Haruo Hanyu

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.

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 Alzheimers 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.

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.

Comparative value of brain perfusion SPECT and [123I]MIBG myocardial scintigraphy in distinguishing between dementia with Lewy bodies and Alzheimer’s disease

PurposeBoth decreased occipital perfusion on brain single-photon emission computed tomography (SPECT) and reduction in cardiac 123I-metaiodobenzylguanidine (MIBG) uptake are characteristic features of dementia with Lewy bodies (DLB), and potentially support the clinical diagnosis of DLB. The aim of this study was to compare the diagnostic value of these two methods for differentiation of DLB from Alzheimer’s disease (AD).MethodsThe study population comprised 19 patients with probable DLB and 39 patients with probable AD who underwent both SPECT with N-isopropyl-p-[123I]iodoamphetamine and MIBG myocardial scintigraphy. Objective and quantitative measurement of perfusion in the medial occipital lobe, including the cuneus and lingual gyrus, was performed by the use of three-dimensional stereotactic surface projections.ResultsMedial occipital perfusion was significantly decreased in the DLB group compared with the AD group. The mean heart/mediastinum ratios of MIBG uptake were significantly lower in the DLB group than in the AD group. Although SPECT failed to demonstrate significant hypoperfusion in the medial occipital lobe in five patients with DLB, marked reduction of MIBG uptake was found in all patients with DLB. Receiver operating characteristic analysis revealed that MIBG myocardial scintigraphy enabled more accurate discrimination between DLB and AD than was possible with perfusion SPECT.ConclusionMIBG myocardial scintigraphy may improve the sensitivity in the detection of DLB. In particular, this method may provide a powerful differential diagnostic tool when it is difficult to distinguish cases of DLB from AD using brain perfusion SPECT.

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10−5 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10−7 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10−9) and rs3781834 (P = 1.04×10−8). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10−5) and rs744373 near BIN1 (P = 1.39×10−4). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

Cerebral microbleeds in Alzheimer’s disease

Sirs: T2*-weighted gradient-echo magnetic resonance imaging (MRI) is a highly sensitive technique for detecting hemosiderin deposits and thus remnants of intracerebral microbleeds (MBs), which are clearly visualized as small areas of signal loss. Postmortem correlative MRI and histopathological studies have confirmed that areas of signal loss on T2*-weighted images represent hemosiderin deposits [2, 7]. Several studies have revealed that patients with small artery disease of the brain, such as hypertensive microangiopathy and cerebral amyloid angiopathy, more often exhibit MBs on T2*-weighted MRI [3, 5, 7]. Since cerebral amyloid angiopathy is commonly found with an incidence of about 80 to 98 % in the brain of Alzheimer’s disease (AD) [4], we hypothesized that AD may show a predisposition to MBs. We obtained T2*-weighted MRI scans to determine the frequency, extent, and pattern of MBs in patients with AD. Patients were prospectively recruited for serial MRI scans from the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, between January 2002 and December 2002. Among patients studied, we identified 59 consecutive patients with AD (25 men and 34 women, aged 61 to 88 years). The clinical diagnosis of AD was based on the NINCDS-ADRDA criteria [6]. The mean Mini-Mental State Examination (MMSE) score (mean ± SD) was 17.9 ± 6.0 (5 to 26). Fifty-five consecutive patients who underwent MRI for observation of headache or dizziness without neurological deficits or cognitive impairment served as controls (22 men and 33 women, aged 58 to 88 years). MRI was performed on a 1.5 T superconducting magnet system (Siemens Magnetom Symphony). Nineteen contiguous axial 5-mmthick slices (1.5-mm interslice gap) were obtained with the following pulse sequence: (1) T1-weighted spin echo (TR, 450 ms; TE, 12 ms; FOV, 250 mm, matrix 256 256), (2) T2-weighted fast spin echo (TR, 3540 ms, TE, 106 ms; FOV, 250 mm, matrix 256 256), and (3) T2*weighted gradient echo (TR, 800 ms; TE, 26 ms, flip angle, 30°; FOV, 250 mm, matrix 256 256). Lacunar infarction was defined as a small deep lesion (usually less than 15 mm in diameter) with a high signal intensity on T2-weighted images and low signal intensity on T1-weighted images. White matter hyperintensities were classified as absent, punctate, early confluent, or confluent abnormalities according to Fazekas et al. [1]. In accordance with previous studies, MBs were defined on gradient-echo T2*weighted images as homogenous rounded lesions of signal loss with a diameter greater than 2 mm [5, 7]. The numbers of MBs were recorded in the following: deep gray matter (basal ganglia and thalamus), deep white matter, cortico-subcortical, and infratentorial regions (brain stem and cerebellum). Based on the numbers of MBs, the extent of MBs was graded as none [0], mild [1–5], moderate [6–10], or severe (≥11). All MR images were reviewed by the same observer blinded to clinical or laboratory data. There were no significant differences in age, sex, risk factors including hypertension and diabetes mellitus, lacunae, or the grade of LETTER TO THE EDITORS

Increased Water Diffusion in Cerebral White Matter in Alzheimer’s Disease

We investigated the changes in water diffusion in the cerebral white matter in 19 patients with Alzheimers disease (AD), including 11 without and 8 with periventricular hyperintensity (PVH) lesions, using diffusion-weighted magnetic resonance imaging (MRI). The apparent diffusion coefficients in the anterior and posterior white matter were significantly higher in the 19 AD patients than in the 10 age-matched controls. The apparent diffusion coefficients were higher in patients with PVH than in those without. The anisotropic ratios, defined as diffusion restricted perpendicular to the direction of the nerve fibers, were significantly higher in AD patients, even in those without PVH, than in the controls. Our results suggest that mild myelin loss occurs in AD patients even in the apparently normal white matter. A definite loss of myelin and axons, including incomplete infarction, occurs in the white matter, as seen on T2-weighted images as PVH. Studies with diffusion-weighted MRI may allow the characterization of different pathological processes and enable the demonstration of underlying white matter lesions in AD that cannot be visualized by conventional MRI.

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.