Changes In Cerebral Metabolism Research Articles

Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.

ObjectivesSudden loss of smell is a very common symptom of coronavirus disease 19 (COVID-19). This study characterizes the structural and metabolic cerebral correlates of dysosmia in patients with COVID-19.MethodsStructural brain magnetic resonance imaging (MRI) and positron emission tomography with [18F]-fluorodeoxyglucose (FDG-PET) were prospectively acquired simultaneously on a hybrid PET-MR in 12 patients (2 males, 10 females, mean age: 42.6 years, age range: 23–60 years) with sudden dysosmia and positive detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on nasopharyngeal swab specimens. FDG-PET data were analyzed using a voxel-based approach and compared with that of a group of healthy subjects.ResultsBilateral blocking of the olfactory cleft was observed in six patients, while subtle olfactory bulb asymmetry was found in three patients. No MRI signal abnormality downstream of the olfactory tract was observed. Decrease or increase in glucose metabolism abnormalities was observed (p < .001 uncorrected, k ≥ 50 voxels) in core olfactory and high-order neocortical areas. A modulation of regional cerebral glucose metabolism by the severity and the duration of COVID-19-related dysosmia was disclosed using correlation analyses.ConclusionsThis PET-MR study suggests that sudden loss of smell in COVID-19 is not related to central involvement due to SARS-CoV-2 neuroinvasiveness. Loss of smell is associated with subtle cerebral metabolic changes in core olfactory and high-order cortical areas likely related to combined processes of deafferentation and active functional reorganization secondary to the lack of olfactory stimulation.

Update: Microdialysis for Monitoring Cerebral Metabolic Dysfunction after Subarachnoid Hemorrhage

Cerebral metabolic dysfunction has been shown to extensively mediate the pathophysiology of brain injury after subarachnoid hemorrhage (SAH). The characterization of the alterations of metabolites in the brain can help elucidate pathophysiological changes occurring throughout SAH and the relationship between secondary brain injury and cerebral energy dysfunction after SAH. Cerebral microdialysis (CMD) is a tool that can measure concentrations of multiple bioenergetics metabolites in brain interstitial fluid. This review aims to provide an update on the implication of CMD on the measurement of metabolic dysfunction in the brain after SAH. A literature review was conducted through a general PubMed search with the terms “Subarachnoid Hemorrhage AND Microdialysis” as well as a more targeted search using MeSh with the search terms “Subarachnoid hemorrhage AND Microdialysis AND Metabolism.” Both experimental and clinical papers were reviewed. CMD is a suitable tool that has been used for monitoring cerebral metabolic changes in various types of brain injury. Clinically, CMD data have shown the dramatic changes in cerebral metabolism after SAH, including glucose depletion, enhanced glycolysis, and suppressed oxidative phosphorylation. Experimental studies using CMD have demonstrated a similar pattern of cerebral metabolic dysfunction after SAH. The combination of CMD and other monitoring tools has also shown value in further dissecting and distinguishing alterations in different metabolic pathways after brain injury. Despite the lack of a standard procedure as well as the presence of limitations regarding CMD application and data interpretation for both clinical and experimental studies, emerging investigations have suggested that CMD is an effective way to monitor the changes of cerebral metabolic dysfunction after SAH in real-time, and alternatively, the combination of CMD and other monitoring tools might be able to further understand the relationship between cerebral metabolic dysfunction and brain injury after SAH, determine the severity of brain injury and predict the pathological progression and outcomes after SAH. More translational preclinical investigations and clinical validation may help to optimize CMD as a powerful tool in critical care and personalized medicine for patients with SAH.

Short-term meditation training influences brain energy metabolism: A pilot study on 31 P MR spectroscopy.

BackgroundMeditation is increasingly attracting interest among neuroimaging researchers for its relevance as a cognitive enhancement technique and several cross‐sectional studies have indicated cerebral changes. This longitudinal study applied a distinct and standardized meditative technique with a group of volunteers in a short‐term training program to analyze brain metabolic changes.MethodsThe effect of 7 weeks of meditation exercises (focused attention meditation, FAM) was assessed on 27 healthy volunteers. Changes in cerebral energy metabolism were investigated using 31P‐MR spectroscopy. Metabolite ratios were compared before (T1) and after training (T2). Additional questionnaire assessments were included.ResultsThe participants performed FAM daily. Depression and anxiety scores revealed a lower level of state anxiety at T2 compared to T1. From T1 to T2, energy metabolism ratios showed the following differences: PCr/ATP increased right occipitally; Pi/ATP decreased bilaterally in the basal ganglia and temporal lobe on the right; PCr/Pi increased in occipital lobe bilaterally, in the basal ganglia and in the temporal lobe on the right side. The pH decreased temporal on the left side and frontal in the right side. The observed changes in the temporal areas and basal ganglia may be interpreted as a higher energetic state, whereas the frontal and occipital areas showed changes that may be related to a down‐regulation in ATP turnover, energy state, and oxidative capacity.ConclusionsThe results of the current study indicate for the first time in a longitudinal study that even short‐term training in FAM may have considerable effects on brain energy state with different local energy management in specific brain regions. Especially higher energetic state in basal ganglia may represent altered function in their central role in complex cerebral distributed networks including frontal and temporal areas. Further studies including different forms of relaxation techniques should be performed for more specific and reliable insights.

Imaging Acute Metabolic Changes in Patients with Mild Traumatic Brain Injury Using Hyperpolarized [1-13C]Pyruvate.

SummaryTraumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of 13C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-13C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO3–) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.

Arterial spin-labelling and magnetic resonance spectroscopy as imaging biomarkers for detection of epileptogenic zone in non-lesional focal impaired awareness epilepsy

BackgroundThe proper identification of an epileptic focus is a pivotal diagnostic issue; particularly in non-lesional focal impaired awareness epilepsy (FIAE). Seizures are usually accompanied by alterations of regional cerebral blood flow (rCBF) and metabolism. Arterial spin labeling-MRI (ASL-MRI) and proton magnetic resonance spectroscopy (1H-MRS) are MRI techniques that can, non-invasively, define the regions of cerebral perfusion and metabolic changes, respectively. The aim of the current study was to recognize the epileptogenic zone in patients with non-lesional FIAE by evaluating the interictal changes in rCBF and cerebral metabolic alterations, using PASL-MRI and 1H-MRS.ResultsFor identification of the epileptogenic zone, increased ASLAI% assessed by PASL-MRI (at a cut-off value ≥ 5.96%) showed 95.78% accuracy, and increased %AF (at a cut-off value ≥ 9.98%) showed 98.14% accuracy, while decreased NAA/(Cho + Cr) ratio estimated by multi-voxels (MV) 1H-MRS (at a cut-off value ≥ 0.59) showed 97.74% accuracy. Moreover, the combined use of PASL-MRI and MV 1H-MRS yielded 100% sensitivity, 98.45% specificity and 98.86% accuracy.ConclusionThe combined use of PASL-MRI and MV 1H-MRS can be considered as in-vivo proficient bio-marker for proper identification of epileptogenic zone in patients with non-lesional FIAE.

Neuroplasticity induced by general anaesthesia: study protocol for a randomised cross-over clinical trial exploring the effects of sevoflurane and propofol on the brain \u2013 A 3-T magnetic resonance imaging study of healthy volunteers

BackgroundAlthough used extensively worldwide, the effects of general anaesthesia on the human brain remain largely elusive. Moreover, general anaesthesia may contribute to serious conditions or adverse events such as postoperative cognitive dysfunction and delirium. To understand the basic mechanisms of general anaesthesia, this project aims to study and compare possible de novo neuroplastic changes induced by two commonly used types of general anaesthesia, i.e. inhalation anaesthesia by sevoflurane and intravenously administered anaesthesia by propofol. In addition, we wish to to explore possible associations between neuroplastic changes, neuropsychological adverse effects and subjective changes in fatigue and well-being.MethodsThis is a randomised, participant- and assessor-blinded, cross-over clinical trial. Thirty healthy volunteers (male:female ratio 1:1) will be randomised to general anaesthesia by either sevoflurane or propofol. Multimodal magnetic resonance imaging (MRI) of the brain will be performed before and after general anaesthesia and repeated after 1 and 8 days. Each magnetic resonance imaging session will be accompanied by cognitive testing and questionnaires on fatigue and well-being. After a wash-out period of 4 weeks, the volunteers will receive the other type of anaesthetic (sevoflurane or propofol), followed by the same series of tests. Primary outcomes: changes in T1-weighted 3D anatomy and diffusion tensor imaging. Secondary outcomes: changes in resting-state functional magnetic resonance imaging, fatigue, well-being, cognitive function, correlations between magnetic resonance imaging findings and the clinical outcomes (questionnaires and cognitive function). Exploratory outcomes: changes in cerebral perfusion and oxygen metabolism, lactate, and response to visual stimuli.DiscussionTo the best of our knowledge, this is the most extensive and advanced series of studies with head-to-head comparison of two widely used methods for general anaesthesia. Recruitment was initiated in September 2019.Trial registrationApproved by the Research Ethics Committee in the Capital Region of Denmark, ref. H-18028925 (6 September 2018). EudraCT and Danish Medicines Agency: 2018-001252-35 (23 March 2018). www.clinicaltrials.gov, ID: NCT04125121. Retrospectively registered on 10 October 2019.

In vivo Imaging With 18F-FDG- and 18F-Florbetaben-PET/MRI Detects Pathological Changes in the Brain of the Commonly Used 5XFAD Mouse Model of Alzheimer's Disease.

Imaging biomarkers of Alzheimer's disease (AD) that are able to detect molecular changes in vivo and transgenic animal models mimicking AD pathologies are essential for the evaluation of new therapeutic strategies. Positron-emission tomography (PET) using either 18F-Fluorodeoxyglucose (18F-FDG) or amyloid-tracers is a well-established, non-invasive tool in the clinical diagnostics of AD assessing two major pathological hallmarks. 18F-FDG-PET is able to detect early changes in cerebral glucose metabolism and amyloid-PET shows cerebral amyloid load. However, the suitability of 18F-FDG- and amyloid-PET in the widely used 5XFAD mouse model of AD is unclear as only a few studies on the use of PET biomarkers are available showing some conflicting results. The aim of this study was the evaluation of 18F-FDG-PET and amyloid-PET in 5XFAD mice in comparison to neurological deficits and neuropathological changes. Seven- and 12-month-old male 5XFAD mice showed a significant reduction in brain glucose metabolism in 18F-FDG-PET and amyloid-PET with 18F-Florbetaben demonstrated an increased cerebral amyloid deposition (n = 4–6 per group). Deficits in spatial reference memory were detected in 12-month-old 5XFAD mice in the Morris Water Maze (n = 10–12 per group). Furthermore, an increased plaque load and gliosis could be proven immunohistochemically in 5XFAD mice (n = 4–6 per group). PET biomarkers 18F-FDG and 18F-Florbetaben detected cerebral hypometabolism and increased plaque load even before the onset of severe memory deficits. Therefore, the 5XFAD mouse model of AD is well-suited for in vivo monitoring of AD pathologies and longitudinal testing of new therapeutic approaches.

A phase II randomized trial of sodium oligomannate in Alzheimer\u2019s dementia

BackgroundSodium oligomannate (GV-971), a marine-derived oligosaccharide, is a novel agent that may improve cognition in AD patients.MethodsThe 24-week multicenter, randomized, double-blind, placebo parallel controlled clinical trial was conducted in AD in China between 24 October 2011 and 10 July 2013. The study included a 4-week screening/washout period, followed by a 24-week treatment period. Patients were randomized in a 1:1:1 ratio to receive GV-971 900 mg, 600 mg, or placebo capsule in treatment period, respectively. The primary outcome was cognitive improvement as assessed by changes in Alzheimer’s Disease Assessment Scale-cognitive subscale 12-item (ADAS-cog12) scores from baseline to week 24. The secondary efficacy outcomes included CIBIC-Plus, ADCS-ADL, and NPI at 24 weeks after treatment compared with baseline. A subgroup study was assessment of the change in cerebral glucose metabolism by fluorodeoxyglucose positron emission tomography measurements.ResultsComparing with the placebo group (n = 83, change − 1.45), the ADAS-cog12 score change in the GV-971 600-mg group (n = 76) was − 1.39 (p = 0.89) and the GV-971 900-mg group (n = 83) was − 2.58 (p = 0.30). The treatment responders according to CIBIC-Plus assessment were significantly higher in the GV-971 900-mg group than the placebo group (92.77% vs. 79.52%, p < 0.05). The GV-971 900-mg subgroup showed a lower decline of cerebral metabolic rate for glucose than the placebo subgroup at the left precuneus, right posterior cingulate, bilateral hippocampus, and bilateral inferior orbital frontal at uncorrected p = 0.05. The respective rates of treatment-related AEs were 5.9%, 14.3%, and 3.5%.ConclusionsGV-971 was safe and well tolerated. GV-971 900 mg was chosen for phase III clinical study.Trial registrationClinicalTrials.gov, NCT01453569. Registered on October 18, 2011.

Synergistic effect of aminoguanidine and l-carnosine against thioacetamide-induced hepatic encephalopathy in rats: behavioral, biochemical, and ultrastructural evidence.

Hepatic encephalopathy depicts the cluster of neurological alterations that occur during acute or chronic hepatic injury. Hyperammonemia, inflammatory injury, and oxidative stress are the main predisposing factors for the direct and indirect changes in cerebral metabolism causing encephalopathy. The aim of this study was to evaluate the possible synergistic effect between aminoguanidine (AG; 100 mg/kg, p.o.) and l-carnosine (CAR; 200 mg/kg, p.o.) on hepatic encephalopathy that was induced by thioacetamide (TAA; 100 mg/kg, i.p.) administered three times weekly for six weeks. Behavioral changes, biochemical parameters, histopathological analysis, and immunohistochemical and ultrastructural studies were conducted 24h after the last treatment. Combining AG with CAR improved TAA-induced locomotor impairment and motor incoordination evidenced by reduced locomotor activity and decline in motor skill performance, as well as ameliorated cognitive deficits. Moreover, both drugs restored the levels of serum hepatic enzymes and serum and brain levels of ammonia. In addition, the combination significantly modulated hepatic and brain oxidative stress biomarkers, inflammatory cytokines, and cleaved caspase-3 expression. Furthermore, they succeeded in activating nuclear erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase-1 (HO-1) activity and ameliorating markers of hepatic encephalopathy, including hepatic necrosis and brain astrocyte swelling. This study shows that combining AG with CAR exerted a new intervention for hepatic and brain damage in hepatic encephalopathy due to their complementary antioxidant, anti-inflammatory effects and hypoammonemic effects via Nrf2/HO-1 activation and NO inhibition.

Cerebral Energy Status and Altered Metabolism in Early Severe TBI: First Results of a Prospective 31P-MRS Feasibility Study.

Severe traumatic brain injury (sTBI) represents a serious public health issue with high morbidity and mortality. Neuroimaging plays a crucial role in the evaluation of sTBI patients. Phosphorous magnetic resonance spectroscopy (31P-MRS) is an imaging technique for evaluation of energy metabolites. The aim of this study is to evaluate the feasibility and the diagnostic potential of ultra-early 31P-MRS to detect changes in cerebral energy metabolism in sTBI. Adult patients with sTBI presenting with GCS ≤ 8 being eligible for MRI were prospectively included in the study and MRI was performed within 72h after trauma. Imaging was performed using a 3 Tesla MRI. 31P-MRS data from the structurally affected side were compared to data from normal appearing contralateral areas symmetrically to the location of the traumatic lesions, and to data of matched healthy controls. Ten sTBI patients (3 female, 7 male), aged between 20 and 75years, with a mean initial GCS of 6 were analyzed. MRI was performed 61h (mean, range 37-71h) after trauma. Statistical analysis revealed no significant differences between the lesioned side and contralaterally. An increased PCr/ATP ratio and a decreased PME/PDE ratio were present in structurally normal appearing, but traumatized tissue when compared to the healthy population, thus indicating significant differences in ATP resynthesis and membrane turnover (F (2,33), P = 0.005 and, P = 0.027, respectively). 31P-MRS could provide a better understanding of pertinent global changes in cerebral energy metabolism in sTBI patients under general anesthesia.

Magnetic resonance markers of bilateral neuronal metabolic dysfunction in patients with unilateral internal carotid artery occlusion.

To evaluate cerebral hemodynamic, metabolic and anatomic changes occurring in patients with unilateral occlusion of the internal carotid artery (ICA). Twenty-two patients with unilateral occlusion of ICA and twenty age and sex matched healthy subjects were included in the study. Single voxel proton magnetic resonance spectroscopy (1H-MRS) of the centrum semiovale, semi-automated hippocampal volumetry in T1-weighted scans and transcranial Doppler examination (TCD) with calculation of Breath Holding Index (BHI) were performed in both groups. Metabolic, anatomic, and hemodynamic features were compared between the two groups. The N-acetylaspartate (NAA)/choline (Cho) ratio was significantly lower in both hemispheres of enrolled patients compared to controls (p = 0.005 for the side with occlusion, p = 0.04 for the side without occlusion). The hippocampus volume was significantly reduced bilaterally in patients compared to healthy subjects (p = 0.049). A statistically significant difference in BHI values was observed between the side with occlusion and without occlusion (p = 0.037) of the patients, as well as between BHI values of the side with occlusion and healthy volunteers (p = 0.014). Patients with unilateral ICA occlusion have reduced NAA/Cho ratio in the white matter of both hemispheres and have bilateral atrophy of hippocampus. The alteration of hemodynamics alone cannot explain these changes.

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG

During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O2 (CMRO2) during wakefulness and sleep, leveraging the ‘OxFlow’ method, which provides venous O2 saturation (SvO2) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45–60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO2 = 118 ± 12 µmol O2/min/100 g, SvO2 = 67.0 ± 3.7% HbO2, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO2 decreased 21% (range: 14%–32%; average nadir = 98 ± 16 µmol O2/min/100 g), while EEG slow-wave activity, expressed in terms of -power, increased commensurately. Following sleep onset, CMRO2 was found to correlate negatively with relative -power (r = −0.6 to −0.8, P < 0.005), and positively with heart rate (r = 0.5 to 0.8, P < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.

Cerebral Metabolic Changes During Visuomotor Adaptation Assessed Using Quantitative fMRI.

The brain retains a lifelong ability to adapt through learning and in response to injury or disease-related damage, a process known as functional neuroplasticity. The neural energetics underlying functional brain plasticity have not been thoroughly investigated experimentally in the healthy human brain. A better understanding of the blood flow and metabolic changes that accompany motor skill acquisition, and which facilitate plasticity, is needed before subsequent translation to treatment interventions for recovery of function in disease. The aim of the current study was to characterize cerebral blood flow (CBF) and oxygen consumption (relative CMRO2) responses, using calibrated fMRI conducted in 20 healthy participants, during performance of a serial reaction time task which induces rapid motor adaptation. Regions of interest (ROIs) were defined from areas showing task-induced BOLD and CBF responses that decreased over time. BOLD, CBF and relative CMRO2 responses were calculated for each block of the task. Motor and somatosensory cortices and the cerebellum showed statistically significant positive responses to the task compared to baseline, but with decreasing amplitudes of BOLD, CBF, and CMRO2 response as the task progressed. In the cerebellum, there was a sustained positive BOLD response in the absence of a significant CMRO2 increase from baseline, for all but the first task blocks. This suggests that the brain may continue to elevate the supply energy even after CMRO2 has returned to near baseline levels. Relying on BOLD fMRI data alone in studies of plasticity may not reveal the nature of underlying metabolic responses and their changes over time. Calibrated fMRI approaches may offer a more complete picture of the energetic changes supporting plasticity and learning.

Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency.

l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT−/−) mice and AGAT−/− mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT−/− and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (Ivd, Lcmt2), creatine metabolism (Slc6a8), cerebral myelination (Bcas1) and neuronal excitability (Kcnip3). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8. Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.

Disrupted functional connectivity of default mode and salience networks in chronic pancreatitis patients

ObjectiveThe functional connectivity of the brain in chronic pancreatitis (CP) remains unknown. This study aimed to investigate functional connectivity in CP patients using resting state functional magnetic resonance imaging (fMRI) and explore the associations to clinical parameters and altered cerebral metabolites. MethodsSeed-based and ROI-to-ROI analyses were performed to assess connectivity within and between the default mode network (DMN) and salience network (SN). Additionally, functional connectivity in these networks were investigated in relation to clinical parameters (CP etiology, pain, medication, etc.) and cerebral glutamate/creatine level in the anterior cingulate cortex. ResultsThirty CP patients and 23 healthy controls were analyzed. CP patients showed hyper-connectivity in DMN and SN as compared to healthy controls. Furthermore, CP patients had reduced anti-correlated functional connectivity between DMN and SN (all P ≤ 0.009). The altered DMN connectivity correlated to glutamate/creatine level (r = 0.503, P = 0.020) in patients with pain, but not to the clinical parameters. ConclusionsCP patients had altered functional connectivity within and between brain networks. Altered DMN functional connectivity had an association to cerebral metabolic changes. SignificanceAltered functional connectivity in CP share similarities with other chronic pain conditions, and support our understanding of altered brain circuitry associated with the CP disease.

Clinical and Cerebral Metabolic Changes in Parkinson's Disease With Basal Forebrain Atrophy.

Cholinergic dysfunction plays a key role in cognitive dysfunction in Parkinson's disease (PD). Recent studies revealed that atrophy in the nucleus basalis of Meynert (NBM), the largest cholinergic nucleus in the basal forebrain, heralds cognitive decline in PD. Despite clinical importance of NBM atrophy in PD, clinical and radiological correlates of NBM atrophy remains to be elucidated. We investigated the longitudinal changes in clinical and cerebral glucose metabolic characteristics in PD with atrophy in the NBM. We analyzed the 3-year longitudinal data of 56 PD patients who underwent motor, nonmotor, and imaging evaluations at baseline. The patients were classified into PD with and without NBM atrophy based on the results of magnetic resonance imaging volumetry. We compared clinical characteristics and cerebral glucose metabolic changes between PD with and without NBM atrophy. At baseline, 20 patients and 36 patients were classified into PD with and without NBM atrophy groups, respectively. At follow-up, the data of the 14 PD patients in the NBM atrophy group and the 18 patients in the group without NBM atrophy completed full assessments and were available for the analysis. The PD with NBM atrophy group showed severe cognitive dysfunction and psychiatric symptoms both at baseline and follow-up. The NBM volume significantly correlated with motor and nonmotor functions. The PD with NBM atrophy showed significantly reduced metabolism in the parietal and occipital cortices both at baseline and follow-up. Basal forebrain atrophy is a simple and sensible marker of faster disease progression and cortical hypometabolism in PD. © 2020 International Parkinson and Movement Disorder Society.

A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.

CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage.

Despite the multifactorial pathogenesis of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH), augmentation of cerebral blood flow (CBF) is still considered essential in the clinical management of DCI. The aim of this prospective observational study was to investigate cerebral metabolic changes in relation to CBF during therapeutic hypervolemia, hemodilution, and hypertension (HHH) therapy in poor-grade SAH patients with DCI. CBF was assessed by bedside xenon-enhanced CT at days 0-3, 4-7, and 8-12, and the cerebral metabolic state by cerebral microdialysis (CMD), analyzing glucose, lactate, pyruvate, and glutamate hourly. At clinical suspicion of DCI, HHH therapy was instituted for 5 days. CBF measurements and CMD data at baseline and during HHH therapy were required for study inclusion. Non-DCI patients with measurements in corresponding time windows were included as a reference group. In DCI patients receiving HHH therapy (n = 12), global cortical CBF increased from 30.4 ml/100 g/min (IQR 25.1-33.8 ml/100 g/min) to 38.4 ml/100 g/min (IQR 34.2-46.1 ml/100 g/min; p = 0.006). The energy metabolic CMD parameters stayed statistically unchanged with a lactate/pyruvate (L/P) ratio of 26.9 (IQR 22.9-48.5) at baseline and 31.6 (IQR 22.4-35.7) during HHH. Categorized by energy metabolic patterns during HHH, no patient had severe ischemia, 8 showed derangement corresponding to mitochondrial dysfunction, and 4 were normal. The reference group of non-DCI patients (n = 11) had higher CBF and lower L/P ratios at baseline with no change over time, and the metabolic pattern was normal in all these patients. Global and regional CBF improved and the cerebral energy metabolic CMD parameters stayed statistically unchanged during HHH therapy in DCI patients. None of the patients developed metabolic signs of severe ischemia, but a disturbed energy metabolic pattern was a common occurrence, possibly explained by mitochondrial dysfunction despite improved microcirculation.

Nonlinear Transfer Entropy to Assess the Neurovascular Coupling in Premature Neonates.

In the adult brain, it is well known that increases in local neural activity trigger changes in regional blood flow and, thus, changes in cerebral energy metabolism. This regulation mechanism is called neurovascular coupling (NVC). It is not yet clear to what extent this mechanism is present in the premature brain. In this study, we explore the use of transfer entropy (TE) in order to compute the nonlinear coupling between changes in brain function, assessed by means of EEG, and changes in brain oxygenation, assessed by means of near-infrared spectroscopy (NIRS). In a previous study, we measured the coupling between both variables using a linear model to compute TE. The results indicated that changes in brain oxygenation were likely to precede changes in EEG activity. However, using a nonlinear and nonparametric approach to compute TE, the results indicate an opposite directionality of this coupling. The source of the different results provided by the linear and nonlinear TE is unclear and needs further research. In this study, we present the results from a cohort of 21 premature neonates. Results indicate that TE values computed using the nonlinear approach are able to discriminate between neonates with brain abnormalities and healthy neonates, indicating a less functional NVC in neonates with brain abnormalities.

Changes in Brain Tissue Oxygenation and Metabolism During Rewarming After Neonatal Encephalopathy are Related to Electrical Abnormality.

Hypoxic ischemic encephalopathy (HIE) leads to significant mortality and morbidity, and therapeutic hypothermia (TH) has become a standard of care following HIE. After TH, the body temperature is brought back to 37°C. Early electroencephalography (EEG) is a reliable outcome biomarker following HIE. We hypothesized that changes in cerebral oxidative metabolism, measured as Δ[oxCCO], in relation to changes in brain tissue oxygenation (measured as Δ[HbD]) during rewarming will correlate with injury severity as evidenced on amplitude integrated EEG/EEG at initial presentation. Broadband near-infrared spectroscopy (NIRS) and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5h. All infants were monitored with video EEG telemetry using a standard neonatal montage. aEEG and EEG background was classified into mild, moderate and severely abnormal groups based on the background pattern. Two infants had mild, 6 infants had moderate and another 6 infants had severe abnormality at presentation. The relationship between [oxCCO] and [HbD] was evaluated between two groups of infants with abnormal electrical activity (mild vs moderate to severe). A significant difference was noted between the groups in the relationship between [oxCCO] and [HbD] (as r2) (p=0.02). This result indicates that the mitochondrial injury and deranged oxidative metabolism persists in the moderate to severely abnormal group during rewarming.