Koji Ogomori

High b value diffusion-weighted imaging is more sensitive to white matter degeneration in Alzheimer's disease

It has been reported that diffusion-weighted imaging (DWI) can detect white matter degeneration in the Alzheimers disease (AD) brain. We hypothesized that imaging of the slow diffusion component using high b value DWI is more sensitive to AD-related white matter degeneration than is conventional DWI, and therefore we studied the effects of high b value on lesion-to-normal contrast and contrast-to-noise ratio (CNR). Seven AD patients and seven age-matched normal subjects were studied with full-tensor DWI at three different b values (1000, 2000, and 4000 s/mm(2)) without changing echo time or diffusion time, and the mean diffusivities in the parietal and occipital regions were measured. Statistical analyses revealed that use of higher b values significantly improves both lesion-to-normal contrast and CNR. We concluded that high b value DWI is more sensitive to AD-related white matter degeneration than is conventional DWI.

Quantitative MRI findings and cognitive impairment among community dwelling elderly subjects

Objectives: To study the factors which influence cognitive impairment among elderly subjects living in a local community, based on both MRI and clinical findings, to further elucidate the causes of dementia, and also to help develop strategies for its prevention. Methods: Cranial MRI and other medical examinations were performed on non-demented elderly subjects who resided in one rural community. A total of 254 subjects aged from 60 to 91 years of age, with a mean age of 73.9 (SD 6.8) were examined. The mini mental state examination (MMSE) was used to identify cognitive impairment. White matter lesions and cerebral atrophy on MR images were measured quantitatively. A multivariate analysis was also performed with the existence of cognitive impairment as the dependent variable, and the MRI findings and clinical observations were used as the independent variables. Results: Cognitive impairment was present in 46 subjects (18.1%). They were older, had a lower educational level, and more frequent hypertension compared with those without cognitive impairment. The packed cell volume was lower in the impaired group. In addition, their MRI findings showed significantly larger quantities of white matter lesions and cerebral atrophy, as well as more infarcts. A logistic regression analysis demonstrated a significant relation among such factors as white matter lesions (odds ratio (OR) 1.575, 95% confidence interval (95% CI) 1.123–2.208), cerebral atrophy (OR 0.761, 95%CI 0.587–0.987), and lower education (OR 0.682, 95%CI 0.544–0.855) for subjects with a cognitive impairment. Conclusions: White matter lesions and cerebral atrophy are factors which induce a cognitive impairment in community dwelling elderly subjects without dementia. It is important to carefully watch for any abnormalities in these factors, and to perform cohort studies to check for the above risk factors, to both prevent and make an early diagnosis of dementia.

Increased senile plaques without microglia in Alzheimer's disease

SummaryTo clarify the association of microglia with senile plaques, the brains from 13 patients with Alzheimers disease (AD) and 23 nondemented aged controls were investigated immunohistochemically by a double-labeling method using anti-β-protein antiserum and anti-ferritin antibody, which is a recently reported microglia marker. In addition, a quantitative analysis was performed. The senile plaques which appeared initially in the nondemented aged controls consisted of a diffuse type without any amyloid cores and these were found in the group aged 50–59 years. The great majority of them were found to contain no ferritin-positive microglia. The number and proportion (percentage) of microglia-containing diffuse plaques increased with age. Classical and compact plaques began to appear in the brains of the group aged 70 years and over, and practically all of them contained microglia. These results suggest that microglia are not associated with initial plaque formation, but correlate with amyloid core formation. In AD, the most prominent feature was that the diffuse plaques, which contained either no or only a few ferritin-positive microglia, increased markedly.

Increased tau accumulation in senile plaques as a hallmark in Alzheimer's disease.

To identify the tau component in senile or kuru plaques, the authors examined brain sections from 12 patients with Alzheimers disease (AD), 6 with Creutzfeldt-Jakob disease (CJD), and 20 nondemented aged controls using anti-beta protein, anti-buman prion protein, and affinity-purified tau-specific antibody. The tau component was identified both in senile and kuru plaques. In AD, tau-positive senile plaques were found in all cerebral cortices of almost all cases, and the tau-positivity of plaques in cerebral cortices was 5.1 to 27.5%. In CJD, tau-positive senile and kuru plaques were restricted to the hippocampus, and the tau-positivity was 4.3 and 1.2%, respectively. In nondemented aged controls, tau-positive senile plaques also were restricted mostly to the hippocampus, and the tau-positivity was 1.3%. Significant differences in the tau-positivity of senile plaques were found between AD and CJD and nondemented aged controls, and no significant differences were found between CJD and nondemented aged controls. These observations are important because increased tau accumulation in senile plaques can be a hallmark of AD.

Skein-like inclusions in the neostriatum from a case of amyotrophic lateral sclerosis with dementia

Abstract Skeins or skein-like inclusions (SLIs) in motor neurons detected by ubiquitin immunohistochemistry are a characteristic finding of amyotrophic lateral sclerosis (ALS). Here we report ubiquitinated SLIs in the putamen and caudate nucleus from a case of ALS with dementia. A 48-year-old Japanese man developed apathy and amimia. Mental and neurological examinations revealed severe character change, muscle atrophy and fasciculation of the distal upper extremities and the tongue, and an exaggeration of the deep tendon reflex. He subsequently showed dysphagia and dysarthria. He died at the age of 51 years, after a total clinical course of about 2.5 years. By immunohistochemistry, ubiquitin-immunoreactive intraneuronal inclusions were observed in the spinal anterior horn cells, the frontal, temporal and entorhinal cortices, dentate fascia of the hippocampus and the amygdala. In addition, ubiquitinated inclusions were also seen in the putamen and caudate nucleus, which appeared as aggregates of thread-like structures similar to SLIs in the spinal anterior horn neurons. They were not seen on hematoxylin-eosin staining, and they also did not show any argentophilia nor did they react with other antibodies, including antibody against tau protein. To our knowledge, this is the first report of the presence of SLIs in non-motor neurons. Our results thus support the notion that ALS is a multisystem disease, and not simply a disease of the motor neurons.

Accumulation of αB-crystallin in brains of patients with Alexander's disease is not due to an abnormality of the 5′-flanking and coding sequence of the genomic DNA

alpha B-Crystallin is a major protein component of Rosenthal fibers, which massively accumulate in the brains of patients suffering from Alexanders disease. To examine whether or not accumulation of alpha B-crystallin is due to any abnormality of the gene structures, we determined the sequence of the alpha B-crystallin gene in two cases of pathologically confirmed Alexanders disease. Direct sequencing of the promoter and coding regions of the alpha B-crystallin gene in patients revealed them to have a normal sequence. Northern blotting showed a single alpha B-crystallin mRNA species expressed in the Alexanders disease brain.

Posterior cingulate hypoperfusion in Alzheimer's disease, senile dementia of Alzheimer type, and other dementias evaluated by three-dimensional stereotactic surface projections using Tc-99m HMPAO SPECT

Hypoperfusion in the posterior cingulate cortex is thought to be useful for the early diagnosis of dementia of Alzheimer type (DAT). In the present study, we compared the incidence of posterior cingulate hypoperfusion in patients with Alzheimers disease (AD), patients with senile dementia of Alzheimer type (SDAT), and patients with other types of dementia, as evaluated by three-dimensional stereotactic surface projection (3D-SSP) imaging. The subjects were 20 AD patients, 20 SDAT patients, 13 frontotemporal dementia patients, and 3 other types of dementia patients. A SPECT study was performed 5 minutes after the injection of 740 MBq technetium-99m hexamethylpropylene amine oxime. 3D-SSP images were obtained with global normalization to perform the statistical analysis. The normal database of 3D-SSP consisted of 15 healthy volunteers. Hypoperfusion was considered to be significant when the Z-score was over 2.5. Posterior cingulate hypoperfusion was observed in 13 of 20 AD patients (65%), in 5 of 20 SDAT patients (25%), but in none of other type of dementia patients. Posterior cingulate hypoperfusion was considered to be a finding specific to DAT, and this finding was thought to be useful to diagnose DAT patients, especially for AD patients. However, it was considered to be difficult to diagnose early-stage SDAT patients.

Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer’s disease patients on11C-N-methyl-4-piperidyl benzilate — Comparison with cerebral blood flow and cerebral glucose metabolism—

We studied the cerebral muscarinic acetylcholinergic receptor (mACh-R) by means of11C-N- methyl-4-piperidyl benzilate (11C-NMPB) and positron emission tomography (PET) in Alzheimer’s disease (AD) cases, and the findings were compared with the cerebral blood flow (CBF) and the glucose metabolism (CMRGlc) to evaluate the relationship between the mACh-R and the CBF or the CMRGlc. The subjects consisted of 18 patients with AD and 18 age and sex matched normal volunteers. The patients were clinically diagnosed according to the criteria of the NINDS-ADRDA as having “probable AD” and were thus classified into two groups (mild and moderate AD) according to the severity of dementia determined by DSM-III-R. The CBF was measured by99mTc-HMPAO SPECT, and the CMRGlc was measured by18FDG PET. The11C-NMPB uptake was evaluated by the graphical method and the ratio method (ROIs/Cerebellum). A significant mACh-R decrease and more severe CMRGlc decrease in the cortical region was seen in mild and moderate AD. The decrease in the CBF was not as obvious as that in the mACh-R and the CMRGlc.Our study thus suggested that the mACh-R decreased in patients with AD, and that the18FDG PET was the most sensitive method for detecting the degenerative regions in patients with AD.

Accumulation of lysosulfatide (sulfogalactosylsphingosine) in tissues of a boy with metachromatic leukodystrophy

Abnormal accumulation of lysosulfatide (sulfogalactosylsphingosine) was evident in autopsied tissues from a boy with late-infantile metachromatic leukodystrophy. The concentration was high in the cerebral white matter, spinal cord and sciatic nerve (116-787 pmol/mg protein) and low in the cerebral gray matter, kidney and liver (4-40 pmol/mg protein). As is the case with galactosylsphingosine, lysosulfatide inhibited cytochrome c oxidase activity, in a dose-dependent manner. Judging from the tissue distribution of the accumulated lysosulfatide and because of the cytotoxicity, the lysosulfatide presumably explains the demyelination seen in the nervous tissues of patients with metachromatic leukodystrophy.

Allelic variation of apolipoprotein E in Japanese sporadic Creutzfeldt-Jakob disease patients

We analyzed apolipoprotein E (apo E) genotypes in 53 Japanese sporadic Creutzfeldt-Jakob disease (CJD) patients and 100 normal controls using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. The apo E allelic frequencies in Japanese sporadic CJD patients and our control population were as follows: epsilon 2, 6.6% versus 7.5%; epsilon 3, 82.1% versus 81.5%; epsilon 4, 11.3% versus 11.0%. The mean ages at onset in Japanese sporadic CJD patients were as follows: epsilon 3/epsilon 3, 63.8 years; epsilon 3/epsilon 4, 66.3 years; epsilon 2/epsilon 3, 68.6 years. These results indicate that there is no association between apo E genotype and sporadic CJD in Japan.