Regional Brain Metabolism Research Articles

Positron emission tomography neuroimaging of [18F]fluorodeoxyglucose uptake and related behavior in the Pink1-/- rat model of Parkinson disease.

Parkinson disease (PD) is a neurodegenerative condition affecting multiple sensorimotor and cognitive systems. The Pink1-/- rat model exhibits vocal, cognitive, and limb use deficits seen in idiopathic PD. We sought to measure glucose metabolism in brain regions in Pink1-/- and wild type (WT) rats, and to associate these to measures of ultrasonic vocalization, cognition, and limb use behavior. Pink1-/- (n = 12) and WT (n = 14) rats were imaged by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in a repeated measures design at approximately 10 months of age and 6 weeks later. Relative regional glucose metabolism was indexed by whole brain normalized FDG uptake, which was calculated for 18 regions identified a priori for comparison. Behavioral measures included tests of communication via ultrasonic vocalization, cognition with 5-Choice Serial Reaction Time Test (5-CSRTT), and limb use with Cylinder Test and Challenge Beam. Relative glucose metabolism was significantly different in Pink1-/- rats in prelimbic area, striatum, nucleus ambiguus, globus pallidus, and posterior parietal association cortex compared to WT controls. For behavioral measures, Pink1-/- rats demonstrated quieter vocalizations with a restricted frequency range, and they showed increased number of foot-faults and hindlimb steps (shuffling) in limb motor tests. Significant behavior vs. brain correlations included associations of ultrasonic vocalization parameters with glucose metabolism indices in locus coeruleus and substantia nigra. FDG PET reveals abnormalities in relative regional brain glucose metabolism in Pink1-/- rats in brain regions that are important to cognition, vocalization, and limb motor control that are also impacted by Parkinson disease. This method may be useful for mechanistic studies of behavioral deficits and therapeutic interventions in translational studies in the Pink1-/- PD model.

Neurochemical Anatomy of Cushing's Syndrome.

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.

Impact of serum leptin and adiponectin levels on brain infarcts in patients with mild cognitive impairment and Alzheimer's disease: a longitudinal analysis.

The adipokines leptin and adiponectin have been associated with atherosclerosis and the risk of cerebral infarcts. Pre-clinical studies, however, suggest a protective role against ischemic brain damage. In this study we analyzed the relationship between serum leptin and adiponectin levels and the onset or progression of brain infarcts in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). All data were extracted from the ADNI database. The final population included 566 subjects, with 58 healthy controls, 396 MCI and 112 AD. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographics, neuropsychological test results, CSF biomarkers, regional brain metabolism with FDG-PET data and the number of brain infarcts on longitudinal MRI scans were extracted. Leptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the groups. Multivariate logistic regression analysis at baseline for the presence of brain infarcts showed a predictive value for leptin but not for adiponectin. Multivariate longitudinal analysis showed that age was the only significant predictor of brain infarcts development at 15-year follow-up, while serum leptin and adiponectin levels did not play a role in this population. The evidence on the pathogenetic or protective role of adipokines on ischemic brain damage is mixed. In this MCI and AD population, serum leptin and adiponectin were not associated with the development of brain infarcts; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.

Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81–0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer's disease.

Neuronal pentraxin-2 (NPTX2), crucial for synaptic functioning, declines in cerebrospinal fluid (CSF) as cognition deteriorates. The variations of CSF NPTX2 across mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and its association with brain metabolism remain elusive, albeit relevant for patient stratification and pathophysiological insights. We retrospectively analyzed 49 MCI-AD patients grouped by time until dementia (EMCI, n = 34 progressing within 2years; LMCI, n = 15 progressing later/stable at follow-up). We analyzed demographic variables, cognitive status (MMSE score), and CSF NPTX2 levels using a commercial ELISA assay in EMCI, LMCI, and a control group of age-/sex-matched individuals with other non-dementing disorders (OND). Using [18F]FDG PET scans for voxel-based analysis, we explored correlations between regional brain metabolism metrics and CSF NPTX2 levels in MCI-AD patients, accounting for age. Baseline and follow-up MMSE scores were lower in LMCI than EMCI (p value = 0.006 and p < 0.001). EMCI exhibited significantly higher CSF NPTX2 values than both LMCI (p = 0.028) and OND (p = 0.006). We found a significant positive correlation between NPTX2 values and metabolism of bilateral precuneus in MCI-AD patients (p < 0.005 at voxel level, p < 0.05 with family-wise error correction at the cluster level). Higher CSF NPTX2 in EMCI compared to controls and LMCI suggests compensatory synaptic responses to initial AD pathology. Disease progression sees these mechanisms overwhelmed, lowering CSF NPTX2 approaching dementia. Positive CSF NPTX2 correlation with precuneus glucose metabolism links to AD-related metabolic changes across MCI course. These findings posit CSF NPTX2 as a promising biomarker for both AD staging and progression risk stratification.

Non‐AD pathologies, as measured using a mismatch index between regional brain metabolism and tau PET signal, are associated with age, sex, and amyloid burden.

AbstractBackgroundBrain hypometabolism in the absence of tauopathy may indicate the presence of non‐AD pathologies. We aimed to investigate the mismatch between regional tau pathology and brain metabolism to characterize the profile of patients suspected to have co‐pathologies.MethodSixty‐one clinically impaired patients, attending the Memory Clinic, performed both a [18F]‐Fluorodeoxyglucose‐PET to assess brain metabolism and a [18F]‐MK6240 Tau‐PET to estimate tau burden. To compare these images, we normalized them using data from clinically normal older adults (n = 30), resulting in FDG and tau z‐scores for 74 FreeSurfer‐defined regions. We computed intra‐subject correlation coefficients between tau and FDG data as a mismatch index between tau and metabolism. We then compared FDG and tau z‐scores using intra‐individual paired sampled t‐tests and identified patients with hypometabolism exceeding tau pathology (suspecting co‐pathologies). To increase sensitivity, the same analysis was repeated using temporal regions only. We finally evaluated demographics, cognition, and amyloid burden in the group of patients with suspected co‐pathologies.ResultsIn the entire cohort, the intra‐subject FDG‐Tau correlation was significantly negative in the temporal lobe (r = ‐0.27, p&lt;0.05), but not in the entire neocortex (r = ‐0.11), demonstrating closer association between modalities in the temporal lobe, and greater mismatch in the other regions. Twenty‐five (41%) patients had significantly greater FDG z‐scores than tau z‐scores, including thirteen (21%) with greater hypometabolism than tau pathology in the temporal lobe. These patients were older and more frequently male than patients with greater tau pathology; those with a temporal mismatch also had lower amyloid pathology (Table 1). Older ages and better cognition were associated with the mismatch index in the entire neocortex (r = 0.25/0.49, p&lt;0.05); in addition, lower amyloid burden was associated with the temporal mismatch index (r = 0.27, p&lt;0.05, Fig.1).ConclusionPatients with greater temporal hypometabolism than tau deposition are older, more frequently males, and have lower amyloid burden than patients with greater temporal tau deposition. These patients are suspected to have temporal non‐AD pathologies.

Non‐AD pathologies, as measured using a mismatch index between regional brain metabolism and tau PET signal, are associated with age, sex, and amyloid burden

AbstractBackgroundBrain hypometabolism in the absence of tauopathy may indicate the presence of non‐AD pathologies. We aimed to investigate the mismatch between regional tau pathology and brain metabolism to characterize the profile of patients suspected to have co‐pathologies.MethodSixty‐one clinically impaired patients, attending the Memory Clinic, performed both a [18F]‐Fluorodeoxyglucose‐PET to assess brain metabolism and a [18F]‐MK6240 Tau‐PET to estimate tau burden. To compare these images, we normalized them using data from clinically normal older adults (n = 30), resulting in FDG and tau z‐scores for 74 FreeSurfer‐defined regions. We computed intra‐subject correlation coefficients between tau and FDG data as a mismatch index between tau and metabolism. We then compared FDG and tau z‐scores using intra‐individual paired sampled t‐tests and identified patients with hypometabolism exceeding tau pathology (suspecting co‐pathologies). To increase sensitivity, the same analysis was repeated using temporal regions only. We finally evaluated demographics, cognition, and amyloid burden in the group of patients with suspected co‐pathologies.ResultIn the entire cohort, the intra‐subject FDG‐Tau correlation was significantly negative in the temporal lobe (r = ‐0.27, p&lt;0.05), but not in the entire neocortex (r = ‐0.11), demonstrating closer association between modalities in the temporal lobe, and greater mismatch in the other regions. Twenty‐five (41%) patients had significantly greater FDG z‐scores than tau z‐scores, including thirteen (21%) with greater hypometabolism than tau pathology in the temporal lobe. These patients were older and more frequently male than patients with greater tau pathology; those with a temporal mismatch also had lower amyloid pathology (Table 1). Older ages and better cognition were associated with the mismatch index in the entire neocortex (r = 0.25/0.49, p&lt;0.05); in addition, lower amyloid burden was associated with the temporal mismatch index (r = 0.27, p&lt;0.05, Fig.1).ConclusionPatients with greater temporal hypometabolism than tau deposition are older, more frequently males, and have lower amyloid burden than patients with greater temporal tau deposition. These patients are suspected to have temporal non‐AD pathologies.

Prospective Randomized Placebo‐Controlled Trial of Long‐Term Durability of Effect of One Year of Grape Consumption on Preventing Decline of Cerebral Function

AbstractBackgroundLong‐term impact of one year of grape consumption on regional brain metabolism and associated neuropsychologic status was examined across multiple years of follow‐up.MethodTwenty subjects (74.6±5.4 years) were randomized to consume an active grape formulation (36g reconstituted freeze‐dried grape powder) or placebo (matched for sweetness and appearance but free of polyphenols) twice daily for one year. Changes in brain metabolism were assessed by PET with radiotracer [F‐18]fluorodeoxyglucose and cognitive performance was measured through neuropsychological testing, at baseline, 1 year after initiating consumption of grape or placebo formulation, and again 2 to 3 years after completing the randomized regimen in half of the subjects on each arm, with all subjects remaining blinded to which regimen they had been assigned until after final assessments. Activity in 47 standardized volumes of interest (sVOI’s) were measured, voxel‐based analyses using statistical parametric mapping were conducted, and associations were examined between interval changes in metabolism and neuropsychologic status.ResultDuring the year while consuming formulations, subjects randomized to placebo underwent metabolic decline in 27 sVOI’s, including particularly inferior posterior temporal (p = 0.006) and inferior frontal (p = 0.004) areas, correlating with neuropsychologic decline, while significant (p&lt;0.05) decline was seen in none of the 47 sVOI’s in the active formulation group. Voxel‐based analyses corroborated differential metabolic decline in placebo and active formulation groups, and direct difference‐of‐differences analyses further documented significantly more decline in the placebo group. Moreover, a significant difference in regional metabolism persisted at the end of follow‐up, after having discontinued randomized formulations for 28.1±5.7 months (40.0±5.4 after baseline), with mean medial temporal sVOI’s demonstrating significant decline in the group that had been randomized to placebo (‐4.6%, p = 0.009), but not in the group that had been in the active arm (‐1.5%, N.S.). Difference of magnitudes of long‐term metabolic decline between arms was significant in direct difference‐of‐differences analysis, and correlated with neuropsychologic decline (p&lt;0.001) in both inferior posterior temporal and inferior frontal regions.ConclusionSubjects randomized to consume reconstituted grapes twice daily enjoyed long‐term protection from loss of cerebral function, as assessed more than two years beyond the last consumed dose.

Relationship Between Memory and Brain Metabolism is Markedly Disordered in non‐Demented Patients Who Have Worsening Sleep Over Time

AbstractBackgroundDisturbances in circadian rhythm often emerge during disease progression in patients with dementia. We recently reported that subjects with worsening sleep experienced significantly faster cerebral decline compared to subjects with improved sleep over comparable timeframes. Here we describe relationships between brain metabolism and memory as a function of changing sleep status.MethodA consecutive series of 2,005 cognitively normal and mildly impaired subjects from more than 50 North American sites participating in the first three phases of the Alzheimer’s Disease Neuroimaging Initiative was studied. Changes in cognition assessed through formal neuropsychological testing, and in regional cerebral metabolism assessed through brain PET using the radiotracer [F‐18]fluorodeoxyglucose (FDG), were examined. Activities in 47 standardized volumes of interest (sVOI’s), as normalized to each subject’s whole brain activity, were longitudinally measured, and significance of changes in memory were evaluated using a Pearson correlational analysis and two‐sided one‐sample t tests.ResultIn this consecutive series of 2005 subjects, 211 were documented to have had a change in insomnia status during their participation: 83 who were documented to have insomnia at baseline that was subsequently alleviated (“improving sleep”), and 128 who were documented to have no insomnia at baseline but developed it during the study period (“worsening sleep”); among them, 62 (29%) underwent FDG‐PET scans during both baseline insomnia and subsequent insomnia‐free status, or both baseline normal sleep and subsequent insomnia status periods. In subjects with improving sleep, baseline metabolism of posterior cingulate cortex, the brain region with metabolism that declines most significantly in the earliest stages of Alzheimer’s disease, was strongly associated with memory domain performance (r = 0.65, p = 0.00003). In marked contrast, this relationship was severely degraded in subjects who had worsening sleep (r = 0.20, p = 0.18). Similar relative relationships, though somewhat less statistically dramatic, were also observed with respect to global cognition, as assessed by both ADAS‐COG and MMSE scores in both groups of subjects.ConclusionSubjects with worsening sleep over time showed a highly disordered relationship between their baseline regional brain metabolism and cognitive function, and this effect was most dramatic with respect to their memory domain performance.

Examining the Effects of Hospitalization in ADNI Subjects: Characterizing Changes in Cognition and Glucose Metabolism Associated with Inpatient Hospital Stays

AbstractBackgroundRisk of inpatient hospitalization and dementia both increase with age, though no study has attempted to characterize lasting changes in regional brain metabolism occurring after inpatient hospitalization.MethodWe screened adverse events reported to the Alzheimer’s Disease Neuroimaging Initiative (ADNI), identifying subjects with minimum one‐night hospitalizations and two pre‐ and two post‐hospitalization ADNI visits. 523 visits from 133 subjects were included in neuropsychological analysis, with 55 subjects hospitalized for major surgery. An analogous “event date” was set in demographically matched control subjects using the median elapsed time from first visit to hospitalization; 352 visits from 88 controls were included. Memory and executive function composite scores were used to calculate pre‐ and post‐event cognitive trajectories. Pre‐ and post‐event FDG‐PET images were acquired and quantitatively examined using standardized volume of interest (sVOI) analysis. Students t‐tests were used to determine the difference in pre‐ and post‐event trajectories within groups and between groups.ResultWithin‐group analysis of inpatient subjects revealed significantly declined trajectory of memory and executive function after hospitalization (p&lt;0.001, p = 0.02), though the difference in pre‐ and post‐event trajectory did not differ significantly from the control group. There was no significant difference in change in trajectory between subjects with surgical and non‐surgical hospitalizations. To prevent the dilution of metabolic alterations that may begin on one‐side, the sVOI with the greatest decline between post‐ and pre‐event trajectory was chosen for all bilateral volumes. Within the inpatient group, significant decline in metabolic trajectory after hospitalization was observed in the inferior lateral anterior and medial anterior temporal volumes (p&lt;0.005, p&lt;0.0005). This change in metabolic trajectory in the anterior temporal volumes after hospitalization was not significantly different between surgical and non‐surgical subjects. Finally, the decline in trajectory observed in the inferior lateral and medial anterior temporal volumes in the inpatient group was significantly greater than the control group (p = 0.05, p = 0.005), in which no significant decline in trajectory was observed.ConclusionInpatient hospitalization is associated with accelerated decline in metabolic trajectory after discharge in two anterior temporal volumes, regardless of whether the hospitalization was associated with a major surgery.

Abstract 015: Pioneering NaF‐PET/CT Imaging for Early Detection of Atherosclerosis: Potential Implications for Neurointerventional Surgery

Introduction Cerebrovascular disease (CVD), particularly carotid artery atherosclerosis, contributes substantially to global morbidity and mortality. The ability to precisely detect atherosclerosis is crucial, as it directly influences patient management, including decisions regarding surgical interventions. Given the high prevalence and severe outcomes of CVD, there is an urgent need for improved early detection methods. Utilizing a novel approach, this study pioneers the use of 18F‐sodium fluoride (NaF) PET/CT imaging for the early identification of microcalcification, a key marker of atherosclerosis. A nuanced understanding of vascular calcification's temporal progression may aid in optimally timing surgical interventions, such as carotid endarterectomy or carotid artery stenting, thereby reducing stroke risk. Methods Our study participant is a 31‐year‐old male with atrial fibrillation, multiple cardiovascular risk factors, and class 2 obesity, enrolled in the Cardiovascular Molecular Calcification Assessed by 18F‐NaF PET/CT (CAMONA) study. The patient underwent both FDG‐PET/CT and NaF‐PET/CT imaging. We utilized OsiriX MD software v.13.0.1 (Pixmeo SARL, Bernex, Switzerland), to compute the standardized uptake value (SUVmean), serving as a measure of disease progression in both the global brain and the bilateral carotid arteries. Subsequently, we employed MIMneuro version 7.1.5 (MIM Software, Inc., Cleveland, OH, USA) to conduct a comprehensive regional brain metabolism analysis, harnessing the power of an integrated anatomical atlas. Results NaF‐PET/CT imaging revealed elevated NaF uptake in the bilateral carotid arteries (z‐score = 0.012), suggesting notable microcalcification. Conversely, FDG‐PET/CT imaging revealed low FDG uptake in the carotid arteries, with an average SUVmean of 0.66 for both right and left carotids and a z‐score of −2.32. Analysis of global brain metabolism demonstrated decreased FDG uptake detected by FDG‐PET/CT (z‐score = ‐2.32). Concurrently, we identified a decline in regional brain metabolism, with prominent decreases observed in regions including the brainstem (z score = −1.95), medial temporal lobe (z‐score = −1.81), cerebellum (z–score = −2.13), hippocampus (z‐score = −2.13), inferior frontal gyrus (z‐score = −3.53), lateral orbital gyrus (z‐score = −3.24), and putamen (z‐score = −2.47) (Figure 1). Conclusion Our findings highlight the potential of NaF‐PET/CT imaging to enhance early detection of carotid artery atherosclerosis and cerebral hypometabolism. These results highlight the subtle, yet potent, potential of NaF‐PET/CT scans to detect active, asymptomatic cases where FDG‐PET/CT scans may not indicate high activity. The findings suggest that NaF‐PET could play a pivotal role in diagnosing and managing CVD where traditional tracers encounter limitations. Early recognition of these alterations facilitates clinical decision‐making, including determining the necessity and timing of surgical intervention. This advanced diagnostic tool presents an opportunity to improve pre‐operative assessments by providing insights into disease progression prior to macrocalcification development, a clear advantage over existing imaging modalities. The correlation between vascular calcification and decreased cerebral metabolism enhances our understanding of CVD pathophysiology, thereby paving the way for transformative therapeutic interventions. While these findings provide preliminary insight, further research is crucial to corroborate our results and delineate their potentially transformative implications on patient care, particularly in the context of surgical interventions.

SEROTONIN IN THE MEDIATION OF BEHAVIORAL EFFECTS OF OMEGA-3 FISH OIL SUPPLEMENTS: A STUDY IN RATS.

Omega-3 polyunsaturated fatty acids (omg-3 PUFAs) are widely prescribed for improving therapeutic strategies in many diseases. There are reports that the use of these supplements can reduce disease-related depression and anxiety in patients taking these supplements. However, pre-clinical research shows mixed results. In view of the role of serotonin (5-hydroxytryptamine, 5-HT) in anxiety and depression, the present study concern effects of omg-3 on anxiety-like behavior and on serotonin metabolism in brain regions known to have a role in anxiety. It was found that administration of omg-3 for 20 days did not alter food intake and body weight. The treatment reduced locomotor activity in an open field arena and enhanced anxiety-like behavior in an elevated plus-maze test. 5-HT concentration increased in the hippocampus (HPC) and midbrain (MB) but decreased in the prefrontal cortex (PFC). Levels of 5-hydroxyindoleacetic acid (5-HIAA) were decreased in these regions. The tryptophan levels were not affected in the PFC but increased in the HPC and MB at a low dose; suggesting that decreases of 5-HT and 5-HIAA were not due to a decrease in the availability of tryptophan. The present study implied that unnecessary use of omg-3 supplements can reduce serotonin neurotransmission via the PFC to predispose to anxiety.

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

Dynamic longitudinal relations between regional brain metabolism and stress-related blood cortisol during the first year of nonhuman primate life

Hypothalamic-pituitary-adrenal(HPA)-activation is critical to the stress response, promoting adaptation and survival. To further understand the developmental time-course of stress-related HPA-activation and its neural correlates in nonhuman primates (NHP), we longitudinally studied infant rhesus monkeys from birth to 1-year. 35 monkeys (24 F/11 M) were assessed 5 times during development (T1-T5; average ages: 11,43,84,168,365 days). At each timepoint, subjects were injected with 18flurodeoxyglucose (FDG) and exposed to 30 minutes of potential threat (No-eye-contact condition of Human Intruder Paradigm, NEC). Subjects were anesthetized, had blood drawn, and underwent a PET scan. We performed timepoint-specific voxel-wise correlations of plasma cortisol levels and FDG-PET metabolism. Threat-induced cortisol levels displayed logarithmic growth across the first year of life (p<0.0002). Cortisol at T1 predicted cortisol levels at T2 and T3 (p<0.001), but not at T4 or T5 (p>0.1). Cortisol levels related to metabolism in different brain regions at each age (p<0.005, uncorrected). At younger ages, higher cortisol levels following NEC were associated with decreased brain metabolism (T1: amygdala; T2: amygdala, anterior hippocampus). At older ages, higher cortisol levels were associated with increased brain metabolism (T4: sublenticular extended amygdala, T5: bed nucleus of stria terminalis, thalamus). These findings demonstrate that the developmental pattern of HPA-activation in young NHPs may be logarithmic in nature. Our findings also indicate changes to the relationship between individual differences in stress-related HPA-activation and regional brain metabolism during this time. Interestingly, cortisol has negative correlations with limbic regions in newborns, later transitioning to adult-like positive correlations with limbic regions.

Correlation analysis between 18F-fluorodeoxyglucose positron emission tomography and cognitive function in first diagnosed Parkinson's disease patients.

Evaluation of the correlation between 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and cognitive function in first-diagnosed and untreated Parkinson's disease (PD) patients. This cross-sectional study included 84 first diagnosed and untreated PD patients. The individuals were diagnosed by movement disorder experts based on the 2015 MDS Parkinson's disease diagnostic criteria. The patients also underwent 18F-FDG PET scans and clinical feature assessments including the Montreal Cognitive Assessment (MoCA) scale. Glucose metabolism rates were measured in 26 brain regions using region of interest (ROI) and pixel-wise analyses with displayed Z scores. The cognitive function was assessed by professionals using the MoCA scale, which covers five cognitive domains. Spearman's linear correlation and linear regression models were used to compare the correlations between 18F-FDG metabolism in each brain region and cognitive domain, using SPSS 25.0 software. The results indicated a positive correlation between executive function and glucose metabolism in the lateral prefrontal cortex of the left hemisphere (p = 0.041). Additionally, a positive correlation between memory function and glucose metabolism in the right precuneus (p = 0.014), right lateral occipital cortex (p = 0.017), left lateral occipital cortex (p = 0.031), left primary visual cortex (p = 0.008), and right medial temporal cortex (p = 0.046). Further regression analysis showed that for every one-point decrease in the memory score, the glucose metabolism in the right precuneus would decrease by 0.3 (B = 0.30, p = 0.005), the glucose metabolism in the left primary visual cortex would decrease by 0.25 (B = 0.25, p = 0.040), the glucose metabolism in the right lateral occipital cortex would decrease by 0.38 (B = 0.38, p = 0.012), and the glucose metabolism in the left lateral occipital cortex would decrease by 0.32 (B = 0.32, p = 0.045). This study indicated that cognitive impairment in PD patients mainly manifests as changes in executive function, visual-spatial function and memory functions, while glucose metabolism mainly decreases in the frontal and posterior cortex. Further analysis shows that executive function is related to glucose metabolism in the left lateral prefrontal cortex. On the other hand, memory ability involves changes in glucose metabolism in a more extensive brain region. This suggests that cognitive function assessment can indirectly reflect the level of glucose metabolism in the relevant brain regions.

Functional PET Neuroimaging in Consciousness Evaluation: Study Protocol.

Ensuring a robust and reliable evaluation of coma deepness and prognostication of neurological outcome is challenging. We propose to develop PET neuroimaging as a new diagnostic and prognosis tool for comatose patients using a recently published methodology to perform functional PET (fPET). This exam permits the quantification of task-specific changes in neuronal metabolism in a single session. The aim of this protocol is to determine whether task-specific changes in glucose metabolism during the acute phase of coma are able to predict recovery at 18 months. Participation will be proposed for all patients coming for a standard PET-CT in our center in order to evaluate global cerebral metabolism during the comatose state. Legally appointed representative consent will be obtained to slightly modify the exam protocol: (1) 18F-fluorodeoxyglucose (18F-FDG) bolus plus continuous infusion instead of a simple bolus and (2) more time under camera to perform dynamic acquisition. Participants will undergo a 55-min fPET session with a 20% bolus + 80% infusion protocol. Two occurrences of three block (5-min rest, 10-min auditory stimulation and 10-min emotional auditory stimulation) will be performed after reaching equilibrium of FDG arterial concentration. We will compare the regional brain metabolism at rest and during the sessions of auditory and emotional auditory stimulation to search for a determinant of coma recovery (18 months of follow-up after the exam). Emotional auditory stimulation should induce an activation of: the auditory cortex, the consciousness areas and the neural circuitry for emotion (function to coma deepness). An activation analysis will be carried out to highlight regional brain activation using dedicated custom-made software based on Python statistical and image processing toolboxes. The association between activation levels and the Coma Recovery Scale-Revisited (CRS-R) will be assessed using multivariate analysis. If successful, the results from this study will help improve coma prognosis evaluation based on the pattern of neuronal metabolism at the onset of the pathology. The study protocol, rationale and methods are described in this paper.

Impact of serum leptin and adiponectin levels on the development of brain infarcts in patients with mild cognitive impairment and Alzheimer’s disease

AbstractBackgroundThe adipokines leptin and adiponectin have been associated with the development of atherosclerosis and the risk of cerebral infarctions. According to pre‐clinical studies, however, they play a protective role against ischemic brain damage. In this study we analysed the relationship between serum leptin and adiponectin levels and the onset or progression of silent brain infarctions in a population of subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).MethodAll data were extracted from the ADNI database. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographic and anamnestic data, neuropsychological test results, tau, phosphotau and amyloid levels in CSF and regional brain metabolism with FDG‐PET data were also extracted. The determination of the number of silent cerebral infarctions was performed on baseline brain MRI. The final population includes 566 subjects, with 58 normal controls, 396 MCI and 112 AD.ResultLeptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the three groups. Multivariate regression analysis in patients with cognitive impairment (MCI + AD, 508 subjects) showed that leptin levels were significantly associated with BMI, arterial hypertension and female sex. By stratifying the three diagnostic groups by the presence or absence of baseline infarctions, leptin levels were significantly higher in patients with AD and brain infarcts than in patients with AD without brain infarcts. However, multivariate logistic regression analysis at baseline for the presence or absence of brain infarcts did not confirm the predictive value of leptin. Multivariate longitudinal analysis did not attribute predictive value to serum leptin levels on the development of silent brain infarcts in this MCI and AD population.ConclusionThe evidence on the pathogenetic or protective role of adipokines on ischemic brain damage in the literature is mixed. In this population affected by MCI and AD, serum leptin and adiponectin levels are not associated with the development of brain infarctions; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.

Neurobiological Dysfunctional Substrates for the Self-Medication Hypothesis in Adult Individuals with Attention-Deficit Hyperactivity Disorder and Cocaine Use Disorder: A Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography Study.

Objectives: Attention-deficit hyperactivity disorder (ADHD) in adulthood shows high co-occurrence rates with cocaine use disorder (CoUD). The self-medication hypothesis (SMH) provides a theoretical explanation for this comorbidity. This study investigates the neurobiological mechanisms that could support SMH in adult patients with attention-deficit hyperactivity disorder with cocaine use disorder (ADHD-CoUD). Materials and Methods: We included 19 ADHD-CoUD patients (84.2% male; age: 32.11 years [7.18]) and 16 CoUD patients (68.7% male; age: 36.63 years [8.12]). All subjects underwent a fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) brain scan. We tested brain metabolism differences between ADHD-CoUD and CoUD patients using voxel-based and regions of interest (ROIs)-based analyses. The correlation between dependence/abstinence duration and regional brain metabolism was also assessed in the two groups. Lastly, we investigated the integrity of brain metabolic connectivity of mesocorticolimbic and nigrostriatal dopaminergic systems, and large-scale brain networks involved in ADHD and addictions. Results: The voxel-wise and ROIs-based approaches showed that ADHD-CoUD patients had a lower metabolism in the thalamus and increased metabolism in the amygdala and parahippocampus, bilaterally, than CoUD subjects and healthy controls (HCs). Metabolism in the thalamus negatively correlated with years of dependence in ADHD-CoUD patients. Moreover, connectivity analyses revealed that ADHD-CoUD patients had a more preserved metabolic connectivity than CoUD patients in the dopaminergic networks and large-scale networks involved in self-regulation mechanisms of attention and behaviors (i.e., anterior default mode network [ADMN], executive network [ECN], and anterior salience network [aSAN]). Conclusions: We demonstrated distinct neuropathological substrates underlying substance-use behaviors in ADHD-CoUD and CoUD patients. Furthermore, we provided neurobiological evidence in support of SMH, demonstrating that ADHD-CoUD patients might experience short-term advantages of cocaine assumption (i.e., compensation of dopaminergic deficiency and related cognitive-behavioral deficits).

Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity

BackgroundOne intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington’s disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions.MethodsThe right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method.ResultsMLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK—compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres.ConclusionsOverall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.

Dynamic Amyloid and Metabolic Signatures of Delayed Recall Performance within the Clinical Spectrum of Alzheimer's Disease.

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer's disease (AD). In this study, we assessed patients' scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer's Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based [18F]florbetapir and [18F]FDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe [18F]FDG uptake, and RAVLT30 scores positively associated with [18F]FDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake in the right frontal lobe. For the AD group, [18F]FDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and [18F]florbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages.