Clinical profiles of late‐onset semantic dementia,compared with early‐onset semantic dementia and late‐onset Alzheimer's disease

Background: Semantic dementia (SD) has been recognized as a representative of dementia with presenile onset; however, recent epidemiological studies have shown that SD also occurs in the elderly. There have been few studies about the differences of clinical profiles between early‐onset SD (EO‐SD) and late‐onset SD (LO‐SD). Age‐associated changes in the brain might cause some additional cognitive and behavioural profiles of LO‐SD in contrast to the typical EO‐SD cases. The aim of the present study was to clarify the characteristics of neuropsychological, and behavioural and psychological symptoms of dementia (BPSD) profiles of LO‐SD patients observed in screening tests in comparison with EO‐SD patients and late‐onset Alzheimer's disease (LO‐AD) patients as controls. Methods: Study participants were LO‐SD (n = 10), EO‐SD (n = 15) and LO‐AD (n = 47). We examined the Mini‐Mental State Examination (MMSE), the Raven's Coloured Progressive Matrices (RCPM), the Short‐Memory Questionnaire (SMQ), the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Results: Both SD groups scored significantly lower than the LO‐AD patients in ‘naming’ of the MMSE. In the ‘construction’ score of the MMSE and the RCPM score, however, the LO‐SD patients as well as the LO‐AD patients were significantly lower than the EO‐SD patients. In the SMQ score, ‘euphoria’ and ‘disinhibition’ scores of the NPI, the SRI total and subscale scores, both SD groups were significantly higher, whereas in the ‘delusion’ score of the NPI, both SD groups were significantly lower than the LO‐AD patients. Conclusions: Visuospatial and constructive skills of LO‐SD patients might be mildly deteriorated compared with EO‐SD patients, whereas other cognitive and behavioural profiles of LO‐SD are similar to EO‐SD. Age‐associated changes in the brain should be considered when we diagnose SD in elderly patients.     

Novel therapeutic strategies for neurodegenerative disease

The activity of protein phosphatase 2A (PP2A) is compromised and believed to be the cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. Activity of PP2A is regulated by two endogeneous inhibitor proteins, called as I₁^PP2A and I₂^PP2A. Previously, we reported that: (i) I₁^PP2A and I₂^PP2A are upregulated with cleavage of I₂^PP2A holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I₂^PP2A colocalized not only with the PP2A catalytic subunit, but also with phosphorylated tau in neuronal cytoplasm. Furthermore, according to preliminary data, the cleavage site of I₂^PP2A is located between amino acids 175 and 176 of the I₂^PP2A sequence. Because the sequence from amino acids 168 to 181 on I₂^PP2A presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I₂^PP2A is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.     

Action of human interleukin-4 and stem cell factor on erythroid and mixed colony formation by peripheral blood-derived CD34+c-kithigh or CD34+c-kitlow cells

We studied the interaction of interleukin (IL)-4 and other burst-promoting activity (BPA) factors, such as IL-3, granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-9 and stem cell factor (SCF), on erythroid burst-forming unit (BFU-E) and erythrocyte-containing mixed (CFU-Mix) colony formation in serum-free culture. IL-4 alone did not support mixed colony formation in the presence of erythropoietin (Epo). However, IL-4 showed weak but significant BPA when peripheral blood (PB)-derived CD34⁺c-kit^low cells were used as the target population. The BPA of IL-4 was much weaker than that of IL-3, which exerted the most potent activity, as previously reported. When CD34⁺c-kit^high cells were used as the target, four factors known to have BPA, IL-3, GM-CSF, IL-9 and SCF, could express BPA. In contrast, IL-4 alone failed to support erythroid burst formation. Interestingly, IL-4 showed a remarkable enhancing effect with SCF in promoting the development of erythroid burst and erythrocyte-containing mixed colonies from CD34⁺c-kit^low and CD34⁺c-kit^high cells. Delayed addition of SCF + Epo or IL-4+Epo to the cultures initiated with either IL-4 or SCF alone clearly demonstrated that SCF was a survival factor for both BFU-E and CFU-Mix progenitors. In contrast, the survival effect of IL-4 was much weaker than that of SCF, and appeared to be more important for progenitors derived from CD34⁺c-kit^low cells than for those derived from CD34⁺c-kit^high cells. It was recently reported that CD34⁺c-kit^low cells represent a more primitive population than CD34⁺c-kit^high cells. Taken together, these results suggest that IL-4 helps to recruit primitive progenitor cells in the presence of SCF.     

The production ratios of AICDε51 and Aβ42 by intramembrane proteolysis of βAPP do not always change in parallel

Background: During intramembrane proteolysis of β‐amyloid protein precursor (βAPP) by presenilin (PS)/γ‐secretase, ε‐cleavages at the membrane‐cytoplasmic border precede γ‐cleavages at the middle of the transmembrane domain. Generation ratios of Aβ42, a critical molecule for Alzheimer's disease (AD) pathogenesis, and the major Aβ40 species might be associated with ε48 and ε49 cleavages, respectively. Medicines to downregulate Aβ42 production have been investigated by many pharmaceutical companies. Therefore, the ε‐cleavages, rather than the γ‐cleavage, might be more effective upstream targets for decreasing the relative generation of Aβ42. Thus, one might evaluate compounds by analyzing the generation ratio of the βAPP intracellular domain (AICD) species (ε‐cleavage‐derived), instead of that of Aβ42. Methods: Cell‐free γ‐secretase assays were carried out to observe de novo AICD production. Immunoprecipitation/MALDI‐TOF MS analysis was carried out to detect the N‐termini of AICD species. Aβ and AICD species were measured by ELISA and immunoblotting techniques. Results: Effects on the ε‐cleavage by AD‐associated pathological mutations around the ε‐cleavage sites (i.e., βAPP V642I, L648P and K649N) were analyzed. The V642I and L648P mutations caused an increase in the relative ratio of ε48 cleavage, as expected from previous reports. Cells expressing the K649N mutant, however, underwent a major ε‐cleavage at the ε51 site. These results suggest that ε51, as well as ε48 cleavage, is associated with Aβ42 production. Only AICDε51, though, and not Aβ42 production, dramatically changed with modifications to the cell‐free assay conditions. Interestingly, the increase in the relative ratio of the ε51 cleavage by the K649N mutation was not cancelled by these changes. Conclusion: Our current data show that the generation ratio of AICDε51 and Aβ42 do not always change in parallel. Thus, to identify compounds that decrease the relative ratio of Aβ42 generation, measurement of the relative level of Aβ42‐related AICD species (i.e., AICDε48 and AICDε51) might not be useful. Further studies to reveal how the ε‐cleavage precision is decided are necessary before it will be possible to develop drugs targeting ε‐cleavage as a means for decreasing Aβ42 production.     

Effects of short‐term reminiscence therapy on elderly with dementia: A comparison with everyday conversation approaches

Background: Recent research has demonstrated the usefulness of reminiscence therapy as a psychosociological approach to the care of the demented elderly. However, to date neither the variables (e.g. evaluation methods and the optimal number of therapy sessions related to this technique) have been established, nor have the differences between reminiscence and other verbal interventions been clarified. In the field of clinical and nursing care in which reminiscence therapy is undertaken, in order to facilitate the participation of as large a number of elderly people as possible, both short‐ and long‐term courses of sessions are needed. The present study conducted five therapy sessions using closed groups. Mainly, a verbal fluency task was used to assess the efficacy of therapy. Method: The results of the five sessions that were conducted with a reminiscence therapy group (reminiscence group; n = 8 ambulant elderly women with Alzheimer's‐type dementia) were compared with those of an everyday conversation group (conversation group; n = 8 ambulant elderly women with Alzheimer's‐type dementia). Results: In the reminiscence group, there was a significant increase in the number of words recalled at the end of the fifth session compared with that recalled at the end of the first session. In addition, the number of words recalled increased significantly compared with that recalled by the conversation group. Furthermore, the interchanges through non‐verbal communication between others in the group improved and a positive change in participants' everyday life circumstances was observed. Moreover, the participants in the reminiscence group reported that they enjoyed the sessions. Conclusions: Reminiscence therapy performed over a short period of time in closed groups was shown to be more effective than everyday conversations in the treatment of elderly people with dementia. It is suggested that the effectiveness of group reminiscence therapy should be ascertained not only by the verbal fluency tasks, but also by changes in patients' interactions with others through non‐verbal communication.