Takayuki Taniwaki

Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease

The amyloid β‐protein (Aβ) ending at 42 plays a pivotal role in Alzheimers disease (AD). We have reported previously that intracellular Aβ42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Aβ42 directly activated the p53 promoter, resulting in p53‐dependent apoptosis, and that intracellular Aβ40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Aβ42 with p53 mRNA elevation in guinea‐pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Aβ42 and p53 was found in some degenerating‐shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Aβ42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Aβ is well known and synaptic/mitochondrial dysfunction by intracellular Aβ42 has recently been suggested, intracellular Aβ42 may cause p53‐dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

Heterozygous deletion of ITPR1, but not SUMF1 in spinocerebellar ataxia type 16

We have previously mapped autosomal dominant spinocerebellar ataxia (SCA) 16 to 3p26, overlapping with the locus of SCA15. Recently, partial deletions of ITPR1 and the neighbouring SUMF1 in the SCA15 and two additional families were reported. In the present study we determined the copy number of these genes by real time quantitative polymerase chain reaction (PCR) and found a heterozygous deletion of exons 1-48 of ITPR1, but not SUMF1 in SCA16. Breakpoint analysis revealed that the size of the deletion is 313,318 bp and the telomeric breakpoint is located in the middle of their intergenic region. Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15.

A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1.

Objective: To characterize a distinct form of autosomal dominant cerebellar ataxia (ADCA) clinically and genetically. Background: ADCAs are a clinically, pathologically, and genetically heterogeneous group of neurodegenerative disorders. Nine responsible genes have been identified for SCA-1, -2, -3, -6, -7, -8, -10, and -12 and dentatorubral-pallidoluysian atrophy (DRPLA). Loci for SCA-4, -5, -11, -13, and -14 have been mapped. Methods: The authors studied a four-generation Japanese family with ADCA. The 19 members were enrolled in this study. The authors performed the mutation analysis by PCR and a genome-wide linkage analysis. Results: Nine members (five men and four women) were affected. The ages at onset ranged from 20 to 66 years. All affected members showed pure cerebellar ataxia, and three patients also had head tremor. Head MRI demonstrated cerebellar atrophy without brain stem involvement. The mutation analysis by PCR excluded diagnoses of SCA-1, -2, -3, -6, -7, -8, and -12 and DRPLA. The linkage analysis suggested linkage to a locus on chromosome 8q22.1-24.1, with the highest two-point lod score at D8S1804 (Z = 3.06 at θ = 0.0). The flanking markers D8S270 and D8S1720 defined a candidate region of an approximately 37.6-cM interval. This candidate region was different from the loci for SCA-4, -5, -10, -11, -13, and -14. Conclusion: The family studied had a genetically novel type of SCA (SCA-16).

Upregulation of vascular growth factors in multiple sclerosis: correlation with MRI findings.

Vascular permeability changes precede the development of demyelinating lesions in multiple sclerosis (MS), and vessel wall thickening and capillary proliferation are frequently seen in autopsied MS lesions. Although vascular growth factors are critical for inducing such vascular changes, their involvement in MS has not been extensively studied. Thus, we examined the involvement of various vascular growth factors in MS according to their clinical phase and subtype. We measured serum levels of vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF) and platelet-derived growth factors (PDGFs)-AA, -AB and -BB in 50 patients with MS (27 opticospinal MS and 23 conventional MS patients) and 33 healthy controls using sandwich enzyme immunoassays. Correlations between growth factor changes and brain and spinal cord MRI findings were then analyzed. Serum VEGF concentrations were significantly higher in MS patients in relapse than in controls (p = 0.0495) and in MS patients in remission (p = 0.0003), irrespective of clinical subtype. Basic FGF was significantly increased in conventional MS patients, but not opticospinal MS patients compared with controls (p = 0.0291), irrespective of clinical phase. VEGF at relapse showed a significant positive correlation with the length of spinal cord lesions on MRI (r = 0.506, p = 0.0319). The results suggest that an increase in serum VEGF concentration might be involved in MS relapse and the formation of longitudinally extensive spinal cord lesions.

Functional network of the basal ganglia and cerebellar motor loops in vivo: Different activation patterns between self-initiated and externally triggered movements

The basal ganglia and cerebellar loops are known to participate differently in self-initiated (SI) and externally triggered (ET) movements. However, no previous neuroimaging studies have illustrated functional organization of these loops in vivo. Here, we aimed to functionally visualize these loops during motor execution using functional magnetic resonance imaging (fMRI) with structural equation modeling (SEM). Twelve normal subjects (24-29 years old) were scanned while performing five different frequencies of sequential left finger movements using either SI or ET movements. Random effect analysis combined with a parametric approach revealed a significant positive linear dependence of cerebral activation upon movement rate in the right Put, GPi, VL, SMC and SMA during SI tasks. During ET tasks, significant positive linear relationships were found in the right SMC, VPL, left CB and DN, whereas tendency for linear relationships was seen in the right PMv. SEM further showed significant interactions within the right basal ganglia-thalamo-motor loop during SI tasks. In contrast, there were significant interactions within the entire right cerebral hemisphere-left cerebellar loop involving CB, DN, VPL, PMv and SMC during ET tasks. Therefore, our modeling approach enabled identification of different contributions of the motor loops of basal ganglia and cerebellum to SI and ET tasks during motor execution.

Changes in the clinical phenotypes of multiple sclerosis during the past 50 years in Japan

In order to clarify whether or not marked changes in the social environment during the past 50 years in Japan may have altered the clinical phenotypes of multiple sclerosis (MS), we retrospectively analyzed 143 consecutive patients with clinically definite MS who developed the disease between 1950 and 1997. Fifty-two patients were classified as Asian type MS showing a selective involvement of the optic nerves and the spinal cord, while 91 patients were considered to have Western type MS which demonstrated the involvement of multiple sites in the central nervous system including the cerebrum, cerebellum and brainstem. The ratio of Asian type versus Western type MS was 1:0.5 in the patients born in the 1920s and 1:1.27, 1:1.64 and 1:1.7 in those born in the 1930s, 1940s and 1950s, respectively, and thereafter it increased to 1:4.67 in those born in the 1960s and 1:4 in those born after the 1970s. As a result, the proportion of Asian type MS significantly decreased in the patients born after 1960 as compared with those born from 1930 to 1959 (P=0.0121). In the Asian type MS, the age of onset was significantly higher in the patients who developed the disease from 1985 to 1997 (42.4+/-13.5 years) than in those who developed the disease from 1950 to 1984 (32.3+/-12.4 years) (P=0.0149), while in the Western type MS no such change in the age of onset was observed. These findings suggest that the frequency of Asian type MS has apparently decreased in younger Japanese born after 1960 when Japans rapid economic growth had just started, and environmental factors are therefore considered to contribute to determine the clinical phenotypes of MS in Asians.

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.

Positron emission tomography (PET) in Machado-Joseph disease

Positron emission tomography studies on the regional cerebral glucose metabolism (rCMRglc) and 18F-fluorodopa (18F-Dopa) uptake were performed in 3 patients with Machado-Joseph disease (MJD), a dominantly inherited degenerative disease in the cerebellum, brainstem and basal ganglia. The rCMRglc in MJD was found to be significantly decreased in the cerebellum, brainstem, striatum and whole cerebral cortex in comparison to that in normal subjects. These results of rCMRglc were different from those for dominantly inherited olivopontocerebellar atrophy (dOPCA) or cerebellar cortical degeneration (CCD), however they were similar to those for sporadic olivopontocerebellar atrophy (sOPCA) and multiple system atrophy (MSA). The 18F-Dopa uptake in MJD was found to be significantly decreased in the putamen and relatively spared in the caudate, which was different from that of MSA. In addition, these results indicate that MJD showed a dysfunction, not only in the regions with apparent pathological involvement such as cerebellum, brainstem and nigro-striatal dopaminergic system, but also in the cerebral cortex and the striatum where no pathology could be observed using conventional morphological techniques.

Age-related alterations of the functional interactions within the basal ganglia and cerebellar motor loops in vivo

Aging may alter the motor functions of the basal ganglia and cerebellum; however, no previous neuroimaging study has investigated the effect of aging on the functional connectivity of the motor loops involving these structures. Recently, using fMRI with a parametric approach and structural equation modeling (SEM), we demonstrated a significant functional interaction within the basal ganglia-thalamo-motor (BGTM) loop during self-initiated (SI) finger movement in young normal subjects, whereas cerebro-cerebellar (CC) loop was mainly involved during externally triggered (ET) movement. We applied this method to 12 normal aged subjects (53-72 years old) in order to study the effect of age on BGTM and CC loops. Compared with the functional connectivity seen in young subjects, SEM showed decreased connectivity in BGTM loops during SI task, decreased interaction in the CC loop during ET task, and increased connectivity within motor cortices and between hemispheres during both types of tasks. These results suggest an age-related decline of cortico-subcortical connectivity with increased interactions between motor cortices. Aging effects on SI and ET movements are probably caused by functional alterations within BGTM and CC loops.

Cerebral metabolic changes in early multiple system atrophy: a PET study

Previous positron emission tomography (PET) studies have shown widespread hypometabolism in the brain of advanced MSA but the time course of these metabolic abnormalities is largely unknown. In order to clarify the principal disease processes in multiple system atrophy (MSA) in the early stage, we investigated regional cerebral glucose metabolism (rCMGglc) and nigral dopaminergic function in nine patients with early stage of MSA using [(18)F]fluorodeoxyglucose (FDG) and 6-L-[(18)F]fluorodopa ((18)F-Dopa) positron emission tomography (PET) (two men and seven women; age, 59.3+/-5.4 years; disease duration, 29.7+/-14.6 months). The rCMRglc in the early MSA patients significantly decreased in the cerebellum, brainstem, and striatum compared with that in nine normal subjects. A significant correlation was found between the severity of autonomic dysfunction and rCMRglc within the brainstem. The severity of extrapyramidal signs also correlated with the decline of F-Dopa uptake but not that of rCMRglc within the striatum. The degree of atrophy on MRI has correlated with neither the clinical symptoms nor rCMRglc at the cerebellum and the brainstem. Our PET studies demonstrated widespread metabolic abnormalities except for the cerebral cortex in the brain of MSA even in the early stage. The hypometabolism in the brainstem was tightly linked to the autonomic dysfunction. Not the striatal dysfunction but the nigral damage may be responsible for the extrapyramidal symptoms in early MSA.