Extracerebral Tissues Research Articles

Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]β-hydroxybutyrate ([11C]OHB) PET in healthy humans

BackgroundKetones are increasingly recognized as an important and possibly oxygen sparing source of energy in vital organs such as the heart, the brain and the kidneys. Drug treatments, dietary regimens and oral ketone drinks designed to deliver ketones for organ and tissue energy production have therefore gained popularity. However, whether ingested ketones are taken up by various extra-cerebral tissues and to what extent is still largely unexplored. It was therefore the aim of this study to use positron emission tomography (PET) to explore the whole body dosimetry, biodistribution and kinetics of the ketone tracer (R)-[1-11C]β-hydroxybutyrate ([11C]OHB). Six healthy subjects (3 women and 3 men) underwent dynamic PET studies after both intravenous (90 min) and oral (120 min) administration of [11C]OHB. Dosimetry estimates of [11C]OHB was calculated using OLINDA/EXM software, biodistribution was assessed visually and [11C]OHB tissue kinetics were obtained using an arterial input function and tissue time-activity curves.ResultsRadiation dosimetry yielded effective doses of 3.28 upmuSv/MBq (intravenous administration) and 12.51 upmuSv/MBq (oral administration). Intravenous administration of [11C]OHB resulted in avid radiotracer uptake in the heart, liver, and kidneys, whereas lesser uptake was observed in the salivary glands, pancreas, skeletal muscle and red marrow. Only minimal uptake was noted in the brain. Oral ingestion of the tracer resulted in rapid radiotracer appearance in the blood and radiotracer uptake in the heart, liver and kidneys. In general, [11C]OHB tissue kinetics after intravenous administration were best described by a reversible 2-tissue compartmental model.ConclusionThe PET radiotracer [11C]OHB shows promising potential in providing imaging data on ketone uptake in various physiologically relevant tissues. As a result, it may serve as a safe and non-invasive imaging tool for exploring ketone metabolism in organs and tissues of both patients and healthy individuals.Trial registrationClinical trials, NCT0523812, Registered February 10th 2022, https://clinicaltrials.gov/ct2/show/NCT05232812?cond=NCT05232812&draw=2&rank=1.

Optimizing a two-layer method for hybrid diffuse correlation spectroscopy and frequency-domain diffuse optical spectroscopy cerebral measurements in adults.

The sensitivity to extracerebral tissues is a well-known confounder of diffuse optics. Two-layer (2L) head models can separate cerebral signals from extracerebral artifacts, but they also carry the risk of crosstalk between fitting parameters. We aim to implement a constrained 2L head model for hybrid diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy (FD-DOS) data and to characterize errors in cerebral blood flow and tissue absorption with the proposed model. The algorithm uses the analytical solution of a 2L cylinder and an a priori extracerebral layer thickness to fit multidistance FD-DOS (0.8 to 4cm) and DCS (0.8 and 2.5cm) data, assuming homogeneous tissue reduced scattering. We characterized the algorithm's accuracy for simulated data with noise generated using a 2L slab and realistic adult head geometries and for in vitro phantom data. Our algorithm recovered the cerebral flow index with 6.3 [2.8, 13.2]% and 34 [30, 42]% (median absolute percent error [interquartile range]) for slab and head geometries, respectively. Corresponding errors in the cerebral absorption coefficient were 5.0 [3.0, 7.9]% and 4.6 [2.4, 7.2]% for the slab and head geometries and 8 [5, 12]% for our phantom experiment. Our results were minimally sensitive to second-layer scattering changes and were robust to cross-talk between fitting parameters. In adults, the constrained 2L algorithm promises to improve FD-DOS/DCS accuracy compared with the conventional semi-infinite approach.

The Influence of Extracerebral Tissue on Continuous Wave Near-Infrared Spectroscopy in Adults: A Systematic Review of In Vivo Studies.

Near-infrared spectroscopy (NIRS) is a non-invasive technique for measuring regional tissue haemoglobin (Hb) concentrations and oxygen saturation (rSO2). It may be used to monitor cerebral perfusion and oxygenation in patients at risk of cerebral ischemia or hypoxia, for example, during cardiothoracic or carotid surgery. However, extracerebral tissue (mainly scalp and skull tissue) influences NIRS measurements, and the extent of this influence is not clear. Thus, before more widespread use of NIRS as an intraoperative monitoring modality is warranted, this issue needs to be better understood. We therefore conducted a systematic review of published in vivo studies of the influence of extracerebral tissue on NIRS measurements in the adult population. Studies that used reference techniques for the perfusion of the intra- and extracerebral tissues or that selectively altered the intra- or extracerebral perfusion were included. Thirty-four articles met the inclusion criteria and were of sufficient quality. In 14 articles, Hb concentrations were compared directly with measurements from reference techniques, using correlation coefficients. When the intracerebral perfusion was altered, the correlations between Hb concentrations and intracerebral reference technique measurements ranged between |r| = 0.45-0.88. When the extracerebral perfusion was altered, correlations between Hb concentrations and extracerebral reference technique measurements ranged between |r| = 0.22-0.93. In studies without selective perfusion modification, correlations of Hb with intra- and extracerebral reference technique measurements were generally lower (|r| < 0.52). Five articles studied rSO2. There were varying correlations of rSO2 with both intra- and extracerebral reference technique measurements (intracerebral: |r| = 0.18-0.77, extracerebral: |r| = 0.13-0.81). Regarding study quality, details on the domains, participant selection and flow and timing were often unclear. We conclude that extracerebral tissue indeed influences NIRS measurements, although the evidence (i.e., correlation) for this influence varies considerably across the assessed studies. These results are strongly affected by the study protocols and analysis techniques used. Studies employing multiple protocols and reference techniques for both intra- and extracerebral tissues are therefore needed. To quantitatively compare NIRS with intra- and extracerebral reference techniques, we recommend applying a complete regression analysis. The current uncertainty regarding the influence of extracerebral tissue remains a hurdle in the clinical implementation of NIRS for intraoperative monitoring. The protocol was pre-registered in PROSPERO (CRD42020199053).

Neuropathology II: diseases of the central and peripheral nervous systems : Outlook on new techniques in electron microscopy

In the diagnosis of diseases of the central and peripheral nervous systems, the use of electron microscopic analyses has become rare these days. However, there are questions in which the method is helpful in confirming the etiopathogenesis of the disease. Hereditary neurodegenerative and metabolic diseases, such as the lysosomal storage disease neuronal ceroid lipofuscinosis, are associated with pathognomonic storage products not only in the central nervous system (CNS) but also in extracerebral tissues such as sweat glands and lymphocytes. These tissues are easily accessible and thus function as "windows to the CNS". In addition, there are new methods that overcome limitations of conventional electron microscopy and may improve ultrastructural diagnostics. This is particularly important for the correct classification of viral particles such as SARS-CoV‑2, leading to abetter understanding of COVID19-associated diseases in the CNS and peripheral nervous system.

Alpha-Synuclein species in oral mucosa as potential biomarkers for multiple system atrophy.

BackgroundThe definitive diagnosis of Multiple system atrophy (MSA) requires the evidence of abnormal deposition of α-Synuclein (α-Syn) through brain pathology which is unable to achieve in vivo. Deposition of α-Syn is not limited to the central nervous system (CNS), but also extended to peripheral tissues. Detection of pathological α-Syn deposition in extracerebral tissues also contributes to the diagnosis of MSA. We recently reported the increased expressions of α-Syn, phosphorylated α-Synuclein at Ser129 (pS129), and α-Syn aggregates in oral mucosal cells of Parkinson’s disease (PD), which serve as potential biomarkers for PD. To date, little is known about the α-Syn expression pattern in oral mucosa of MSA which is also a synucleinopathy. Here, we intend to investigate whether abnormal α-Syn deposition occurs in oral mucosal cells of MSA, and to determine whether α-Syn, pS129, and α-Syn aggregates in oral mucosa are potential biomarkers for MSA.MethodsThe oral mucosal cells were collected by using cytobrush from 42 MSA patients (23 MSA-P and 19 MSA-C) and 47 age-matched healthy controls (HCs). Immunofluorescence analysis was used to investigate the presence of α-Syn, pS129, and α-Syn aggregates in the oral mucosal cells. Then, the concentrations of α-Syn species in oral mucosa samples were measured using electrochemiluminescence assays.ResultsImmunofluorescence images indicated elevated α-Syn, pS129, and α-Syn aggregates levels in oral mucosal cells of MSA than HCs. The concentrations of three α-Syn species were significantly higher in oral mucosal cells of MSA than HCs (α-Syn, p < 0.001; pS129, p = 0.042; α-Syn aggregates, p < 0.0001). In MSA patients, the oral mucosa α-Syn levels negatively correlated with disease duration (r = −0.398, p = 0.009). The area under curve (AUC) of receiver operating characteristic (ROC) analysis using an integrative model including age, gender, α-Syn, pS129, and α-Syn aggregates for MSA diagnosis was 0.825, with 73.8% sensitivity and 78.7% specificity.ConclusionThe α-Syn levels in oral mucosal cells elevated in patients with MSA, which may be promising biomarkers for MSA.

Assessing the Sensitivity of Multi-Distance Hyperspectral NIRS to Changes in the Oxidation State of Cytochrome C Oxidase in the Brain.

Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO2) are frequently used during vascular and cardiac surgeries as a non-invasive means of assessing brain health; however, signal contamination from extracerebral tissues remains a concern. As an alternative, hyperspectral (hs)NIRS can be used to measure changes in the oxidation state of cytochrome c oxidase (ΔoxCCO), which provides greater sensitivity to the brain given its higher mitochondrial concentration versus the scalp. The purpose of this study was to evaluate the depth sensitivity of the oxCCO signal to changes occurring in the brain and extracerebral tissue components. The oxCCO assessment was conducted using multi-distance hsNIRS (source-detector separations = 1 and 3 cm), and metabolic changes were compared to changes in StO2. Ten participants were monitored using an in-house system combining hsNIRS and diffuse correlation spectroscopy (DCS). Data were acquired during carotid compression (CC) to reduce blood flow and hypercapnia to increase flow. Reducing blood flow by CC resulted in a significant decrease in oxCCO measured at rSD = 3 cm but not at 1 cm. In contrast, significant changes in StO2 were found at both distances. Hypercapnia caused significant increases in StO2 and oxCCO at rSD = 3 cm, but not at 1 cm. Extracerebral contamination resulted in elevated StO2 but not oxCCO after hypercapnia, which was significantly reduced by applying regression analysis. This study demonstrated that oxCCO was less sensitive to extracerebral signals than StO2.

BEAN: Brain Extraction and Alignment Network for 3D Fetal Neurosonography

Brain extraction (masking of extra-cerebral tissues) and alignment are fundamental first steps of most neuroimage analysis pipelines. The lack of automated solutions for 3D ultrasound (US) has therefore limited its potential as a neuroimaging modality for studying fetal brain development using routinely acquired scans. In this work, we propose a convolutional neural network (CNN) that accurately and consistently aligns and extracts the fetal brain from minimally pre-processed 3D US scans. Our multi-task CNN, Brain Extraction and Alignment Network (BEAN), consists of two independent branches: 1) a fully-convolutional encoder-decoder branch for brain extraction of unaligned scans, and 2) a two-step regression-based branch for similarity alignment of the brain to a common coordinate space. BEAN was tested on 356 fetal head 3D scans spanning the gestational range of 14 to 30 weeks, significantly outperforming all current alternatives for fetal brain extraction and alignment. BEAN achieved state-of-the-art performance for both tasks, with a mean Dice Similarity Coefficient (DSC) of 0.94 for the brain extraction masks, and a mean DSC of 0.93 for the alignment of the target brain masks. The presented experimental results show that brain structures such as the thalamus, choroid plexus, cavum septum pellucidum, and Sylvian fissure, are consistently aligned throughout the dataset and remain clearly visible when the scans are averaged together. The BEAN implementation and related code can be found under www.github.com/felipemoser/kelluwen.

Assessment by Multi‐Distance Hyperspectral NIRS of Changes in the Oxidation State of Cytochrome C Oxidase (oxCCO) to Carotid Artery Compressions

IntroductionThe occlusion of the common carotid artery (CCA) during carotid endarterectomy (CEA) is associated with a risk of cerebral ischemia due to inadequate collateral blood flow1. By monitoring tissue oxygen saturation (StO2), near‐infrared spectroscopy (NIRS) is frequently employed during CEA2 to determine sufficient oxygen delivery. However, StO2 is only a proxy of oxygen metabolism and an unreliable marker of ischemic injury. In contrast, cytochrome c oxidase (oxCCO) is an enzyme in the mitochondrial electron transport chain and therefore a specific marker of aerobic metabolism3. Thus, the aim of this study was to assess the ability of a multi‐distance hyperspectral (hs) NIRS to monitor changes in StO2 and oxCCO during CCA compressions in healthy participants. We hypothesized that changes in oxCCO concentration would be greater in the brain (i.e., long source‐detector distance, SDD) than in the extracerebral tissue (i.e., short SDD), and this difference would be larger than that of StO2.MethodsWe modified an in‐house built hsNIRS4 to include a second channel for acquiring data at two SDD (1 and 3 cm) to detect potential changes in the extracerebral tissue. Data from 10 young, healthy participants was acquired continuously during one 30‐second unilateral digital CCA compression, performed ipsilateral to the location of the optic probes. In addition, cerebral blood flow index was determined using diffuse correlation spectroscopy and mean arterial blood pressure by finger photoplethysmography.ResultsDuring CCA compression, the change in oxCCO at 3 cm vs. 1 cm (0.4 ± 0.3 µM vs. 0.06 ± 0.1 µM, p = 0.027) was approximately 50% greater than the change in StO2 at 3 cm vs. 1cm (‐4.0 ± 2.2% vs. 1.2 ± 0.7% p = 0.007). The corresponding decrease in cerebral blood flow was 57 ± 14% (p &lt; 0.001 vs. baseline). Mean arterial blood pressure increased 4 ± 1 mmHg (p &lt; 0.001 vs. baseline).DiscussionA larger difference between the two distances was observed for oxCCO than StO2, likely due to the greater concentration of mitochondria in the brain compared to extracerebral tissues. Collecting multi‐distance hsNIRS demonstrated the enhanced sensitivity of oxCCO to the brain. Lastly, this study demonstrates the utility of momentary unilateral CCA compressions as a fast, easy, and strong perturbation for transiently altering cerebral inflow and metabolism.References(1) Aceto, Eur. J. Anestesiol.(2020); (2) Yu, Cochrane Database Syst. Rev.(2014); (3) Bale, J. Biomed. Opt. (2020); (4) Rajaram, Brain Sci (2020).

The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery

Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood.We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdhki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC.A significant increase of plasmatic ammonium concentrations was found in Gcdhki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdhki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdhki/ki rats, but not in WT rats. It seems that Gcdhki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdhki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdhki/ki rats showed imbalance of intra- and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation.We successfully created the first rat model for GA-I. Characterization of this Gcdhki/ki strain confirmed that it is a suitable model not only for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.

Physiological relevance of the neuronal isoform of inositol-1,4,5-trisphosphate 3-kinases in mice

Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is the neuronal isoform of ITPKs and exhibits both actin bundling and InsP3kinase activity. In addition to neurons, ITPKA is ectopically expressed in tumor cells, where its oncogenic activity increases tumor cell malignancy. In order to analyze the physiological relevance of ITPKA, here we performed a broad phenotypic screening of itpka deficient mice. Our data show that among the neurobehavioral tests analyzed, itpka deficient mice reacted faster to a hotplate, prepulse inhibition was impaired and the accelerating rotarod test showed decreased latency of itpka deficient mice to fall. These data indicate that ITPKA is involved in the regulation of nociceptive pathways, sensorimotor gating and motor learning. Analysis of extracerebral functions in control and itpka deficient mice revealed significantly reduced glucose, lactate, and triglyceride plasma concentrations in itpka deficient mice. Based on this finding, expression of ITPKA was analyzed in extracerebral tissues and the highest level was found in the small intestine. However, functional studies on CaCo-2 control and ITPKA depleted cells showed that glucose, as well as triglyceride uptake, were not significantly different between the cell lines. Altogether, these data show that ITPKA exhibits distinct functions in the central nervous system and reveal an involvement of ITPKA in energy metabolism.

Transcranial photobiomodulation with near-infrared light from childhood to elderliness: simulation of dosimetry.

.Significance: Major depressive disorder (MDD) affects over 40 million U.S. adults in their lifetime. Transcranial photobiomodulation (t-PBM) has been shown to be effective in treating MDD, but the current treatment dosage does not account for head and brain anatomical changes due to aging.Aim: We study effective t-PBM dosage and its variations across age groups using state-of-the-art Monte Carlo simulations and age-dependent brain atlases ranging between 5 and 85 years of age.Approach: Age-dependent brain models are derived from 18 MRI brain atlases. Two extracranial source positions, F3–F4 and Fp1–Fpz–Fp2 in the EEG 10–20 system, are simulated at five selected wavelengths and energy depositions at two MDD-relevant cortical regions—dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC)—are quantified.Results: An overall decrease of energy deposition was found with increasing age. A strong negative correlation between the thickness of extracerebral tissues (ECT) and energy deposition was observed, suggesting that increasing ECT thickness over age is primarily responsible for reduced energy delivery. The F3–F4 position appears to be more efficient in reaching dlPFC compared to treating vmPFC via the Fp1–Fpz–Fp2 position.Conclusions: Quantitative simulations revealed age-dependent light delivery across the lifespan of human brains, suggesting the need for personalized and age-adaptive t-PBM treatment planning.

Limitation of Near Infrared Spectroscopy Cerebral Oximetry in Predicting Neurologic Intolerance during Carotid Artery Stenting with Proximal Protection

AbstractProximal balloon occlusion prior to carotid artery stenting is considered a relatively safe practice during endovascular treatment of carotid artery stenosis. Transient neurological deterioration affecting the ipsilateral hemisphere is seen soon after balloon inflation, when placed proximal to the stenotic segment. This occurs in cases of bilateral carotid disease due to insufficient collateral blood flow from the contralateral side. Near infrared spectroscopy cerebral oximetry (NIRS) is a valuable tool in detecting hypoperfusion- induced cerebral tissue desaturation (rSO2) during these procedures. This helps the interventional radiologist to deflate the balloon at the earliest to re-establish the cerebral blood flow. The non-invasive nature and continuous real-time interpretation make NIRS an attractive adjunct in the neuroanesthesiolgist's armamentarium for monitoring cerebral ischemia. However, significant contribution from chromophores in the extra-cerebral tissues and external carotid artery circulation can limit its sensitivity during occlusion of the internal carotid artery. In our case, it did not reflect brain ischemia during hypotension and when the neurologic symptoms were obvious. Commonly available cerebral oximetry sensors placed over the frontal region do not cover the parietal lobe where ischemia is likely to occur during occlusion of the carotid artery. In such scenarios, it has been shown that multi-channel NIRS has a better sensitivity in detecting cerebral ischemia. This case report highlights the importance of frequent neurological examination during carotid stenting as rSO2 values might not always suggest cerebral ischemia.

Cerebral oximetry performance testing with a 3D-printed vascular array phantom.

Cerebral oximetry based on near-infrared spectroscopy represents a unique noninvasive tool for real-time surgical monitoring, yet studies have shown a significant discrepancy in accuracy among commercial systems. Towards the establishment of a standardized method for performance testing, we have studied a solid phantom approach - based on a 3D-printed cerebrovascular module (CVM) incorporating an array of 148 cylindrical channels - that has several advantages over liquid phantoms. Development and characterization of a CVM prototype are described, including high-resolution imaging and spectrophotometry measurements. The CVM was filled with whole bovine blood tuned over an oxygen saturation range of 30-90% and molded-silicone layers simulating extracerebral tissues were used to evaluate penetration depth. Saturation measurement accuracy was assessed in two commercially-available clinical cerebral oximeters. For one oximeter, both neonatal and pediatric sensors showed a high degree of precision, whereas accuracy was strongly dependent on saturation level and extracerebral geometry. The second oximeter showed worse precision, yet greater robustness to variations in extracerebral layers. These results indicate that 3D-printed channel array phantoms represent a promising new approach for standardized testing of clinical oximeters.

Clinical Brain Monitoring with Time Domain NIRS: A Review and Future Perspectives

Near-infrared spectroscopy (NIRS) is an optical technique that can measure brain tissue oxygenation and haemodynamics in real-time and at the patient bedside allowing medical doctors to access important physiological information. However, despite this, the use of NIRS in a clinical environment is hindered due to limitations, such as poor reproducibility, lack of depth sensitivity and poor brain-specificity. Time domain NIRS (or TD-NIRS) can resolve these issues and offer detailed information of the optical properties of the tissue, allowing better physiological information to be retrieved. This is achieved at the cost of increased instrument complexity, operation complexity and price. In this review, we focus on brain monitoring clinical applications of TD-NIRS. A total of 52 publications were identified, spanning the fields of neonatal imaging, stroke assessment, traumatic brain injury (TBI) assessment, brain death assessment, psychiatry, peroperative care, neuronal disorders assessment and communication with patient with locked-in syndrome. In all the publications, the advantages of the TD-NIRS measurement to (1) extract absolute values of haemoglobin concentration and tissue oxygen saturation, (2) assess the reduced scattering coefficient, and (3) separate between extra-cerebral and cerebral tissues, are highlighted; and emphasize the utility of TD-NIRS in a clinical context. In the last sections of this review, we explore the recent developments of TD-NIRS, in terms of instrumentation and methodologies that might impact and broaden its use in the hospital.

Effects of Valproic Acid on Cerebral Nutrient Carriers' Expression in the Rat.

Objective: The antiepileptic drug valproate has been shown to affect the expression of carriers for essential compounds and drugs in extracerebral tissues. The aim of the current study was to evaluate in vivo the effect of valproate treatment on the cerebral expression of carriers and selected genes of the blood-brain barrier (BBB) in the rat.Methods: Male Wistar rats were treated daily for 7 days by intraperitoneal injections of valproate (75, 150, or 300 mg/kg/day) or the vehicle. mRNA was isolated from the cerebral cortex and the hippocampus. Transcript levels of 37 genes were measured using a customized gene expression assay. Quantitative histone acetylation was evaluated by western blotting. Glucose6-phosphate (G6P) tissue levels were used as a surrogate of cerebral glucose concentrations.Results: Valproate treatment was associated with significant reduction (up to 22%; P < 0.05) in cortical and hippocampal claudin 5-normalized Slc2a1 (Glut1) mRNA expression. G6P levels were not significantly altered, but were correlated with Slc2a1 transcript levels (r = 0.499; P < 0.02). None of the other 36 screened genes were significantly affected by valproate. Cortical histone hyperacetylation indicated cerebral activity of valproate on a major pathway regulating gene expression (P < 0.02).Significance: The effect of valproate on nutrient carriers appears to be tissue-specific and even brain area-specific. If validated in humans, the changes in Glut1 expression might have clinical implications in positron emission tomography (PET) imaging. Further studies are required for elucidating the relevance of these findings to the clinic.

Multiwavelength time-resolved near-infrared spectroscopy of the adult head: assessment of intracerebral and extracerebral absorption changes.

An optical technique based on diffuse reflectance measurement combined with indocyanine green (ICG) bolus tracking is extensively tested as a method for the clinical assessment of brain perfusion at the bedside. We report on multiwavelength time-resolved diffuse reflectance spectroscopy measurements carried out on the head of a healthy adult during the intravenous administration of a bolus of ICG. Intracerebral and extracerebral changes in absorption were estimated from an analysis of changes in statistical moments (total number of photons, mean time of flight and variance) of the distributions of times of flight (DTOF) of photons recorded simultaneously at 16 wavelengths from the range of 650-850 nm using sensitivity factors estimated by diffusion approximation based on a layered model of the studied medium. We validated the proposed method in a series of phantom experiments and in-vivo measurements. The results obtained show that changes in the concentration of the ICG can be assessed as a function of time of the experiment and depth in the tissue. Thus, the separation of changes in ICG concentration appearing in intra- and extracerebral tissues can be estimated from optical data acquired at a single source-detector pair of fibers/fiber bundles positioned on the surface of the head.

On the importance of albumin binding for the flux of 7α-hydroxy-3-oxo-4-cholestenoic acid in the brain

We confirmed previous findings by a Japanese group that there is an accumulation of 7α-hydroxy-3-oxo-4-cholestenoic acid (7-Hoca) in human subdural hematomas. The accumulation correlated with the time from the bleeding to the sample collection. We present evidence that these accumulations are likely to be caused by the strong affinity of 7-Hoca to albumin and the marked difference between plasma and brain with respect to levels of albumin. In the circulation, 80-90% of 7-Hoca is bound to albumin with a ratio between the steroid acid and albumin of ∼1.4 ng/mg. In cerebrospinal fluid (CSF), the ratio between 7-Hoca and albumin is ∼30 ng/mg. When albumin or hemolyzed blood in a dialysis bag was exposed to CSF, there was a flux of 7-Hoca from CSF to the albumin. We suggest that the major explanation for accumulation of 7-Hoca in subdural hematoma is a flux from the brain into the hematoma due to the high affinity to albumin and the high capacity of 7-Hoca to pass biomembranes. We discuss the possibility that the markedly different ratios between 7-Hoca and albumin in circulation and brain can explain the flux of 7-Hoca from the brain into circulation against a concentration gradient.

Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission.

More than 30 proteins form amyloid in humans, most of them outside of the brain. Deposition of amyloid in extracerebral tissues is very common and seems inevitable for an aging person. Most deposits are localized, small, and probably without consequence, but in some instances, they are associated with diseases such as type 2 diabetes. Other extracerebral amyloidoses are systemic, with life-threatening effects on the heart, kidneys, and other organs. Here, we review how amyloid may spread through seeding and whether transmission of amyloid diseases may occur between humans. We also discuss whether cross-seeding is important in the development of amyloidosis, focusing specifically on the amyloid proteins AA, transthyretin, and islet amyloid polypeptide (IAPP).

Reciprocal Control of Thyroid Binding and the Pipecolate Pathway in the Brain.

Thyroid hormones have long been known to play an essential role in brain growth and development, with cytoplasmic thyroid hormone binding proteins (THBPs) playing a critical role in thyroid hormone bioavailability. A major mammalian THBP is μ-crystallin (CRYM), which was originally characterized by its ability to strongly bind thyroid hormones in an NADPH-dependent fashion. However, in 2011 it was discovered that CRYM is also an enzyme, namely ketimine reductase (KR), which catalyzes the NAD(P)H-dependent reduction of -C=N- (imine) double bonds of a number of cyclic ketimine substrates including sulfur-containing cyclic ketimines. The enzyme activity was also shown to be potently inhibited by thyroid hormones, thus suggesting a novel reciprocal relationship between enzyme catalysis and thyroid hormone bioavailability. KR is involved in a number of amino acid metabolic pathways. However, the best documented biological function of KR is its role as a ∆1-piperideine-2-carboxylate (P2C) reductase in the pipecolate pathway of lysine metabolism. The pipecolate pathway is the main L-lysine degradation pathway in the adult brain, whereas the saccharopine pathway predominates in extracerebral tissues and in infant brain, suggesting that KR has evolved to perform specific and important roles in neural development and function. The potent regulation of KR activity by thyroid hormones adds further weight to this suggestion. KR is also involved in L-ornithine/L-glutamate/L-proline metabolism as well as sulfur-containing amino acid metabolism. This review describes the pipecolate pathway and recent discoveries related to mammalian KR function, which have important implications in normal and pathological brain functions.

Mitochondrial Respiratory Function in Peripheral Blood Cells from Huntington's Disease Patients.

Patients with Huntington's disease display symptoms from both the central nervous system and peripheral tissues. Mitochondrial dysfunction has been implicated as part of the pathogenesis of the disease and has been reported in brain tissue and extracerebral tissues, such as muscle and blood cells, but the results are inconsistent. Therefore, the authors performed a refined evaluation of mitochondrial function in 2 types of peripheral blood cells from 14 patients with Huntington's disease and 21 control subjects. Several hypotheses were predefined, including impaired mitochondrial complex II function (primary), complex I function (secondary), and maximum oxidative phosphorylation capacity (secondary) in patient cells. High-resolution respirometry was applied to viable platelets and mononuclear cells. Data were normalized to cell counts, citrate synthase activity, and mitochondrial DNA copy numbers. Normalized to citrate synthase activity, platelets from patients with Huntington's disease displayed respiratory dysfunction linked to complex I, complex II, and lower maximum oxidative phosphorylation capacity. No difference was seen in mononuclear cells or when platelet data were normalized to cell counts or mitochondrial DNA. The ratio of complex I respiration through maximum oxidative phosphorylation was significantly decreased in patients compared with controls. The corresponding ratio for complex II was unaffected. The data indicate decreased function of mitochondrial complex I in peripheral blood cells from patients with Huntington's disease, although this could not be uniformly confirmed. The results do not confirm a systemic complex II dysfunction and do not currently support the use of mitochondrial function in blood cells as a biomarker for the disease.