Benzodiazepine receptor quantification in Huntington's disease with [(123)I]omazenil and SPECT

OBJECTIVES: Increasing evidence suggests that metabolic changes predate neuronal death in Huntington's disease and emission tomography methods (PET and SPECT) have shown changes in glucose consumption and receptor function in early and possibly even presymptomatic disease. Because the GABA(A)-benzodiazepine receptor complex (BZR) is expressed on virtually all cerebral neurons BZR density images may be used to detect neuronal death. In this study the regional cerebral [(123)I]iomazenil binding to BZR was determined in patients with Huntington's disease and normal controls by a steady state method and SPECT. METHODS: Seven patients mildly to moderately affected by Huntington's disease and seven age matched controls were studied. Brain CT was performed on all subjects. In each subject two [(123)I]iomazenil-SPECT measurements were acquired-one with and one without infusion of flumazenil. The affinity constant of flumazenil (Kd) was calculated from the paired distribution volumes (DV) and the free plasma flumazenil concentration. The distribution volume of [(123)I]iomazenil in the unblocked condition (DV(0)) reflects the ratio between BZR density and Kd. RESULTS: Flumazenil Kd was similar in the Huntington's disease group and the control group (11.3 v 11.2 mM). For the Huntington's disease group a 31% reduction in striatal DV(0) (p=0.03) was found. In the cortical regions, DV(0) was similar in patients and in controls. In Huntington's disease, DV(0) correlated significantly with functional capacity (p=0.04) and chorea symptoms (p=0.02). The clinically least affected patients displayed DV(0)s within the range of those of the control group (19-35 ml/ml). CONCLUSIONS: The finding of an unchanged Kd of flumazenil in patients indicates that the BZR is functionally intact in Huntington's disease. That is, the reduction in DV(0) for BZR represents a selective decrease in the number of striatal BZRs. DV(0) significantly correlated with functional loss and [(123)I]iomazenil-SPECT could be an important tool for validation of the effect of future therapeutic strategies aimed at limiting oxidative stress and free radicals in Huntington's disease.     

PET in coma and in vegetative state

Advances in resuscitation and critical care management have resulted in the survival of many patients despite severe brain damage. These patients may remain in coma or in vegetative state. The probability of recovery of conscious function is dependent on the extent of structural brain damage, which is difficult to assess by clinical, laboratory or functional tests. Positron emission tomography (PET) of 18F‐fluordeoxyglucose (FDG) can be used to investigate metabolic and functional impairment of the brain. In acute vegetative state (AVS, duration < 1 month), overall glucose utilization was significantly reduced in comparison with age‐matched controls. In a few cases with locked‐in syndrome, cortical metabolism was in the normal range. 11C‐Flumazenil (FMZ) measures the density of benzodiazepine receptors (BZRs) and thereby furnishes an estimate of neuronal integrity. PET with this tracer demonstrated a considerable reduction in BZRs in cortical areas, but indicated that the cerebellum was spared from neuronal loss. The comparison of FDG‐ and FMZ‐PET findings in AVS demonstrates that alterations of cerebral glucose consumption do not represent mere functional inactivation, but also irreversible structural damage. In some cases with minimally conscious state, auditory stimuli with emotional valence induced more brain activation (investigated by H215O‐PET) than meaningless noise; such studies can be used to detect residual cortical function. To improve prognostication of chances for recovery, a combination of functional activation studies and assessment of the extent of neuronal damage might be the optimal procedure and should be tested in larger cohorts of patients with comatose states of different severity.     

Cerebellar reorganization following cortical injury in humans: effects of lesion size and age

OBJECTIVE: The authors investigated chronic cerebellar reorganization following unilateral cortical lesions in children and adults using PET to measure benzodiazepine receptor (BZR) binding with [11C]flumazenil (FMZ) and glucose metabolism with 2-deoxy-2[18F]fluoro-D-glucose (FDG). BACKGROUND: Crossed cerebellar diaschisis (CCD) is defined as decreased metabolism or blood flow in the cerebellum contralateral to a cortical insult measured by functional neuroimaging, and is typically seen in adults with large frontal or parietal lesions. The authors previously reported that CCD of glucose metabolism was not as prominent in children as in adults, and that some children showed a paradoxical pattern of increased glucose utilization in cerebellar cortex contralateral to the cortical lesion. The current study investigated whether CCD is associated with alterations in the gamma-aminobutyric acid (GABA(A))/BZR complex. METHODS: Patients with frontal lesions alone or with parietal lesions were compared with patients with temporal lesions, which are typically not associated with CCD. RESULTS: Children with lesion onset before 1 year of age showed significantly higher glucose utilization in contralateral posterior quadrangular and superior semilunar lobules of cerebellar cortex than did adults. Two patterns of change in cerebellar BZR binding were seen in children: 1) Five of 10 children showed increased BZR binding in the dentate nucleus contralateral to the lesion, and 2) the remaining five children showed no increase in dentate nucleus BZR binding but showed increased binding in the lateral lobules of the cerebellar cortex contralateral to the lesion. Adults showed increased binding only in contralateral dentate nucleus and not in cerebellar cortex. The size and severity of the supratentorial lesion, as well as age at the time of injury, were important factors in these findings. CONCLUSIONS: Reorganization of GABA-mediated mechanisms and glucose metabolism in cerebellum following cortical injury differs with size of lesion and age at the time of injury.     

Atrophy of the corpus callosum associated with a decrease in cortical benzodiazepine receptor in large cerebral arterial occlusive diseases

OBJECTIVES: It remains controversial whether selective neuronal ischaemic change develops in patients with occlusion of the large cerebral arteries. Previous studies have shown atrophy of the corpus callosum with reduced cortical oxygen metabolism in large cerebral arterial occlusive diseases, which might be indirect evidence of loss of the neurons in cortical layer 3. Recent studies of patients with ischaemic cerebrovascular diseases have demonstrated reduced central benzodiazepine receptor (BZR) binding in the normal appearing cortical areas, which might be more direct evidence of changes of the neurons. Although pathophysiology of the decreased BZR is unclear, a decrease in the cortical BZR binding with neuronal loss would cause atrophy of the corpus callosum. The purpose of this study was to determine whether atrophy of the corpus callosum is associated with a decrease in cortical BZR binding in large cerebral arterial occlusive diseases. METHODS: Seven patients with occlusive diseases of the middle cerebral or internal carotid artery and only minor subcortical infarctions were studied. Single photon emission tomographic images of (123)I labelled iomazenil (IMZ) obtained 180 minutes after injection were analysed for BZR binding. The midsagittal corpus callosum area/skull area ratio (on T1 weighted magnetic resonance images) was compared with the cerebral IMZ uptake/cerebellar IMZ uptake ratio. RESULTS: Compared with 23 age and sex matched control subjects, the patients had significantly decreased callosal area/skull area ratio. The degree of corpus callosum atrophy was significantly and strongly (rho=0.99, p<0.02) correlated with that of the decreases in the mean cerebral cortical IMZ uptake ratio. CONCLUSION: Corpus callosum atrophy may occur in association with a decrease in cortical BZR binding in large cerebral arterial occlusive diseases. Corpus callosum atrophy with decreased cortical BZR binding might reflect cortical neuronal damage in large cerebral arterial occlusive diseases.     

Interictal hippocampal benzodiazepine receptors in temporal lobe epilepsy: comparison with coregistered hippocampal metabolism and volumetry

The significance of benzodiazepine receptor (BZR) concentration in comparison with hippocampal metabolism and volumetry was assessed in 14 patients diagnosed with temporal lobe epilepsy (TLE) without hippocampal signal change on T2-weighted magnetic resonance imaging (MRI) scans. Focus lateralization was achieved by clinical, electroencephalographic and neuropsychological examinations. Three-dimensional positron emission tomography (PET) and MRI scans were coregistered for determination of hippocampal 11C-flumazenil (FMZ) binding, normalized to average cortical values for glucose metabolism (rCMRglc) and volume. The hippocampi were individually outlined on T1-weighted MRI. Volumes of interest (VOI) were used for calculation of asymmetries between clinically affected and unaffected sides. Eleven out of 14 TLE patients presented a significant reduction in hippocampal volume. In nine of these 11 patients hippocampal FMZ binding and in seven cases hippocampal CMRglc was also reduced. In two patients without hippocampal volume asymmetry FMZ binding was markedly reduced in the mesial temporal lobe appropriately to the clinically diagnosed side. In our study volumetry is therefore the most sensitive tool for the detection of hippocampal abnormality in TLE. However, in cases without hippocampal atrophy the reduction of FMZ may indicate functional impairment of BZR before neuronal loss becomes evident. Our results emphasize the complementary nature of these tests in TLE patients.     

Reduced postnatal cerebral glucose metabolism measured by PET after asphyxia in near term fetal lambs.

The effects of fetal asphyxia on cerebral function and development, involve the transition from fetal to neonatal life. Changes in cerebral glucose metabolism may be an early postnatal indicator of fetal asphyxia. The objective is to develop an experimental lamb model involving the transition from fetal to neonatal life and to examine the effect of fetal asphyxia with cerebral hypoxic ischemia on early postnatal cerebral glucose metabolism. Fetal asphyxia was induced by total umbilical cord occlusion in eight near-term fetal lambs (134-138 days) with the ewe under isoflurane-opiate anesthesia. The mean occlusion time until cardiac arrest was 14.5 (4.2) min (SD). Lambs were immediately delivered and standardized resuscitation was instituted after 2 min asystole. At 4 hr postnatal age, [18-F]Fluoro-2-deoxy-glucose (18-FDG) was injected intravenously in eight asphyxiated lambs and in eight controls. Cerebral glucose metabolism was examined by positron emission tomography (PET). As a result the mean arterial blood pressure, acid-base values, blood glucose and serum lactate at 4 hr postnatal age did not differ significantly between lambs subjected to umbilical cord occlusion and controls. EEG was abnormal in all lambs subjected to cord occlusion and normal in the controls at 4 hr postnatal age. Global cerebral metabolic rate (CMRgl) as determined by PET was significantly lower in lambs subjected to cord occlusion mean/median (SD) 22.2/19.6 (8.4) micromol/min/100 g) than in controls mean/median (SD) 37.8/35.9 (6.1); P < 0.01). Global CMRgl is significantly reduced in newborn lambs 4 hr after fetal asphyxia induced by umbilical cord occlusion. A reduction in CMRgl is an early indicator of global hypoxic cerebral ischemia.     

PET measures of benzodiazepine receptors in progressive supranuclear palsy

OBJECTIVE: To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP). METHODS: The cerebral distribution of [11C]flumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and [18F]fluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest. RESULTS: There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction. CONCLUSIONS: PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.     

11C-Flumazenil positron emission tomography demonstrates reduction of both global and local cerebral benzodiazepine receptor binding in a patient with Stiff Person Syndrome

Stiff Person Syndrome (SPS) is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD-Ab), the key enzyme in γ-aminobutyric acid synthesis (GABA). In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [¹¹C]flumazenil (FMZ) positron emission tomography (PET) in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS.     

Decreased benzodiazepine receptor density in the cerebellum of early blind human subjects

As a first approach to study the effect of early visual deprivation in the GABA-ergic inhibitory system, the distribution of benzodiazepine receptors (BZR) was accurately estimated using [11C]flumazenil ([11C]FMZ). Measurements were carried out in five subjects who became blind early in life and in five sighted control subjects. The interactions between [11C]FMZ and BZR were described using a non-linear compartmental analysis which permitted to estimate the BZR synaptic density independently of other model parameters. The distribution of BZR in the visual areas and other cortical regions of blind subjects was qualitatively and quantitatively similar to that of controls. However, the BZR density in the cerebellum was significantly lower in blind than in control subjects (P<0.01). Our findings suggest that modifications of the cerebellar neural circuitry may be concomitant to the already observed compensatory reorganization in cerebral areas of blind subjects.     

Ischemic cortical neuronal damage and cognitive impairments in atherosclerotic occlusive disease of the major cerebral artery: a PET study

In atherosclerotic internal carotid artery (ICA) or middle cerebral artery (MCA) disease, selective neuronal damage can be detected as a decrease in central benzodiazepine receptors (BZRs) in an apparently normal cerebral cortex. To investigate the association between cortical BZRs decreases and executive dysfunctions, we measured BZRs using positron emission tomography (PET) and (11)C-flumazenil in 60 non-disabled patients with unilateral atherosclerotic ICA or MCA disease and no cortical infarction. Using 3-dimensional stereotactic surface projections, we calculated the BZR index, a measure of abnormally decreased BZRs in the cerebral cortex within the anterior cerebral artery (ACA) or MCA territory, and found that it to be correlated with the patient's score on the Wisconsin Card Sorting Test (WCST). Based on the WCST results, 39 patients were considered abnormal (low categories achieved) for their age. The BZR index of the ACA territory in the hemisphere affected by arterial disease was significantly higher in abnormal patients than in normal patients. The BZR index of the MCA territory differed significantly between the 2 groups when patients with left arterial disease (n = 28) were analyzed separately. The BZR indices of the anterior cingulate gyrus and the middle frontal gyrus carrelated significantly and positively with the total number of WCST errors. In atherosclerotic ICA or MCA disease, selective neuronal damage that is manifested as a decrease in BZRs in the non-infarcted cerebral cortex is associated with executive dysfunction. PET imaging of BZRs is useful as an objective measure of cognitive impairments in atherosclerotic occlusive disease of the major cerebral artery.     

Glucose and [11C]flumazenil positron emission tomography abnormalities of thalamic nuclei in temporal lobe epilepsy

OBJECTIVES: To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND: Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS: Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS: The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS: Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.     

Functional imaging of vegetative state applying single photon emission tomography and positron emission tomography

Nuclear medicine techniques, such as single photon emission tomography (SPECT) and positron emission tomography (PET) have been applied in patients in a vegetative state to investigate brain function in a non-invasive manner. Parameters investigated include glucose metabolism, perfusion at rest, variations of regional perfusion after stimulation, and benzodiazepine receptor density. Compared to controls, patients in a vegetative state show a substantial reduction of glucose metabolism and perfusion. While patients post-anoxia exhibit a rather homogenous cortical reduction of glucose metabolism, patients after head trauma often show severe cortical and sub-cortical reductions at the site of primary trauma. To distinguish reduced glucose metabolism due to neuronal inactivation from neuronal loss, flumazenil-PET, an indicator of benzodiazepine receptor density, could add valuable information on the extent of brain damage. Activation studies focus on the evaluation of residual brain network, looking for processing in secondary projection fields. So far the predictive strength concerning possible recovery for the individual patient is limited, and PET and SPECT are not routine procedures in the assessment of patients in a vegetative state.     

PET determination of regional cerebral glucose metabolism in alcohol-dependent men and healthy controls using 11C-glucose

Regional brain glucose metabolism was determined in 9 male alcohol-dependent inpatients and 12 male healthy controls. All the patients were socially impaired by the alcohol abuse. All the subjects had abstained from alcohol and drugs for more than four weeks before entering the study. Brain glucose metabolism was determined by positron emission tomography (PET) with 11C-glucose as the tracer. Regions of interest were drawn on displayed computed tomographic (CT) images of the brain. Regions were transferred to corresponding PET slices, allowing the determination of regional glucose metabolism. In the healthy volunteers there was a reduction in glucose metabolism with age. In 11 of the 19 brain regions examined, the alcoholics had a 20% to 30% lower glucose metabolism than the controls. This was true for both cortical and subcortical structures. The distribution of relative regional metabolic rates indicated that parietal cortical areas were most affected. Atrophic changes as shown by CT were not correlated to the reduced metabolism in the alcohol-dependent patients.     

Effect of deep pentobarbital anesthesia on neurotransmitter metabolism in vivo: on the correlation of total glucose consumption with glutamatergic action.

The effect of deep barbiturate anesthesia on brain glucose transport, TCA cycle flux, and aspartate, glutamate, and glutamine metabolism was assessed in the rat brain using 13C nuclear magnetic resonance spectroscopy at 9.4 T in conjunction with [1-13C] glucose infusions. Brain glucose concentrations were elevated, consistent with a twofold reduced cerebral metabolic rate for glucose (CMRglc) compared with light alpha-chloralose anesthesia. Using a mathematical model of neurotransmitter metabolism, several metabolic reaction rates were extracted from the rate of label incorporation. Total oxidative glucose metabolism, CMRglc(ox), was 0.33 +/- 0.03 micromol x g(-1) x min(-1). The neuronal TCA cycle rate was similar to that in the glia, 0.35 +/- 0.03 micromol x g(-1) x min(-1) and 0.26 +/- 0.06 micromol x g(-1) x min(-1), respectively, suggesting that neuronal energy metabolism was mainly affected. The rate of pyruvate carboxylation was 0.03 +/- 0.01 micromol x g(-1) x min(-1). The exchange rate between cytosolic glutamate and mitochondrial 2-oxoglutarate, Vx, was equal to the rate of neuronal pyruvate dehydrogenase flux. This indicates that Vx is coupled to CMRglc(ox), implying that the malate-aspartate shuttle is the major mechanism that facilitates label exchange across the inner mitochondrial membrane. The apparent rate of glutamatergic neurotransmission, V(NT), was 0.04 +/- 0.01 micromol x g x min, consistent with strong reductions in electrical activity. However, the rates of cerebral oxidative glucose metabolism and glutamatergic neurotransmission, CMRglc(ox)/V(NT), did not correlate with a 1:1 stoichiometry.     

Benzodiazepine-GABAA Receptors in Idiopathic Generalized Epilepsy Measured with [11C]Flumazenil and Positron Emission Tomography

Summary The neurochemical basis of absence seizures and the mechanism of their suppression by valproate (VPA) are uncertain. We used positron emission tomography (PET) to determine whether an abnormality of [¹¹C]flumazenil binding to benzodiazepine (BZD)-GABA_A receptors exists in patients with childhood and juvenile absence epilepsy and to examine the effects of VPA on [¹¹C] flumazenil binding. The regional cerebral volume of distribution ( V _d) of [¹¹C]flumazenil in patients not treated with VPA was not different from that in normal controls; V _d was lower in patients treated with VPA, and the number of receptors available for binding was significantly reduced in such patients as compared with normal controls. There was no evidence of a primary abnormality of the BZD-GABA, receptor in childhood and juvenile absence epilepsy (CAE/JAE), but the data suggest that treatment with VPA is associated with a reduction in [¹¹C]flumazenil binding that may be relevant to its mode of action in CAE/JAE.     

Decreased regional brain metabolism after ect

OBJECTIVE: The antidepressant action of ECT may be related to its anticonvulsant properties. Positron emission tomography (PET) studies of regional cerebral metabolic rate for glucose were used to test this hypothesis. METHOD: Ten patients with major depression were studied with PET before and approximately 5 days after a course of bilateral ECT. Statistical parametric mapping was used to identify regions of decreased cerebral glucose metabolism. RESULTS: Widespread regions of decreased regional cerebral glucose metabolism were identified after ECT, especially in the frontal and parietal cortex, anterior and posterior cingulate gyrus, and left temporal cortex. A region-of-interest analysis similarly indicated post-ECT reductions in regional cerebral glucose metabolism. CONCLUSIONS: ECT reduces neuronal activity in selected cortical regions, a potential anticonvulsant and antidepressant effect.     

Cerebral glucose metabolism in type I alpha-N-acetylgalactosaminidase deficiency: an infantile neuroaxonal dystrophy.

Cerebral glucose metabolism was investigated in a 4.8-year-old boy with alpha-N-acetylgalactosaminidase deficiency using 2-[18F]fluoro-2-deoxy-D-glucose and positron emission tomography (PET). In comparison to normal values for age, the overall cerebral glucose metabolism was reduced and the regional cerebral glucose metabolism was decreased in proportion to the degree of atrophy. In the supratentorial cortical regions, the hypometabolism was asymmetric. However, the level of regional cerebral glucose metabolism in all cortical regions excluded a persistent vegetative state. In the lentiform nucleus and the head of the caudate, comparatively increased regional cerebral glucose metabolism was documented, similar to findings in neurodegenerative disorders with active epilepsy. In contrast, the infratentorial structures (cerebellar hemispheres, brain stem, mesencephalon, and hypothalamus), which are predominantly affected by the atrophic process, showed distinct and symmetric hypometabolism. Thus, the 2-[18F]-fluoro-2-deoxy-D-glucose PET scans provided additional insight into and correlation of the functional and structural disturbances in type I alpha-N-acetylgalactosaminidase deficiency, in addition to documenting the hypometabolism due to brain atrophy.     

Cortical glucose metabolism is altered in aged transgenic Tg2576 mice that demonstrate Alzheimer plaque pathology

Alzheimer's disease is associated with markedly impaired cerebral glucose metabolism as detected by reduced cortical desoxyglucose utilization, by altered activities of key glycolytic enzymes or by reduced densities of cortical glucose transporter subtypes. To determine whether formation and/or deposition of beta-amyloid plays a role in the pathology of glucose metabolism, transgenic Tg2576 mice that overexpress the Swedish mutation of the human amyloid precursor protein and demonstrate a progressive, age-related cortical and hippocampal deposition of beta-amyloid plaques, were used to study expression and activity of key enzymes of brain glycolysis (phosphofructokinase, PFK) and glyconeogenesis (fructose1,6-bisphosphatase; FbPase). Quantitative RT-PCR revealed high expression levels of both C- and M-type PFK mRNA in non-transgenic mouse cerebral cortex, whilst there was little expression of the L-type. In 24-month-old transgenic Tg2576 mouse cortex, but not in 7-, 13-, and 17-month-old mice, the copy number of PFK-C mRNA was significantly reduced in comparison to non-transgenic littermates, while the mRNA level of the other PFK isoforms and FbPase did not differ between transgenic and non-transgenic tissue samples. In situ hybridization in brain sections from aged Tg2576 mice revealed reduced PFK-C mRNA expression in beta-amyloid plaque-associated neurons and upregulation in reactive astrocytes surrounding beta-amyloid deposits. The decreased PFK-C protein level detected by Western analysis in cerebral cortical tissue from 24-month-old transgenic Tg2576 mice was accompanied by reduced enzyme activity of PFK in comparison to non-transgenic littermates. Our data demonstrate that impairment of cerebral cortical glucose metabolism occurs only due to the long-lasting high beta-amyloid burden. This results from a reduction in glycolytic activity in beta-amyloid plaque-associated neurons and a concomitant upregulation in reactive, plaque-surrounding astrocytes.     

Distinct cerebral cortical perfusion patterns in idiopathic normal-pressure hydrocephalus

The aims of the study are to evaluate idiopathic normal-pressure hydrocephalus (INPH)-related cerebral blood flow (CBF) abnormalities and to investigate their relation to cortical thickness in INPH patients. We investigated cortical CBF utilizing surface-based early-phase ¹⁸F-florbetaben (E-FBB) PET analysis in two groups: INPH patients and healthy controls. All 39 INPH patients and 20 healthy controls were imaged with MRI, including three-dimensional volumetric images, for automated surface-based cortical thickness analysis across the entire brain. A subgroup with 37 participants (22 INPH patients and 15 healthy controls) that also underwent ¹⁸F-fluorodeoxyglucose (FDG) PET imaging was further analyzed. Compared with age- and gender-matched healthy controls, INPH patients showed statistically significant hyperperfusion in the high convexity of the frontal and parietal cortical regions. Importantly, within the INPH group, increased perfusion correlated with cortical thickening in these regions. Additionally, significant hypoperfusion mainly in the ventrolateral frontal cortex, supramarginal gyrus, and temporal cortical regions was observed in the INPH group relative to the control group. However, this hypoperfusion was not associated with cortical thinning. A subgroup analysis of participants that also underwent FDG PET imaging showed that increased (or decreased) cerebral perfusion was associated with increased (or decreased) glucose metabolism in INPH. A distinctive regional relationship between cerebral cortical perfusion and cortical thickness was shown in INPH patients. Our findings suggest distinct pathophysiologic mechanisms of hyperperfusion and hypoperfusion in INPH patients.     

Measurement of human tricarboxylic acid cycle rates during visual activation by (13)C magnetic resonance spectroscopy.

Measurement by (13)C magnetic resonance spectroscopy (MRS) of the incorporation of label from [1-(13)C] glucose, initially into C4 of glutamate, allows the regional tricarboxylic acid (TCA) cycle flux (F(TCA)) to be determined in the human brain. In this study, a direct (13)C MRS approach was used at 3T, with NOE enhancement and (1)H decoupling with WALTZ16, to determine basal F(TCA) in six volunteers. The values found in the visual cortex are similar to those reported in previous (13)C MRS studies, and consistent with PET measurements of the cerebral metabolic rate for glucose, CMRglc. In two preliminary activation studies using light emitting diode (LED) goggles flashing at 8 Hz, compared to darkness as control, increases in F(TCA) were found from 0.60 +/- 0.10 to 0.94 +/- 0.03 micromol/min/g (56%) and from 0.34 +/- 0.14 to 0.56 +/- 0.07 micromol/min/g (65%). These are upper estimates, but they are similar to the increases in CMRglc reported in PET studies, and strongly suggest, in contrast to these PET studies, that cerebral glucose is metabolized oxidatively, even during intense visual stimulation. This is supported by the observation that very little (13)C label is incorporated into C3 lactate, as would be expected if glucose were metabolized anaerobically. There is evidence for incorporation of glucose into cerebral glycogen, but this is a relatively minor component of cerebral glucose metabolism.