Disease: A Cerebrospinal Fluid-Based Study

Background: Several biomarkers have been evaluated in Parkinson’s disease (PD); cerebrospinal fluid (CSF) levels of lactate may reflect cerebral metabolism function and CSF amyloid-β42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) concentrations may detect an underlying neurodegenerative process. Objective: CSF levels of lactate, Aβ 42, t-tau, and p-tau were measured in patients with mild to moderate PD. It also assessed CSF levels of dopamine (DA) and its metabolite 3,4-Dihydroxyphenylacetic acid (DOPAC), exploring their relations with the other CSF biomarkers. Methods: 101 drug-naive PD patients and 60 controls were included. Participants underwent clinical assessments and CSF biomarker analysis. Patients were divided into subgroups according to their H&Y stage (PD-1, PD-2, PD-3). Results: PD patients showed higher lactate levels (M = 1.91; p = 0.03) and lower Aβ 42 (M = 595; p < 0.001) and DA levels (M = 0.32; p = 0.04) than controls (Mlactate = 1.72; MAβ42 = 837; MDA = 0.50), while no significant differences were found in t-tau, p-tau and DOPAC concentrations. Considering the subgroup analysis, PD-3 group had higher lactate (M = 2.12) and t-tau levels (M = 333) than both PD-1 (Mlactate = 1.75, p = 0.006; Mt - tau = 176, p = 0.008) and PD-2 groups (Mlactate = 1.91, p = 0.01; Mt - tau = 176, p = 0.03), as well as the controls (Mlactate = 1.72, p = 0.04; Mt - tau = 205, p = 0.04). PD-2 group showed higher lactate levels than PD-1 group (p = 0.04) and controls (p = 0.03). Conclusion: This CSF-based study shows that lactate levels in PD correlated with both clinical disease progression and neurodegeneration biomarkers, such as tau proteins and DA. Further studies should explore the clinical potential of measuring CSF biomarkers for better understanding the role of brain energy metabolism in PD, for research and therapeutic options.

Microenvironmental Variations After Blood-Brain Barrier Breakdown in Traumatic Brain Injury

Traumatic brain injury (TBI) is linked to several pathologies. The blood-brain barrier (BBB) breakdown is considered to be one of the initial changes. Further, the microenvironmental alteration following TBI-induced BBB breakdown can be multi-scaled, constant, and dramatic. The microenvironmental variations after disruption of BBB includes several pathological changes, such as cerebral blood flow (CBF) alteration, brain edema, cerebral metabolism imbalances, and accumulation of inflammatory molecules. The modulation of the microenvironment presents attractive targets for TBI recovery, such as reducing toxic substances, inhibiting inflammation, and promoting neurogenesis. Herein, we briefly review the pathological alterations of the microenvironmental changes following BBB breakdown and outline potential interventions for TBI recovery based on microenvironmental modulation.

Sex Differences in the Effect of Diabetes on Cerebral Glucose Metabolism

The neuroimaging literature indicates that brain structure and function both deteriorate with diabetes, but information on sexual dimorphism in diabetes-related brain alterations is limited. This study aimed to ascertain whether brain metabolism is influenced by sex in an animal model of diabetes. Eleven rats (male, n = 5; female, n = 6) received a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to develop diabetes. Another 11 rats (male, n = 5; female, n = 6) received the same amount of solvent through a single intraperitoneal injection. Longitudinal positron emission tomography scans were used to assess cerebral glucose metabolism before and 4 weeks after STZ or solvent administration. Before STZ or solvent injections, there was no evidence of sexual dimorphism in cerebral metabolism (p > 0.05). Compared with healthy control animals, rats with diabetes had significantly decreased brain metabolism in all brain regions (all p < 0.05). In addition, female diabetic rats exhibited further reduction in cerebral metabolism, relative to male diabetic rats (p < 0.05). The results of this study may provide some biological evidence, supporting the existence of a sexual dimorphism in diabetes-related complications.

A Noninvasive Quantification Approach for Monitoring Brain Metabolic Alterations After Surgical Intervention in Ischemic Cerebrovascular Disease

Purpose: Non-invasive quantification of cerebral metabolic rate for glucose (CMRGlc) and characterizing cerebral metabolism of cerebrovascular territories are useful for the understanding of ischemic cerebrovascular disease (ICVD). Here, we proposed a non-invasive quantification approach based on image-derived input function (IDIF) suitable for ICVD patients and monitored the pathophysiological changes after surgical intervention.Methods: Sixteen healthy controls and 26 ischemic cerebrovascular disease patients with baseline and after surgical visits underwent 18F-FDG PET/MR imaging. The voxel-wise CMRGlc maps were derived via our proposed IDIF method. The CMRGlc and standardized uptake value ratio (SUVR) maps were subsequently used to extract quantitative values within 7 volumes of interest (gray matter, white matter, anterior, middle, and posterior cerebral artery, basilar artery, and cerebellar artery territory). Intraclass correlation coefficient (ICC) and absolute percentage error were employed to measure consistency in healthy controls. The quantitative differences of healthy controls and patients at baseline and after surgical visits were statistically analyzed. Results: For healthy controls, there were no significant differences for region CMRGlc values across bilateral and unilateral IDIF measurements (ICC: 0.91-0.98). Significant differences in CMRGlc were observed across the cohorts in all territories (P< 0.001). The CMRGlc values in the ipsilateral side were significantly increased after surgery intervention (P < 0.05) for all territories (percentage changes: 7.4%~22.5%). Only the posterior cerebral artery and basilar artery territories (-2.8% and 1.9%) were significant differences for SUVR (P < 0.05). The diagnostic ability of CMRGlc in various territories (area under curve: 0.923-0.966) was significantly higher than of SUVR. There was a significant association between CMRGlc with the national institutes of health stroke scores (r: -0.54, P = 0.0041).Conclusion: These observations suggested the non-invasive quantification approach based on IDIF allowed the individual metabolism measurement of cerebrovascular territories after surgery and identified the glucose pathology changes underlying territories.

Intranasal insulin for treatment of delirium in older hospitalised patients: study protocol for a randomised controlled trial

IntroductionDelirium is one of the most common conditions diagnosed in hospitalised older people and is associated with numerous adverse outcomes, yet there are no proven pharmacological treatments. Recent research has identified cerebral glucose hypometabolism as a pathophysiological mechanism offering a therapeutic target in delirium. Insulin, delivered via the intranasal route, acts directly on the central nervous system and has been shown to enhance cerebral metabolism and improve cognition in patients with mild cognitive impairment and dementia. This trial will determine whether intranasal insulin can reduce the duration of delirium in older hospitalised patients.Methods and analysisThis is a prospective randomised, placebo-controlled, double-blind study with 6 months follow-up. One hundred patients aged 65 years or older presenting to hospital with delirium admitted under geriatric medicine will be recruited. Participants will be randomised to intranasal insulin detemir or placebo administered twice daily until delirium resolves, defined as Confusion Assessment Method (CAM) negative for 2 days, or discharge from hospital. The primary outcome measure will be duration of delirium using the CAM. Secondary outcome measures will include length of hospital stay, severity of delirium, adherence to treatment, hospital complications, new admission to nursing home, mortality, use of antipsychotic medications during hospital stay and cognitive and physical function at 6 months postdischarge.Ethics and disseminationThis trial has been approved by the South Eastern Sydney Human Research and Ethics Committee. Dissemination plans include submission to a peer-reviewed journal for publication and presentation at scientific conferences.Trial registration numberACTRN12618000318280.

Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral ‘mitochondrial dysfunction’ (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification. Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(−12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.