Cerebral Content Research Articles

Cortical N-acetylaspartate concentrations are impacted in chronic stroke but do not relate to motor impairment: A magnetic resonance spectroscopy study.

Magnetic resonance spectroscopy (MRS) measures cerebral metabolite concentrations, which can inform our understanding of the neurobiological processes associated with stroke recovery. Here, we investigated whether metabolite concentrations in primary motor and somatosensory cortices (sensorimotor cortex) are impacted by stroke and relate to upper‐extremity motor impairment in 45 individuals with chronic stroke. Cerebral metabolite estimates were adjusted for cerebrospinal fluid and brain tissue composition in the MRS voxel. Upper‐extremity motor impairment was indexed with the Fugl‐Meyer (FM) scale. N‐acetylaspartate (NAA) concentration was reduced bilaterally in stroke participants with right hemisphere lesions (n = 23), relative to right‐handed healthy older adults (n = 15; p = .006). Within the entire stroke sample (n = 45) NAA and glutamate/glutamine (GLX) were lower in the ipsilesional sensorimotor cortex, relative to the contralesional cortex (NAA: p < .001; GLX: p = .003). Lower ipsilesional NAA was related to greater extent of corticospinal tract (CST) injury, quantified by a weighted CST lesion load (p = .006). Cortical NAA and GLX concentrations did not relate to the severity of chronic upper‐extremity impairment (p > .05), including after a sensitivity analysis imputing missing metabolite data for individuals with large cortical lesions (n = 5). Our results suggest that NAA, a marker of neuronal integrity, is sensitive to stroke‐related cortical damage and may provide mechanistic insights into cellular processes of cortical adaptation to stroke. However, cortical MRS metabolites may have limited clinical utility as prospective biomarkers of upper‐extremity outcomes in chronic stroke.

252 Non-Invasive Quantification of Human Brain Lactate Concentrations Across Sleep-Wake Cycles

Abstract Introduction Cellular mechanisms underlying changes in small animal brain lactate concentrations have been investigated for more than 70 years and report sharp reductions in lactate (12-35%) during sleep or anesthesia relative to wakefulness. The goal of this study was to investigate alterations in human cerebral lactate concentrations across sleep-wake cycles. Toward this goal, we developed a novel non-invasive methodology, quantified changes in human cerebral lactate during sleep stages, and investigated potential mechanisms associated with changes in lactate. Methods Nine subjects (four females, five males; 21-27 y-o, mean age 24.2 ±2) were sleep deprived overnight, and underwent (5:45~11:00 am) experiments combining simultaneous MR-spectroscopy (MRS) and polysomnography (PSG) in a 3 T MR instrument using a 64-channel head/neck coil. A single voxel MRS (1H-MRS) acquired signals from a volume of interest (12~24 cm3) for every 7.5-s for 88~180-min. Lactate signal intensity was determined from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epochs. Artifact corrected PSG data were scored for each 30-s epoch using the standard criteria and classified into one of four stages: W, N1, N2 and N3. Group mean lactate levels were quantified using LCModel. Three subjects returned for lactate diffusivity measurements using diffusion-sensitized PRESS MRS sequence. Results Compared to W, group mean lactate levels within each sleep stage showed a reduction of [4.9 ± 4.9] % in N1, [10.4 ± 5.2] % in N2, and [24.0 ± 5.8] % in N3. We observed a significant decrease in lactate apparent diffusion coefficient (ADC) accompanied by reduced brain lactate in sleep compared to wake (P&amp;lt;0.002). There were no differences in ADC values between wake and sleep for H2O, NAA, tCr, or Cho. Conclusion This is the first in-vivo report of alterations in human brain lactate concentrations across sleep-wake cycles. Observed decline in lactate levels during sleep compared to wakefulness is consistent with, and extends results from invasive small animal brain studies first reported more than 70 years ago, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain. Support (if any) The Paul. G. Allen Family Foundation funded the study.

Inverse correlation of fluctuations of cerebral blood and water concentrations in humans

Near-infrared spectroscopy (fNIRS) measures concentrations of oxygenated (HbO) and deoxygenated (HbR) hemoglobin in the brain. Recently, we demonstrated its potential also for measuring concentrations of cerebral water (hbox {cH}_{2}hbox {O}). We performed fNIRS measurements during rest to study fluctuations in concentrations of hbox {cH}_{2}hbox {O}, HbO and HbR in 33 well-rested healthy control subjects (HC) and 18 acutely sleep-deprived HC. Resting-state fNIRS signal was filtered in full-band, cardiac, respiratory, low-, and very-low-frequency bands. The sum of HbO and HbR constitutes the regional cerebral blood volume (CBV). CBV and hbox {cH}_{2}hbox {O} concentrations were analyzed via temporal correlation and phase synchrony. Fluctuation in concentrations of hbox {cH}_{2}hbox {O} and CBV was strongly anti-correlated across all frequency bands in both frontal and parietal cortices. Fluctuation in concentrations of {hbox {cH}}_{2}{hbox {O}} and CBV showed neither a completely synchronous nor a random phase relationship in both frontal and parietal cortices. Acutely sleep-deprived subjects did not show significant differences in temporal correlation or phase synchrony between fluctuations in {hbox {cH}}_{2}{hbox {O}} and CBV concentrations compared with well-rested HC. The reciprocal interrelation between fluctuations in CBV and {hbox {cH}}_{2}{hbox {O}} concentrations is consistent with the Munro–Kellie doctrine of constant intracranial volume. This coupling may constitute a functional mechanism underlying glymphatic circulation, which persists despite acutely disturbed sleep patterns.

Concentrations of estradiol, progesterone and testosterone in serum and cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage correlate weakly with transcranial Doppler flow velocities

BackgroundThe implication of the steroids estradiol, progesterone and testosterone in cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) has not been comprehensively assessed. In rodents, studies suggested beneficial effects of steroids on cerebral vasospasm after experimental SAH. Studies in humans are warranted, however, a general dilemma of human studies on neuroactive substances is that the brain is not directly accessible and that concentrations in the periphery may not adequately parallel concentrations in the central compartments. In the present study, concentrations of estradiol, progesterone and testosterone in serum and cerebrospinal fluid (CSF) of patients with aSAH were determined. Blood flow velocities in cerebral arteries were measured by transcranial Doppler sonography (TCD). The aim of this study was to evaluate the correlations between the cerebral blood flow velocities and levels of estradiol, progesterone and testosterone in CSF and serum.ResultsSamples of serum and CSF of 42 patients with aSAH were collected concomitantly daily or every other day via the arterial line and the external ventricular drainage for two weeks after the hemorrhage. Blood flow velocities in the cerebral arteries were determined by TCD. Total estradiol, progesterone and testosterone concentrations were measured by electro-chemiluminescence immunoassay. The strength of correlation was assessed by Spearman’s rank correlation coefficient. The correlation analysis revealed very weak correlations between cerebral blood flow velocities and concentrations of estradiol, progesterone and testosterone levels in both compartments with correlation coefficients below 0.2.ConclusionsIn humans with aSAH, merely very weak correlations between flow velocities in cerebral arteries and concentrations of estradiol, progesterone and testosterone in serum and CSF were demonstrated. These results suggest a limited influence of the respective steroids on cerebral vascular tone although vasodilatory effects were described in rodent studies. Thus, the implication of steroids in processes of neurological deterioration warrants further clarification.

Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging

Detecting Alzheimer's disease (AD) at an early stage brings a lot of benefits including disease management and actions to slow the progression of the disease. Here, we demonstrate that reduced creatine chemical exchange saturation transfer (CrCEST) contrast has the potential to serve as a new biomarker for early detection of AD. The results on wild type (WT) mice and two age-matched AD models, namely tauopathy (Tau) and Aβ amyloidosis (APP), indicated that CrCEST contrasts of the cortex and corpus callosum in the APP and Tau mice were significantly reduced compared to WT counterpart at an early stage (6-7 months) (p < 0.011). Two main causes of the reduced CrCEST contrast, i.e. cerebral pH and creatine concentration, were investigated. From phantom and hypercapnia experiments, CrCEST showed excellent sensitivity to pH variations. From MRS results, the creatine concentration in WT and AD mouse brain was equivalent, which suggests that the reduced CrCEST contrast was dominated by cerebral pH change involved in the progression of AD. Immunohistochemical analysis revealed that the abnormal cerebral pH in AD mice may relate to neuroinflammation, a known factor that can cause pH reduction.

Passive immunotherapy with a novel antibody against 3pE-modified Aβ demonstrates potential for enhanced efficacy and favorable safety in combination with BACE inhibitor treatment in plaque-depositing mice

The imbalance between production and clearance of amyloid β (Aβ) peptides and their resulting accumulation in the brain is an early and crucial step in the pathogenesis of Alzheimer's disease (AD). Therefore, Aβ is strongly positioned as a promising and extensively validated therapeutic target for AD. Investigational disease-modifying approaches aiming at reducing cerebral Aβ concentrations include prevention of de novo production of Aβ through inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and clearance of Aβ deposits via passive Aβ immunotherapy.We have developed a novel, high affinity antibody against Aβ peptides bearing a pyroglutamate residue at amino acid position 3 (3pE), an Aβ species abundantly present in plaque deposits in AD brains. Here, we describe the preclinical characterization of this antibody, and demonstrate a significant reduction in amyloid burden in the absence of microhemorrhages in different mouse models with established plaque deposition. Moreover, we combined antibody treatment with chronic BACE1 inhibitor treatment and demonstrate significant clearance of pre-existing amyloid deposits in transgenic mouse brain, without induction of microhemorrhages and other histopathological findings. Together, these data confirm significant potential for the 3pE-specific antibody to be developed as a passive immunotherapy approach that balances efficacy and safety. Moreover, our studies suggest further enhanced treatment efficacy and favorable safety after combination of the 3pE-specific antibody with BACE1 inhibitor treatment.

Cadmium induced cerebral toxicity via modulating MTF1-MTs regulatory axis

Metal-responsive transcription factor 1 (MTF1) participates in redox homeostasis and heavy metals detoxification via regulating the expression of metal responsive genes. However, the exact role of MTF1 in Cd-induced cerebral toxicity remains unclear. Herein, we explored the mechanism of Cd-elicited cerebral toxicity through modulating MTF1/MTs pathway in chicken cerebrum exposed to different concentrations of Cd (35 mg, 70 mg, and 140 mg/kg CdCl2) via diet. Notably, cerebral tissues showed varying degrees of microstructural changes under Cd exposure. Cd exposure significantly up-regulated the expression of metal transporters (DMT1, ZIP8, and ZIP10) with concomitant elevated Cd level, as determined by ICP-MS. Cd significantly altered other cerebral biometals concentrations (particularly, Zn, Fe, Se, Cr, Mo, and Pb) and redox balance, resulting in increased cerebral oxidative stress. More importantly, Cd exposure suppressed MTF1 mRNA and nuclear protein levels and its target metal-responsive genes, notably metallothioneins (MT1 and MT2), and Fe and Cu transporter genes (FPN1, ATOX1, and XIAP). Moreover, Cd disrupted the regulation of expression of selenoproteome (particularly, GPxs and SelW), and cerebral Se level. Overall, our data revealed that molecular mechanisms associated with Cd-induced cerebral damage might include over-expression of DMT1, ZIP8 and ZIP10, and suppression of MTF1 and its main target metal-responsive genes as well as several selenoproteins.

Pregabalin Treatment does not Affect Amyloid Pathology in 5XFAD Mice.

Background:Calcium dysregulation has been proposed to play a causative role in the development of Alzheimer’s disease pathology. Pregabalin is a compound already approved for human use, marketed as the prescription drug Lyrica. It binds the α2-δ subunit of P/Q-type voltage-gated calcium channels, lowering calcium influx and providing effective treatment for epilepsy and neuropathic pain.Objective:We hypothesize that increased resting calcium in neuronal processes near amyloid plaques plays a role in the development of neuritic dystrophies and further progression of amyloid pathology.Methods:5XFAD mice were treated orally for 12 weeks with pregabalin, then immunoblotting and immunofluorescent imaging were used to quantify neuritic dystrophy and amyloid deposition in pregabalin compared to placebo-treated mice.Results:The treatment did not decrease markers of neuritic dystrophy or amyloid deposition. The image analysis of neuritic dystrophy on a plaque-by-plaque basis showed a small non-significant increase in the relative proportion of LAMP1 to Aβ42 in plaques with areas of 50-450 μm2 in the cortex of pregabalin-treated mice. In addition, there was a statistically significant positive correlation between the measured cerebral concentration of pregabalin and the relative levels of BACE1 and Aβ in the cortex. This relationship was not observed in the hippocampus, and there was no increase in average Aβ levels in pregabalin treated mice compared to placebo. We confirmed previous findings that smaller amyloid plaques are associated with a greater degree of neuritic dystrophy.Conclusion:Pregabalin may have an effect on Aβ that merits further investigation, but our study does not suggest that pregabalin contributes substantially to amyloid pathology.

Heat transfer, physiological responses, and subjective perceptions during short contact time with wood or other materials

This study investigates the physiological responses and subjective perceptions of touching wood. In particular, it focuses on their respective relationships with the amount of heat transfer across the hand–material interface during contact. The study participants included 55 university students (20 females and 35 males) who gave written informed consent. The participants’ blood pressure, pulse rate, and cerebral blood hemoglobin concentrations were measured continuously for 90 s while they gently held vertical bar-shaped specimens of Japanese cypress (Chamaecyparis obtusa), Japanese oak (Quercus crispula), polyethylene, and aluminum. The specimens also included wood with a surface coating. We measured subjective warmth and comfort as well as the heat flux between the palm and the surface of the material. The wooden materials were rated as significantly warmer compared to aluminum and polyethylene, regardless of the wood species (cypress or oak) or its coating; this result corresponds with smaller heat transfers in the wooden materials. Additionally, the wooden materials were more comfortable to hold as compared to the aluminum bar. Based on the changes in blood pressure, touching Japanese cypress and uncoated Japanese oak were interpreted to induce less physiological stress. Therefore, we can conclude that wood, with lower thermal conductivity, feels warm, and it causes relatively smaller physiological changes compared to other materials with higher thermal conductivity. Thus, they may present less physiological burdens when touched.

DDRE-31. FEASIBILITY AND BIOLOGIC ACTIVITY OF A KETOGENIC / INTERMITTENT FASTING DIET IN GLIOMA PATIENTS

BACKGROUNDThere has been increasing interest in exploring ketogenic diet therapies (KDT) in patients with glioma given the poor prognosis. The purpose of this single-arm, open label phase 2 study was to rigorously examine the feasibility, safety, systemic biological activity, and cerebral activity of a KDT in patients with glioma.METHODS25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories<20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8.RESULTS21 patients completed the study. 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Higher total choline (tCho) and glutamine (Gln) levels were observed in lesional as compared to contralateral brain at baseline, and both decreased following intervention. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs0.52, p=0.05). There were no differences in cerebral metabolites in IDH-mutant glioma after controlling for ketonuria.CONCLUSIONSThe GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Participant ketonuria correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.

Serum biomarkers and cerebral autoregulation as early warnings of delayed cerebral ischemia risk in patients after aneurysmal subarachnoid haemorrhage

BackgroundIdentifying patients at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) remains challenging. This study aimed to evaluate the concentration of serum biomarkers along with cerebral autoregulation impairment on DCI. Methods55 patients suffering from aSAH were enrolled in the study. Serum S100protein B (S100B) was tested both on the day of admission and over three consecutive days following the occurrence of aSAH. Cerebral autoregulation was assessed using a tissue oxygenation index (TOxa) based on near-infrared spectroscopy. ResultsChanges in serum S100B levels interacted with DCI status (presence vs. absence): F = 3.84, p = 0.016. Patients with DCI had higher S100B concentration level on day 3 than those without DCI (3.54 ± 0.50 ng/ml vs. 0.58 ± 0.43 ng/ml, p = 0.001). S100B concentration on day 3 following aSAH predicted DCI (AUC = 0.77, p = 0.006). Raised level of serum S100B on day 3 was related with higher TOxa, thus with impaired cerebral autoregulation (rS = 0.52,p = 0.031). Multivariate logistic regression analysis showed thatimpaired cerebral autoregulation andelevatedS100B concentration on day 3 increasethe likelihood of DCI. ConclusionsTracking changes in the serum biomarkers concentration along with monitoring of cerebral autoregulation, may play a role in early detection of patients at risk of DCI after aSAH. These results need to be validated in larger prospective cohorts.

Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke

Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke

Minute changes of cerebral parenchymal non-contrast computed tomography attenuation reflect cerebral volume alterations of blood.

Non-infarcted acute cerebral ischaemic areas appear hypo-attenuated on non-contrast narrow-window computed tomography images. We aimed to determine the mechanism underlying minute computed tomography hypo-attenuation and visualise these attenuation changes on non-contrast computed tomography images. The cerebral parenchyma was defined by pixels with attenuation of 20-50 Hounsfield units. We calculated the mean cerebral parenchymal attenuation in non-contrast computed tomography images. We analysed the correlation of complete blood counts with corresponding mean cerebral parenchymal attenuation values using linear regression analysis. Moreover, we developed an image processing method that involved pixel colorisation based on the noise-reduced attenuation value for minute cerebral parenchymal attenuation visualisation. Haemoglobin, haematocrit and red blood cell counts positively correlated with mean cerebral parenchymal attenuation values. The cerebral haematocrit is correlated with the blood haematocrit; therefore, cerebral parenchymal attenuation correlated linearly with cerebral haemoglobin concentration. Haemoglobin contents in a pixel partially determine the X-ray absorption dose and attenuation value. Pixel haemoglobin contents are determined by the cerebral volume of blood in a pixel. Image processed computed tomography images reflected cerebral volume of blood and showed the same alterations with regional cerebral blood volume maps of perfusion computed tomography. Cerebral parenchymal attenuation correlated with cerebral haemoglobin concentration and cerebral volume of blood. Infarcted cerebral parenchyma shows about 5 Hounsfield units gray matter attenuation decrease. Attenuation decrease by less than 5 Hounsfield units means decreased cerebral volume of blood, indicating a reversible functional change. One cannot recognise minute hypo-attenuation (<5 Hounsfield units) in routine computed tomography images. However, it can be visualised through an image processing method on non-contrast computed tomography images. It may detect pre-infarction cerebral volume of blood and regional cerebral blood volume alterations.

Long-term music adjuvant therapy enhances the efficacy of sub-dose antiepileptic drugs in temporal lobe epilepsy.

AimsNoninvasive music adjuvant therapy shows great potential in improving seizure control when combined with routine antiepileptic drugs. However, the diversity of previous music protocols has resulted in disparate outcomes. The optimized protocol and features for music adjuvant therapy are still not fully understood which limits its feasibility.MethodsBy applying different regimens of music therapy in various temporal lobe epilepsy models, we evaluated the effect of music in combination with sub‐dose drugs on epileptic seizures to determine the optimized protocol.ResultsA subgroup of kindled mice that were responsive to music adjuvant therapy was screened. In those mice, sub‐dose drugs which were noneffective on kindled seizures, alleviated seizure severity after 12 h/day Mozart K.448 for 14 days. Shorter durations of music therapy (2 and 6 h/day) were ineffective. Furthermore, only full‐length Mozart K.448, not its episodes or other music varieties, was capable of enhancing the efficacy of sub‐dose drugs. This music therapeutic effect was not due to increasing cerebral drug concentration, but instead was related with the modulation of seizure electroencephalogram (EEG) spectral powers in the hippocampus.ConclusionThese results indicate that long‐term full‐length Mozart K.448 could enhance the anti‐seizure efficacy of sub‐dose drugs and may be a promising noninvasive adjuvant therapy for temporal lobe epilepsy.

Time-evolving coupling functions for evaluating the interaction between cerebral oxyhemoglobin and arterial blood pressure with hypertension.

This study aimed to investigate the network coupling between arterial blood pressure (ABP) and changes in cerebral oxyhemoglobin concentration (Δ [O2 Hb]/Δ [HHb]) oscillations based on dynamical Bayesian inference in hypertensive subjects. Two groups of subjects, consisting of 30 healthy (Group Control, 55.1±10.6y), and 32 hypertensive individuals (Group AH, 58.9±8.7y), participated in this study. A functional near-infrared spectroscopy system was used to measure the Δ [O2 Hb] and Δ [HHb] signals in the bilateral prefrontal cortex (LPFC/RPFC), motor cortex (LMC/RMC), and occipital lobe (LOL/ROL) during the resting state (12min). Based on continuous wavelet analysis and coupling functions, the directed coupling strength (CS) between ABP and cerebral hemoglobin was identified and analyzed in three frequency intervals (I: 0.6-2Hz, II: 0.145-0.6Hz, III: 0.01-0.08Hz). The Pearson correlations between the CS and blood pressure parameters were calculated in the hypertension group. In interval I, Group AH exhibited a significantly higher CS for the coupling from ABP to Δ [O2 Hb] than Group Control in LMC, RMC, LOL, and ROL. In interval III, the CS from ABP to Δ [O2 Hb] in LPFC, RPFC, LMC, RMC, LOL, and ROL was significantly higher in Group AH than in Group Control. For the patients with hypertension, diastolic blood pressure was negatively and pulse pressure was positively related to the CS from ABP to Δ [O2 Hb] oscillations in interval III. The higher CS from ABP to Δ [O2 Hb] in interval I indicated that the components of cardiac activity in cerebral hemoglobin oscillations were more directly responsive to the changes in systematic ABP in patients with hypertension than in healthy subjects. Meanwhile, the higher CS from ABP to Δ [O2 Hb] in interval III indicated that the cerebral hemoglobin oscillations were susceptible to changes in blood pressure in hypertensive subjects. The results may serve as evidence of impairment in cerebral autoregulation after hypertension. The Pearson correlation results showed that diastolic blood pressure and pulse pressure might be regarded as predictors of cerebral autoregulation function in patients with hypertension, and may be useful for hypertension stratification. This study provides novel insights into the interaction mechanism between ABP and cerebral hemodynamics and could help in the development of new assessment techniques for cerebral vascular disease.

Cerebral Metabolite Concentrations Are Associated With Cortical and Subcortical Volumes and Cognition in Older Adults.

BackgroundCerebral metabolites are associated with different physiological processes in brain aging. Cortical and limbic structures play important roles in cognitive aging; however, the relationship between these structures and age remains unclear with respect to physiological underpinnings. Regional differences in metabolite levels may be related to different structural and cognitive changes in aging.MethodsMagnetic resonance imaging and spectroscopy were obtained from 117 cognitively healthy older adults. Limbic and other key structural volumes were measured. Concentrations of N-acetylaspartate (NAA) and choline-containing compounds (Cho) were measured in frontal and parietal regions. Neuropsychological testing was performed including measures of crystallized and fluid intelligence and memory.ResultsNAA in the frontal voxel was associated with limbic and cortical volumes, whereas Cho in parietal cortex was negatively associated with hippocampal and other regional volumes. Hippocampal volume was associated with forgetting, independent of age. Further, parietal Cho and hippocampal volume contributed independent variance to age corrected discrepancy between fluid and crystallized abilities.ConclusionThese findings suggest that physiological changes with age in the frontal and parietal cortices may be linked to structural changes in other connected brain regions. These changes are differentially associated with cognitive performance, suggesting potentially divergent mechanisms.

Alterations in cerebral and cardiac mitochondrial function in a porcine model of acute carbon monoxide poisoning

Objectives The purpose of this study is the development of a porcine model of carbon monoxide (CO) poisoning to investigate alterations in brain and heart mitochondrial function. Design Two group large animal model of CO poisoning. Setting Laboratory. Subjects Ten swine were divided into two groups: Control (n = 4) and CO (n = 6). Interventions Administration of a low dose of CO at 200 ppm to the CO group over 90 min followed by 30 min of re-oxygenation at room air. The Control group received room air for 120 min. Measurements Non-invasive optical monitoring was used to measure cerebral blood flow and oxygenation. Cerebral microdialysis was performed to obtain semi real time measurements of cerebral metabolic status. At the end of the exposure, both fresh brain (cortical and hippocampal tissue) and heart (apical tissue) were immediately harvested to measure mitochondrial respiration and reactive oxygen species (ROS) generation and blood was collected to assess plasma cytokine concentrations. Main results Animals in the CO group showed significantly decreased Complex IV-linked mitochondrial respiration in hippocampal and apical heart tissue but not cortical tissue. There also was a significant increase in mitochondrial ROS generation across all measured tissue types. The CO group showed a significantly higher cerebral lactate-to-pyruvate ratio. Both IL-8 and TNFα were significantly increased in the CO group compared with the Control group obtained from plasma. While not significant there was a trend to an increase in optically measured cerebral blood flow and hemoglobin concentration in the CO group. Conclusions Low-dose CO poisoning is associated with early mitochondrial disruption prior to an observable phenotype highlighting the important role of mitochondrial function in the pathology of CO poisoning. This may represent an important intervenable pathway for therapy and intervention.

The effect of free glycerol intake on cerebral glycerol concentration.

Cerebral microdialysis (CMD) is a method used to measure the concentration of metabolites and glycerol in the interstitium of the brain. The aim of this study was to investigate the effect of parenterally applied medication and nutrition containing external free glycerol (EFG) on cerebral values of glycerol in patients monitored and treated for non-traumatic subarachnoid hemorrhage (SAH). In 13 patients, the values of CG concentrations were measured using CMD. The amounts of parenterally applied EFG (in hourly intervals) were calculated from patient records. All data were gathered retrospectively. To analyze the association between the parameters of interest and their relationship, Spearman´s correlation and p-values were calculated. There was no evident relationship between the CG and EFG concentrations when the dataset was analyzed as a whole (r = -0.146). However, when the analysis was applied to single patients, a varying degree of correlations was discovered in 7 patients (r = 0.431-0.867). The possible effect of externally administered glycerol contained in pharmaceuticals and nutrition on its brain concentrations must be considered when interpreting data of CMD (Tab. 2, Fig. 4,Ref. 16) Keywords: glycerol, microdialysis, brain, subarachnoid hemorrhage.

Upregulation of hemeoxygenase enzymes HO-1 and HO-2 following ischemia-reperfusion injury in connection with experimental cardiac arrest and cardiopulmonary resuscitation: Neuroprotective effects of methylene blue.

Oxidative stress plays an important role in neuronal injuries after cardiac arrest. Increased production of carbon monoxide (CO) by the enzyme hemeoxygenase (HO) in the brain is induced by the oxidative stress. HO is present in the CNS in two isoforms, namely the inducible HO-1 and the constitutive HO-2. Elevated levels of serum HO-1 occurs in cardiac arrest patients and upregulation of HO-1 in cardiac arrest is seen in the neurons. However, the role of HO-2 in cardiac arrest is not well known. In this review involvement of HO-1 and HO-2 enzymes in the porcine brain following cardiac arrest and resuscitation is discussed based on our own observations. In addition, neuroprotective role of methylene blue- an antioxidant dye on alterations in HO under in cardiac arrest is also presented. The biochemical findings of HO-1 and HO-2 enzymes using ELISA were further confirmed by immunocytochemical approach to localize selective regional alterations in cardiac arrest. Our observations are the first to show that cardiac arrest followed by successful cardiopulmonary resuscitation results in significant alteration in cerebral concentrations of HO-1 and HO-2 levels indicating a prominent role of CO in brain pathology and methylene blue during CPR followed by induced hypothermia leading to superior neuroprotection after return of spontaneous circulation (ROSC), not reported earlier.

Does supply meet demand? A comparison of perfusion strategies on cerebral metabolism in a neonatal swine model

ObjectiveWe aimed to determine the effects of selective antegrade cerebral perfusion compared with other perfusion strategies on indices of cerebral blood flow, oxygenation, cellular stress, and mitochondrial function. MethodsOne-week-old piglets (n = 41) were assigned to 5 treatment groups. Thirty-eight were placed on cardiopulmonary bypass. Of these, 30 were cooled to 18°C and underwent deep hypothermic circulatory arrest (n = 10), underwent selective antegrade cerebral perfusion at 10 mL/kg/min (n = 10), or remained on continuous cardiopulmonary bypass (deep hypothermic cardiopulmonary bypass, n = 10) for 40 minutes. Other subjects remained on normothermic cardiopulmonary bypass (n = 8) or underwent sham surgery (n = 3). Novel, noninvasive optical measurements recorded cerebral blood flow, cerebral tissue oxyhemoglobin concentration, oxygen extraction fraction, total hemoglobin concentration, and cerebral metabolic rate of oxygen. Invasive measurements of cerebral microdialysis and cerebral blood flow were recorded. Cerebral mitochondrial respiration and reactive oxygen species generation were assessed after the piglets were killed. ResultsDuring hypothermia, deep hypothermic circulatory arrest piglets experienced increases in oxygen extraction fraction (P < .001), indicating inadequate matching of oxygen supply and demand. Deep hypothermic cardiopulmonary bypass had higher cerebral blood flow (P = .046), oxyhemoglobin concentration (P = .019), and total hemoglobin concentration (P = .070) than selective antegrade cerebral perfusion, indicating greater oxygen delivery. Deep hypothermic circulatory arrest demonstrated worse mitochondrial function (P < .05), increased reactive oxygen species generation (P < .01), and increased markers of cellular stress (P < .01). Reactive oxygen species generation was increased in deep hypothermic cardiopulmonary bypass compared with selective antegrade cerebral perfusion (P < .05), but without significant microdialysis evidence of cerebral cellular stress. ConclusionsSelective antegrade cerebral perfusion meets cerebral metabolic demand and mitigates cerebral mitochondrial reactive oxygen species generation. Excess oxygen delivery during deep hypothermia may have deleterious effects on cerebral mitochondria that may contribute to adverse neurologic outcomes. We describe noninvasive measurements that may help guide perfusion strategies.