Patricio F. Reyes

Presence of both odor identification and detection deficits in alzheimer's disease

Recent studies of Alzheimers disease patients have demonstrated (a) marked structural and biochemical alterations in brain regions associated with olfactory function (including the olfactory bulb and entorhinal cortex) and (b) decrements in the ability to identify odorants. In light of such findings, we administered the University of Pennsylvania Smell Identification Test (UPSIT) and a forced-choice phenyl ethyl alcohol odor detection threshold test to a relatively large number of patients diagnosed, on the basis of stringent criteria, as having mild to moderately severe Alzheimers disease. Compared to age-, gender-, and race-matched normal controls, these individuals evidenced consistent and marked decrements on both types of olfactory tests (ps less than 0.001). Surprisingly few of the patients were aware of their disorder, despite its appearance early in the disease process. These findings indicate that both odor identification and odor detection problems are present in dementia of the Alzheimers type, and raise the possibility that the odor identification problem may be secondary to the odor detection problem.

Rat strain and age differences in kainic acid induced seizures

This study reports comparative dose-response data for kainic acid (KA) induced seizures in juvenile (35-40 days old) and adult (70-90 days old) Wistar-Furth (WF), Fisher 344 (F344), Sprague-Dawley (SD) and Long-Evans Hooded (LEH) rats. Juvenile male WF (n = 51), F344 (n = 55), SD (n = 60), LEH (n = 50) and adult male WF (n = 48), F344 (n = 52), SD (n = 52), LEH (n = 53) rats were given KA 6, 8, 10, 12 or 14 mg/kg, sc. As previously demonstrated adult WF and F344 rats showed the greatest sensitivity and most reliable convulsant responses to kainic acid; SD and LEH rats were less sensitive and showed more variable convulsant responses. Regardless of strain, all juvenile rats exhibited greater sensitivity and less variable convulsant response to KA compared to adults. This was most evident in juvenile SD and LEH rats. Results suggest that while seizure sensitivity to KA decreases with age, genetic factors may regulate the expression of this resistance.

Odor identification deficit of the parkinsonism‐dementia complex of Guam Equivalence to that of Alzheimer's and idiopathic Parkinson's disease

Olfactory dysfunction is among the first signs of Alzheimers disease (AD), idiopathic Parkinsons disease (PD), and the parkinsonism-dementia complex (PDC) of Guam. We have recently demonstrated that the odor identification and detection deficits of patients with PD are equivalent to those of patients with mild AD when subtle differences in cognitive function are statistically controlled for by analysis of covariance. In contrast, patients with progressive supranuclear palsy (PSP) and patients with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism evidence olfactory function much more similar to that of normal controls. In the present study, we administered the University of Pennsylvania Smell Identification Test and the Picture Identification Test to 24 patients with early signs of the PDC of Guam and statistically compared their test scores to those of 24 early-stage AD and 24 early-stage PD patients of similar age and gender from the United States mainland. Although the PDC group evidenced slightly more difficulty in identifying pictures than did the other 2 groups, the odor identification deficit associated with this disorder was of the same magnitude as that observed in AD and PD, suggesting that olfactory testing cannot be used to distinguish among these 3 diseases and that the olfactory dysfunction of these disorders may reflect a common neurologic substrate.

Computer analysis of EEG activity in dementia of the Alzheimer's type and Huntington's disease

Computer analysis of the EEG was obtained in the course of evaluation of 35 patients with Dementia of the Alzheimers Type (DAT) and Huntingtons disease (HD), and compared to 20 age-matched normal controls. On-line computer analysis of the EEG consisted of: 1) compressed spectral array (CSA) displays (2-6 channels); 2) relative frequency power (4 bands) and 3) an averaged frequency power function [( alpha/alpha + theta power (microV 2)] X 100 = % EEG Power function). Frequency power reflected increased theta, and reduced alpha components, in patient groups. Significant correlation was obtained between % EEG Power function, and clinical stage of dementia. This function correctly identified 17/25 DAT, and 7/10 HD patients, and gave additional quantification to the primary EEG.

In vivo modulation of excitatory amino acid receptors: microdialysis studies on N-methyl-d-aspartate-evoked striatal dopamine release and effects of antagonists

Striatal dopamine (DA) release was measured following intrastriatal (i.s.) administration of N-methyl-D-aspartate (NMDA) to unanesthetized, freely-moving rats. One hour after insertion of a removable microdialysis probe and perfusion with normal Ringers solution, a modified Ringers solution containing 100 mM potassium (high-K+ Ringers) was used to standardize the preparation. DA release following i.s. administration of NMDA (12.5 mM in normal Ringers) was dose-dependent. When NMDA (12.5 mM) was administered in high-K+ Ringers, DA release was greatly potentiated. Administration of the competitive NMDA receptor antagonist aminophosphonovalerate (APV) in normal Ringers prior to treatment with NMDA in high-K+ Ringers resulted in a significant reduction of DA release compared to control animals. In contrast, administration of APV priot to treatment with NMDA in normal Ringers resulted in a significantly increased release of DA compared to controls. Administration of the non-competitive NMDA antagonist, dextromethorphan (DXT) prior to treatment with NMDA in normal Ringers or NMDA in high-K+ Ringers caused significant reductions of DA release compared to controls. Intrastriatal DXT also caused dose-dependent inhibition of high-K+ Ringers-induced DA release. Similarly, administration of the non-specific calcium channel blocker, cadmium, prior to treatment with NMDA resulted in a significant decrease when compared to control values. Results of this study indicate that dose-dependent NMDA-induced striatal DA release is greatly potentiated by potassium suggesting that under physiological conditions in vivo, striatal NMDA receptors are mostly inactivated.(ABSTRACT TRUNCATED AT 250 WORDS)

Olfactory-related changes in Alzheimer's disease: A quantitative neuropathologic study

Neuropathological studies of 10 confirmed cases of Alzheimers disease (AD) revealed increased numbers of neurofibrillary tangles and neuritic plaques in olfactory cortex compared to other brain regions. This was most evident when AD tissues were compared to tissues from seven gender- and age-matched controls. In the AD cases, examination of other brain regions which receive olfactory projections also revealed high concentrations of neuritic plaques and neurofibrillary tangles. These data also confirm previous observations that neurofibrillary tangle formation is more prevalent than neuritic plaque formation in AD. This is the first quantitative neuropathological study that demonstrates significant damage to various components of the central olfactory apparatus in AD. Our data suggest that damage to these areas may be related to the behavioral, emotional, and cognitive abnormalities commonly observed in affected patients. The use of antemortem evaluation of the olfactory system as a diagnostic tool for AD is discussed.

Strain differences in convulsive response to the excitotoxin kainic acid.

We describe a strain of rats (Wistar-Furth) that is highly susceptible to the neurotoxic effects of kainic acid (KA) and presents a reliable and quantifiable (with low within-group variability) animal model of status epilepticus. Wistar-Furth rats are more sensitive and demonstrate a less variable convulsant response than Sprague-Dawley and Long-Evans rats when tested for total time in seizure activity, latency to onset of first seizure, latency to status epilepticus, seizure severity scores, and percentage exhibiting behavioral seizures and status epilepticus. Results suggest that significant heterogeneity exists in the rodent population with regard to neuronal sensitivity to an excitotoxic amino acid and indicate that strain differences are an important consideration in studies using KA.

Partial characterization of kainic acid-induced striatal dopamine release using in vivo microdialysis

The aim of this study was to characterize interactions between striatal kainate (KA) receptors and dopamine (DA) release using in vivo microdialysis. After insertion of a microdialysis probe and establishment of baseline DA release, each preparation was standardized with a pulse of an iso-osmotic solution of 100 mM KCl in Ringers solution. DA release following pharmacological manipulation was compared to potassium-induced release and expressed as a percent value. In one group of animals, KA (12.5 mM in Ringers solution) was administered via the microdialysis probe in 2, 3, 5 or 10 min pulses 30 min following standardization with potassium resulting in release of DA which was 15.7 +/- 3.9, 30.3 +/- 11.3, 67.5 +/- 15.0 and 92.9 +/- 19.8% of potassium-induced DA release, respectively. Perfusion of CdCl2 (0.6 mM in Ringers solution) 30-45 min prior to a 10 min KA pulse significantly reduced KA-induced DA release compared to control values. Intrastriatal administration of kynurenate (Kyn) attenuated KA-induced DA release in a dose-dependent manner. Levels of DA metabolites in striatal perfusates were significantly reduced following KA administration. This effect was partially reversed by cadmium pretreatment but not affected by Kyn pretreatment. Findings of this study indicate that KA induces striatal DA release in a dose-dependent manner, and this effect is at least partially dependent upon activation of calcium channels. Results also indicate dose-dependent inhibition of KA-induced striatal DA release by the excitatory amino acid receptor antagonist, Kyn, suggesting that this compound interacts with striatal KA receptors and that these receptors are involved with modulating striatal DA release in vivo.

Identification of an S-antigen-like molecule in human choroid plexus and cerebrospinal fluid

Sensitisation to retinal S-antigen has been implicated in the pathogenesis of several clinical forms of posterior uveitis. S-antigen-like molecules have recently been demonstrated in the brain and choroid plexus of experimental animals. We used a panel of four monoclonal antibodies (MAbs), MAbF4-C1, MAbC10-C10, MAbA2-G5 and MAbA9-C6, which define specific epitopes in the amino, mid and carboxyl terminal portions of S-antigen in order to identify an S-antigen-like molecule in human choroid plexus and cerebrospinal fluid (CSF). Three MAbs, MAbF4-C1, MAbC10-C10 and MAbA9-C6, localised an S-antigen-like molecule to the cytoplasm of the epithelial cells of the human choroid plexus. Polymerase chain reaction of cDNA from choroid plexus verified the presence of S-antigen homologues in the choroid plexus. The presence of an S-antigen-like molecule in the CSF was demonstrated by western blots in seven CSF samples from patients with a variety of neuropathological disorders. It is proposed that immunological cross-reactivity and biochemical similarity between retinal S-antigen and an S-antigen-like molecule in human choroid plexus and CSF could form a basis for neurological manifestations observed in certain clinical forms of uveitides.