Hirofumi Sakurai

Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease

To test the effects of the PPAR-γ agonist pioglitazone on cognition, regional cerebral blood flow (rCBF), and plasma levels of Aβ40 and Aβ42, we conducted a 6-month, randomized, open-controlled trial in patients with mild Alzheimer disease (AD) accompanied with type II diabetes mellitus. We randomly assigned 42 patients to either the group treated with 15-30 mg pioglitazone daily (n=21, pioglitazone group) or not (n=21, control group). The pioglitazone group improved cognition and rCBF in the parietal lobe, while the control group showed no such improvement. The plasma Aβ40/Aβ42 ratio increased in the control group, but showed no significant change in the pioglitazone group. Both groups showed good control of diabetes during the study. In addition, pioglitazone treatment resulted in a decrease in fasting plasma insulin levels, indicating enhanced insulin sensitivity. The results of this pilot study demonstrated that pioglitazone exhibited cognitive and functional improvements, and stabilization of the disease in diabetic patients with AD. Pioglitazone may offer a novel strategy for the treatment of AD.

Diffusion-weighted MR imaging of the hippocampus and temporal white matter in Alzheimer's disease.

We investigated the changes in water diffusion in the hippocampus and the temporal white matter (the temporal stem) in eight patients with possible Alzheimers disease (AD), 10 patients with probable AD, and 10 age-matched controls, using coronal diffusion-weighted magnetic resonance (MR) imaging. Apparent diffusion coefficients (ADCs) were derived for the three orthogonal axes and an index of diffusion anisotropy (IDA = ADC(max-min)/ADC(mean)) was then calculated. Although no significant differences were found in ADC and IDA values in the hippocampal body between controls and patients, vertical (superior-inferior) ADC values and ADC(mean) values in the temporal stem of patients with AD were significantly higher than those in controls, and IDA values were therefore significantly lower in patients with possible or probable AD than those in controls. Moreover, IDA values in the temporal stem were significantly correlated with the clinical severity. These results suggest that decreased fiber density, such as the disruption and loss of axonal membranes or myelin, occur early in the temporal stem, probably due to secondary degeneration related to grey matter pathology including the medial temporal lobe.

Diffusion-weighted and magnetization transfer imaging of the corpus callosum in Alzheimer's disease.

We investigated structural changes of the corpus callosum in patients with Alzheimers disease (AD) using sagittal diffusion-weighted (DW) and magnetization transfer (MT) imaging. Patients with AD (n=23) had a significantly decreased area only in the posterior portion of the corpus callosum. Apparent diffusion coefficient (ADC) values perpendicular to the commisural fiber orientation were significantly higher in the anterior portion of the corpus callosum without definite atrophy, as well as in the posterior portion with significant atrophy, in patients with AD than in controls (n=16) and thus diffusion in these regions showed a significantly lower degree of anisotropy in patients than in controls. MT ratios were also significantly lower in patients with AD in the anterior and posterior portions of the corpus callosum than in controls. These findings probably reflect structural changes in the corpus callosum including axonal loss and/or demyelination. DW and MT imagings may be useful in detecting degeneration of the corpus callosum in AD.

Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus.

DISCUSSION Vitamin D is a safe, inexpensive strategy to reduce falls and associated medical costs. This study showed that older fallers have a low rate of meeting the vitamin D RAI, especially men, older individuals, those without prior fracture, and those not taking calcium supplements. Patients and providers need greater education on the importance of vitamin D for prevention of falls and fractures. Written instructions and regular telephone follow-up appear to increase vitamin D intake in elderly fallers. This finding, if verified in additional studies, may prove an effective public health strategy to decrease falls in older adults.

Atrophy of the Substantia innominata on Magnetic Resonance Imaging Predicts Response to Donepezil Treatment in Alzheimer’s Disease Patients

To investigate whether atrophy of the substantia innominata as shown on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, predicts response to donepezil treatment in patients with Alzheimer’s disease (AD), we studied correlations between the thickness of the substantia innominata and clinical efficacy. Eighty-two patients were divided into responders, including transiently and continuously responding groups, and nonresponders, based on the changes in the Mini-Mental State Examination (MMSE) score from baseline at 3 months and at 12 months. Atrophy of the substantia innominata was more pronounced in transiently and continuously responding groups than nonresponders, but no significant change in the thickness between transiently and continuously responding groups was found. The MMSE score changes from baseline at 3 months and at 12 months significantly inversely correlated with the thickness of the substantia innominata. Logistic regression analysis revealed that the overall discrimination rate with the thickness of the substantia innominata was 70% between responders and nonresponders. We conclude that atrophy of the substantia innominata on MRI helps to predict response to donepezil treatment in patients with AD.

The role of 123I-metaiodobenzylguanidine myocardial scintigraphy in the diagnosis of Lewy body disease in patients with dementia in a memory clinic.

Reduction in cardiac 123I-metaiodobenzylguanidine (MIBG) uptake is a characteristic feature of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and is useful in distinguishing them from other neurodegenerative disorders. The aim of this study was to investigate the role of this method of scintigraphy in the differential diagnosis of dementia in our Memory Clinic. We performed MIBG scintigraphy in patients with dementia referred to the Memory Clinic and compared the heart-to-mediastinum (H/M) ratio of MIBG uptake. Thirty out of 32 patients with DLB and all 9 PD with dementia patients had reduced H/M ratios, whereas 37 out of 40 patients with Alzheimer’s disease had normal H/M ratios. Most patients with vascular dementia, frontotemporal dementia, and other dementias had normal H/M ratios. The overall sensitivity to positively identify patients with Lewy body disease (including DLB and PD with dementia) was 95%, and the specificity to distinguish them from patients with other types of dementias was 87%. MIBG scintigraphy showed a high sensitivity for the detection of Lewy body disease, and also a high specificity for discrimination from other types of dementia. The scintigraphy may provide a valuable and adjunctive method in the diagnosis of Lewy body disease and a differential diagnostic tool for patients with dementias.

Magnetization transfer measurements of the hippocampus in the early diagnosis of Alzheimer's disease

We measured magnetization transfer ratios (MTRs) of the hippocampus in 38 patients with Alzheimers disease (AD), including very mild (Clinical Dementia Rating [CDR] 0.5, n=12), mild (CDR 1, n=14), and moderate stages (CDR 2, n=12), and in 21 healthy elderly control subjects. Medial temporal lobe atrophy was graded subjectively on a five-point scale by two observers blinded to clinical data. Compared with the controls, each of the AD groups, including the very mild group, had significant atrophy of the medial temporal lobe and a decrease in MTRs of the hippocampus. Logistic regression analysis revealed that the overall discrimination rate with MTR measurement and visual analysis of the atrophy was 85% and 73% between the control group and the CDR 0.5 group, 89% and 80% between the control group and the CDR 1 group, and 100% and 91% between the control group and the CDR 2 group, respectively. MTR measurements may provide additional information in detecting structural damage of the hippocampus of AD and be helpful in providing improved diagnosis and early detection of AD.

Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer's disease

Aim:  Recent studies have shown that some antihypertensive medications are associated with a significant reduction in the incidence of Alzheimers disease (AD). However, it remains uncertain whether antihypertensive drugs may have a preventive effect on cognitive decline in patients with AD. We investigated the effects of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator‐activated receptor γ‐stimulating activity, on cognition and regional cerebral blood flow (rCBF) in elderly hypertensive patients with AD.

Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer's disease and cerebrovascular disease: a pilot study.

Aim:  It remains unknown whether antiplatelet agents have a preventive effect on cognitive decline in patients with Alzheimers disease (AD). We investigated the effects of cilostazol, an antiplatelet agent and cyclic adenosine monophosphate phosphodiesterase 3 inhibitor, on cognition and regional cerebral blood flow (rCBF) in elderly patients with AD and cerebrovascular disease (CVD).

Magnetisation transfer measurements of the subcortical grey and white matter in Parkinson's disease with and without dementia and in progressive supranuclear palsy.

Abstract We measured the magnetisation transfer ratio (MTR) in the subcortical grey and white matter of 11 patients with idiopathic Parkinsons disease (PD) without dementia, six with PD with dementia (PDD), six with progressive supranuclear palsy (PSP), and 12 elderly control subjects to assess regional differences in structural brain damage. There were no significant differences in MTR in any region between PD and controls. However, patients with PDD had significantly lower MTR in the subcortical white matter, including the frontal white matter and the genu of the corpus callosum than the controls, whereas PSP had significantly lower MTR in the subcortical grey matter, including the putamen, globus pallidus and thalamus, in addition to the subcortical white matter. This suggests that regional patterns of structural brain damage can be detected using the magnetisation transfer technique. Measurement of MTR in the subcortical grey and white matter may be useful in differential diagnosis.