Levodopa challenge test and (123) I-metaiodobenzylguanidine scintigraphy for diagnosing Parkinson's disease.

OBJECTIVES: To explore the possibility of a generally applicable tool for the immediate diagnosis of Parkinson's disease (PD) in its early stage, we compared the sensitivity and specificity of an acute levodopa challenge test with that of (123) I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. MATERIALS AND METHODS: A consecutive series of 45 patients with extrapyramidal symptoms were recruited to the acute levodopa challenge and evaluated for improvement by use of the Unified Parkinson's Disease Rating Scale motor scores. Of these patients, 32 of them were also examined by MIBG scintigraphy. The patients were followed up for at least 24 months, and 22 patients were diagnosed as having clinically definite PD. RESULTS: The sensitivity and specificity of the acute levodopa challenge test to predict clinical diagnosis of PD were 81.8% and 81.8%, respectively, which were better than those obtained by MIBG scintigraphy (62.5% and 62.5%). In both early- and middle-stages of PD, the test gave better sensitivity than MIBG scintigraphy. CONCLUSIONS: Considering that the well-established and frequently referred clinical diagnostic criteria require longitudinal observation for at least 24 months, the acute levodopa challenge test can be used as an immediate diagnostic tool for PD with sensitivity and specificity comparable to those of MIBG.

Regionally different immunoreactivity for Smurf2 and pSmad2/3 in TDP-43-positive inclusions of amyotrophic lateral sclerosis.

AIMS: Smad ubiquitination regulatory factor-2 (Smurf2), an E3 ubiquitin ligase, can interact with Smad proteins and promote their ubiquitin-dependent degradation, thereby controlling the cellular levels of these signalling mediators. We previously reported that phosphorylated Smad2/3 (pSmad2/3) was sequestered in transactive response DNA-binding protein-43 (TDP-43) inclusions in the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Recent biochemical and immunohistochemical studies on spinal cord and brain of ALS patients demonstrated that the composition of the TDP-43 inclusions is regionally distinct, suggesting different underlying pathogenic processes. We aimed to elucidate regional differences in pathomechanisms and composition of TDP-43 inclusions in relation to pSmad2/3 and Smurf2. METHODS: The spinal cord and brain tissues of 13 sporadic ALS (SALS) patients were investigated using immunohistochemical analysis. RESULTS: TDP-43-positive inclusions in lower motor neurones of SALS patients were immunopositive for Smurf2 and pSmad2/3. Multiple immunofluorescence staining for Smurf2, pSmad2/3, TDP-43 and ubiquitin revealed co-localization of these four proteins within the inclusions in lower motor neurones of SALS patients. Furthermore, the loss of nuclear pSmad2/3 immunoreactivity was observed in cells bearing TDP-43 inclusions. In contrast, TDP-43-positive inclusions in the extramotor neurones in the brain of SALS patients were noticeably negative for Smurf2 and pSmad2/3. In addition, pSmad2/3 immunoreactivity was preserved in the nuclei of inclusion-bearing cells. CONCLUSIONS: This regional difference in the expression of Smurf2 and pSmad2/3 within TDP-43-positive inclusions might be one of the pathomechanisms underlying the loss of lower motor neurones and comparatively spared cortical neurones seen in ALS.

Smad ubiquitination regulatory factor-2 in progressive supranuclear palsy.

AIMS: Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ligase that belongs to the HECT domain ubiquitin ligase family. Smurf2 can interact with Smad proteins and promote their ubiquitin-dependent degradation, thereby controlling the cellular levels of these signalling mediators. Phosphorylated Smad2/3 (pSmad2/3) was recently identified in phosphorylated tau (phospho-tau) inclusions in patients with progressive supranuclear palsy (PSP). As Smurf2 is the E3 ligase of pSmad2, we aimed at investigating the relationship among Smurf2, pSmad2/3 and phospho-tau in this study. METHODS: The brains of six PSP and three control patients without neurological disorder were investigated by immunohistochemical analysis. RESULTS: In the control subjects, Smurf2 immunoreactivity was not demonstrable in the neurones and glial cells, and that for pSmad2/3 was observed exclusively in neuronal and glial nuclei. In PSP patients, the pathognomonic neuronal and glial phospho-tau inclusions were immunopositive for both Smurf2 and pSmad2/3. The intensity of pSmad2/3 immunosignals of neuronal and glial nuclei containing phospho-tau inclusions was less than that for the cells without the inclusions. Triple immunofluorescence staining for Smurf2, pSmad2/3 and phospho-tau revealed co-localization of these proteins within the neuronal and glial inclusions; and in some globose neurofibrillary tangles, the Smurf2 immunoreactivity appeared more centrally distributed than that of pSmad2/3 and phospho-tau. CONCLUSIONS: This is the first demonstration of the presence of Smurf2 immunoreactivity in the phospho-tau inclusions in PSP. These findings suggest that Smurf2 plays a significant role in the pathomechanism of PSP by causing abnormal redistribution of neuronal nuclear pSmad2/3 to the cytoplasm.

Clinicopathologic investigation of a family with expanded SCA8 CTA/CTG repeats.

We investigated a family manifesting progressive ataxia, with expanded SCA8 CTA/CTG repeats. Neuropathologically, degeneration of Purkinje, inferior olivary, and nigral neurons and periaqueductal gliosis were evident. The sites of Purkinje cell loss were occupied by fibrillary accumulations. The remaining Purkinje cells showed somatic sprouts, and intracytoplasmic 1C2-positive granular structures were recognizable. This characteristic distribution of neurodegeneration and Purkinje cell cytopathology were distinct from those of other hereditary spinocerebellar ataxias previously reported.