Altered Brain Glucose Metabolism Research Articles

Association of dysphagia with altered brain glucose metabolism in Parkinson's disease.

Dysphagia is a major clinical concern in Parkinson's disease (PD). However, the relationship between the development of phase-specific dysphagia and the regional brain glucose metabolism remains unclear. Our objective was to investigate the distributions of brain glucose metabolism specific to oral and pharyngeal phases of dysphagia in PD. In this retrospective cross-sectional study, patients with PD who underwent videofluoroscopic swallowing study (VFSS) and 18 F-fluorodeoxy-glucose positron emission tomography at intervals of <1 month were included. Each swallow was assessed by the binarized Videofluoroscopic Dysphagia Scale with 14 subitems, seven each for the oral and pharyngeal phases. Metabolism mapping was performed by superimposing significant clusters of subitems belonging to each of the two phases using voxel-wise Firth's penalized binary logistic regression model, adjusting for age and PD duration at VFSS. Eighty-two patients with PD who met the inclusion criteria were included in the analysis. The oral phase dysphagia-specific overlap map showed hypermetabolism in the right inferior temporal gyrus, bilateral cerebellum, superior frontal gyrus, and anterior cingulate cortices. Hypometabolism in the bilateral orbital and triangular parts of the inferior to middle frontal gyrus was also correlated with the occurrence of oral phase dysphagia. The development of pharyngeal phase dysphagia was related to hypermetabolism of posterior aspects of the bilateral parietal lobes, cerebellum, and hypometabolism of the mediodorsal aspects of anterior cingulate and middle to superior frontal gyri. These findings suggest that phase-specific distribution of brain glucose metabolism may explain the dysphagia of PD.

The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats.

Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/-OC. Adolescent and adult Sprague-Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/-OC (combined OC or placebo delivered via oral gavage) for 16-21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats.

Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases.

Several neurological diseases share pathological alterations, even though they differ in their etiology. Neuroinflammation, altered brain glucose metabolism, oxidative stress, mitochondrial dysfunction and amyloidosis are biological events found in those neurological disorders. Altered insulin-mediated signaling and brain glucose hypometabolism are characteristic signs observed in the brains of patients with certain neurological diseases, but also others such as type 2 diabetes mellitus and vascular diseases. Thus, significant reductions in insulin receptor autophosphorylation and Akt kinase activity, and increased GSK-3 activity and insulin resistance, have been reported in these neurological diseases as contributing to the decline in cognitive function. Supporting this relationship is the fact that nasal and hippocampal insulin administration has been found to improve cognitive function. Additionally, brain glucose hypometabolism precedes the unmistakable clinical manifestations of some of these diseases by years, which may become a useful early biomarker. Deficiencies in the major pathways of oxidative energy metabolism have been reported in patients with several of these neurological diseases, which supports the hypothesis of their metabolic background. This review remarks on the significance of insulin and brain glucose metabolism alterations as keystone common pathogenic substrates for certain neurological diseases, highlighting new potential targets.

Enhanced Fear Memories and Altered Brain Glucose Metabolism (18F-FDG-PET) following Subanesthetic Intravenous Ketamine Infusion in Female Sprague-Dawley Rats.

Although women and men are equally likely to receive ketamine following traumatic injury, little is known regarding sex-related differences in the impact of ketamine on traumatic memory. We previously reported that subanesthetic doses of an intravenous (IV) ketamine infusion following fear conditioning impaired fear extinction and altered regional brain glucose metabolism (BGluM) in male rats. Here, we investigated the effects of IV ketamine infusion on fear memory, stress hormone levels, and BGluM in female rats. Adult female Sprague–Dawley rats received a single IV ketamine infusion (0, 2, 10, or 20 mg/kg, over a 2-h period) following auditory fear conditioning (three pairings of tone and footshock). Levels of plasma stress hormones, corticosterone (CORT) and progesterone, were measured after the ketamine infusion. Two days after ketamine infusion, fear memory retrieval, extinction, and renewal were tested over a three-day period. The effects of IV ketamine infusion on BGluM were determined using 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) and computed tomography (CT). The 2 and 10 mg/kg ketamine infusions reduced locomotor activity, while 20 mg/kg infusion produced reduction (first hour) followed by stimulation (second hour) of activity. The 10 and 20 mg/kg ketamine infusions significantly elevated plasma CORT and progesterone levels. All three doses enhanced fear memory retrieval, impaired fear extinction, and enhanced cued fear renewal in female rats. Ketamine infusion produced dose-dependent effects on BGluM in fear- and stress-sensitive brain regions of female rats. The current findings indicate that subanesthetic doses of IV ketamine produce robust effects on the hypothalamic–pituitary–adrenal (HPA) axis and brain energy utilization that may contribute to enhanced fear memory observed in female rats.

18F-FDG-PET brain imaging may highlight brain metabolic alterations in dysautonomic syndrome after human papilloma virus vaccination.

The aim of this study was to evaluate brain glucose metabolism by means of [18F]-fluoro-deoxygluycose (F-FDG) PET in a group of patients presenting dysautonomic syndrome after human papilloma virus (HPV) immunization. Medical records of patients, referred to the 'Second Opinion Medical Consulting Network' Medical Centre (Modena, Italy) diagnosed with dysautonomic syndrome were searched. Inclusion criteria were presence in the medical history of adverse drug reactions following HPV vaccine; a Montreal Cognitive Assessment score <25 and good quality of a F-FDG-PET brain scan performed within 12 months from the diagnosis of dysautonomic syndrome. F-FDG-PET images of patients (HPV-group) were compared to a control group, matched for age and sex, using statistical parametric mapping (SPM). The F-FDG-PET study was available for five female patients. The SPM-group analysis revealed significant hypometabolism (P < 0.05 false discovery rate corrected) in the right superior and medial temporal gyrus (Brodmann areas 22, 21) and insula (Brodmann area 13). At a threshold of P < 0.001 (uncorrected), further hypometabolic regions were revealed in the right superior temporal gyrus (Brodmann area 42) and caudate head and in the left superior temporal gyrus (Brodmann area 22), frontal subcallosal gyrus (Brodmann area 47) and insula (Brodmann area 13). Relative hypermetabolism (P = 0.001) was revealed in the right premotor cortex (Brodmann area 6). This study revealed the possibility of altered brain glucose metabolism in subjects with dysautonomic syndrome post-immunization with HPV vaccine. These results could reinforce the hypothesis of a causal relationship between HPV vaccine, or some component included in the vaccine and the development of clinical manifestations.

Changes in brain glucose metabolism and connectivity in somatoform disorders: an 18F-FDG PET study.

Somatoform disorders (SFD) are defined as a syndrome characterized by somatic symptoms which cannot be explained by organic reasons. Chronic or recurrent forms of somatization lead to heavy emotional and financial burden to the patients and their families. However, the underlying etiology of SFD is largely unknown. The purpose of this study is to investigate the changed brain glucose metabolic pattern in SFD. In this study, 18 SFD patients and 21 matched healthy controls were enrolled and underwent an 18F-FDG PET scan. First, we explored the altered brain glucose metabolism in SFD. Then, we calculated the mean 18F-FDG uptake values for 90 AAL regions, and detected the changed brain metabolic connectivity between the most significantly changed regions and all other regions. In addition, the Pearson coefficients between the neuropsychological scores and regional brain 18F-FDG uptake values were computed for SFD patients. We found that SFD patients showed extensive hypometabolism in bilateral superolateral prefrontal cortex, insula, and regions in bilateral temporal gyrus, right angular gyrus, left gyrus rectus, right fusiform gyrus, right rolandic operculum and bilateral occipital gyrus. The metabolic connectivity between right insula and prefrontal areas, as well as within prefrontal areas was enhanced in SFD. And several brain regions were associated with the somatic symptoms, including insula, putamen, middle temporal gyrus, superior parietal gyrus and orbital part of inferior frontal gyrus. Our study revealed widespread alterations of the brain glucose metabolic pattern in SFD patients. Those findings might elucidate the neuronal mechanisms with glucose metabolism and shed light on the pathology of SFD.

Altered Brain Glucose Metabolism Assessed by 18F-FDG PET Imaging Is Associated with the Cognitive Impairment of CADASIL

Recurrent stroke and cognitive impairment are the primary features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The cognitive deficits in these patients are known to be correlated with structural brain changes, such as white matter lesions and lacunae, and resting-state functional connectivity in brain networks. However, the associations between changes in brain glucose metabolism based on 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) imaging and cognitive scores in CADASIL patients remain unclear. In the present study, 24 CADASIL patients and 24 matched healthy controls underwent 18F-FDG PET imaging. Brain glucose metabolism was measured in all subjects and Pearson's correlation analyses were performed to evaluate relationships between abnormal glucose metabolism in various brain areas and cognitive scores. Compared to controls, CADASIL patients exhibited significantly lower metabolism in the right cerebellar posterior lobe, left cerebellar anterior lobe, bilateral thalamus and left limbic lobe. Additionally, hypermetabolism was observed in the left precentral and postcentral gyri. Importantly, glucose metabolism in the left limbic lobe was positively associated with cognitive scores on the Mini-Mental State Examination (MMSE). Furthermore, glucose metabolism in the left precentral gyri was negatively correlated with cognitive scores on the Montreal Cognitive Assessment (MoCA). The present findings provide strong support for the presence of altered brain glucose metabolism in CADASIL patients as well as the associations between abnormal metabolism and cognitive scales in this population. The present findings suggest that patterns of brain glucose metabolism may become useful markers of cognitive impairment in CADASIL patients.

Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia

Memory is robustly impaired in schizophrenia (SZ) and related to functional outcome. Memory dysfunction has been shown to be related to altered brain glucose metabolism and brain insulin resistance in animal models and human studies of Alzheimer's disease. In this study, differences in brain glucose using magnetic resonance spectroscopy (MRS) and blood Extracellular Vesicle (EV) biomarkers of neuronal insulin resistance (i.e. Akt and signaling effectors) between SZ and controls were investigated, as well as whether these measures were related to memory impairments. Neuronal insulin resistance biomarkers showed a trend for being lower in SZ compared to controls, and memory measures were lower in SZ compared to controls. Occipital cortex glucose was higher in SZ compared to controls indicating lower brain glucose utilization. Linear regression analyses revealed significant relationships between neuronal insulin resistance biomarkers, memory measures, and brain glucose. More specifically, p70S6K, an insulin signaling effector, was related to verbal learning and brain MRS glucose in the SZ group. For the first time, we show that memory impairments in SZ may be related to brain glucose and brain insulin resistance. These data suggest that brain insulin resistance may play a role in the pathophysiology of learning and memory dysfunction in SZ.

Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

Huntington’s disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP) impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to mediate the hGluT3 protective effects, whereas, in addition, the PPP provides increased protection to oxidative stress.

Weight Loss After Bariatric Surgery Reverses Insulin-Induced Increases in Brain Glucose Metabolism of the Morbidly Obese

Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery.

The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain.

Augmented Acquisition of Cocaine Self-Administration and Altered Brain Glucose Metabolism in Adult Female but not Male Rats Exposed to a Cannabinoid Agonist during Adolescence

Marijuana consumption during adolescence has been proposed to be a stepping-stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self-administration (1 mg/kg), food-reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food-restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [(18)F]-fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP-treated rats showed a higher rate of cocaine self-administration as compared to vehicle-treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food-reinforced operant task, pointing to the cocaine-specific nature of the effect seen in self-administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP-treated females when compared to their vehicle-treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo-entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self-administration, in a sex-specific fashion. This increased susceptibility could be related to the changes in brain metabolic activity induced by cannabinoids during adolescence.

Altered cerebral glucose metabolism in an animal model of diabetes insipidus: A micro-PET study

The Brattleboro rat is an animal model of genetically induced central diabetes insipidus. These rats show cognitive and behavioral disorders, but no neurodegenerative disease has been observed. We studied brain glucose uptake, a marker of neuronal activity, in 6 Brattleboro rats, in comparison with 6 matched Long–Evans (LE) control rats. A group of 3 Brattleboro rats and 3 Long–Evans rats was studied in vivo and another group of animals was studied ex vivo. In vivo studies were performed using fluorodeoxyglucose labeled with fluorine 18 ( 18F-FDG) and a dedicated small-animal PET device. At 30 min and 60 min p.i., 18F-FDG uptake was significantly higher in the frontal cortex, striatum, thalamus and cerebellum of Brattleboro rats than in LE rats when measured by PET in vivo ( p < 0.05), but only a trend towards higher values was found ex vivo. Our results show for the first time that brain glucose metabolism is modified in Brattleboro rats. This altered brain glucose metabolism in Brattleboro rats may be related to the observed cognitive and behavioral disorders. Functional analyses of brain metabolism are promising to investigate cognitive behavioral disturbances observed in Brattleboro rats and their link to diabetes insipidus.

Structural and metabolic brain changes in the striatum associated with methamphetamine abuse

To review structural, chemical and metabolic brain changes, particularly those in the basal ganglia, in individuals who used methamphetamine, as well as in children with prenatal methamphetamine exposure. Magnetic resonance imaging (MRI) and positron emission tomography (PET) studies that evaluated brain structural, chemical and metabolite changes in methamphetamine subjects, or children with prenatal methamphetamine exposure, were reviewed and summarized. Relevant pre-clinical studies that provided insights to the interpretations of these imaging studies were also reviewed. In adults who used methamphetamine, MRI demonstrates enlarged striatal volumes, while MR spectroscopy shows reduced concentrations of the neuronal marker N-acetylasparate and total creatine in the basal ganglia. In contrast, children with prenatal methamphetamine exposure show smaller striatal structures and elevated total creatine. Furthermore, PET studies consistently showed reduced dopamine transporter (DAT) density and reduced dopamine D(2) receptors in the striatum of methamphetamine subjects. PET studies also found lower levels of serotonergic transporter density and vesicular monoamine transporter (VMAT2) across striatal subregions, as well as altered brain glucose metabolism that correlated with severity of psychiatric symptoms in the limbic and orbitofrontal regions. Neuroimaging studies demonstrate abnormalities in brain structure and chemistry convincingly in individuals who used methamphetamine and in children with prenatal methamphetamine exposure, especially in the striatum. However, many important questions remain and larger sample sizes are needed to validate these preliminary observations. Furthermore, longitudinal studies are needed to evaluate the effects of treatment and abstinence on these brain changes and to determine whether imaging, and possibly genetic, markers can be used to predict treatment outcome or relapse.

Brain glucose metabolism and temperament in relation to severe somatization

Little is known about the pathophysiology of somatization. The authors' aim was to explore associated factors with somatoform disorders. The authors studied 10 female patients with a diagnosis of somatization disorder or undifferentiated somatoform disorder with no comorbid current Diagnostic and Statistical Manual of Mental Disorders (4th edn) Axis I disorder and 12 healthy female volunteers. The predicting variables were temperament factors of the 240-item Temperament and Character Inventory instrument and regional brain glucose metabolism. Low novelty-seeking and high harm avoidance temperament traits and low caudate and low putamen glucose metabolism were statistically significantly associated with severe somatization (P < 0.05). In the present study, severe somatization associates with both altered brain glucose metabolism and temperament factors. No other studies on association of somatization with brain glucose metabolism and temperament have been published. The results are still considered exploratory due to the small number of subjects.

Altered brain glucose metabolism in transgenic-PFKL mice with elevated l-phosphofructokinase: in vivo NMR studies

The gene for the liver-type subunit of phosphofructokinase (PFKL) resides on chromosome 21 and is overexpressed in Down syndrome (DS) patients. Transgenic PFKL (Tg-PFKL) mice with elevated levels of PFKL were used to determine whether, as in DS, overexpression of PFKL was also associated with altered sugar metabolism. We found that Tg-PFKL mice had an abnormal glucose metabolism with reduced clearance rate from blood and enhanced metabolic rate in brain. Transgenic-PFKL mice exhibited elevated activity of phosphofructokinase in both blood and brain, as compared to control non-transgenic (ntg) mice. Following glucose infusion, the rate of glucose clearance from the blood of Tg-PFKL mice was significantly slower than that of control ntg mice, although the basal blood glucose levels were similar. However, unlike the slower rate of glucose metabolism in blood, the initial rate of glucose utilization in the brain of the transgenic mice, was 58% faster than in control ntg mice. This was determined by infusion of [1- 13 C ]-glucose followed by in vivo nuclear magnetic resonance (NMR) measurements of brain glucose metabolism. The faster utilization of glucose in Tg-PFKL brain is similar to the increased rate of cerebral glucose metabolism found in the brain of young adult DS patients, which may play a role in the etiology of their cognitive disabilities.

Impaired cerebral glucose metabolism in myotonic dystrophy: a triplet-size dependent phenomenon

Myotonic dystrophy (DM) is caused by an expansion of a CTG triplet repeat sequence in the 3′-noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. Impaired glucose penetration into brain tissues has been described in DM patients and is a phenomenon that remains unexplained. The present study shows that altered brain glucose metabolism is triplet repeat dependent. We studied brain glucose metabolism (CMRGlu, μmol/100 g/min) by the use of positron emission tomography and 18F-fluoro-2-deoxy- d-glucose in 11 ambulatory non-obese DM patients and in 11 age and sex matched healthy subjects. All subjects underwent a glucose tolerance test with plasma insulin determinations. The expansion of CTG triplet repeats was analyzed in patients with the probe cDNA25 after EcoRI digestion. As compared to controls, in DM patients, the CMRGlu was significantly decreased (26.26±5.05 vs. 33.43±2.18, μmol/100 g/min, P=0.004), and after oral glucose loading, plasma insulin levels were significantly higher and plasma glucose levels remained unchanged (respectively, F=11.21, P=0.004 and F=0.20, P=0.66). Subsequently, the glucose/insulin ratio was significantly lower in DM patients ( F=6.25, P=0.02). The length of the expansion of the CTG repeats correlated negatively with the CMRGlu ( r 2=0.63, P=0.003) and positively with the area under the curve for insulin changes over time after oral glucose ( r 2=0.49, P=0.016). We conclude that, in DM patients, the brain metabolism of glucose is impaired in a repeat dependent manner.

Glyceraldehyde-3-Phosphate dehydrogenase activity in developing brain during experimental cretinism

1. 1. Among areas of the central nervous system investigated, the activity of glyceraldehyde-3-phosphate dehydrogenase ( d-glyceraldehyde-3-phosphate:NAD + oxidoreductase, EC 1.2.2.12) was found to be highest in the cerebellum and was lowest in the spinal cord, when expressed on a per g tissue basis. However,when calculated as per mg DNA, cerebellum contained the lowest levels of glyceraldehyde-3-phosphate dehydrogenase activity. 2. 2. The activity of glyceraldehyde-3-phosphate dehydrogenase in the cerebral cortex and cerebellum increased markedly during the first 30 days after birth. Thereafter, enzyme activity remained relatively constant until adulthood. 3. 3. Neonatal thyroidectomy of rats with 100 μ Ci 131 I resulted in an state of experimental cretinism and inhibited the developmental increases of glyceraldehyde- 3-phosphate dehydrogenase in the cerebral cortex and cerebellum. 4. 4. Treatment of neonatally thyroidectomized rats with l-triiodothyronine in early life led to significant increases in the activity of brain glyceraldehyde-3-phosphate dehydrogenase. When initiation of triiodothyronine treatment was delayed until the cretinous rats reached adulthood, the hormone was unable to exert any measurable effect on enzyme activity. This indicates that the age of the animal, when hormone replacement therapy is begun, is important in determining the degree of influence of triiodothuronine on brain development. 5. 5. Evidence for the involvement of de novo protein synthesis in the observed stimulation of brain glyceraldehyde-3-phosphate dehydrogenase by triiodothyronine in cretinous rats was obtained with the use of cycloheximide. This inhibitor of protein biosynthesis prevented the triiodothyronine-induced increases in cerebro-cortical and cerebellar enzyme activity when administered simultaneously with the hormone. 6. 6. Our results indicate that thyroid hormone is involved in the regulation of glyceraldehyde-3-phosphate dehygrogenase activity in the developing central nervous system nd raise the possibility that the altered brain glucose metabolism following neonatal thyroidectomy may be related to an impaired development of glyceraldehyde- 3-phosphate dehydrogenase and other enzymes involved in the glycolytic pathway.