Brain Metabolism Research Articles

Elevated blood glucose levels are associated with the progression of brain hypometabolism, and HDL-C and APOE4 add to this association.

Brain glucose hypometabolism has consistently been found in neurodegenerative disorders, including Alzheimer's disease (AD). High blood glucose and HDL cholesterol (HDL-C) levels have also been linked to neurodegeneration and AD. However, there is limited understanding of the relationships between dementia-related risk factors in the brain and blood. A linear mixed model was used to examine the relationship between blood glucose and HDL-C levels and the progression of brain hypometabolism, adjusting for APOE4 and other clinical covariates. The hypometabolic convergence index (HCI) was measured by fluorodeoxyglucose-18 (FDG) positron emission tomography (PET) in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data visualizations were generated to understand the joint effects of plasma glucose, HDL-C, and APOE4 on HCI. There were 336 individuals (781 observations), of whom 22.62% had AD. The majority were male (63.98%) and of white race, and 48.51% were carriers of APOE4. Over time, high blood glucose level was associated with the progression of brain glucose hypometabolism (β=0.33, 95% CI: 0.02, 0.64, p<0.05). A high plasma HDL-C level (β=1.22, 95% CI: 0.09, 2.35, p<0.05), more study visits (β=1.67, 95% CI: 1.37, 1.98, p<0.001), and being an APOE4 allele carrier (β=1.29, 95% CI: 0.15, 2.42, p<0.05) were also significant predictors of brain hypometabolism progression. APOE4 carrier status and number of visits account for the largest proportion of the variance from the fixed effects model. Random effects due to participant characteristics and fixed effects together accounted for 95.2% of the model variance. Subgroup analysis revealed that these effects were observed only in those without AD. High plasma glucose levels facilitated the progression of brain hypometabolism. The effect was more prominent in the APOE4 double-carriers with elevated HDL-C. Elevated blood glucose may reflect systemic insulin resistance, which could impair brain glucose uptake, resulting in brain hypometabolism. Controlling blood glucose and HDL-C levels in APOE4 carriers may improve brain metabolism, potentially delaying the onset of dementia.

Accumulation of Cerebrospinal Fluid, Ventricular Enlargement, and Cerebral Folate Metabolic Errors Unify a Diverse Group of Neuropsychiatric Conditions Affecting Adult Neocortical Functions.

Cerebrospinal fluid (CSF) is a fluid critical to brain development, function, and health. It is actively secreted by the choroid plexus, and it emanates from brain tissue due to osmolar exchange and the constant contribution of brain metabolism and astroglial fluid output to interstitial fluid into the ventricles of the brain. CSF acts as a growth medium for the developing cerebral cortex and a source of nutrients and signalling throughout life. Together with perivascular glymphatic and interstitial fluid movement through the brain and into CSF, it also acts to remove toxins and maintain metabolic balance. In this study, we focused on cerebral folate status, measuring CSF concentrations of folate receptor alpha (FOLR1); aldehyde dehydrogenase 1L1, also known as 10-formyl tetrahydrofolate dehydrogenase (ALDH1L1 and FDH); and total folate. These demonstrate the transport of folate from blood across the blood-CSF barrier and into CSF (FOLR1 + folate), and the transport of folate through the primary FDH pathway from CSF into brain FDH + ve astrocytes. Based on our hypothesis that CSF flow, drainage issues, or osmotic forces, resulting in fluid accumulation, would have an associated cerebral folate imbalance, we investigated folate status in CSF from neurological conditions that have a severity association with enlarged ventricles. We found that all the conditions we examined had a folate imbalance, but these folate imbalances were not all the same. Given that folate is essential for key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, and neurotransmitter synthesis, we conclude that ageing or some form of trauma in life can lead to CSF accumulation and ventricular enlargement and result in a specific folate imbalance/deficiency associated with the specific neurological condition. We believe that addressing cerebral folate imbalance may therefore alleviate many of the underlying deficits and symptoms in these conditions.

Cardiovascular Disease, Brain Glucose Metabolism, and Neurocognitive Decline in People With Human Immunodeficiency Virus.

Cardiovascular disease (CVD) and neuroinflammation are thought to exacerbate neurocognitive dysfunction in treated people with human immunodeficiency virus (PWH). Here, we longitudinally measured brain glucose metabolism as a measure of neuronal integrity in treated PWH using [18F]Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in correlation with atherosclerotic cardiovascular disease (ASCVD) scores, cerebrospinal fluid (CSF) neuroinflammatory markers, neurocognitive outcomes, and other clinical and laboratory variables (CLVs). Well-controlled PWH (n = 36) underwent baseline and follow-up FDG PET/CT obtained 3.5 years apart on average. Longitudinal changes in whole brain and regional relative FDG uptake, brain volumes, CLVs, CSF cytokines, and neuropsychological measures were measured. A variable selection model identified baseline variables related to future brain metabolic changes while multivariable models explored neuropsychological implications of brain metabolism and volumetrics. High ASCVD scores predicted future decreased thalamic uptake (slope = -0.0068, P = .027) and decreasing thalamic uptake correlated with worsening cognition (slope = 15.80, P = .020). Despite longitudinal greater than expected gray matter loss, whole brain FDG uptake did not change over the follow-up period. Most CSF cytokines decreased longitudinally but were not predictive of FDG changes. We found that high ASCVD scores in a group of treated PWH were related to thalamic hypometabolism, which in turn correlated with neurocognitive decline. Our findings support the contribution of CVD to neurocognitive dysfunction. More proactive CVD management may have a role in mitigating progression of cognitive impairment. Lack of change in global brain glucose metabolism despite documented accelerated gray matter volume loss over the same period suggests that FDG PET might underestimate neuronal injury in PWH compared to structural magnetic resonance imaging.

Synthesis and Evaluation of 18F-Labeled Phenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron Emission Tomography Imaging.

The dopamine D3 receptor (D3R) is important in the pathophysiology of various neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, drug addiction, and Parkinson's disease. Positron emission tomography (PET) with innovative radioligands provides an opportunity to assess D3R in vivo and to elucidate D3R-related disease mechanisms. Herein, we present the synthesis of eight 18F-labeled phenylpiperazine-like D3R-selective radioligands possessing good radiochemical purity (>97%), in vitro stability (>95%), and befitting lipophilicity. Based on in vitro binding assays and static microPET studies, the phenylpiperazine-like radioligands [18F]FBPC01 and [18F]FBPC03 were chosen as lead radioligands targeting D3R. Molecular docking further elucidated their binding mechanism. Radiolabeling conditions were optimized and then applied to an automated radiolabeling process, affording products with high specific activity (>112 GBq/μmol). Dynamic rat PET study demonstrated the specific binding of [18F]FBPC01 and [18F]FBPC03 to D3R in the brain ventricles and the pituitary gland. Validated by dynamic PET data analysis, biodistribution study, and metabolism analysis, [18F]FBPC03 exhibited the highest PET signal-to-noise ratio, good D3R-specific binding in the brain ventricles and pituitary gland of rats with few off-target binding, negligible defluorination, and stable brain metabolism, which indicated that [18F]FBPC03 was a promising D3R radioligand.

Acute exercise alters brain glucose metabolism in aging and Alzheimer's disease.

There is evidence that aerobic exercise improves brain health. Benefits may be modulated by acute physiological responses to exercise, but this has not been well characterized in older or cognitively impaired adults. The randomized controlled trial 'AEROBIC' (NCT04299308) enrolled 60 older adults who were cognitively healthy (n=30) or cognitively impaired (n=30) to characterize the acute brain responses to moderate [45-55% heart rate reserve (HRR)] and higher (65-75% HRR) intensity acute exercise. Each participant received two fluorodeoxyglucose positron emission tomography (FDG-PET) scans, one at rest and one following acute exercise. Change in cerebral glucose metabolism from rest to exercise was the primary outcome. Blood biomarker responses were also characterized as secondary outcomes. Whole grey matter FDG-PET standardized uptake value ratio (SUVR) differed between exercise (1.045±0.082) and rest (0.985±0.077) across subjects [Diff=-0.060, t(58)=13.8, P<0.001] regardless of diagnosis. Exercise increased lactate area under the curve (AUC) [F(1,56)=161.99, P<0.001] more in the higher intensity group [mean difference (MD)=97.0±50.8] than the moderate intensity group (MD=40.3±27.5; t=-5.252, P<0.001). Change in lactate AUC and FDG-PET SUVR correlated significantly (R2=0.179, P<0.001). Acute exercise decreased whole grey matter cerebral glucose metabolism. This effect tracked with the systemic lactate response, suggesting that lactate may serve as a key brain fuel during exercise. Direct measurements of brain lactate metabolism in response to exercise are warranted. KEY POINTS: Acute exercise is associated with a drop in global brain glucose metabolism in both cognitively healthy older adults and those with Alzheimer's disease. Blood lactate levels increase following acute exercise. Change in brain metabolism tracks with blood lactate, suggesting it may be an important brain fuel. Acute exercise stimulates changes in brain-derived neurotrophic factor and other blood biomarkers.

The impact of isoflurane anesthesia on brain metabolism in mice: An MRI and electroencephalography study.

Isoflurane is one of the most widely used anesthetic agents in rodent imaging studies. However, the impact of isoflurane on brain metabolism has not been fully characterized to date, primarily due to a scarcity of noninvasive technologies to quantitatively measure the brain's metabolic rate in vivo. In this study, using noncontrast MRI techniques, we dynamically measured cerebral metabolic rate of oxygen (CMRO2) under varying doses of isoflurane anesthesia in mice. Concurrently, systemic parameters of heart and respiration rates were recorded alongside CMRO2. Additionally, electroencephalogram (EEG) recording was used to identify changes in neuronal activities under the same anesthetic regimen employed in the MRI experiments. We found suppression of the CMRO2 by isoflurane in a dose-dependent manner, concomitant with a diminished high-frequency EEG activity. The degree of metabolic suppression by isoflurane was strongly correlated with the respiration rate, which offers a potential approach to calibrate CMRO2 measurements. Furthermore, the metabolic level associated with neural responses of the somatosensory and motor cortices in mice was estimated as 308.2μmol/100 g/min. These findings may facilitate the integration of metabolic parameters into future studies involving animal disease models and anesthesia usage.

Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer's Disease: Clues from [18F]FDG PET Voxel-Wise Analysis.

Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.

Assessment of Mannitol-Induced Chronic Blood-Brain Barrier Dysfunction In Vivo Using Magnetic Resonance.

The blood-brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer's disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus/week (2.0 g/kg), Group 2 received 3 boluses/week (1.5 g/kg), and Group 3 received 3 boluses/week (2.5 g/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research.

Interactions between mild depressive symptoms and amyloid pathology on the trajectory of neurodegeneration, cognitive decline, and risk of Alzheimer's disease

BackgroundAlzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and β-amyloid (Aβ) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aβ on AD development. MethodsLongitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of β-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence. ResultsIndividuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001). ConclusionThese findings emphasized that the MDS-Aβ interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage.

Sevoflurane in the Acute Phase of Severe Traumatic Brain Injury

The aim of the study was to evaluate the usefulness and safety of sevoflurane in patients in the acute phase of severe traumatic brain injury (TBI).Materials and methods. A prospective, randomized, pilot clinical trial was conducted at the Sklifosovsky Research Institute for Emergency Medicine (Moscow) in adults with acute severe TBI, aged 18 years and older, undergoing intensive intracranial pressure (ICP)-guided therapy. To achieve the desired sedative effect, the inhaled anesthetic sevoflurane was administered in the main group, and standard doses of intravenous propofol were administered in the control group. ICP and cerebral oxygen extraction fraction (OEF) were monitored in all patients. Hemodynamic and respiratory support parameters, transcranial Doppler ultrasound scan, brain bioelectrical activity, brain CT scan, laboratory parameters, markers of inflammation, patients' need for sedation and mechanical ventilation, and length of ICU stay were also evaluated.Results. The use of inhalation sedation contributed to the reduction of ICP on day 2 (9.5 mmHg in the sevoflurane group and 17.3 mmHg in the propofol group, P=0.003) and day 3 (10 mmHg and 14.2 mmHg, respectively, P=0.005). BIS monitoring showed no significant difference in depth of sedation between groups on day 2 (60 vs. 48.5, P=0.070) and day 3 (61 vs. 46, P=0.095). Inhalation sedation reduced cerebral OEF on the injury side compared to propofol on day 2 (23.3 vs. 30.2%, P=0.006) and day 3 (22.7 vs. 31.2%, P&lt;0.001). After 24 hours of sedation therapy, there was a significant difference in P/F (PaO₂/FiO₂) ratios between the groups. On days 1, 3, and 7, the sevoflurane group had P/F ratios of 340, 324, and 323 mmHg, while the propofol group had significantly lower ratios of 271, 278, and 275 mmHg (P&lt;0.001). Pneumonia was documented in 9 cases in the sevoflurane group vs. 18 cases in the propofol group (P=0.028), and a similar trend was observed in the total number of infectious complications: 13 vs. 21 cases, respectively (P=0.046).Conclusion. Sevoflurane in the acute phase of severe TBI was not only safe, but also improved several vital functions, including ICP, blood pressure, P/F ratio, and also slowed brain metabolism via reduced oxygen consumption without affecting the depth of sedation according to BIS monitoring data. All of the above suggests that inhalation sedation may improve the prognosis for patient recovery. However, multicenter randomized clinical trials are needed to identify and verify all positive and negative effects of inhalation sedation in this patient population.

Differences in subcortical functional connectivity in patients with epilepsy.

Epilepsy is a disease characterized by abnormal paroxysmal bioelectrical activity in the brain cortex and subcortical structures. Seizures per se change brain metabolism in epileptic focus and in distal parts of the brain. However, interictal phenomena can also affect functional connectivity (FC) and brain metabolism in other parts of the brain. We hypothesised that epilepsy affects functional connectivity not only among cortical, but also between subcortical, structures of the brain in a resting state condition. Investigating functional connectivity in patients with epilepsy could provide insights into the underlying pathophysiological mechanisms. Better understanding may lead to more effective treatment strategies. Functional connectivity was analysed in 35 patients with epilepsy and in 28 healthy volunteers. The group of patients was divided into generalised and focal epilepsy (temporal and extratemporal subgroups). Each patient and healthy volunteer underwent an fMRI resting-state session. During the study, EEG signals were simultaneously recorded with fMRI to facilitate the subsequent detection of potential interictal epileptiform discharges (IEDs). Their potential impact on BOLD signals was mitigated through linear regression. The data was processed and correlation coefficients (FC values) between the BOLD signal from selected structures of the central nervous system were determined and compared between study groups. The results were presented as significant differences in correlation coefficients between brain/subcortical structures in the epilepsy and control groups. Lower FC values for the epilepsy group compared to the control group were shown for connections related to the MPFC, hippocampus, thalamus, amygdala, and the parahippocampal gyrus. Epilepsy alters the functional connectivity of resting state subcortical networks. Patterns of pathological changes of FC differ between epilepsy subtypes, with predominant lower FC between the hippocampus, parahippocampal gyrus, amygdala and thalamus in patients with epilepsy. This study suggests that epilepsy affects subcortical structures. Identifying distinct patterns of altered FC in epilepsy subtypes may help to tailor treatment strategies. Changes in FC detected by fMRI may precede clinical symptoms, aiding in the early diagnosis of cognitive and emotional disorders in focal epilepsy.

Neuroimaging Biomarkers in Addiction.

As a neurobiological process, addiction involves pathological patterns of engagement with substances and a range of behaviors with a chronic and relapsing course. Neuroimaging technologies assess brain activity, structure, physiology, and metabolism at scales ranging from neurotransmitter receptors to large-scale brain networks, providing unique windows into the core neural processes implicated in substance use disorders. Identified aberrations in the neural substrates of reward and salience processing, response inhibition, interoception, and executive functions with neuroimaging can inform the development of pharmacological, neuromodulatory, and psychotherapeutic interventions to modulate the disordered neurobiology. Based on our systematic search, 409 protocols registered on ClinicalTrials.gov include the use of one or more neuroimaging paradigms as an outcome measure in addiction, with the majority (N=268) employing functional magnetic resonance imaging (fMRI), followed by positron emission tomography (PET) (N=71), electroencephalography (EEG) (N=50), structural magnetic resonance imaging (MRI) (N=35) and magnetic resonance spectroscopy (MRS) (N=35). Furthermore, in a PubMed systematic review, we identified 61 meta-analyses including 30 fMRI, 22 structural MRI, 8 EEG, 7 PET, and 3 MRS meta-analyses suggesting potential biomarkers in addictions. These studies can facilitate the development of a range of biomarkers that may prove useful in the arsenal of addiction treatments in the coming years. There is evidence that these markers of large-scale brain structure and activity may indicate vulnerability or separate disease subtypes, predict response to treatment, or provide objective measures of treatment response or recovery. Neuroimaging biomarkers can also suggest novel targets for interventions. Closed or open loop interventions can integrate these biomarkers with neuromodulation in real-time or offline to personalize stimulation parameters and deliver the precise intervention. This review provides an overview of neuroimaging modalities in addiction, potential neuroimaging biomarkers, and their physiologic and clinical relevance. Future directions and challenges in bringing these putative biomarkers from the bench to the bedside are also discussed.

Transdiagnostic depression severity and its relationship to global and prefrontal-amygdala structural properties in people with major depression and post-traumatic stress disorder.

While some studies have used a transdiagnostic approach to relate depression to metabolic or functional brain alterations, the structural substrate of depression across clinical diagnostic categories is underexplored. In a cross-sectional study of 52 patients with major depressive disorder and 51 with post-traumatic stress disorder, drug-naïve, and spanning mild to severe depression severity, we examined transdiagnostic depressive correlates with regional gray matter volume and the topological properties of gray matter-based networks. Locally, transdiagnostic depression severity correlated positively with gray matter volume in the right middle frontal gyrus and negatively with nodal topological properties of gray matter-based networks in the right amygdala. Globally, transdiagnostic depression severity correlated positively with normalized characteristic path length, a measure implying brain integration ability. Compared with 62 healthy control participants, both major depressive disorder and post-traumatic stress disorder patients showed altered nodal properties in regions of the fronto-limbic-striatal circuit, and global topological organization in major depressive disorder in particular was characterized by decreased integration and segregation. These findings provide evidence for a gray matter-based structural substrate underpinning depression, with the prefrontal-amygdala circuit a potential predictive marker for depressive symptoms across clinical diagnostic categories.

Multi-modal, Label-free, Optical Mapping of Cellular Metabolic Function and Oxidative Stress in 3D Engineered Brain Tissue Models.

Brain metabolism is essential for the function of organisms. While established imaging methods provide valuable insights into brain metabolic function, they lack the resolution to capture important metabolic interactions and heterogeneity at the cellular level. Label-free, two-photon excited fluorescence imaging addresses this issue by enabling dynamic metabolic assessments at the single-cell level without manipulations. In this study, we demonstrate the impact of spectral imaging on the development of rigorous intensity and lifetime label-free imaging protocols to assess dynamically over time metabolic function in 3D engineered brain tissue models comprising human induced neural stem cells, astrocytes, and microglia. Specifically, we rely on multi-wavelength spectral imaging to identify the excitation/emission profiles of key cellular fluorophores within human brain cells, including NAD(P)H, LipDH, FAD, and lipofuscin. These enable development of methods to mitigate lipofuscin's overlap with NAD(P)H and flavin autofluorescence to extract reliable optical metabolic function metrics from images acquired at two excitation wavelengths over two emission bands. We present fluorescence intensity and lifetime metrics reporting on redox state, mitochondrial fragmentation, and NAD(P)H binding status in neuronal monoculture and triculture systems, to highlight the functional impact of metabolic interactions between different cell types. Our findings reveal significant metabolic differences between neurons and glial cells, shedding light on metabolic pathway utilization, including the glutathione pathway, OXPHOS, glycolysis, and fatty acid oxidation. Collectively, our studies establish a label-free, non-destructive approach to assess the metabolic function and interactions among different brain cell types relying on endogenous fluorescence and illustrate the complementary nature of information that is gained by combining intensity and lifetime-based images. Such methods can improve understanding of physiological brain function and dysfunction that occurs at the onset of cancers, traumatic injuries and neurodegenerative diseases.

Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports

Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson’s disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient’s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.

Metabolic and dopaminergic correlates of intellectual enrichment in de-novo Parkinson's disease patients.

Cognitive reserve (CR) is an expression of brain resilience in response to damage. Education, occupational experience and leisure activities are thought to increase CR and have beneficial effects on global cognition and cognitive decline in Parkinson's disease (PD). We aimed to disclose brain metabolic and dopaminergic correlates of CR in de-novo PD patients. Sixty-two drug-naïve de-novo PD patients underwent [18F]FDG-PET and DAT-SPECT. CR was quantified through the Cognitive-Reserve-Index questionnaire including total-CR and 3 subscores (educational-CR, occupational-CR, leisure-CR). Specific binding ratios (SBRs) and Z-scores in basal ganglia were obtained with 'BasGan-V2'. Z-scores were used as dependent variables in general linear models to assess the interaction between dopaminergic function and CR. Voxel-based correlation between brain metabolism and CR-scores and between SBR and [18F]FDG-PET was evaluated using SPM12 (P<0.05 FWE-corrected at peak and cluster level considered significant). Dopaminergic deficit in the most affected hemisphere (MAH) putamen was significantly less marked in higher CR patients (Z-score -1.7±0.1 highly-educated versus -2.1±0.1 poorly-educated, P<0.02). Total and leisure-related-CR resulted correlated directly with z-scores of the MAH putamen (P<0.018 and P<0.003) and inversely with brain metabolism in both cerebellar hemispheres (P<0.001). MAH-putamen SBR correlated directly with metabolism in occipital and parietal cortex (P<0.003) and inversely in cerebellar hemispheres (P<0.02). CR proxies demonstrated to correlate directly with dopaminergic function and inversely with metabolism in cerebellar hemispheres in de-novo PD patients. The present multi-modal approach including both metabolic and dopaminergic correlates of CR allowed to identify possible compensation mechanisms, highlighting a potential role of the cerebellum that deserves further investigation.

Influence of the Onset of Menopause on the Risk of Developing Alzheimer's Disease.

Menopause is a natural phase marked by the permanent cessation of menstrual cycles, occurring when the production of reproductive hormones from the ovaries stops for at least 12 consecutive months. Studies have suggested a potential connection between menopause and a heightened risk of developing Alzheimer's disease (AD), underscoring the significant role of reduced estrogen levels in the development of AD. Estrogen plays a crucial role in brain metabolism, influencing energy metabolism, synaptic plasticity, and cognitive functions. The cognitive benefits associated with hormone replacement therapy (HRT) are believed to be linked to estrogen's neuroprotective effects, either through direct action on the brain or indirectly by improving cardiovascular health. Extensive literature supports the positive impact of estrogen on brain cells. While the physiological effects of estrogen on the brain have not been consistently replicated in clinical trials, further research is crucial to provide more definitive recommendations to menopausal patients regarding the influence of HRT on AD. This review aims to comprehensively explore the interplay between menopause and AD, as well as the potential of HRT to mitigate cognitive decline in post-menopausal individuals.

Effect of optimizing cerebral oxygen saturation on postoperative delirium in older patients undergoing one-lung ventilation for thoracoscopic surgery.

This randomized controlled trial investigated whether the regional cerebral oxygenation saturation (rScO2)-guided lung-protective ventilation strategy could improve brain oxygen and reduce the incidence of postoperative delirium (POD) in patients older than 65 years. This randomized controlled trial enrolled 120 patients undergoing thoracic surgery who received one-lung ventilation (OLV). Patients were randomly assigned to the lung-protective ventilation group (PV group) or rScO2-oriented lung-protective ventilation group (TPV group). rScO2 was recorded during the surgery, and the occurrence of POD was assessed. The incidence of POD 3 days after surgery-the primary outcome-was significantly lower in the TPV group (23.3% versus 8.5%). Meanwhile, the levels of POD-related biological indicators (S100β, neuron-specific enolase, tumor necrosis factor-α) were lower in the TPV group. Considering the secondary outcomes, both groups exhibited a lower oxygenation index after OLV, whereas partial pressure of carbon dioxide and mean arterial pressure were significantly increased in the TPV group. In addition, minimum rScO2 during surgery and mean rScO2 were higher in the TPV group than in the PV group. Continuous intraoperative monitoring of brain tissue oxygenation and active intervention measures guided by cerebral oxygen saturation are critical for improving brain metabolism and reducing the risk of POD.

Effect of Infection on the Incidence of Hyperglycemic Hemichorea: A Case-Series.

To explore the effect of infection on hyperglycemic hemichorea. The clinical data of 11 patients with hyperglycemic hemichorea admitted to the Affiliated People' s Hospital of Xinxiang Medical College and the Second People's Hospital of Xinxiang were retrospectively analyzed, including gender, age, clinical symptoms, imaging features, blood glucose, glycated hemoglobin, infection indicators, and treatment conditions. Eleven patients had acute or sub-acute onset, including 9 females and 2 males, with an average age of 74.55 years. Nine patients presented with unilateral limb involuntary movement and 2 patients presented with bilateral limb involuntary movement. Imaging findings of 9 patients showed abnormalities in the basal ganglia region. Random blood glucose levels were all elevated at admission, with an average blood glucose value of 26.20 mmol/l. Urine ketone bodies were positive in 2 patients, inflammatory indexes were elevated in 7 patients, symptoms of hypoglycemic treatment and anti-infection treatment in 10 patients disappeared, and symptoms of 1 patient disappeared after improved microcirculation treatment. The disease tends to occur in middle-aged and elderly women, and the blood glucose may fluctuate significantly during the onset. Infection may lead to the occurrence and development of the disease. Active control of blood sugar, inflammation and improvement of brain metabolism can effectively control symptoms and prevent recurrence.

18F-FDG brain PET: a metabolic predictive factor for gait improvement after cerebrospinal fluid shunting in normal pressure hydrocephalus?

The pathophysiology of normal pressure hydrocephalus (NPH) has not been fully elucidated. Treating NPH with cerebrospinal fluid shunts to improve gait disturbances may have some risks and inconsistent benefits. No clear predictive factor has been identified thus far. This preliminary study aimed to evaluate the predictive value of preoperative brain 18F-FDG positron emission tomography (PET) on overall gait response in patients with NPH. Sixteen patients with NPH who underwent 18F-FDG PET before shunt surgery between 2012 and 2022 were included retrospectively and separated into two groups based on their gait response one year after surgery: responders (R) or nonresponders (NR). Brain glucose metabolism was assessed using visual and semiquantitative analyses using SPM8 software (Welcome Department of Cognitive Neurology, University College, London, UK). Five regions of interest were selected: global cortex, cerebellum, thalamus, striatum, and midbrain. Visual interpretation showed more frequent hypometabolism of the striatum, thalamus and global cortex in NR. None of the patients showing hypometabolism of these regions were R. Based on these results, the visual interpretation allowed us to identify 3/8 NR and 8/8 R. Semiquantitative analysis confirmed significantly lower thalamic metabolism in the NR group (P=0.037) and a trend towards lower metabolism of the striatum (P=0.075) with an area under the curve of 0.77 for thalamic metabolism to discriminate between R and NR. This preliminary study using brain 18F-FDG PET suggests that reduced brain metabolism in the thalamus and striatum along with cortical hypometabolism may be associated with poorer gait response to CSF shunting in normal pressure hydrocephalus (NPH). Although these findings suggest that preoperative brain 18F-FDG PET could potentially aid in selecting appropriate candidates for shunt surgery, further research with larger sample sizes is needed to confirm these results.