Akito Kume

Testosterone Reduction Prevents Phenotypic Expression in a Transgenic Mouse Model of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.

Neuronal cell loss of the striatonigral system in multiple system atrophy

We investigated the longitudinal as well as lateral loss of striatal and nigral cells and its distribution in 7 cases of multiple system atrophy. Loss of striatal small cells and nigral pigmented cells was more prominent in the caudal part than in the rostral and mid-parts. Cell loss was especially high in the dorsolateral zone of the caudal putamen and in the lateral zone of the caudal nigra. These findings indicate that MSA predominantly disturbs the striatal and nigral efferent systems, which interlink the caudal and dorsolateral putamen with the caudolateral nigra. In less severe cases, the rostral to mid-parts of the putamen or substantia nigra were almost intact while its caudal portion was clearly affected. The degenerative process of MSA seems to occur initially in the caudal parts of the putamen and substantia nigra, extending later to the rostral parts. Thus striatal small cells and nigral pigmented cells degenerate according to anatomical relationship. In MSA, degeneration of the striatonigral system could well be explained as being transsynaptic.

A histometrical and comparative study on Purkinje cell loss and olivary nucleus cell loss in multiple system atrophy.

We examined pathologically 21 cases of multiple system atrophy (MSA). Density of Purkinje cell in 16 cases and of olivary nucleus cell in 20 cases was quantitatively measured, and their distribution as well as degree were studied. Contrary to the findings of previous reports, Purkinje cell loss was more pronounced in the vermis than in the hemispheres. Olivary nucleus cell loss was more outstanding in the accessory nucleus than in the inferior nucleus. A topographical characteristic of cell degeneration exists between the Purkinje layer and the olivary nucleus. Significant sparing of the nodulus apparently related to that of the vestibular system was found. While the common distribution of cell loss was seen, its degree varied considerably case by case. The degree was related to both duration of illness and, to some extent, clinical subtypes of MSA.

A study of parkinsonism in multiple system atrophy: clinical and MRI correlation.

We investigated clinical and MRI correlation in 18 patients with clinically‐diagnosed multiple system atrophy (MSA) and 16 age‐matched controls, using 1.5 T magnetic resonance imaging (MRI). We evaluated the severity of parkinsonism in each MSA patient. In assessing the MRI findings, we examined three parameters quantitatively: width of the pars compacta of the substantia nigra (SNc); putaminal hypointensity on T2‐weighted images; and putaminal atrophy. As in previous studies, SNc width was narrowed and the putaminal signal intensity was decreased in patients with MSA compared with controls. The clinical severity of parkinsonism did not correlate significantly with the SNc width or the score of putaminal hypointensity in MSA. However, not only did putaminal atrophy occur, but correlated well with the severity of parkinsonism in MSA. A significant correlation could not be established between narrowing of SNc and shrinkage of the putamen. These findings suggest that putaminal atrophy is associated with the clinical manifestations of parkinsonism and do not support the hypothesis that transsynaptic degeneration occurs in MSA.

Hemi-parkinsonism in multiple system atrophy: a PET and MRI study

We selected 6 patients presenting with hemi-parkinsonism from a total of 20 patients with probable multiple system atrophy (MSA) and studied their nigrostriatal lesions using magnetic resonance (MR) imaging and positron emission tomography (PET) with 18F-labeled 2-deoxy-2-fluoro-D-glucose (FDG). T2 weighted MR images demonstrated a decreased signal intensity in the putamen of all patients. This decreased signal was more intense in the nucleus contralateral to the affected body side in 5 patients. A decreased signal in the substantia nigra was found, expanding more on the contralateral side in 3 patients. T1-weighted images showed that the contralateral putamen was smaller in size than the ipsilateral. These findings indicated that the iron deposit and the neuronal cell loss in the degenerative process were more remarkable in the contralateral nuclei. FDG uptake in 5 patients had likewise declined more in the contralateral than in the ipsilateral putamen. The study shows that these patients have the nigrostriatal lesions as described in previous reports on MSA and that an asymmetric lesion relating to clinical signs is present in the nigrostriatal system. When a patient presents with hemi-parkinsonism alone, MR imaging and PET/FDG are useful for the clinical diagnosis of MSA.

Cerebrospinal fluid 28-kDa calbindin-D as a possible marker for Purkinje cell damage

To examine the clinical value of 28-kDa calbindin-D (CaBP) in cerebrospinal fluid (CSF) as a marker for the damage to Purkinje cells, we measured CSF CaBP levels using an enzyme immunoassay method in 107 patients with cerebellar and other neurological diseases, and 26 controls. The mean CaBP level was markedly elevated in patients with cerebellar diseases, and the elevation of CaBP level was more frequent in the diseases involving Purkinje cells, such as multiple system atrophy (MSA) and subacute cerebellar degeneration in association with lung cancer. Further, in MSA patients, the CaBP levels decreased with duration of illness. The mean levels of CaBP were also elevated in some of the other diseases. We conclude that the elevations of CaBP levels are not specific for cerebellar diseases, but CSF CaBP may be a useful marker for examining the Purkinje cell involvement in cerebellar diseases.

Pathology of spinal vascular disease

Pathological changes of spinal vascular disease due to dissecting aortic aneurysm, atheroma emboli, cardiac arrest and pencil‐shaped softening are described. Spinal cord damage in four patients who developed paraplegia secondary to the dissecting aortic aneurysm varied significantly from case to case. The extent of aortic dissection, the level of radicular artery, the vascular supply pattern in the transverse section of the spinal cord, and the vulnerability to ischemia were suggested to be very important factors contributing to the spinal cord damage. Atheroma emboli of spinal cord vessels were found in 7/604 autopsied cases. Atheroma emboli of spinal cord vessels is one cause of myelopathy in aged persons with hypertension, renal failure, myocardial infarction, or diabetis mellitus. Atheroma emboli were often observed at the vessels of lumbosacral segmental level. Necrosis of the spinal cord was only observed in two cases of atheroma emboli. Ischemic changes of the spinal cord were observed in 7/15 cases in which the cerebral cortex showed lamellar necrosis due to cardiac arrest. The damaged areas were found more predominantly in the lumbosacral segment. In the cross section, the area from the mid‐portion of gray matter to the base of the posterior horn was predominantly affected. Histological findings of 13 cases of pencil‐shaped softening, in which the spinal cord showed transverse necrosis by compression of extradural metastatic tumors are described. The continuity between the cavity of pencil‐shaped softening, the area of transverse necrosis was confirmed. For the pathogenesis of pencil‐shaped softening, mechanical compression was considered to be an important factor.

Spinal Pencil‐shaped Softening: Report of an Autopsy Case Studied Using a Three‐dimensional Model

The pathologic features of a case of spinal pencil‐shaped softening (PS) were studied by detailed step‐sectioning and reconstruction using a three‐dimensional (3D) model. The spinal cord was obtained at autopsy from a patient who had developed paraplegia due to extradural involvement of lung cancer. Above and below the area of transverse necrosis were PSs containing necrotic debris. They compressed the surrounding tissue and extended longitudinally over several segments. The PS was continuous with the area of transverse necrosis. These findings support the hypothesis that PS is formed by penetration of necrotic debris. The 3D model revealed that the PS was cylindrical to spindle‐shaped. It showed a remarkable change in width along its course, with an unusual expanding shape. The PS was mainly located in the ventral part of the posterior column but was also observed in other locations in the segment near the transverse necrosis. Detailed stepsectioning showed that the PS changed in width mainly in response to intrapial pressure, and that it occurred where the parenchymal tissue was fragile. The expansion produced by penetration of necrotic debris may thus play an important role in the morphogenesis of this unusual lesion. Furthermore, the condition of the surrounding tissue may also be an important factor influencing the width and location of PS.