Efficacy, Safety, and Tolerability of Switching from Oral Cholinesterase Inhibitors to Rivastigmine Transdermal Patch with 1-Step Titration in Patients with Mild to Moderate Alzheimer's Disease: A 24-Week, Open-Label, Multicenter Study in Japan.

BACKGROUND: Few studies have investigated treatment options for patients with Alzheimer's disease (AD) showing a poor response to oral cholinesterase inhibitors (ChEIs) in Japan. OBJECTIVE: To investigate the efficacy and safety of switching from oral ChEIs to rivastigmine transdermal patch in patients with AD. METHODS: In this multicenter, open-label, phase IV study in outpatient clinics in Japan, patients with mild-moderate AD who had a poor response to or experienced difficulty in continuing donepezil or galantamine were switched to rivastigmine transdermal patch (5 cm2; loaded dose 9 mg, delivery rate 4.6 mg/24 h) with a 1-step titration in week 4 (10 cm2; loaded dose 18 mg, delivery rate 9.5 mg/24 h), which was continued for 4 weeks in the titration period and 16 weeks in a maintenance period. The primary endpoint was the change in Mini-Mental State Examination (MMSE) total score from baseline to week 24. RESULTS: A total of 118 patients were enrolled and switched to rivastigmine, of which 102 completed the 24-week study. The MMSE total score was essentially unchanged during the study, with a least-square mean change (SD) of -0.35 (2.64) at week 24 (p = 0.1750). Exploratory analysis with a mixed-effect model comparing changes in MMSE between the pre- and post-switch periods suggested that switching to rivastigmine prevented a worsening of MMSE. Application site skin reactions/irritations occurred in 30.5% of patients overall, in 22.0% in the 8-week titration period, and in 10.2% in the 16-week maintenance period. CONCLUSION: Within-class switching from an oral ChEI to rivastigmine transdermal patch might be an efficacious and tolerable option for AD patients showing a poor or limited response to a prior oral ChEI.

Rate of progression of Alzheimer's disease in younger versus older patients: a longitudinal single photon emission computed tomography study.

AIM: Although several researchers have examined the effect of age on disease progression in patients with Alzheimer's disease (AD), the results are controversial. We investigated the effect of age on the rate of progression of cognitive impairment and on regional cerebral blood flow (rCBF) deficits using longitudinal single photon emission computed tomography (SPECT) studies. METHODS: We divided 75 patients with AD who were followed up for 24-90 months into the younger AD group (n=32, age at initial examination ≤ 75 years) and the older AD group (n=43, age at initial examination >75 years). We assessed changes in Mini-Mental State Examination (MMSE) scores and rCBF between initial and final examinations. RESULTS: The change in the annual MMSE score was greater in the younger AD group than in the older AD group. The mean annual MMSE score changes correlated significantly with age at the initial examination. The initial and follow-up SPECT studies showed more severe and extensive rCBF deficits in the younger AD group than in the older AD group. CONCLUSION: Our longitudinal SPECT study showed that the rate of progression of cognitive impairment and the rCBF deficits were higher in younger patients with AD than in older patients with AD. Therefore, age is an important factor to consider, not only in the diagnosis, but also in the treatment and prognosis of patients with AD.

Efficacy of a high dosage of donepezil for Alzheimer's disease as examined by single-photon emission computed tomography imaging.

BACKGROUND: The efficacy of donepezil 10 mg/day against Alzheimer's disease (AD) was examined, with a primary focus on changes in cerebral blood flow (CBF) as determined by single-photon emission computed tomography imaging. METHODS: The subjects were 24 outpatients who had been diagnosed with probable AD, which had progressed to advanced AD. Mini-Mental State Examination and Alzheimer's Disease Assessment Scale (ADAS) scores were determined before and after the donepezil dosage increase. (99m) Tc-ethylcysteinate dimer single-photon emission computed tomography was performed to evaluate changes in CBF. Then, a comparative study evaluated changes after the donepezil dosage increased. RESULTS: After the donepezil dosage increase, adverse effects associated with gastrointestinal symptoms were observed in one patient, and irritability was observed in three. The average Mini-Mental State Examination score changed from 15.25 ± 6.24 to 14.67 ± 6.07; significant changes were not observed. Seventeen subjects were evaluated with the Alzheimer's Disease Assessment Scale-cognitive subscale. After the dosage increase, the average subscale score decreased from 24.52 ± 13.39 to 21.56 ± 9.14, and significant improvement was observed (P = 0.021). With respect to changes in the CBF, the values of all three indicators decreased after the higher dosage increased CBF. However, no significant differences were observed in CBF. Analysis performed after the donepezil dosage increase revealed significant increases in CBF in the right occipital and temporal lobes, left temporal lobe, right parietal lobe, and both parts of the posterior cerebellum. CONCLUSION: Increasing the donepezil dosage from 5 mg/day to 10 mg/day is effective for the treatment of AD.

Clinical results and issues of acute myeloid leukemia in elderly patients aged 75 years and older.

AIM: Clinical outcomes of acute myeloid leukemia (AML) in elderly patients still remain unsatisfactory and the optimal treatment has yet to be clearly established. This report describes the results of a retrospective study of clinical outcomes and prognostic factors of AML in patients aged 75 years and older. In addition, we aimed to elucidate the situation of patients with AML accompanied by dementia, which has been largely ignored in previous studies. METHODS: The subjects consisted of 31 patients with untreated AML (including previous myelodysplastic syndrome: AML/MDS). All patients underwent chemotherapy, with 25 undergoing conventional therapy and six undergoing low-intensity therapy. RESULTS: Complete remission was obtained in 16 of the 31 cases (51.6%), with a 3-year survival rate of 11.5%. However, in seven cases, Alzheimer's disease (AD) was observed. Although we were able to perform induction therapy in each of these cases, consolidation therapy was difficult in cases of moderate AD. CONCLUSION: The results of this study suggest that even very elderly patients can benefit from chemotherapy. However, it is thought that the treatment selection for cases which are complicated by moderate to severe dementia should be determined carefully while considering the patient's quality of life.

Changes in cognitive functions of patients with dementia of the Alzheimer type following long-term administration of donepezil hydrochloride: relating to changes attributable to differences in apolipoprotein E phenotype.

AIM: We conducted a study of changes in cognitive functions by long-term monitoring of dementia of Alzheimer type (DAT) patients to investigate the relationship between the progression of DAT symptoms and the presence of apolipoprotein (ApoE)4. METHODS: The subjects consisted of 40 DAT patients who had been treated with donepezil for 3 years or more. The Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale - Cognitive Subscale Japanese version (ADAS-Jcog), were conducted annually. The patients were categorized into ApoE4(+) and ApoE4(-) groups. Changes in initial cognitive function assessment score (0 years) were then studied longitudinally at each stage of the observation period (1, 2, 3 years) (Wilcoxon's signed-rank test). Moreover, the scores at each time period were compared cross-sectionally between the two groups (Mann-Whitney U-test). RESULTS: Significant decreases in MMSE scores were observed at the three time periods in both groups (P < 0.01) in the cross-sectional study. In the longitudinal study, the ApoE4(+) group demonstrated a lower trend (P < 0.1) after 1 year only. Significantly poorer ADAS-Jcog scores were observed in the ApoE4(+) group at the 3-year point both in the longitudinal and in the cross-sectional study (P < 0.05). For ADAS-Jcog sub-items, in the longitudinal study, orientation was demonstrated to be significantly poorer in the ApoE4(+) group in the third year (P < 0.05). CONCLUSION: ApoE4 was suggested to not only be a risk factor for disease onset, but also a risk factor for exacerbation of symptoms with respect to long-term prognosis.

Peripheral T-cell lymphoma presenting as myelofibrosis with the expression of basic fibroblast growth factor.

Myelofibrosis is often observed in chronic myeloproliferative disorders (CMPD), but non-Hodgkin's lymphoma with diffuse myelofibrosis is rare. We describe an elderly case with peripheral T-cell lymphoma-unspecified (PTCL) presenting as diffuse myelofibrosis. Bone marrow biopsy revealed infiltration of atypical lymphocytes and diffuse myelofibrosis without any increase in megakaryocytes. To discuss the pathogenesis of fibrosis, we examined cytokines relative to fibrosis using immunostaining. The expression of basic fibroblast growth factor (bFGF) was diffusely detected in the area of extracellular matrix of bone marrow. In addition, in situ hybridization revealed that infiltrating lymphoma cells expressed bFGF mRNA. Basic FGF, originally identified based on its mitogenicity for fibroblasts, has multiple potential, influencing neoangiogenesis, bone marrow fibrosis and the proliferation of tumor cells. Basic FGF might play an important role in the pathogenesis of myelofibrosis in the present case.

A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia.

The effectiveness and safety of yokukansan (TJ-54), a traditional Japanese medicine (kampo) for the treatment of the behavioural and psychological symptoms of dementia (BPSD), were evaluated in 106 patients diagnosed as having Alzheimer's disease (AD) (including mixed-type dementia) or dementia with Lewy bodies. Patients were randomly assigned to group A (TJ-54 treatment in period I and no treatment in period II; each period lasting 4 wk) or group B (no treatment in period I and TJ-54 treatment in period II). BPSD and cognitive functions were evaluated using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE), respectively. Activities of daily living (ADL) were evaluated using Instrumental Activities of Daily Living (IADL) in outpatients and the Barthel Index in in-patients. For the safety evaluation, adverse events were investigated. Significant improvements in mean total NPI score associated with TJ-54 treatment were observed in both periods (Wilcoxon test, p=0.040 in period I and p=0.048 in period II). The mean NPI scores significantly improved during TJ-54 treatment in groups A and B (p=0.002 and p=0.007, respectively) but not during periods of no treatment. Among the NPI subscales, significant improvements were observed in delusions, hallucinations, agitation/aggression, depression, anxiety, and irritability/lability. The effects of TJ-54 persisted for 1 month without any psychological withdrawal symptoms in group A. TJ-54 did not show any effect on either cognitive function or ADL. No serious adverse reactions were observed. The present study suggests that TJ-54 is an effective and well-tolerated treatment for patients with BPSD.

[The efficacy and adverse effects of rituximab with CHOP or THP-COP in old-old and extremely old patients with diffuse large B cell lymphoma].

AIM: We examined the efficacy and adverse effects of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) or THP-COP (pirarubicin, cyclophosphamide, vincristin, prednisone) in previously untreated old-old and extremely old patients with diffuse large B cell lymphoma (DLBCL). METHODS: Subjects were 13 initial DLBCL patients consisting of 7 men and 8 women with a median age of 79 years (range 75-91 years). These patients received CHOP or THP-COP plus 375mg/m2 rituximab intravenously given on the day before each cycle. The dose was adjusted depending on the patient's age and associated complications. Administration was performed for 6 to 8 cycles, whenever possible. RESULTS: Seven patients (54%) achieved a complete response (CR), 4 (31%) achieved a partial response (PR), 2 (15%) failed to respond. The 2-year survival rates were 62%. The CR rate and survival rate were higher than in patients previously treated with CHOP alone in our hospital, but there was no statistically significant difference. The most frequent adverse effect was bone marrow suppression, observed in 9 patients (69.2%). Adverse effects that seemed to be infusion reaction occurred in 4 patients (30.7%). These adverse effects related to infusion reaction disappeared by reducing or stopping rituximab. Four (30.7%) patients died and 3 of those died due to disease progression. One of those died 1.5 month after he began chemotherapy and the cause of death was unknown. CONCLUSION: This result suggested that both CHOP and THP-COP combined with rituximab were safe and effective for old-old and extremely old patients.

Implications of carotid arteriomegaly in patients with aortic aneurysm.

The pathophysiology of aortic aneurysm is complex and it has remained unclear how frequently arteriomegaly, a diffuse dilatation of the artery, is associated with aneurysm. Therefore, ultrasonic study of the carotid artery was conducted to clarify this issue in a large number of subjects. Carotid ultrasonography was performed in 1,108 Japanese men aged 50 or older, and the results of 379 patients with arteriosclerotic aortic aneurysm (AA) were compared with those of 211 patients with peripheral arterial disease, 65 patients with aortic dissection, 232 hypertensive subjects, and 221 normotensive subjects. The carotid diameter was measured bilaterally at two points on the common carotid artery, and we defined carotid arteriomegaly as an arterial diameter in the 95th percentile or above that in the normotensive control group according to the relevant age subgroups. The incidence of carotid arteriomegaly in the AA group (25.9%) was significantly higher than in the other groups (p < 0.01) even when adjusted for body height and blood pressure. In the arteriomegaly subgroup, hypertension and cigarette smoking was significantly more frequent than in the non-dilated artery subgroup. This study demonstrates that one fourth of patients with aortic aneurysm have arteriomegaly as a generalized systemic abnormality in the arterial wall.

Demonstration and distribution of tau-positive glial coiled body-like structures in white matter and white matter threads in early onset Alzheimer's disease.

The present report concerns the demonstration and distribution of tau-positive structures in the frontal and temporal white matter of five autopsy cases of early onset Alzheimer's disease (AD). The relationship between white matter lesions and tau positive structures was also investigated. Five early onset AD brains, which had not only unambiguous white matter lesions, but also no or rare atherosclerosis and minimal amyloid angiopathy, were examined. There were several tau-positive coiled body-like structures and many thread-like structures in the white matter, although previous reports showed only a few coiled bodies in the white matter in the AD brain. No relationship was found between the degree of each white matter lesion and number or distribution of tau-positive structures in the white matter. The results suggest that the AD brain has tau-positive structures in the white matter similar to some neurodegenarative brain diseases such as progressive supranuclear palsy, corticobasal degeneration, and dementia with grains. However, tau abnormalities may have fewer effects when they are located in white matter lesions in AD.