Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study.

This study was designed to evaluate whether subjects with amyloid beta (Aß) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aß pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aß+) or negative (Aß-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aß+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aß+ MCI subjects demonstrated greater worsening compared with Aß- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aß+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aß+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aß+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aß+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aß+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aß- subjects do.

Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography.

OBJECTIVE: To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 ([(18)F]-AV-45) and cognitive performance in a pilot study. DESIGN: Cross-sectional comparison of [(18)F]-AV-45 in AD patients versus controls. SETTING: Three specialty memory clinics. PARTICIPANTS: Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants. MEASUREMENTS: Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of [(18)F]-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency. RESULTS: Greater [(18)F]-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had [(18)F]-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment. CONCLUSION: [(18)F]-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD.

The use of the exploratory IND in the evaluation and development of 18F-PET radiopharmaceuticals for amyloid imaging in the brain: a review of one company's experience.

AIM AND METHODS: The regulatory mechanism of exploratory INDs established in 2006 by the US Food and Drug Administration (FDA) is useful for the evaluation of tracer dose radiopharmaceutical agents, and especially valuable for development of amyloid imaging agents because of the absence of appropriate animal models. The authors employed exploratory INDs to study four related novel 18F-labeled positron emission tomography (PET) amyloid imaging agents, 18F-AV-19, 18F-AV-45, 18F-AV-138 and 18F-AV-144. These exploratory INDs contained preclinical data on the mechanism of action, secondary pharmacology, biodistribution, pharmacokinetics and dosimetry and results from a single dose, extended acute toxicology study. Each compound was then tested in a human PET study in up to 15 healthy elderly controls (HC) and 15 patients with AD. Compared to HC, patients with AD showed accumulation of tracer in cortical areas expected to be high in amyloid deposition with all four tracer compounds, and no serious adverse events were observed for any of the tracers. RESULTS: .18F-AV-45 showed the best imaging characteristics and was chosen for further development under a traditional IND. CONCLUSIONS: In summary the exploratory IND pathway was very useful for comparing four related agents with respect to efficacy (amyloid plaque binding), kinetics and dosimetry.

Further developments in the measurement of working memory in rodents.

This article reviews automated test procedures that can be used to study memory for discrete/trial-unique events in rodents and other animals. A distinction is made between delayed response tasks, i.e. those tasks for which all information necessary to determine the correct response is available prior to the retention interval, and delayed comparison tasks, i.e. tasks in which the subject must compare stimuli presented prior to and after the retention interval in order to determine the correct response. Delayed comparison procedures potentially provide a purer estimate of the subject's memory capacities, but have also been more difficult for rodents to acquire. Suggestions are offered for potential directions for improved delayed comparison tasks.

NPC 16377, a potent and selective sigma-ligand. I. Receptor binding, neurochemical and neuroendocrine profile.

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI (NPC 16377), a structurally novel compound, was found to be a highly potent and selective ligand for sigma-sites. Although 5-fold less potent than haloperidol and 2-fold less potent than ifenprodil to inhibit 1,3-di-o-tolylguanidine binding, NPC 16377 (IC50 = 36 nM) was more potent than alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl butanol (BMY 14802), rimcazole and the atypical antipsychotic, clozapine. A similar rank order of potency was observed when [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperdine was used as the radioligand. Like BMY, rimcazole and clozapine, NPC 16377 (IC50 = 2671 nM) had low affinity for dopamine type 2 receptors. Additionally, the compound was only weakly active in 35 additional receptor binding assays including those for serotonin2 and serotonin1C receptors. In vivo, NPC 16377 potently inhibited the binding of [3H]-(+)-N-allylnormetazocine to sigma sites after both intraperitoneal and oral administration. At doses 30-fold in excess of the ID50 to inhibit [3H](+)N-allylnormetazocine, NPC 16377 failed to displace [3H]raclopride from dopamine type 2 binding sites. Unlike haloperidol, BMY 14802, ifenprodil and clozapine, behaviorally effective doses of NPC 16377 did not increase dopamine turnover in the frontal cortex, nucleus accumbens or corpus striatum of rats. In contrast, each of these agents increased circulating levels of both adrenocorticotropin and corticosterone, but only NPC 16377 decreased circulating plasma levels of prolactin. The results of the current study are consistent with the notion that NPC 16377 is a potent, selective and orally active sigma site ligand. At behaviorally relevant doses the compound produces neuroendocrine effects both similar to, and different from, neuroleptics, other sigma-ligands and atypical antipsychotics, while having no effect on dopamine turnover. Given these data, NPC 16377 should prove to be a useful compound to explore further the physiological and functional significance of sigma-sites in brain.

NPC 16377, a potent and selective sigma-ligand. II. Behavioral and neuroprotective profile.

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for toxicity. Like haloperidol, clozapine and remoxipride, and the sigma-ligands BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamine-induced hyperactivity and apomorphine-induced climbing in mice. Additional evidence for antipsychotic activity was obtained in rats with NPC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that did not reduce escape behavior. NPC 16377 did not induce catalepsy in mice, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypoxic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either intraperitoneal or oral administration. NPC 16377 did not disrupt prepulse inhibition or block the disruption of prepulse inhibition induced by the phencyclidine site-selective ligand (+)MK-801. In rats trained to discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion that selective sigma-agents may possess antipsychotic and neuroprotective activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyclidine-like effects.

Effects of strychnine-insensitive glycine receptor antagonists and sigma agents on working memory performance: comparison with dizocilpine and scopolamine.

The strychnine insensitive glycine receptor antagonists (+/-) HA 966 (2.5, 3.5, 4.25 and 5.0mg/kg) and 7 chlorokynurenic acid (5.0, 10.0, and 15.0mg/kg), the putative sigma agents NPC 16377 (5.0 and 8.0mg/kg), BMY 14802 (5.0, 7.5 and 10.0mg/kg), and ifenprodil (5.0 and 7.0mg/kg) and the reference agents scopolamine and dizocilpine [(+) MK 801] were evaluated in a nonspatial delayed matching to sample working memory task in rats. (+/-) HA 966 impaired accuracy at the longest retention interval and decreased response probability measures. 7-Chlorokynurenic acid was essentially without effect. The noncompetitive NMDA antagonist dizocilpine reduced accuracy at all retention intervals, decreased the probability of a choice response and increased the probability of an intertrial interval response. The anticholinergic agent scopolamine selectively reduced accuracy at the longest retention interval but did not affect other performance measures. Sigma agents decreased response probability measures but did not affect accuracy at any retention interval. The results support the notion that sigma agents, glycine antagonists and NMDA antagonists produce different effects in cognitive tasks including working memory performance.

A patient with primary biliary cirrhosis and multiple sclerosis.

A 48-year-old woman with primary biliary cirrhosis (PBC) and multiple sclerosis (MS) is reported. She presented with a visual deficit in 1975. In the course of a diagnostic evaluation, she was found to have PBC. In 1986, the diagnosis of MS was made. The patient's liver function deteriorated and liver transplantation was performed in May 1988. This is the third known case of this association.

N-methyl-D-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranolol, diazepam, and phenylisopropyladenosine.

The effects of the competitive N-methyl-D-aspartate (NMDA) antagonists CPP (5 & 10 mg/kg) and NPC 12626 (25 & 40 mg/kg) and the noncompetitive NMDA antagonists phencyclidine (1, 3, & 6.25 mg/kg) and MK 801 (0.1 & 0.2 mg/kg) on performance of rats on a nonspatial delayed matching-to-sample working memory task were evaluated. At the highest dose, each NMDA antagonist reduced choice accuracy at all retention intervals. In contrast, the reference anticholinergic agent scopolamine selectively reduced accuracy at long retention intervals, suggesting that scopolamine but not the NMDA antagonists directly interfered with time-dependent working memory retention. Propranolol, diazepam, and phenylisopropyladenosine had little or no effect on choice accuracy, suggesting that noradrenergic, gamma-aminobutyric acid-diazepam, and adenosine receptors may be relatively unimportant for working memory performance as assessed in this task. The NMDA antagonists also differed from scopolamine in that doses of NMDA antagonists that reduced response accuracy also reduced response probability, altered bias (competitive antagonists only), and increased intertrial interval responding (noncompetitive antagonists only). It was concluded that NMDA antagonists disrupt cognitive functions including, but not limited to, those required for accurate working memory performance.

Photochemically induced thrombosis of the precentral cortex impairs operant variable-interval spatial delayed alternation performance by rats.

A variable-interval spatial delayed alternation memory task was used to quantify the behavioral effects of photochemically induced thrombic infarction of the precentral (frontal) cortex. Upon achieving criterion on the behavioral task, rats received thrombicischemic lesions, predominantly limited to the medial precentral cortex, induced by injection of the fluorescein dye Rose Bengal and illumination of the skull above the target area. Beginning six days after surgery, rats were retested on the memory task. Compared to Sham-operated controls (n = 5), rats with precentral cortex lesions (n = 5) demonstrated a retention interval-dependent accuracy deficit (impaired at the longest retention interval only) and slower reaction time (increased response latency). These effects were significant only during the first week of postoperative testing. Rats with lesions also demonstrated a greater probability of a choice response throughout the three postoperative test weeks. The results suggest that photochemical thrombosis in the precentral cortex produces functional, behavioral consequences in rats which can be reliably and objectively measured.

Possible cerebroprotective and in vivo NMDA antagonist activities of sigma agents.

The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.

[3H]DTG and [3H](+)-3-PPP label pharmacologically distinct sigma binding sites in guinea pig brain membranes.

The interaction of various compounds with sigma binding sites was examined in membranes prepared from whole guinea pig brain. Whereas [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine labeled a single population of binding sites exhibiting a Kd of 43 nM, [3H]1,3-di-o-tolylguanidine bound to two sites having Kds of 35 and 212 nM, and to a greater maximum number of sites than [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. Haloperidol, 1,3-di-o-tolylguanidine, BMY 14802, and (-)-pentazocine each displayed nearly equal affinity for binding sites labeled by [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H]1,3-di-o-tolylguanidine, whereas (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine was 3 times more potent in inhibiting [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding. In contrast, (+)-SKF 10,047, (+)-cyclazocine and (+)-pentazocine exhibited more than 9-fold higher affinity for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding sites. Dextromethorphan was 15-fold more potent against [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine, inhibited [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in a biphasic manner, and inhibited [3H]haloperidol and [3H](+)-SKF 10,047 binding with potencies similar to those obtained against [3H]1,3-di-o-tolylguanidine and [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, respectively. Phenytoin increased [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H](+)-SKF 10,047 binding, but did not enhance [3H]1,3-di-o-tolylguanidine or [3H]haloperidol binding. However, the potency of dextromethorphan to inhibit [3H]1,3-di-o-tolylguanidine binding was increased in the presence of phenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Dextromethorphan for treatment of complex partial seizures.

We performed a double-blind, crossover, add-on study of the antitussive agent dextromethorphan (DM 120 mg/d) as therapy for seizures on 9 patients suffering from severe complex partial seizures. DM had no significant influence on key laboratory values, nor on anticonvulsant drug levels. Side effects were negligible. Complex partial seizure frequency increased 25% during the DM arm of the study, although this increase was not clinically significant.

Individual differences in aging: behavioral and neurobiological correlates.

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

Age-related cognitive impairments as assessed with an automated repeated measures memory task: implications for the possible role of acetylcholine and norepinephrine in memory dysfunction.

Although there exists a general agreement that certain aspects of learning and memory, and certain associated neuronal systems may be impaired with aging, systematic parametric studies are needed to characterize the nature and limits of these age-related impairments and to identify the underlying neuronal mechanisms. We review a series of experiments that examined the effects of aging and experimental treatments on rats' performance of a continuous nonmatching-to-sample, working memory task. In these studies, disruption of cholinergic transmission produced robust impairments that increased with retention interval duration, but could be observed even at the shortest intervals tested. In contrast, age-related impairments were less robust. With tone and light discriminative stimuli age-related impairments were not observed under conditions that were sensitive to disruption of cholinergic transmission, but were observed with increased retention interval duration. Finally, disruption of noradrenergic transmission produced a marginal disruption of memory performance, at worst. The generality of these results, and possible implication for future studies and animal models of dementia are discussed.

Dextromethorphan inhibits NMDA-induced convulsions.

Dextromethorphan, its metabolite dextrorphan, phencyclidine, ketamine, MK-801, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and DL-2-amino-7-phosphonoheptanoic acid were evaluated for potency to antagonize N-methyl-D-aspartate-induced convulsions following intraperitoneal administration using male CF-1 mice. Whereas reference anticonvulsants (e.g., phenytoin) were ineffective in this model, dextromethorphan and all competitive and noncompetitive N-methyl-D-aspartate antagonists blocked seizures. The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.

Anticonvulsant effects of dextrorphan in rats: possible involvement in dextromethorphan-induced seizure protection.

The major metabolite of the non-opioid anticonvulsant/antitussive dextromethorphan is dextrorphan. In the present study, the effects of dextrorphan were determined in an experimental model of seizure activity (maximal electroshock convulsions) (MES). Subcutaneous administration of dextrorphan produced dose-related blockade of tonic hindlimb extension (THE) and a decrease in the duration of tonic forelimb extension (TFE). The anticonvulsant effect of dextrorphan was linear and maximally efficacious. Compared to the prototypical anticonvulsant drug diphenylhydantoin, dextrorphan was 2.5 times more potent (ED50's = 30 mumol/kg and 12 mumol/kg, respectively). Pretreatment with naloxone failed to antagonize dextrorphan-induced blockade of THE. Moreover, pretreatment with dextrophan failed to significantly enhance the anticonvulsant potency of diphenylhydantoin. It is likely that the anticonvulsant effects of dextrorphan are related to its actions at the phencyclidine/N-methyl-D-aspartate receptor complex, whereas the anticonvulsant effects of dextromethorphan have been attributed to binding to a specific dextromethorphan site in the brain. Therefore, we suggest that while metabolism to dextrorphan could possibly contribute to the anticonvulsant effects of dextromethorphan, it is probably through an unrelated receptor mechanism.

A system for assessing toxicity of chemicals by continuous monitoring of homecage behaviors.

A noninvasive system is described for continuous recording of behaviors in the home cages of rats. Commercially available mesh cages were used so as to conform with housing conditions in most toxicological studies. A minicomputer controlled environmental lighting and recorded eating, drinking, rearing, and horizontal activity. The system's sensitivity was comparable to more complex systems. Validity was demonstrated through manipulation of environmental lighting, food deprivation, and the effects of amphetamine, scopolamine, ethanol, methylscopolamine, triethyltin, and trimethyltin. Advantages over other systems are practicality, economy, the simultaneous analyses of several naturalistic behaviors of individual rats, and the quantification of diurnal rhythms.