Cerebral Content Research Articles

Time course of cerebral oxygenation and cerebrovascular reactivity in Kyrgyz highlanders. A five-year prospective cohort study.

Introduction: This prospective cohort study assessed the effects of chronic hypoxaemia due to high-altitude residency on the cerebral tissue oxygenation (CTO) and cerebrovascular reactivity. Methods: Highlanders, born, raised, and currently living above 2,500m, without cardiopulmonary disease, participated in a prospective cohort study from 2012 until 2017. The measurements were performed at 3,250m. After 20min of rest in supine position while breathing ambient air (FiO2 0.21) or oxygen (FiO2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO2) and cerebral near-infrared spectroscopy assessing CTO and change in cerebral haemoglobin concentration (cHb), a surrogate of cerebral blood volume changes and cerebrovascular reactivity, were applied. Arterial blood gases were obtained during ambient air breathing. Results: Fifty three highlanders, aged 50 ± 2years, participated in 2017 and 2012. While breathing air in 2017 vs. 2012, PaO2 was reduced, mean ± SE, 7.40 ± 0.13 vs. 7.84 ± 0.13kPa; heart rate was increased 77 ± 1 vs. 70 ± 1bpm (p < 0.05) but CTO remained unchanged, 67.2% ± 0.7% vs. 67.4% ± 0.7%. With oxygen, SpO2 and CTO increased similarly in 2017 and 2012, by a mean (95% CI) of 8.3% (7.5-9.1) vs. 8.5% (7.7-9.3) in SpO2, and 5.5% (4.1-7.0) vs. 4.5% (3.0-6.0) in CTO, respectively. Hyperventilation resulted in less reduction of cHb in 2017 vs. 2012, mean difference (95% CI) in change with air 2.0 U/L (0.3-3.6); with oxygen, 2.1 U/L (0.5-3.7). Conclusion: Within 5years, CTO in highlanders was preserved despite a decreased PaO2. As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.

Increased brain microvascular hemoglobin concentrations in children with cerebral malaria.

Brain swelling is associated with death from cerebral malaria, but it is unclear whether brain swelling is caused by cerebral edema or vascular congestion-two pathological conditions with distinct effects on tissue hemoglobin concentrations. We used near-infrared spectroscopy (NIRS) to noninvasively study cerebral microvascular hemoglobin concentrations in 46 Malawian children with cerebral malaria. Cerebral malaria was defined by the presence of the malaria parasite Plasmodium falciparum on a blood smear, a Blantyre coma score of 2 or less, and retinopathy. Children with uncomplicated malaria (n = 33) and healthy children (n = 29) were enrolled as comparators. Cerebral microvascular hemoglobin concentrations were higher among children with cerebral malaria compared with those with uncomplicated malaria [median (25th, 75th): 145.2 (95.2, 190.0) μM versus 82.9 (65.7, 105.4) μM, P = 0.008]. Cerebral microvascular hemoglobin concentrations correlated with brain swelling score determined by MRI (r = 0.37, P = 0.03). Fluctuations in cerebral microvascular hemoglobin concentrations over a 30-min time period were characterized using detrended fluctuation analysis (DFA). DFA determined self-similarity of the cerebral microvascular hemoglobin concentration signal to be lower among children with cerebral malaria compared with those with uncomplicated malaria [0.63 (0.54, 0.70) versus 0.91 (0.82, 0.94), P < 0.0001]. The lower self-similarity of the hemoglobin concentration signal in children with cerebral malaria suggested impaired regulation of cerebral blood flow. The elevated cerebral tissue hemoglobin concentration and its correlation with brain swelling suggested that excess blood volume, potentially due to vascular congestion, may contribute to brain swelling in cerebral malaria.

Reproducibility of cerebral blood flow, oxygen metabolism, and lactate and N-acetyl-aspartate concentrations measured using magnetic resonance imaging and spectroscopy.

In humans, resting cerebral perfusion, oxygen consumption and energy metabolism demonstrate large intersubject variation regardless of methodology. Whether a similar large variation is also present longitudinally in individual subjects is much less studied, but knowing the time variance in reproducibility is important when designing and interpreting longitudinal follow-up studies examining brain physiology. Therefore, we examined the reproducibility of cerebral blood flow (CBF), global cerebral metabolic rate of oxygen (CMRO2), global arteriovenous oxygen saturation difference (A-V.O2), and cerebral lactate and N-acetyl-aspartate (NAA) concentrations measured using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques through repeated measurements at 6h, 24h, 7days and several weeks after initial baseline measurements in young healthy adults (N = 26, 13 females, age range 18-35years). Using this setup, we calculated the correlation, limit of agreement (LoA) and within-subject coefficient of variation (CoVWS) between baseline values and the subsequent repeated measurements to examine the longitudinal variation in individual cerebral physiology. CBF and CMRO2 correlated significantly between baseline and all subsequent measurements. The strength of the correlations (R2) and reproducibility metrics (LoA and CoVWS) demonstrated the best reproducibility for the within-day measurements and generally declined with longer time between measurements. Cerebral lactate and NAA concentrations also correlated significantly for all measurements, except between baseline and the 7-day measurement for lactate. Similar to CBF and CMRO2, lactate and NAA demonstrated the best reproducibility for within-day repeated measurements. The gradual decline in reproducibility over time should be considered when designing and interpreting studies on brain physiology, for example, in the evaluation of treatment efficacy.

Cerebral Glucose Concentration in Neonatal Hypoxic–Ischemic Encephalopathy during Therapeutic Hypothermia

To determine cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during therapeutic hypothermia (TH). This was an observational study in which cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan. Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected. The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist. Student t test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were performed. Three-hundred-sixty blood glucose values and 402MR spectra from 54 infants (30 female infants; mean gestational age 38.6± 1.9weeks) were analyzed. In total, 41 infants had normal-mild and 13 had moderate-severe injury. Median GIR and blood glucose during TH were 6.0mg/kg/min (IQR 5-7) and 90mg/dL (IQR 80-102), respectively. GIR did not correlate with blood or cerebral glucose. Cerebral glucose was significantly greater during than after TH (65.9± 22.9 vs 60.0± 25.2mg/dL, P<.01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r=0.42, thalamus: r=0.42, cortical gray matter: r=0.39, white matter: r=0.39, all P<.01). There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern. During TH, cerebral glucose concentration is partly dependent on blood glucose concentration. Further studies to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection are needed.

Prefrontal NIRS signal is unaffected by forehead Doppler flux during incremental cycling exercise.

Near-infrared spectroscopy (NIRS) is used to measure tissue concentrations of oxyhemoglobin (O2 Hb) and deoxyhemoglobin (HHb). In the context of exercise, NIRS confers a higher signal-to-noise ratio than other neuroimaging techniques. However, part of the signal may be influenced by thermoregulatory hyperemia in the superficial cutaneous capillaries of the forehead. The degree to which NIRS signals during exercise reflect cerebral or extracerebral hemodynamic changes is a continuing source of controversy. However, the influence of skin blood flow may be attenuated depending on the NIRS technique (e.g., frequency domain machines with maximal optode separation distances >3.5 cm). The purpose of this study was to compare the changes in forehead skin blood flow and cerebral hemoglobin concentration during incremental exercise versus direct vasodilation of the forehead skin induced by gradual local heating. Thirty participants (12 females, 18 males; age: 20.8 ± 3.2 years; body mass index: 23.8 ± 3.7 kg·m-2 ) participated in the study. Forehead skin blood flow was quantified laser Doppler flux and absolute concentrations of cerebral O2 Hb and HHb were measured by NIRS. Local heating significantly increased the Doppler flux signal across time and these changes were significantly correlated with skin temperature. During incremental exercise, skin temperature, Doppler flux, O2 Hband HHb increased however, the only significant change that was consistently correlated with Doppler flux was skin temperature. Therefore, a significant change in forehead skin blood flow may not significantly the NIRS hemoglobin data, depending on the type of NIRS device used.

Quantification of Cerebral Glucose Concentrations via Detection of the H1-α-Glucose Peak in 1 H MRS at 7 T.

Sensitive detection and quantification of cerebral glucose is desired. To quantify cerebral glucose by detecting the H1-α-glucose peak at 5.23 ppm in 1 H magnetic resonance spectroscopy at 7 T. Prospective. Twenty-eight non-fasted healthy subjects (aged 20-28 years). Short echo time stimulated echo acquisition mode (short-TE STEAM) and semi-localized by adiabatic selective refocusing (semi-LASER) at 7 T. Single voxel spectra were obtained from the posterior cingulate cortex (27-mL) using a 32-channel head coil. The H1-α-glucose peak in the spectrum with retrospective removal of the residual water peak was fitted using LCModel with a glucose basis set of only the H1-α-glucose peak. Conventional spectral analysis was performed with a glucose basis set of a full spectral pattern of glucose, also. Fitting precision was evaluated with Cramér-Rao lower bounds (CRLBs). The repeatability of glucose quantification via the semi-LASER sequence was tested. Paired or Welch's t-test were used for normally distributed values. A P value of <0.05 was considered significant. The repeatability of measures was analyzed using coefficient of variation (CV). Removal of the residual water peak improved the flatness and stability of baselines around the H1-α-glucose peak and reduced CRLBs for fitting the H1-α-glucose peak. The semi-LASER sequence was superior to the short-TE STEAM in the higher signal-to-noise ratio of the H1-α-glucose peak (mean ± SD 7.9 ± 2.5, P < 0.001). The conventional analysis overfitted the H1-α-glucose peak. The individual CVs of glucose quantification by detecting the H1-α-glucose peak were smaller than the corresponding CRLBs. Cerebral glucose concentration is quantitated to be 1.07 mM by detecting the H1-α-glucose peak in the semi-LASER spectra. Despite requiring long scan times, detecting the H1-α-glucose peak allows true glucose quantification free from the influence of overlapping taurine and macromolecule signals. 2 TECHNICAL EFFICACY STAGE: 1.

Aortic stiffness and impairments in cerebrovascular function in cancer survivorship

An established consequence of anti-cancer treatment is increased aortic stiffness, which impairs the aortic damping of cardiac-generated pulsatile pressure and blood flow. These increased pulsations may result in vascular injury in the microcirculation of target end organs like the brain. The aim of the present study was to determine the ramifications of elevated aortic stiffness on cerebral macro- and microvascular pulsatility and autoregulatory function in cancer survivors. We hypothesized that cerebrovascular pulsatility would be enhanced, and cerebrovascular reactivity (CVR) to elevations in arterial CO 2 would be impaired, both in the large and small cerebral vessels in patients with a history of cancer and anti-cancer treatment versus healthy age- and sex-matched non-cancer controls. Aortic arch pulse wave velocity (aaPWV), a regional measure of stiffness in the proximal aorta, was calculated from echocardiographic views of the aortic valve and the descending aortic arch. Subjects then breathed room air for 60s followed by ~2 minutes of rebreathing with simultaneous collection of end-tidal pressure of CO 2 (P ET CO 2 ). Middle cerebral artery blood flow velocity (MCAv) was assessed using transcranial doppler. Oxygenated (oxy-[Hb]) and deoxygenated (deoxy-[Hb]) cerebral microvascular hemoglobin concentrations were monitored using two near-infrared spectroscopy probes placed over the prefrontal cortices. Pulsatility was assessed at baseline using Gosling’s Pulsatility Index (PI) for both the microvasculature and MCA. To account for changes in perfusion pressure, MAP was collected via finger plethysmography and cerebrovascular conductance indices were calculated for both oxy-[Hb] (CVCi oxy ) and MCAv (CVCi MCA ). CVR was calculated as the slope of CVCi oxy and CVCi MCA over P ET CO 2 during rebreathing. Six women were recruited (n = 3/group). Age was similar between the healthy non-cancer controls (HC) and patients with a history of cancer and anti-cancer treatment (CS) (31.0 ± 7 vs. 32.7 ± 13 years). Baseline ventilatory (P ET CO 2 ), central and cerebral hemodynamics were also similar (all p &gt; 0.05). aaPWV was significantly elevated in CS compared to HC (5.3 ± 0.6 vs. 3.1 ± 1.1 m/s, p = 0.04). Cerebral microcirculation PI in CS was significantly elevated (0.04 ± 0.01 vs. 0.02 ± 0.01, p = 0.02), but MCA PI was not different (p &gt; 0.05). CVR-CVCi oxy was impaired in CS (-3.6 ± 2.8 vs. 1.5 ± 0.5 nM·mmHg -1 /mmHg, p = 0.03), and CVR-CVCi MCA was similarly reduced (-0.05 ± 0.06 vs. 0.15 ± 0.01 mm/sec·mmHg -1 /mmHg, p &lt; 0.01). The increase in MAP during hypercapnia was similar between groups. Consistent with our hypothesis, both CVR-CVCi oxy and CVR-CVCi MCA were attenuated in patients with a history of anti-cancer treatment. Additionally, the microvascular pulsatility was greater in CS. This suggests an impaired cerebrovascular function, possibly related to increased transmission of pulsatility into the brain, in the years following cancer diagnoses and treatment. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Traumatic Brain Injury Alters Cerebral Concentrations and Redox States of Coenzymes Q9 and Q10 in the Rat.

To date, there is no information on the effect of TBI on the changes in brain CoQ levels and possible variations in its redox state. In this study, we induced graded TBIs (mild TBI, mTBI and severe TBI, sTBI) in male rats, using the weight-drop closed-head impact acceleration model of trauma. At 7 days post-injury, CoQ9, CoQ10 and α-tocopherol were measured by HPLC in brain extracts of the injured rats, as well as in those of a group of control sham-operated rats. In the controls, about the 69% of total CoQ was in the form of CoQ9 and the oxidized/reduced ratios of CoQ9 and CoQ10 were, respectively, 1.05 ± 0.07 and 1.42 ± 0.17. No significant changes in these values were observed in rats experiencing mTBI. Conversely, in the brains of sTBI-injured animals, an increase in reduced and a decrease in oxidized CoQ9 produced an oxidized/reduced ratio of 0.81 ± 0.1 (p < 0.001 compared with both controls and mTBI). A concomitant decrease in both reduced and oxidized CoQ10 generated a corresponding oxidized/reduced ratio of 1.38 ± 0.23 (p < 0.001 compared with both controls and mTBI). An overall decrease in the concentration of the total CoQ pool was also found in sTBI-injured rats (p < 0.001 compared with both controls and mTBI). Concerning α-tocopherol, whilst no differences compared with the controls were found in mTBI animals, a significant decrease was observed in rats experiencing sTBI (p < 0.01 compared with both controls and mTBI). Besides suggesting potentially different functions and intracellular distributions of CoQ9 and CoQ10 in rat brain mitochondria, these results demonstrate, for the first time to the best of knowledge, that sTBI alters the levels and redox states of CoQ9 and CoQ10, thus adding a new explanation to the mitochondrial impairment affecting ETC, OXPHOS, energy supply and antioxidant defenses following sTBI.

Dynamic Alterations in Cerebral Hemodynamics Measured by Portable Near-Infrared Spectroscopy in Orthostatic Hypotension and Intolerance.

We aimed to evaluate dynamic alterations in cerebral total hemoglobin concentration (HbT) in individuals with orthostatic hypotension (OH) and orthostatic intolerance (OI) symptoms using a portable near-infrared spectroscopy (NIRS) system. Participants comprised 238 individuals (mean age, 47.9 years) without a history of cardiovascular, neurodegenerative, or cerebrovascular diseases, including those with unexplained OI symptoms and healthy volunteers. Participants were categorized by the presence of OH based on the supine-to-stand blood pressure (BP) drop and OI symptoms using on OH questionnaires: classic OH (OH-BP), OH symptoms alone (OH-Sx), and control groups. Random case-control matching sets were constructed, resulting in 16 OH-BP and 69 OH-Sx-control sets. The time-derivative of HbT change in the prefrontal cortex during the squat-to-stand maneuver was measured using a portable NIRS system. There were no differences in demographics, baseline BP, and heart rate among matched sets. The peak time of maximum slope variation in HbT change, indicating the recovery rate and speed of cerebral blood volume (CBV) change, was significantly longer in OH-Sx and OH-BP groups than in the control group under transition to a standing position after squatting. In the OH-BP subgrouping, the peak time of maximum slope variation in HbT change was significantly longer only in OH-BP with OI symptoms, but did not differ between OH-BP without OI symptoms and controls. Our results suggest that OH and OI symptoms are associated with dynamic alterations in cerebral HbT. Regardless of the severity of the postural BP drop, OI symptoms are associated with prolonged CBV recovery.

Intra‐oral gingival massage activates human cerebral prefrontal cortex and enhances cognitive performance

AbstractAimOral care is associated with improved quality of life and changing cognitive performance in daily life. The association of trigeminal nerve‐stimulatory oral care methods, such as tooth brushing and intra‐oral cold stimuli, with cerebral activation has been studied. This study aimed to elucidate the effects of intra‐oral gingival massage on the cerebral prefrontal cortex (PFC) region activation and the changes in cognitive performance.MethodsA total of 18 men participated in this study. Near‐infrared spectroscopy was used to acquire data on the cerebral hemoglobin concentrations. Cognitive function was determined using the Stroop cognitive test performed with and without intra‐oral gingival massage stimulus.ResultsParticipants who performed intra‐oral gingival massage showed significantly increased blood flow in the cerebral PFC region, including the left dorsolateral PFC (DL‐PFC) region, compared with those who mimicked the movements of the gingival massage (control group) (p = 0.0104 by Wilcoxon signed rank method). Furthermore, gingival massage showed a significant association with increased cognitive performance (p &lt; 0.0001 by Wilcoxon signed rank method) that coincided with the enhanced left DL‐PFC region activation (p = 0.039 by Fisher's exact probability test).ConclusionIntra‐oral gingival massage activated the cerebral PFC regions correlating with enhanced cognitive performance, suggesting that gingival massage may help improve cognitive performance.

Change in medial frontal cerebral metabolite concentrations following bariatric surgery.

Obesity is associated with adverse effects on brain health, including an increased risk of neurodegenerative diseases. Changes in cerebral metabolism may underlie or precede structural and functional brain changes. While bariatric surgery is known to be effective in inducing weight loss and improving obesity-related medical comorbidities, few studies have examined whether it may be able to improve brain metabolism. In the present study, we examined changes in cerebral metabolite concentrations in participants with obesity who underwent bariatric surgery. Thirty-five patients with obesity (body mass index ≥ 35 kg/m2 ) were recruited from a bariatric surgery candidate nutrition class. They completed single voxel proton magnetic resonance spectroscopy at baseline (presurgery) and within 1 year postsurgery. Spectra were obtained from a large medial frontal brain region using a PRESS sequence on a 3-T Siemens Verio scanner. The acquisition parameters were TR = 3000 ms and TE = 37 ms. Tissue-corrected metabolite concentrations were determined using Osprey. Paired t-tests were used to examine within-subject change in metabolite concentrations, and correlations were used to relate these changes to other health-related outcomes, including weight loss and glycated hemoglobin (HbA1c ), a measure of blood sugar levels. Bariatric surgery was associated with a reduction in cerebral choline-containing compounds (Cho; t [34] = - 3.79, p < 0.001, d = -0.64) and myo-inositol (mI; t [34] = - 2.81, p < 0.01, d = -0.47) concentrations. There were no significant changes in N-acetyl-aspartate, creatine, or glutamate and glutamine concentrations. Reductions in Cho were associated with greater weight loss (r = 0.40, p < 0.05), and reductions in mI were associated with greater reductions in HbA1c (r = 0.44, p < 0.05). In conclusion, participants who underwent bariatric surgery exhibited reductions in cerebral Cho and mI concentrations, which were associated with improvements in weight loss and glycemic control. Given that elevated levels of Cho and mI have been implicated in neuroinflammation, reduction in these metabolites after bariatric surgery may reflect amelioration of obesity-related neuroinflammatory processes. As such, our results provide evidence that bariatric surgery may improve brain health and metabolism in individuals with obesity.

Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning.

Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.

In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion.

In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood-brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane-free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects.

Abstract TP117: Temporal Serum Iron And Hemoglobin Changes In Patients From The High Dose Deferoxamine In Intracerebral Hemorrhage Trial

Introduction: Following intracerebral hemorrhage (ICH), elevated cerebral tissue iron concentrations are seen. It is unclear how peripheral serum iron concentrations change over time and how they relate to anemia after ICH. Given the known impacts of iron concentrations and anemia on clinical outcomes, we explored serum iron biomarker and hemoglobin concentration changes after acute ICH. Methods: A post hoc analysis of patients with available serial (baseline and 5 day) serum biomarker data from the multicenter, High Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF) trial was performed. Changes of serum hemoglobin, iron, transferrin, and ferritin were assessed using repeated measure ANOVA analyses. Deferoxamine treatment and poor 90 day modified Rankin Scale 4-6 were separately assessed as between subject factors for these laboratory changes. Results: Of 42 ICH patients analyzed, the mean age was 64, 62% were male, median ICH volume was 15.7mL (IQR 5.7-37.5), and baseline anemia was seen in 19%. We identified significant decrements of hemoglobin (mean difference -1.4 g/dL; 95%CI: -1.9 to -0.9; p&lt;0.0001), iron (mean difference -16.9 ug/dL; 95%CI: -29.7 to -4.1; p=0.01), transferrin (mean difference -43.9 ng/mL; 95%CI: -56.6 to -31.3; p&lt;0.0001), and conversely, significant ferritin elevations (mean difference 104.5 ug/L; 95%CI: 52.5-156.6; p&lt;0.0001) at 5 days. Anemia was identified in 43% of patients at 5 days. Deferoxamine did not have a significant impact on these repeated measures. Patients with poor long-term outcomes had greater decrements in hemoglobin compared to those with good outcomes (mean difference: -1.5 g/dL; 95%CI: -2.6 to -0.3; p=0.01). Conclusions: Serum iron and hemoglobin concentrations decrease significantly over time following ICH. Patients with worse long term ICH outcomes had greater hemoglobin decrements during their hospitalization. The aggregate iron biomarker and hemoglobin concentration changes suggest anemia development may be due to anemia of inflammation. Further work is required to address the pathophysiologic difference between systemic and central iron homeostasis mechanisms following ICH and the impacts that ICH has on inflammation, systemic iron homeostasis, anemia, and clinical outcomes.

Cerebral microdialysis and glucopenia in traumatic brain injury: A review.

Traditionally, intracranial pressure (ICP) and partial brain tissue oxygenation (PbtO2) have been the primary invasive intracranial measurements used to guide management in patients with severe traumatic brain injury (TBI). After injury however, the brain develops an increased metabolic demand which may require an increment in the oxidative metabolism of glucose. Simultaneously, metabolic, and electrical dysfunction can lead to an inability to meet these demands, even in the absence of ischemia or increased intracranial pressure. Cerebral microdialysis provides the ability to accurately measure local concentrations of various solutes including lactate, pyruvate, glycerol and glucose. Experimental and clinical data demonstrate that such measurements of cellular metabolism can yield critical missing information about a patient's physiologic state and help limit secondary damage. Glucose management in traumatic brain injury is still an unresolved question. As cerebral glucose metabolism may be uncoupled from systemic glucose levels due to the metabolic dysfunction, measurement of cerebral extracellular glucose concentrations could provide more predictive information and prove to be a better biomarker to avoid secondary injury of at-risk brain tissue. Based on data obtained from cerebral microdialysis, specific interventions such as ICP-directed therapy, blood glucose increment, seizure control, and/or brain oxygen optimization can be instituted to minimize or prevent secondary insults. Thus, microdialysis measurements of parenchymal metabolic function provides clinically valuable information that cannot be obtained by other monitoring adjuncts in the standard ICU setting.

Effectiveness of cerebellar vermis intermittent theta-burst stimulation in improving trunk control and balance function for patients with subacute stroke: a randomised controlled trial protocol

IntroductionBalance impairments frequently occur after stroke. Achieving effective core trunk stability is the key to improving balance ability. However, there is still a lack of advanced well-defined rehabilitation protocols for...

In Vivo Measurement of Cerebral SPIO Concentration in Nonhuman Primate Using Magnetic Particle Imaging Detector

<i>In Vivo</i> Measurement of Cerebral SPIO Concentration in Nonhuman Primate Using Magnetic Particle Imaging Detector

Role of neurochemistry in amyloid pathology using 5xFAD transgenic mouse model of AD: A single‐voxel Magnetic Resonance Spectroscopy (MRS) study

AbstractBackgroundChanges in cerebral metabolic concentrations are markers of aging and are also associated with various neurological disorders. Neurotransmitter and membrane metabolisms are affected in Alzheimer’s disease (AD). These metabolic alterations are suggested to occur in the hippocampus and rhinal cortex during the early stages of AD pathology. Higher levels of glutamine (Gln) in the blood and cerebral spinal fluid are associated with an increased risk of developing AD. Since Gln is capable of crossing the blood‐brain barrier and is involved in the metabolic cycle with glutamate (Glu), elevated levels of Gln in the presence of Aβ pathology may suggest a protective role of Gln in the early stage of the disease. Therefore, alteration in Glu/Gln cycle may serve as an early biomarker in the pathogenesis of AD. Choline‐containing compounds (tCho) are essential for phospholipid synthesis and degradation of cell membranes. Abnormal alterations of tCho levels are indicative of imbalanced cell membrane phospholipid metabolism. At the early stage of Aβ pathology, high levels of tCho in conjunction with elevated levels of Gln may suggest the involvement of compensatory mechanisms to counter declining acetylcholine. Thus, investigating metabolic changes in the hippocampus may improve our understanding of metabolic mechanisms associated with Aβ pathology.MethodMale 5xFAD mice (N=4) at 6‐months‐old and age‐matched littermates (N=5) were used in this study. Single‐voxel MRS was acquired on a 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. STEAM spectra was acquired from a 2mm3 voxel positioned on the left hippocampus region. Glu, Gln, tCho and total Creatine (tCr) levels were estimated with LC Model. A general linear model (GLM) was used to estimate group‐wise differences in Glu/Gln ratio, tCho.Gln and tCr.ResultCerebral metabolic concentration levels suggest group‐level differences between wild‐type (WT) and 5xFAD mice. Glu/Gln ratio was significantly higher in WT mice than 5xFAD (pFWE&lt;0.05; d=3.4) and tCho.Gln was significantly lower in WT than 5xFAD (pFWE&lt;0.05; d=2.8).ConclusionSingle‐voxel MRS in the hippocampus region can identify the neurochemical profile of multiple cerebral metabolites, which may be sensitive to the Aβ burden at the early stages of the pathology.

Milk fat globule membrane concentrate as a nutritional supplement prevents age-related cognitive decline in old rats: A lipidomic study of synaptosomes

Aging is associated with a decline in cognitive abilities, mainly in memory and executive functioning. A similar but premature deterioration in cognitive capacities is the hallmark of mild cognitive impairment, Alzeimer’s disease and dementia. The biochemical mechanisms that cause these neurodegenerative disorders are poorly understood. However, some evidence suggests that insufficient dietary intakes of some phospholipids could impact on brain function and increase the risk of future cognitive impairment and dementia. We evaluated the cognitive and biochemical effects of supplementation with a milk fat globule membrane (MFGM) concentrate in aged rats.We observed that, compared to control animals, MFGM supplemented rats showed enhanced spatial working memory, but both groups exhibited similar reference spatial learning and emotional memory abilities. No significant differences between BDNF levels in the hippocampus and frontal cortex of treated rats as compared to controls were found. The nootropic effects observed were accompanied by significant changes in the lipid composition of synaptic membranes. MFGM supplementation increased the levels of EPA and DHA acids as well as the plasmalogens content in the synaptosomes isolated from the hippocampus (Synapt-HP) and the frontal cortex (Synapt-FC). In addition enhanced levels of phosphatidyl serine (PS), particularly PS(18:1/18:1), and phosphatidyl inositol (PI) molecular species were observed in Synapt-HP and Synapt-FC of treated animals.Lipidomic analysis also revealed greater concentration of phosphatidyl ethanolamine (PE) molecular species containing very long-chain fatty acids and PE plasmenyls in Synapt-HP as well as an increase of the SM content in Synapt-FC from the MFGM group. Although further studies are needed to confirm the underlying mechanism (individual or synergistic), these results suggest that MFGM supplementation could be employed as a dietary implement to restore the proper cerebral concentration of some bioactive lipids and prevent or slow the progression of age-related cognitive impairment.