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Little is known about the relationship between regional cerebral blood flow (rCBF) change and clinical improvement in patients with Parkinson's disease (PD). Single-photon emission computed tomography (SPECT) measurement of cerebral blood flow allows evaluation of temporal changes in brain function, and using SPECT, we aimed to identify motor improvement-related rCBF changes in response to the administration of antiparkinsonian drugs. Thirty PD patients (16 without dementia; 14 with dementia) were scanned with technetium-99m labeled ethyl cysteinate dimer SPECT and were rated with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III, both before and after a single administration of antiparkinsonian drugs. The SPECT data were processed using Statistical Parametric Mapping 2, the easy Z-score Imaging System, and voxel-based Stereotactic Extraction Estimation. The rCBF responses in the deep brain structures after administration of antiparkinsonian drugs tended to be larger than those in cortical areas. Among these deep brain structures, the rCBF increases in the substantia nigra (SN), lateral geniculate (LG) body, and medial geniculate (MG) body correlated with drug efficacy (p<0.05, respectively). A subgroup analysis revealed that the motor improvement-related rCBF change in the MG was statistically significant, irrespective of cognitive function, but the significant changes in the LG and SN were not found in subjects with dementia. In conclusion, our SPECT study clearly exhibited drug-driven rCBF changes in PD patients, and we newly identified motor improvement-related rCBF changes in the LG and MG. These results suggest that rCBF changes in these regions could be considered as candidates for clinical indicators for objective evaluation of disease progression. Furthermore, functional studies focusing on the LG and MG, especially in relation to therapies using audio-visual stimuli, may bring some new clues to explain the pathophysiology of PD. [ABSTRACT FROM AUTHOR]

Background and Purpose. Dot-like low-intensity spots (dot-like hemosiderin spots: dotHSs) on gradient echo T2*-weighted (-w) brain magnetic resonance imaging (MRIs) are frequently associated with cerebral small vessel disease (SVD), including deep intracerebral hemorrhages and lacunar infarctions. This study investigated how numbers of newly appeared dotHSs contribute to recurrent SVD. Methods. We prospectively analyzed numbers of newly appeared dotHSs in 12 patients with prior SVD (8 males, 4 females; mean 67.6 ± 10.7 years old) readmitted with recurring SVD between October 2001 and March 2003. Numbers of appeared dotHSs per year were counted on T2*-w MRI scans after SVD recurrence and compared to previous MRIs. Seventy-one outpatients (35 males, 36 females; mean 64.3 ± 9.6 years old) with histories of intracerebral hemorrhages (ICH) that came to the hospital during the study period served as controls. The hazard ratio (HR) for recurrence was estimated from a multivariate logistic regression model, using the number of appeared dotHSs (per year) and other risk factors. Results. Multivariate analyses revealed that an elevated rate of recurrence was found in patients with substantial numbers of appeared dotHSs (≥5/year) (HR, 7.34; P= 0.0008). We also analyzed factors associated with the numbers of appeared dotHSs. A number of appeared dotHSs (≥5/year) was significantly and independently associated with the initial number of dotHSs (≥10) on T2*-w MRIs following the first SVD (HR, 18.6; P= 0.0001). Conclusions. Though a small sample size limited the power of our analyses, our findings suggest that a number of newly appeared dotHSs may be associated with SVD recurrence. [ABSTRACT FROM AUTHOR]

Although more than 130 years have gone by since the first description in 1869 by Jean-Martin Charcot, the mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS (FALS) and by the development and analysis of mutant SOD1 transgenic mouse models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. To approach genes causative or critical for ALS, gene expression profiling in tissues primarily affected by the disease has represented an attractive research strategy. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of ALS. However, we have barely arrived at the starting point and are confronting an enormous number of genes whose roles remain undetermined. Challenging tasks lie ahead of us such as identifying which genes are really causative for ALS and developing a disease model of SALS with due consideration for the expression changes in those genes. [ABSTRACT FROM AUTHOR]

Background and Purpose. Dot-like low intensity spots (dot-like hemosiderin spots: dotHSs) on gradient echo T2*-weighted MRI have been histologically diagnosed to represent old cerebral microbleeds associated with microangiopathies. They have also been correlated to the fragility of small vessels and the tendency to bleed. Therefore, a substantial number of dotHSs might be associated with a large-sized, deep intracerebral hematoma (ICH). On the other hand, dotHSs may reflect old microbleeds that did not enlarge to symptomatic size. Methods. To investigate how dotHSs are related to the size (maximal diameter) of primary deep ICH, we analyzed the diameter and the number of dotHSs in 151 patients with deep ICH not associated with subarachnoid hemorrhage or intraventricular hemorrhage (75 males and 76 females, age ranged from 37 to 90 [65.7 ± 11.3 years old] who were consecutively admitted to Hakodate Municipal Hospital. The hazard ratio (HR) for a maximal diameter of deep ICH ≤2 cm was estimated, using the number of dotHSs and risk factors for stroke. Results. The number of dotHSs associated with the diameter ≤2 cm was 9.2 ± 11.5, significantly larger than that with the diameter ≥2 cm (4.7 ± 7.0, P= .012). Multivariate analysis revealed that a maximal diameter of deep ICH of ≤2 cm was found in patients with dotHS (HR, 3.7; 95% confidence interval [CI], 1.4-10.1; P= .009). Conclusion. Though small sample size limited the power of our analyses, these findings suggest that the number of dotHSs may be associated with a small diameter of deep ICH. [ABSTRACT FROM AUTHOR]

Background and Purpose. Microangiopathy, a disorder often related to hypertension, is an important cause of deep intracerebral hematoma (ICH). The microangiopathy is associated with dot-like low-intensity spots (a dot-like hemosiderin spot: dotHS) on gradient-echo T2*-weighted MR images that have been histologically diagnosed as old microbleeds. The locations of dotHS are consistent with deep ICH. Methods. To investigate how dotHS or other risk factors contribute to nonhypertensive deep ICH, the number and location of dotHSs, as well as other risk factors were examined in 213 deep ICH patients (106 males, 107 females, age: 37-94 (65.8 ± 11.2) years) consecutively admitted to Hakodate Municipal Hospital. Patients were divided into two subgroups according to the presence or absence of hypertension. DotHSs were also divided into deep and subcortical dotHS and investigated independently. Odds ratios (ORs) were estimated from logistic regression analyses. Furthermore, nonhypertensive ICH patients were compared with nonhypertensive healthy volunteers matched for age and sex. Results. No risk factors were identified in the 31 nonhypertensive deep ICH patients that differed from those found in the 182 hypertensive deep ICH patients. Deep dotHS ≥ 1 (OR: 25.5; 95% CI: 4.76-137; P= .0002), subcortical dotHS ≥ 1 (OR: 9.0; 95% CI: 1.79-44.9; P= .046), diabetes mellitus (OR: 9.0; 95% CI: 1.53-52.3; P= .015), and smoking (OR, 9.6; 95% CI; 1.8-49.8, P= .007) significantly elevated the risk of nonhypertensive ICH, compared to the healthy volunteers. Conclusions. Our findings suggest that deep and subcortical dotHSs may be risk factors for the development of non-hypertensive deep ICH. [ABSTRACT FROM AUTHOR]

Dorfin is a RING -finger type ubiquitin ligase for mutant superoxide dismutase 1 (SOD1) that enhances its degradation. Mutant SOD1s cause familial amyotrophic lateral sclerosis (FALS) through the gain of unelucidated toxic properties. We previously showed that the accumulation of mutant SOD1 in the mitochondria triggered the release of cytochrome c , followed by the activation of the caspase cascade and induction of neuronal cell death. In the present study, therefore, we investigated whether Dorfin can modulate the level of mutant SOD1 in the mitochondria and subsequent caspase activation. We showed that Dorfin significantly reduced the amount of mutant SOD1 in the mitochondria, the release of cytochrome c and the activation of the following caspase cascade, thereby preventing eventual neuronal cell death in a neuronal cell model of FALS. These results suggest that reducing the accumulation of mutant SOD1 in the mitochondria may be a new therapeutic strategy for mutant SOD1-associated FALS, and that Dorfin may play a significant role in this. [ABSTRACT FROM AUTHOR]

To analyze the genes related to the pathophysiology of sporadic amyotrophic lateral sclerosis (SALS) we performed gene profiling of SALS spinal cords using molecular indexing combined with cDNA microarray. Eighty-four fragments were cloned in the first screening procedure with molecular indexing. Subsequent quantitative microarray screening revealed 11 genes which were differentially expressed in SALS. Real-time RT-PCR verified that the expression level of the following six genes was altered in SALS: dorfin, metallothionein-3, 30 kDa TATA-binding protein-associated factor, neugrin, ubiquitin-like protein 5 and macrophage-inhibiting factor-related protein-8. These results indicated that genes associated with the ubiquitin–proteasome system, oxidative toxicity, transcription, neuronal differentiation and inflammation might be involved in the pathogenesis of SALS. [Copyright &y& Elsevier]