Hidetaka Shinjo

Serotonin Transporter Gene Polymorphism and BPSD in Mild Alzheimer's Disease

The purpose of the present study was to confirm an association of functional polymorphism within the serotonin transporter (5-HTT) gene with Alzheimers disease (AD) and behavioral and psychological symptoms of dementia (BPSD) in mild AD. Apolipoprotein E (ApoE) gene polymorphism and 2 types of functional polymorphism in the 5-HTT gene, 5-HTT-linked polymorphic region (5-HTTLPR) and a 5-HTT variable number of tandem repeats sequence (5-HTTVNTR) were analyzed longitudinally in outpatients with mild AD to find out whether there was a relation between any such polymorphisms and the occurrence of BPSD. No significant differences in genotype distribution or allele frequencies were identified for 5-HTTLPR or 5-HTTVNTR between AD patients and age- and sex-matched non-demented controls regardless of ApoE epsilon4 allele. No significant differences were noted in 5-HTTLPR genotype or allele distributions between AD patients with or without BPSD. However, significant associations were observed between presence of 5-HTTVNTR allele 10 and BPSD or aggressiveness. This difference was independent of the presence of the ApoE epsilon4 allele. As a result, 5-HTT polymorphisms are unlikely to play any substantial role in susceptibility to AD. Conversely, 5-HTTVNTR influences the risk of developing BPSD or aggressiveness and genetic variations in the 5-HTT gene may be involved in the development of symptomatology for mild AD.

Synapse alteration in hippocampal CA3 field following entorhinal cortex lesion

To model one aspect of the neurodegeneration observed in Alzheimers disease and to investigate the synaptic alteration of the hippocampus associated with entorhinal cortex lesion, ibotenic acid was used to produce selective unilateral neuronal loss in rat entorhinal cortex. Immunohistological and microdensitometrical analyses confirmed ibotenic acid lesion of the entorhinal cortex after 3 months and showed a decrease of synaptophysin-immunoreactive substances in the stratum lucidum of the CA3 field. This study demonstrates that entorhinal cortex lesion can lead to synaptic alterations and cause damage to presynaptic terminals with projecting area in the disruption of the entorhinal cortex hippocampus relay passage.

Depression in multiple system atrophy: A case report

Abstract A 53‐year‐old woman who developed depression as the first symptom of multiple system atrophy was treated. Depression was followed successively by autonomic failure, parkinsonism and cerebellar ataxia. Treatment with L‐DOPA, L‐threo‐DOPS, and thyroid releasing hormone was associated with improvement of autonomic failure and parkinsonism. As for depression, scores on the Zung scale and the Hamilton scale improved from 58 to 49 and from 30 to 22, respectively. This case is remarkable in that depression preceded neurologic dysfunction and was managed successfully by antiparkinsonian medication. A common underlying disturbance may be responsible for the depression and neurologic dysfunction in multiple system atrophy.

Dopamine D3 Receptor Gene Polymorphism Influences on Behavioral and Psychological Symptoms of Dementia (BPSD) in Mild Dementia of Alzheimer's Type

Dopamine D3 receptor (DRD3) is present in the limbic system, which is thought to regulate affect, cognition, and activity. Thus a functional change in the DRD3 gene could in turn affect the cognitive and psychiatric symptoms of dementia of Alzheimers type (DAT). We investigated a possible association of DRD3 genotype with DAT and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for DRD3 and apolipoprotein E (ApoE) was determined using restriction fragment length polymorphism in 210 patients with mild DAT and 224 age- and sex-matched non-demented controls. The occurrence of BPSD during the course of mild dementia was demonstrated using the Behavioral Pathology in Alzheimers Disease rating scale (BEHAVE-AD). No significant differences in DRD3 genotype were identified between DAT and controls, regardless of ApoE epsilon4. Among the DAT with BPSD, however, a significant association was observed between the presence of the DRD3 glycine allele and paranoid and delusional ideation, regardless of ApoE epsilon4. In conclusion, DRD3 gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of paranoid and delusional ideation during the course of mild DAT.

Effect of entorhinal cortex lesion on hippocampal cholinergic system in rat in operant learning task as studied by in vivo brain microdialysis

An in vivo microdialysis method was used to study the cholinergic alteration of the hippocampus in entorhinal cortex-lesioned rats performing a positive reinforcement operant learning task. Rats with bilateral entorhinal cortex lesions were implanted with a dialysis probe into the hippocampal CA3 after ten learning sessions. After 7 days, the bilateral entorhinal cortex-lesioned rats showed impaired acquisition of positive reinforcement operant learning. The basal level of the acetylcholine efflux decreased within 30 min before the beginning of a learning session. The hippocampal acetylcholine efflux showed a significantly diminished increase and rapidly returned to the basal level during the 60 min after the beginning of a learning session. These results suggested that enorhinal cortex lesion may cause damage to the hippocampal cholinergic system with disruption of the entorhinal cortex-hippocampus relay passage.

IDE Gene Polymorphism Influences on BPSD in Mild Dementia of Alzheimer's Type

Insulin degrading enzyme (IDE) degrades amyloid β (Aβ), which may inhibit the accumulation of Aβ in a brain affected with dementia of Alzheimers type (DAT). A decrease in the activity of IDE results in changes in glucose utilization in the brain, which could affect the cognitive and psychiatric symptoms of DAT. We investigated a possible association of IDE gene polymorphism and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for IDE and apolipoprotein E (ApoE) was determined in 207 patients with mild DAT and 215 controls. The occurrence of BPSD was demonstrated using the Behavioral Pathology in Alzheimers Disease Rating Scale (BEHAVE-AD). IDE gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of affective disturbance through the course of mild DAT, regardless of the presence of an ApoE ε4 allele. The present data could be the result of a small sample size. Further investigations using larger samples are thus required to clarify the correlation between IDE gene polymorphism, susceptibility to DAT, and emergence of BPSD.

Long-term synaptic alteration in the rat hippocampal CA3 field following an entorhinal cortex lesion

Abstract The entorhinal cortex is a key initial relay for cortical input to the hippocampus. To better understand hippocampal dysfunction resulting from early entorhinal cortex involvement in Alzheimer’s disease, we stereotaxically injected ibotenic acid to produce unilateral entorhinal cortex lesions in rats. We then serially examined the CA3 hippocampal region by neuronal counts, histochemistry for acetylcholinesterase, and synaptophysin immunohistochemistry. Over 12 months, the neuronal counts did not change. Acetylcholinesterase‐positive fibers were persistently but non‐progressively beginning at 3 months. Synaptophysin immunoreactivity progressively declined over 12 months. Since much of the entorhinal cortex output proceeds to CA3 via the dentate gyrus, transsynaptic degeneration is suspected.