Analysis of DNA variations in promoter region of HCNP gene with Alzheimer's disease.

Hippocampal cholinergic neurostimulating peptide (HCNP), which enhances acetylcholine synthesis and induces cholinergic phenotype development of the septohippocampal system, is derived from HCNP precursor protein (HCNPpp), also known as phosphatidylethanolamine binding protein (PEBP) and Raf kinase inhibitor protein (RKIP). Our previous study demonstrated that expression of HCNPpp mRNA was decreased in the hippocampi of autopsied brains of Alzheimer's disease (AD) patients, indicating the association of HCNP with the pathogenesis of AD. To clarify the involvement of gene variations in the promoter region of the gene encoding HCNPpp in this mRNA reduction, we analyzed DNA polymorphisms or mutations within this gene promoter region in AD patients by direct sequencing. The promoter was found to contain a CpG island without a TATA box, an element of housekeeping gene promoters. Moreover, no disease-specific polymorphisms or mutations were identified, suggesting that the decrease of mRNA can be ascribed to transcriptional or posttranscriptional changes in activity.

Differential expression of HCNP-related antigens in hippocampus in senescence-accelerated mice.

Hippocampal cholinergic neurostimulating peptide (HCNP), originally isolated from soluble fraction of young rat hippocampus and released from hippocampus by the stimulation of N-methyl-d-aspartate (NMDA) receptors, enhances the cholinergic phenotype development in vitro. HCNP precursor protein (HCNP-pp) has multiple functions, not only acting as the precursor of HCNP but also serving as an inhibitor of phosphorylation of Erk and contributing to neuronal growth and memory formation. In this study, the accumulation of HCNP and/or HCNP precursor in hippocampus was found to progress from 2 to 5 months of age in senescence-accelerated mouse-prone 8 (SAM P8). This HCNP surge in the hippocampus appears to correspond to the age of onset of memory deterioration, reduction of amount of NMDA-type receptor, and morphological aberration in this dementia model mouse, SAM P8. The present findings, together with our previously published results, suggest that the HCNP and/or HCNP precursor is involved in the dysfunction of the cholinergic neuronal system and memory deterioration in this model mouse via NMDA-type receptor signaling and the activation of the MAP cascade.

[An adult case of cyclic vomiting syndrome in which tricyclic antidepressant was effective].

A 30-year-old man presented with a 10-year history of recurrent, stereotypic episodes of incapacitating nausea and vomiting. Initially, he had been diagnosed as having superior mesenteric artery syndrome, and had undergone abdominal surgery at age 20. The patient was in good health between episodes. During each episode, oral intake was impossible and total parenteral nutrition and sedation were necessary. Conventional antiemetics such as metoclopramide were not effective, and the 5-HT3 antagonist ondansetron hydrochloride was only partially effective. Investigations into gastrointestinal, hormonal, and metabolic function were unremarkable, as was psychiatric evaluation. Diagnosing this to be an adult case of cyclic vomiting syndrome, we administered amitriptyline hydrochloride; a prophylactic agent for migraine. This resulted in rapid resolution of the episodes, which have not recurred over several years' follow up. Recently, cyclic vomiting syndrome has been considered a subtype of migraine. In the present case, effectiveness of the tricyclic antidepressant amitriptyline hydrochloride indicated that migraine and cyclic vomiting syndrome have a common pathology. Clinicians should be aware that cyclic vomiting syndrome can affect adults as well as children, and that treatment for migraine may be effective.

Cognitive conditions of pathologically confirmed dementia with Lewy bodies and Parkinson's disease with dementia.

The relationship between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) has been insufficiently described, and it is still problematic. Twenty-nine cases of DLB and 10 cases of PDD were investigated in the present study. DLB cases disclosed a significantly older disease onset and shorter disease duration than PDD cases (p<0.01 each). However, they showed no significant difference in dementia onset or dementia duration (p>0.05 each). Motor symptoms (parkinsonism) were suspected as the cause of the younger disease onset in PDD cases. Compared with 10 age-matched cases of definite Alzheimer's disease, both 19 DLB cases and 6 PDD cases had significantly better scores in the final test of mini-mental state examination (MMSE) and revised version of Hasegawa's Dementia Scale (HDSR) within 12 months before death, although no significant differences between DLB and PDD were indicated. DLB and PDD were suspected to show cognitive impairment of similar severity in the terminal stage. They would thus be difficult to classify as completely different entities.

Specific binding of 125I-hippocampal cholinergic neurostimulating peptide (HCNP) to rat brain membranes: characterization and regional distribution.

An undecapeptide-hippocampal cholinergic neurostimulating peptide (HCNP), originally purified from young rat hippocampus, enhances cholinergic phenotype development in the medial septal nucleus in vitro. To survey and characterize the HCNP receptor within the central nervous system, we used iodinated HCNP as a labeled ligand. In preliminary experiments, [125I]HCNP binding was highest in the crude P2 membrane fraction, so all subsequent experiments were performed using this fraction. The binding was saturable and reversible, and unlabeled ligand inhibited it. Scatchard analysis of the concentration-dependent saturation of binding indicated a single population of non-interacting sites with K(d) 4.0+/-0.7 nM and B(max) 10.7+/-3.8 pmol/mg protein. Dissociation experiments revealed a dissociation constant (K(-1)) of 0.07 min(-1). Inhibition experiments using HCNP and its shorter peptide fragments suggested that the active binding site resided close to the peptide's C-terminal sequence. Since [125I]HCNP binding was found in crude P2 membrane fractions from animals at all ages examined, HCNP may also perform important functional roles in the adult brain. Further, the predominant distribution of the receptor in the P2 membrane fraction, and the similarity in distribution patterns between the binding site and HCNP-precursor protein mRNA expression suggest that the peptide exerts its functions in the vicinity of the dendrites of the neurons that produce it.

Subtype analysis of neuropathologically diagnosed patients in a Japanese geriatric hospital.

Dementia is a social problem in Japan, as it is in other countries. Recently, there has been an increase in the number of patients with Alzheimer-type dementia (ATD) in the population. We analyzed 239 cases of patients autopsied at Fukushimura Hospital over a 10-year period. Clinicopathologically, 66% of these cases (158 cases) presented with dementia symptoms. The predominant form of illness was ATD. We found dementia with Lewy bodies (DLB) to be as frequent as vascular dementia (VD). Although the numbers were small, limbic neurofibrillary tangle dementia (LNTD) and Pick's disease (PiD) followed a clinical course typical of these diseases. On the other hand, senile dementia of the Alzheimer's type (SDAT) and the common form of neocortical type DLB (diffuse Lewy body disease; DLBD) were difficult to distinguish from each other. We attempted to uncover differences between these dementias in terms of how they affect male and female patients. The clinical course of the male patients with the common form of neocortical type DLB was more or less typical, while that of the female patients was not.