Beneficial effects of vitamin D on falls and fractures: is cognition rather than bone or muscle behind these benefits?

The beneficial effect of vitamin D on bone tissue has long been attributed mainly to its positive effect on the intestinal absorption of calcium and on bone mineralization, which increases the bone mineral density (BMD) and thus decreases the risk of fracture. Recently, numerous extra osseous effects of vitamin D have been described, amongst them a positive effect on neuromuscular and cognitive functions. Several lines of evidence suggest that the beneficial effects of vitamin D on fall and fracture risk can be explained more by its action on the neuromuscular and cognitive functions than by its direct effect on bone metabolism. In this review, we first report on the relationships between vitamin D and osteoporotic fracture risk. Then, we present the data from the literature regarding the effects of vitamin D on risk factors such as fall risk and reduction in BMD, physical performance, and cognitive performance. Specific emphasis is put on the latter because there is evidence of a relationship between low concentration of serum 25-hydroxyvitamin D (the primary indicator of vitamin D status) and low cognitive abilities which have been shown to be a risk factor for falling. It can be further suggested that high risk of fracture in cognitively impaired adults could be explained by lower protective reaction when falling, which would result, for instance, from a lack of planning and foresight of the fall. Future studies are nonetheless needed to elucidate the associations between vitamin D and different risk factors, in particular the link between vitamin D and various cognitive functions.

Functioning of the three attentional networks and vigilance in primary insomnia.

BACKGROUND: Results from cognitive measures in primary insomnia (PI) patients are not consistent with the difficulties in performing daily living tasks of which these patients complain about. Lack of sensitivity of the tests and the data concerning some cognitive functions may explain this discordance. The aim of the present investigation was to better characterize cognitive deficits of PI patients in order to further understand their cognitive complaints. We looked at attentional and executive function because of their high involvement in daily living tasks. METHODS: A total of 21 PI patients and 16 good sleepers completed the Attentional Network Test (ANT). We only included untreated PI patients since sleep medication could be a confounding factor when assessing cognition. RESULTS: While PI patients, compared to good sleepers, were found to have a longer overall reaction time (RT) and perform more slowly in the incongruent flanker condition (ie, conflict situation) than in the congruent condition, no group effects were observed for the variables representing the three attentional networks (ie, alerting, orienting, and executive functions). CONCLUSIONS: The present study revealed a conflict resolution deficit in untreated PI patients. This impairment may be linked to the prefrontal alterations reported in neuroimaging studies in these patients. Patients had also an impaired vigilance compared to good sleepers, likely due to the high cognitive load of the ANT. These results would serve to explain the complaints of PI patients about difficulties performing daily living tasks that are demanding and of long duration.

Mapping the visual recognition memory network with PET in the behaving baboon.

By means of a novel 18F-fluoro-deoxyglucose PET method designed for cognitive activation imaging in the baboon, the large-scale neural network involved in visual recognition memory in the nonhuman primate was mapped for the first time. In this method, the tracer is injected in the awake, unanesthetized, and unrestrained baboon performing the memory task, and brain imaging is performed later under light anesthesia. Brain maps obtained during a computerized trialunique delayed matching-to-sample task (lists of meaningless geometrical patterns and delay > 9 seconds) were statistically compared pixel-by-pixel to maps obtained during a specially designed visuomotor control task. When displayed onto the baboon's own anatomic magnetic resonance images, foci of significant activation were distributed along the ventral occipitotemporal pathway, the inferomedial temporal lobe (especially the perirhinal cortex and posterior hippocampal region), and the orbitofrontal cortex, consistent with lesion, single-unit, and autoradiographic studies in monkeys, as well as with activation studies in healthy humans. Additional activated regions included the nucleus basalis of Meynert, the globus pallidus and the putamen. The results also document an unexpected left-sided advantage, suggesting hemispheric functional specialization for recognition of figural material in nonhuman primates.

Effects of damage to the basal forebrain on brain glucose utilization: a reevaluation using positron emission tomography in baboons with extensive unilateral excitotoxic lesion.

Neuronal loss in the basal forebrain cholinergic structures and frontotemporal hypometabolism are two characteristics of Alzheimer's disease, but their interrelations still are unsettled. We previously reported that unilateral electrolytic lesions of the nucleus basalis of Meynert in baboons were associated with marked but transient cortical hypometabolism. The current study reevaluates this issue using improved methodology. Baboons with unilateral ibotenic acid lesion of all three basal forebrain cholinergic structures (IBO group) were compared with sham-operated animals. The CMRglc was measured with high-resolution coronal positron emission tomography scanning coregistered with magnetic resonance imaging, before surgery and serially between 4 and 72 days afterward. Severe histologic basal forebrain damage and a decrease of more than 50% in cortical choline acetyltransferase activity were found postmortem in the IBO group. Transient and nonspecific hypometabolism was found in the needle track area in both groups. Compared with the sham-operated group, only marginally significant decreases in ipsilateral-contralateral CMRglc ratios were observed in the IBO group, affecting only 1 of 14 neocortical areas investigated (the anterior temporal cortex) at a single postsurgical time (day 14), and the posterior hippocampal region at days 14 and 38. Furthermore, there was no consistently significant correlation between ipsilateral-contralateral CMRglc ratios and cortical choline acetyltransferase activity values in any of the four regions analyzed. These results suggest that cholinergic deafferentation play at best a marginal role in the brain hypometabolism observed in Alzheimer's disease.

Regional specific binding of [11C]RO 15 1788 to central type benzodiazepine receptors in human brain: quantitative evaluation by PET.

The central type benzodiazepine receptors were studied in 17 healthy human subjects with 11C-RO 15 1788 and positron emission tomography (PET). The brain regional distribution of the tracer in eight control studies performed after injection of trace doses of 11C-RO 15 1788 was consistent with that of benzodiazepine receptors. Saturation studies with co-injected cold RO 15 1788 in the remaining subjects showed a dose-dependent decrease of brain radiotracer until full inhibition of specific binding was achieved with doses above 0.1 mg/kg (four studies). Based on the results, a simple method to estimate the specifically bound 11C-RO 15 1788 regionally in a single PET study is proposed, using the data from the full-saturation studies as a stable estimate of the nondisplaceable radioligand concentration. Using this method, it was found that quasiequilibrium between the estimated specifically bound and nondisplaceable components was achieved at times equal to or longer than 20 min after tracer administration. The validity of this method was partly supported by further results, showing a good agreement between the regional specific binding so calculated and postmortem data of receptor density.

Effects of unilateral lesion of the nucleus basalis of Meynert on brain glucose utilization in callosotomized baboons: a PET study.

Prior work has demonstrated that unilateral lesions of the nucleus basalis of Meynert (NbM) in baboons induce a marked reduction in glucose utilization of the ipsilateral cerebral cortex, linearly proportional to the depression in cortical choline acetyltransferase (ChAT) activity achieved. Unexpectedly, there was also marked hypometabolism of the contralateral cerebral cortex, and glucose utilization recovered gradually on both sides despite persistent deficit in cortical ChAT activity. To investigate the role of the corpus callosum (CC) in this bilateral metabolic effect and subsequent recovery, three baboons were subjected to unilateral electrolytic NbM lesion greater than 3 months following section of the anterior CC. Brain glucose utilization was sequentially studied by positron emission tomography; ChAT activity was measured and histological sections obtained after death. In these animals, the NbM lesion also induced significant metabolic depression over the ipsilateral cortex, proportional to the reduction in ChAT activity. Corpus callosotomy did not prevent the contralateral metabolic effects, suggesting that the latter do not normally operate through the CC. However, there was no significant recovery of glucose utilization, suggesting that, following unilateral NbM lesion, the CC normally mediates, at least in part, the recovery of cortical glucose utilization.

Pentylenetetrazol-induced seizure is not mediated by benzodiazepine receptors in vivo.

The selective benzodiazepine antagonist RO 15-1788, labelled with carbon 11 [11C] RO 15-1788, as a specific marker, together with positron emission tomography, allows the in vivo study of benzodiazepine receptors in primates. In addition, when coupled with recordings of electroencephalographic activity, this method offers the feasibility of studying the correlation between occupancy of benzodiazepine receptors and the convulsant action of drugs acting at the benzodiazepine-GABA receptor complex in vivo. The present study showed that convulsant doses of pentylenetetrazol (PTZ) could affect the binding of [11C] RO 15-1788 in vivo in two ways, depending on the doses tested: at concentrations of 20 and 30 mg/kg, pentylenetetrazol increased the binding of [11C] RO 15-1788 whereas larger concentrations displaced the binding of [11C] RO 15-1788. The direct correlation between the occupancy of respective benzodiazepine receptors, afforded by increasing convulsant doses of pentylenetetrazol, revealed that competitive interaction with benzodiazepine receptors was not necessary for pentylenetetrazol to induce the appearance of seizures in vivo.

Anticonvulsant activity of the diaryltriazine, LY81067: studies using electroencephalographic recording and positron emission tomography.

It is reported that LY81067, a new diaryltriazine, possesses anticonvulsant properties against grand mal status epilepticus induced by intravenous administration of picrotoxin binding site ligands (Ro 5-4864 and pentylenetetrazole) in the baboon. Intravenous administration of LY81067 during the seizures blocked grand mal type electroencephalographic (EEG) paroxysmal discharges and led to a long electrical silence, progressively replaced by spike-and-wave discharges of low frequency (2 c/sec). A transient blocking effect was also observed when LY81067 was injected during grand mal status epilepticus induced by the benzodiazepine inverse agonist methyl beta-carboline-3-carboxylate; however, the long electrical silence observed after administration of LY81067 was rapidly followed by grand mal type paroxysmal discharges in the EEG, which could be stopped by a subsequent injection of Ro 15-1788. However, LY81067 also displayed intrinsic epileptogenic properties. Administration of this drug alone led to the appearance of rhythmic EEG (2-3 c/sec) associated with myoclonia. Concomitantly with the EEG studies, interactions of all these drugs with benzodiazepine receptors were observed in vivo using [11C]Ro 15-1788 as radioligand and positron emission tomography (PET) as a non-invasive technique to measure the binding of the [11C]benzodiazepine antagonist in brain, in vivo. The [11C]Ro 15-1788 bound in the brain could not be displaced by the administration of LY81067 but rather, the [11C]antagonist binding in the brain was somewhat enhanced. Administration of pentylenetetrazole or Ro 5-4864 decreased the rate of wash-out of the radioligand. This fast effect of these two convulsant drugs was partially inhibited by the subsequent administration of LY81067. The concomitant blocking of the grand mal status epilepticus was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo bidirectional modulatory effect of benzodiazepine receptor ligands on GABAergic transmission evaluated by positron emission tomography in non-human primates.

The central type benzodiazepine receptor (BDZr), an allosteric modulatory site of the GABAA receptor-anion channel, has been shown in vitro to respond to drugs with positive efficacy (agonists), zero efficacy (competitive antagonists) and drugs with negative efficacy (inverse agonists). However, this general concept of the function of BDZr drugs has rarely been assessed in intact living brain. We report here in on a non-invasive in vivo assessment of the intrinsic efficacies of BDZr drugs in the brain of non-human primates. We have performed an in vivo simultaneous determination of fractional BDZr occupancy and the resulting pharmacological efficacies of the full agonist diazepam, the partial agonist bretazenil, the antagonist flumazenil (Ro15-1788), the partial inverse agonist Ro15-4513 and the full inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM). Positron emission tomography (PET) was used to estimate fractional BDZr occupancy measured as the in vivo displacement in the brain of the positron emitter radioligand, [11C]flumazenil. Simultaneously, the proconvulsant or anticonvulsant efficacies of the BDZr drugs were measured as their abilities to facilitate or counteract the central effects of an infusion of pentylenetetrazol, a non-competitive GABA antagonist acting on the picrotoxin site of the receptor complex. This was measured using electroencephalographic recording (EEG). Our results show that, in vivo, the fractional receptor occupancy by a given drug is perfectly correlated with its resulting graded pharmacological effects, as predicted from the competitive drug receptor interaction theory. Furthermore, the slope of the relationship between fractional receptor occupancies and the resulting pharmacological effects (an index of intrinsic efficacy) strictly depends on the BDZr ligand considered. Diazepam displayed a strong positive intrinsic efficacy, and, in contrast, beta-CCM a marked negative one. Between these two extremes, the partially active drugs bretazenil and Ro15-4513, which required a large fractional receptor occupancy to produce significant anti- or proconvulsant effects, respectively, displayed only a weak intrinsic efficacy. Flumazenil did not produce any significant pharmacological effect. We observed that the in vivo intrinsic efficacies of diazepam, flumazenil and beta-CCM correlate with their intrinsic efficacies as measured by their modulatory effects on the GABA-dependent membrane chloride conductance in vitro. Thus, the intrinsic efficacies measured using PET and EEG are likely to reflect the different in vivo abilities of BDZr drugs to induce or stabilize the GABAA-benzodiazepine chloride channel in a given conformation.(ABSTRACT TRUNCATED AT 400 WORDS)

Status epilepticus induced by pentylenetetrazole modulates in vivo [11C]Ro 15-1788 binding to benzodiazepine receptors. Effects of ligands acting at the supramolecular receptor complex.

Positron emission tomography (PET) was used to investigate, in the living baboon, the in vivo modulation of [11C]Ro 15-1788 binding to benzodiazepine receptors in brain and the changes with ligands acting at the supramolecular complex during status epilepticus induced by pentylenetetrazole. The central type benzodiazepine receptors were labelled in vivo by intravenous injection of [11C]Ro 15-1788. Simultaneous positron emission tomography and electroencephalographic activity recording evidenced a modulation of the brain binding of [11C]Ro 15-1788 during pentylenetetrazole-induced status epilepticus. We investigated the changes in the modulation of radioligand kinetics and in seizure activity after intravenous administration of a benzodiazepine agonist (diazepam, 1.5 mg/kg), a benzodiazepine antagonist (Ro 15-1788, 2 mg/kg), a GABA agonist (progabide, 50 mg/kg) and a ligand of the picrotoxin/barbiturate binding sites (LY81067, 3.5 mg/kg). The results showed that there is an in vivo competitive interaction of pentylenetetrazole with the benzodiazepine receptors, as reflected by the low displacement of [11C]Ro 15-1788 in the first 10 min of the status epilepticus. However, in contrast to diazepam, progabide and LY81067, a dose (2 mg/kg) of Ro 15-1788 that saturates the benzodiazepine receptors was unable to block the seizures induced by pentylenetetrazole. This indicates that the benzodiazepine receptors play only a minor role in the status epilepticus induced by pentylenetetrazole. The contribution of other binding sites within the supramolecular complex is assessed.

Benzodiazepine receptors studied in living primates by positron emission tomography: antagonist interactions.

After labelling the brain benzodiazepine receptors of sub-human primates with [11C]RO15-1788, the interactions of different benzodiazepine receptor antagonist ligands were studied by positron emission tomography (PET). Various doses of either RO15-1788, RO15-3505 or propyl beta-carboline-3-carboxylate were injected intravenously 20 min after the radiotracer, and induced an immediate and specific dose-dependent displacement of the brain radioactivity. However, a comparison of the dose-receptor occupancy patterns of these three antagonists established from the displacement experiments revealed that only propyl beta-carboline-3-carboxylate displayed clear biphasic dose-receptor occupancy curves. This indicates that, in the living primate brain, there are two different benzodiazepine receptor subpopulations (which can be either different benzodiazepine receptor subtypes or distinct conformational states of a single receptor).

Interaction of suriclone with central type benzodiazepine receptors in living baboons.

The interaction of suriclone and two of its main metabolites with central type benzodiazepine receptors, which had been labeled in vivo with the radioligand [11C]RO 15-1788, was investigated in living baboons. The concentration of radioligand bound to the receptors, as measured in brain transverse sections by positron emission tomography, decreased rapidly after the i.v. administration of suriclone at doses known to induce pharmacological effects. The rate and extent to which [11C]RO 15-1788 binding was displaced increased with increasing doses of suriclone. The half-inhibitory dose (ID50) was determined to be 0.08 mg/kg in vivo. The rapid inhibitory effect of suriclone on the in vivo binding of [11C]RO 15-1788 in the brain seems to reflect its ability to act at the GABA-benzodiazepine receptor complex, at or near to the benzodiazepine binding site, to induce its pharmacological activity. The i.v. injection of the demethylated metabolite of suriclone, RP 35,489, only caused a slight displacement of [11C]RO 15-1788 binding even at a dose of 2 mg/kg. Thus, suriclone appears to be more potent than RP 35,489 to displace the benzodiazepine 11C antagonist in vivo. The sulfoxide metabolite, RP 46,166, did not significantly change the kinetics of [11C]RO 15-1788 binding in the brain. The slight effects produced by high doses of RP 35,489 and RP 46,166 on [11C]RO 15-1788 binding in the brain suggest that these metabolites are probably not responsible for the expression of biological activity of suriclone mediated by benzodiazepine receptors.

Benzodiazepine receptors studied in living primates by positron emission tomography: inverse agonist interactions.

The convulsant actions of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and of methyl beta-carboline-3-carboxylate (beta-CCM) were evaluated in the baboon (Papio papio). DMCM, 0.6-4 mg/kg, induced epileptic seizures with short latency. DMCM convulsive seizures could be blocked by i.v. administration of the benzodiazepine agonist diazepam (10 mg). Similarly, beta-CCM, 0.3-3 mg/kg i.v., provoked generalized seizures in the baboons. These seizures were also reversed by the administration of propyl beta-carboline-3-carboxylate (3 mg/kg) or of diazepam (5 mg/kg). Combining the results from Positron Emission Tomography and the EEG assessments, benzodiazepine receptor occupancy by beta-CCM and DMCM was directly correlated with their convulsant actions in the living baboon. beta-CCM exerted its convulsant action in the living baboon at 76 and 74% benzodiazepine receptor occupancy in, respectively, occipital and temporal cortices whereas DMCM displayed a similar convulsive activity when only 58 and 65% of these receptors in the above regions were occupied.

In vivo visualization of central muscarinic receptors using [11C]quinuclidinyl benzilate and positron emission tomography in baboons.

The muscarinic antagonist, quinuclidinyl benzilate (QNB), labeled with carbon 11 was used as a radioligand to visualize in vivo by positron emission tomography (PET) the central muscarinic acetylcholine receptors (mAChR) in baboons (Papio papio). The binding characteristics of [11C]QNB showed its specific binding to central mAChR. [11C]QNB brain uptake was high in cerebral cortex and striatum, areas that are rich in mAChR, whereas it decreased rapidly in cerebellum, evidencing non-specific binding in this structure that is almost devoid of mAChR. These results are consistent with the known cerebral distribution of mAChR in primates. [11C]QNB specific cerebral binding was enhanced by pretreatment with methyl-QNB, a peripherally acting muscarinic antagonist. Specifically labeled binding sites alone were blocked by prior administration of dexetimide, a muscarinic antagonist. Specific radioactivity was driven out from mAChR-rich regions by atropine and dexetimide, drugs with high affinity for mAChR. This competition was stereospecific since only dexetimide, the pharmacologically active isomer of benzetimide, was able to compete with the radioligand on its binding sites. A relationship between the occupancy of [11C]QNB-labeled receptors by atropine or dexetimide and the concomitant induction of a pharmacological effect was also detected by simultaneous PET scanning and electroencephalographic recording. Since mAChR form an important part of choline receptors in the central nervous system, [11C]QNB appears to be a suitable radiotracer to monitor cerebral physiological or pathological phenomena linked to the cholinergic system in living subjects.

Relationships between benzodiazepine receptors, impairment of GABAergic transmission and convulsant activity of beta-CCM: a PET study in the baboon Papio papio.

Central type benzodiazepine receptors were studied in vivo by positron emission tomography in brain areas of 2 different groups of the baboon Papio papio: non-photosensitive (group 1) and those with an allylglycine-induced decrease in GABA-mediated inhibition (group 2). Further, a naturally photosensitive Papio papio (+3 level of photosensitive response) was compared to both groups. Regional brain binding of the specific benzodiazepine receptor ligand, [11C]Ro 15-1788, was not significantly different between groups 1 and 2. In addition, the data from the naturally photosensitive Papio papio did not seem to differ markedly from groups 1 and 2 either. Pharmacological effects of increasing doses of beta-CCM (0.05-3 mg/kg i.v.) and regional benzodiazepine receptor occupancy by the drug were simultaneously studied using electroencephalographic activity recording and positron emission tomography. A positive correlation was observed between the degree of photosensitivity of the baboon and sensitivity to the action of beta-CCM, with increasing convulsant efficacy of beta-CCM in going from group 1 to the naturally photosensitive baboon, then to group 2. Dose-related displacement curves of [11C]Ro 15-1788 binding by beta-CCM revealed that reduction in brain GABA concentration did not modify the inhibitory potency of beta-CCM on [11C]Ro 15-1788 binding in cerebral cortex. This suggests a lack of detectable in vivo allosteric effects of GABA on beta-CCM binding during beta-CCM-induced seizures. Thus, a given dose of beta-CCM displayed increasing pharmacological potency in going from baboons with the lowest photosensitivity to those with the highest, whereas benzodiazepine receptor occupancy by beta-CCM was similar in the cerebral cortex of the different baboons. Conversely, a given level of convulsant activity of beta-CCM was related to a different benzodiazepine receptor occupancy by the drug, depending on the photosensitivity of Papio papio. A given dose of a drug may, thus, have a different pharmacological potency when occupying the same number of receptors, depending on the physiopathological state of the subject.

Positron emission tomography study of brain benzodiazepine receptors in Friedreich's ataxia.

Central type benzodiazepine receptors were studied in 9 patients with Friedreich's ataxia and 12 healthy subjects using positron emission tomography (PET) and [11C]Ro 15-1788, a specific antagonist of the central type benzodiazepine receptors, as radioligand. A standard PET procedure was used in 5 patients and 8 controls to obtain brain kinetics of the total binding of the radioligand. The remaining subjects were intravenously injected with a saturating dose of unlabeled Ro 15-1788, 30 minutes after the tracer injection, to determine the nondisplaceable binding of [11C]Ro 15-1788. A semi-quantitative method was used to quantify the [11C]Ro 15-1788 data. None of the quantification indices in the cerebellar hemispheres, or in the other brain areas investigated, was significantly modified in patients with Friedreich's ataxia. These findings suggest that brain benzodiazepine receptors are unaffected in Friedreich's ataxia.

Impaired inhibition after total sleep deprivation using an antisaccade task when controlling for circadian modulation of performance.

OBJECTIVE: Sleep deprivation affects several cognitive functions subserved by the prefrontal cortex. Conflicting results have, nonetheless, been reported for inhibitory function, which could be explained by methodological bias. The present study aimed to assess the effects of sleep deprivation on response inhibition using a particularly suitable inhibition test, the antisaccade, while controlling for circadian influences on performance. For this purpose, testing was conducted at: (1) the same time of day in both the control and sleep deprivation conditions; and (2) at a time of day when inhibitory performance has been found not to be at its lowest level. Two other neuropsychological tasks (go no-go and incompatibility) were used for comparison. METHODS: Twelve healthy young participants performed the three tasks in the early afternoon after a normal night and after a total sleep deprivation (TSD) night in a study with a balanced, crossover design. RESULTS: TSD significantly impaired the error rate, the latency, and the intra-individual coefficient of variation of latency in the antisaccade task. None of these parameters were affected in the two neuropsychological tasks. CONCLUSIONS: When circadian modulation of performance is controlled, TSD impairs inhibition assessed by an antisaccade test. This result emphasizes that it is crucial to control for circadian effects when assessing cognitive performance in TSD studies since the time of testing may reveal or mask cognitive and behavioral impairments. The discrepant findings obtained with the go no-go and incompatibility tests are probably explained by the specific task demands and differences in recruitment of prefrontal regions.

Relationship between mood state and information processing of negative versus positive emotional stimuli in brain-damaged patients.

The present study investigates the relationship between affective mood state as assessed by self- and hetero-rating scales and information processing of negative versus positive emotional stimuli in unilateral brain-damaged patients. Results show a high positive correlation between depressive mood scores and rating of self-awareness. Left brain-damaged (LBD) patients do not differ significantly from right brain-damaged (RBD) patients on both rating scales. RBD patients mismatch negative emotional stimuli in the nonverbal matching task. Results are discussed with reference to interaction between expression of emotion and cognition. The selective neglect of negative information is interpreted as a more basic emotional impairment.

Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer's disease.

Temporoparietal glucose hypometabolism, neuronal loss in the basal forebrain cholinergic structures and preferential accumulation of neurofibrillary tangles in the rhinal cortex (i.e. in the entorhinal and perirhinal cortices) are three early characteristics of Alzheimer's disease. Based on studies of the effects of neurotoxic lesions in baboons, we previously concluded that damage to the cholinergic structures plays, at best, a marginal role in the association neocortex hypometabolism of Alzheimer's disease. In the present study, we have assessed the remote metabolic effects of bilateral neurotoxic lesions of both entorhinal and perirhinal cortices. Using coronal PET coregistered with MRI, the cerebral metabolic rate for glucose (CMR(glc)) was measured before surgery and sequentially for 2-3 months afterward (around days 30, 45 and 80). Compared with sham-operated baboons, the lesioned animals showed a significant and long-lasting CMR(glc) decline in a small set of brain regions, especially in the inferior parietal, posterior temporal, posterior cingulate and associative occipital cortices, as well as in the posterior hippocampal region, all of which also exhibit glucose hypometabolism in Alzheimer's disease. Remarkably, the degree of CMR(glc) decline in four of these regions significantly correlated with the severity of histologically determined damage in the rhinal cortex, strongly supporting the specificity of the observed metabolic effects. There were also differences between the metabolic pattern observed in the lesioned animals and that classically reported in Alzheimer's disease; for instance, the hypometabolism we found in the stratum has not been reported in early Alzheimer's disease, although this structure can be affected in late stages of the disease and has direct anatomical connections with the rhinal cortex. Nevertheless, this study shows for the first time that the temporoparietal and hippocampal hypometabolism found in Alzheimer's disease may partly result from neuroanatomical disconnection with the rhinal cortex. This, in turn, further strengthens the hypothesis that neuronal damage and dysfunction in the rhinal cortices play a major role in the expression of Alzheimer's disease.