MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

Autoimmune thyroiditis and a rapidly progressive dementia: global hypoperfusion on SPECT scanning suggests a possible mechanism.

We report the clinical, laboratory, EEG, and SPECT findings in a 59-year-old euthyroid woman with previously undiagnosed autoimmune thyroiditis, subclinical hypothyroidism, and rapidly progressive dementia. We made a diagnosis of Hashimoto's encephalopathy based on elevated thyrotropin, abnormal EEG, and clinical improvement after thyroid hormone replacement. SPECT demonstrated global hypoperfusion with normalization on clinical recovery, suggesting a possible mechanism for the pathogenesis of Hashimoto's encephalopathy.

Evidence for a tonic GABAergic control of serotonin neurons in the median raphe nucleus.

We examined whether serotonin (5-HT)-containing neurons of the midbrain raphe nuclei are subject to an inhibitory control by GABA. We found that injection into the median raphe nucleus of the GABA antagonists picrotoxin and bicuculline and the GABA agonist muscimol increase and decrease, respectively, the 5-HT turnover and the steady-state content of 5-hydroxyindoleacetic acid. The results provide evidence of a tonic inhibition by GABA of 5-HT neuronal activity in the median raphe nucleus; this inhibitory effect is potentiated by benzodiazepines.

Striatal cholinergic receptors and dyskinetic motor activity in the rat.

An injection of D-tubocurarine into the rat striatum produces a complex motor syndrome resembling in part that induced by picrotoxin. The destruction of the dopaminergic terminals by 6-hydroxydopamine does not prevent these effects of D-tubocurarine on motor activity. Hence neither dopamine release nor the presynaptic acetylcholine receptors are responsible for the D-tubocurarine-induced movements. On the other hand, lesion of the striatum by kainic acid abolishes the motor abnormalities due to D-tubocurarine but not those due to picrotoxin injection. Therefore, the effects of picrotoxin might be attributable to an action on GABA receptors still present in the kainic acid-treated striatum, whereas the effects of D-tubocurarine might be due to its action on striatal postsynaptic acetylcholine receptors.

Norfloxacin in prostatitis: correlation between HPLC tissue concentrations and clinical results.

Prostatic infections are difficult both to diagnose and to treat and have negative influences on the fertility of the patient. Norfloxacin, a new quinolone antibacterial agent particularly active in urinary tract infections, gave excellent results (400 mg every 12 h for 10 days) in the treatment of chronic-relapsing prostatitis in a group of 20 patients. An 85% success rate was recorded at the end of a follow-up period of 30 days without any undesired effects. This clinical study was paralleled by a pharmacokinetic evaluation of the serum, urine and prostatic tissue concentrations attained by the drug, measured by an HPLC assay on biological fluids and tissue extracts from surgical specimens of 15 patients suffering from benign prostatic hypertrophy and given two 400 mg doses of norfloxacin in the 12 h preceding prostatectomy. The average tissue concentrations (1 microgram/gm), as compared with the MIC90 of the drug for the pathogens sustaining prostatic infections, appear quite sufficient to control the bacterial foci responsible for the chronic-relapsing course of prostatitis and easily account for the clinical success rate.

Serotonin and gamma-aminobutyric acid turnover after injection into the median raphe of substance P and D-ala-met-enkephalin amide.

The raphe nuclei [which contain serotonin (5-HT) cell bodies] are also known to contain axons that store substance P, met-enkephalin, and gamma-aminobutyric acid (GABA). We have previously shown that GABA has a tonic inhibitory action on 5-HT turnover. To examine other possible interactions of these neuronal systems, we assessed the effect on 5-HT turnover of injecting substance P and 2-D-ala-met-enkephalin into the median raphe nucleus, and the effects of substance P on GABA turnover. Serotonin turnover was increased by 30% in the hippocampus after the injection of substance P (4 micrograms) into the median raphe, indicating an excitatory effect of substance P on the raphe-hippocampal system. Local injection of the metabolically stable metenkephalin analog 2-D-ala-met-enkephalin amide (10 micrograms) increased the hippocampal steady state content of 5-hydroxyindoleacetic acid (5-HIAA) by 60%. The data suggest an excitatory effect of met-enkephalin within the raphe nucleus. We attempted to estimate GABA turnover from the rate of disappearance of GABA after inhibition of glutamic acid decarboxylase by isoniazid and by the rate of accumulation of GABA after inhibition of GABA transaminase by gabaculine. Isoniazid, which is a competitive inhibitor, had too short and incomplete an action to be of use when injected intranuclearly. Gabaculine, which is an irreversible inhibitor, induced a rapid-onset increase in GABA content. This accumulation was linear up to 90 min. The injection fo gabaculine (80 ng) into the raphe increased GABA content by five times the control values, but hippocampal 5-HT and 5-HIAA contents were not significantly changed. Substance P injection increased the GABA turnover by 30%. Gabaculine seems a promising tool for detecting changes in GABA turnover.

Dopaminergic and non-dopaminergic neurons in substantia nigra: differential response to bromocriptine.

Bromocriptine reduces the spontaneous firing rate of neurons in the pars compacta of the substantia nigra but does not change the electrical activity of the neurons located in the pars reticulata. On the other hand, bromocriptine induces contralateral circling behaviour in rats with unilateral 6-hydroxydopamine nigral lesion. This increased motor activity follows an initial period of hypomotility. The decrease of the neuronal firing rate in the pars compacta of the substantia nigra coincides with the hypomotility observed in the lesioned rats.

Neuroexcitatory properties of kainic acid. I) Electroencefalographic changes following intracerebral microinjections in behavioural rats. Preliminary note.

Microdoses of kainic acid injected into dorsal hippocampus, into striatum and into substantia reticularis pontis cause specific epileptic-like patterns associated with neuronal degeneration. Epileptic patterns seem to be dose-related and depend on the injected brain areas.

Neuroexcitatory properties of kainic acid. II) Neuronal damages following intracerebreal microinjections in behavioural rats.

Microinjection of low doses of kainic acid, a neurotoxic analogue of glutammate, in different brain areas (striatum, hippocampus, substantia reticularis pontis) induces neuronal damages in injected and distant areas. Particularly severe neuronal damages have been observed in striatum and CA3 hippocampal area; neuronal degeneration has also been observed in substantia nigra following kainic acid infusion into the substantia reticularis pontis.

Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors.

A brain polypeptide termed diazepam-binding inhibitor (DBI) and thought to be chemically and functionally related to the endogenous effector of the benzodiazepine recognition site was purified to homogeneity. This peptide gives a single band of protein on NaDodSO4 and acidic urea gel electrophoresis. A single UV-absorbing peak was obtained by HPLC using three different columns and solvent systems. DBI has a molecular mass of approximately equal to 11,000 daltons. Carboxyl-terminus analysis shows that tyrosine is the only residue while the amino-terminus was blocked. Cyanogen bromide treatment of DBI yields three polypeptide fragments, and the sequences of two of them have been determined for a total of 45 amino acids. DBI is a competitive inhibitor for the binding of [3H]diazepam, [3H]flunitrazepam, beta-[3H]carboline propyl esters, and 3H-labeled Ro 15-1788. The Ki for [3H]-diazepam and beta-[3H]carboline binding were 4 and 1 microM, respectively. Doses of DBI that inhibited [3H]diazepam binding by greater than 50% fail to change [3H]etorphine, gamma-amino[3H]butyric acid, [3H]-quinuclidinyl benzilate, [3H]dihydroalprenolol, [3H]adenosine, and [3H]imipramine binding tested at their respective Kd values. DBI injected intraventricularly at doses of 5-10 nmol completely reversed the anticonflict action of diazepam on unpunished drinking and, similar to the anxiety-inducing beta-carboline derivative FG 7142 (beta-carboline-3-carboxylic acid methyl ester), facilitated the shock-induced suppression of drinking by lowering the threshold for this response.