Kenichiro Nakamura

Corticobasal degeneration presenting with progressive conduction aphasia

We report the case of a woman with primary progressive aphasia (PPA) presenting with conduction aphasia. Neurological findings showed bilateral finger tremor and signe de poignet figé in her right hand. Memory, orientation, and activities of daily living were well preserved. Linguistic examination showed severe impairment in repetition, fluent spontaneous speech with phonemic paraphasia, and relatively well preserved comprehension. Limb-kinetic apraxia and parkinsonism were not observed during the course of her illness. T1-weighted magnetic resonance imaging revealed severe atrophy of the left temporal lobe and dilatation of the left Sylvian fissure. Neuropathological findings demonstrated the most severe atrophy in the left superior temporal gyrus and Gallyas-Braak-positive or phosphorylated tau-immunoreactive cytoskeletal structures, which were consistent with corticobasal degeneration (CBD). We speculate that the progressive conduction aphasia of our patient might have been caused by left temporal lobe impairment. We suggest that progressive conduction aphasia may be a feature of CBD presenting with PPA.

Induction of GNE in myofibers after muscle injury.

Objective: The aim of the present study was to clarify the expression of uridine diphospho-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) protein and mRNA in damaged or regenerating myofibers. Methods: We investigated the muscle expression pattern of GNE protein by immunohistochemistry using a murine model involving intramuscular injection of cardiotoxin (CTX), and the expression level of GNE mRNA by quantitative real-time polymerase chain reaction analysis of damaged or regenerating myofibers that had been collected directly from tissue sections using laser-capture microdissection. Results: The expression of GNE protein was increased in severely damaged myofibers as well as in regenerating myofibers with central nuclei, both of which also showed an increase in the expression of GNE mRNA. In regenerating myofibers, immunoreactivity for GNE protein in nuclei relative to that in the cytoplasm was higher at 7 days than at 4 days after CTX injection. Conclusion: Our findings suggest that GNE expression is induced when myofibers are damaged or regenerating, and that GNE plays a role in muscle regeneration.

Monofocal large inflammatory demyelinating lesion, mimicking brain glioma

Here we report two cases of pathologically confirmed tumor-like demyelinating lesions. In comparison with common primary demyelinating diseases, our cases demonstrated atypical radiologic features, such as a large monofocal lesion with mild brain edema, and open ring-like or focal enhancement on magnetic resonance images, suggesting brain tumors. The clinical manifestations included focal neurologic signs due to the lesions, monophasic episodes without relapse over a long follow-up period, and efficacy of oral corticosteroid therapy. Histological analysis of brain biopsy specimens showed the inflammatory demyelination and preserved axons without tumor cells. The present cases suggest the importance of considering inflammatory demyelinating disease in the different diagnosis of monofocal tumor-like lesion.

ROLE OF UBIQUITIN-PROTEASOME PROTEOLYSIS IN MUSCLE FIBER DESTRUCTION IN EXPERIMENTAL CHLOROQUINE-INDUCED MYOPATHY

Previous studies have documented the presence of rimmed vacuoles, atrophic fibers, and increased lysosomal cathepsin activity in skeletal muscle from animal models of chloroquine‐induced myopathy, suggesting that muscle fibers in this type of myopathy may be degraded via the lysosomal‐proteolysis pathway. Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, in this study we chose to examine the significance of the ubiquitin–proteasome proteolytic system in the process of muscle fiber destruction in experimental chloroquine myopathy. Expression of ubiquitin, 26S proteasome proteins, and ubiquitin ligases, such as muscle‐specific RING finger‐1 (MuRF‐1) and atrogin‐1/muscle atrophy F‐box protein (MAFbx), was analyzed in innervated and denervated rat soleus muscles after treatment with either saline or chloroquine. Abnormal accumulation of rimmed vacuoles was observed only in chloroquine‐treated denervated muscles. Ubiquitin and proteasome immunostaining, and ubiquitin, MuRF‐1, and atrogin‐1/MAFbx mRNAs were significantly increased in denervated soleus muscles from saline‐ and chloroquine‐treated rats when compared with contralateral innervated muscles. Further, ubiquitin and ubiquitin ligase mRNA levels were higher in denervated muscles from chloroquine‐treated rats when compared with saline‐treated rats. These data demonstrate increased proteasomes and ubiquitin in denervated muscles from chloroquine‐treated rats and suggest that the ubiquitin–proteasome proteolysis pathway as well as the lysosomal‐proteolysis pathway mediate muscle fiber destruction in experimental chloroquine myopathy. Muscle Nerve 39: 521–528, 2009

Relationship between White Matter Lesions and Progression of Cognitive Decline in Alzheimer's Disease.

Background: This study examined the relationship between baseline white matter lesions (WMLs) and the progression of cognitive decline in patients with late-onset Alzheimers disease (AD). Methods: Fifty-six patients with AD were included in the study (23 men, 33 women; mean age, 77.8 years). All subjects were treated with acetylcholinesterase inhibitors and followed up for approximately 1 year. The Mini-Mental State Examination (MMSE) score was assessed at least twice to evaluate the progressive cognitive impairment. All subjects underwent brain MRI at baseline and were divided into WMLs(-), mild WMLs(+), and moderate WMLs(+) groups based on WML severity. Changes in MMSE scores between baseline and follow-up were analyzed using the Wilcoxon signed-rank test. Results: MMSE scores at baseline did not differ significantly among the three groups (p = 0.1658), whereas MMSE scores at the follow-up evaluation were significantly lower in the moderate WMLs(+) group than in the WMLs(-) group (p = 0.0257). The mean MMSE scores remained above baseline values during the approximately 1-year follow-up in the WMLs(-) group, whereas they were decreased in the mild and moderate WMLs(+) groups. Moreover, the frequency of improvement in patients from the WMLs(-) group tended to be higher than that in patients from the WMLs(+) groups. Conclusion: Baseline WMLs may be associated with the heterogeneous progression of cognitive decline in patients with AD.

Skeletal muscle expression of clathrin and mannose 6-phosphate receptor in experimental chloroquine-induced myopathy.

Previous studies suggest that the muscle fiber lysosome system plays a central role in the increased formation of autophagosomes and autolysosomes that occurs in the context of chloroquine‐induced myopathy. The goal of this study was to characterize the contribution of receptor‐mediated intracellular transport, particularly the endosomal pathway, to the abnormal accumulation of vacuoles in experimental chloroquine myopathy. Expression of the mannose 6‐phosphate receptor (M6PR) and clathrin were analyzed in innervated and denervated rat soleus muscles after treatment with either saline or chloroquine. Accumulation of vacuoles was observed only in chloroquine‐treated denervated muscles. Further, clathrin immunostaining and M6PR messenger ribonucleic acid (mRNA) were significantly increased in denervated soleus muscle from saline‐ and chloroquine‐treated rats compared to contralateral, innervated muscles. However, there was no difference in clathrin levels when comparing saline‐ and chloroquine‐treated denervated muscles. These data suggest that chloroquine activates the transport of newly synthesized lysosomal enzymes from the secretory pathway via the trans‐Golgi network of the Golgi apparatus (an endosomal pathway) as well as autophagosome formation (an autophagic process) in skeletal muscles. Vacuoles may subsequently accumulate secondary to abnormal formation or turnover of autolysosomes at or after fusion of autophagosomes with early endosomes.

Induction of Genes Expressed in Endothelial Cells of the Corpus Callosum in the Chronic Cerebral Hypoperfusion Rat Model

Background: Cerebrovascular white matter lesions (WMLs) are associated with cognitive impairment in patients with subcortical vascular dementia. We performed a comprehensive gene expression analysis to elucidate genes associated with WML development in a chronic cerebral hypoperfusion rat model. Methods: Brains of rats with bilateral carotid ligation (2VO, n = 10) and sham-operated rats (n = 5-10/group) were removed on days 1, 7, or 28 after surgery. Total RNA isolated from the corpus callosum was evaluated by microarray analysis and quantitative reverse transcription-polymerase chain reaction. Results: On days 7 and 28, WMLs exhibited histologic changes. On day 7, 16 genes were differentially expressed between groups. mRNA levels of Ptprb, Kcnj8, Crispld2, Bcl6b, and Gja5 were differentially expressed in 2VO rats on day 7, but then returned to normal, whereas mRNA levels of Vwf and Trappc6a were upregulated after day 7. Immunohistochemistry showed that GJA5 and vWF were detected in endothelial cells, KCNJ8 in endothelial cells and astrocytes, CRISPLD2 in neurons and astrocytes, and TRAPPC6A in neurons. Conclusion: Our findings indicate novel genes that may be associated with WML development in the chronic cerebral hypoperfusion rat model, and suggest an important role of neurovascular dysfunction in the pathophysiology.

Portal‐systemic shunt encephalopathy presenting with diffuse cerebral white matter lesion: An autopsy case

We report herein an autopsy case of portal‐systemic encephalopathy (PSE) presenting with diffuse tissue rarefaction in the cerebral deep white matter. Clinically, the patient showed recurrent episodes of unconsciousness, abnormal behavior and urinary incontinence, as well as flapping tremor. Cognitive impairment and peripheral neuropathy developed following recurrent episodes. Although conventional arterial portography revealed a small portal‐systemic collateral vessel of a left gastro‐renal venous shunt, abdominal CT and liver biopsy showed no evidence of liver cirrhosis and serum ammonia level showed a mild increase. T2‐weighted MRI demonstrated symmetrical signal hyperintensities in the deep white matter. Neuropathological findings showed Alzheimer type II astrocytes in the deep layers of the cerebral cortices and severe tissue rarefaction with no or slight reactive astrocytosis in the subcortical and deep white matter. These white matter changes have been reported infrequently in patients with PSE. The present case suggests that chronic PSE without liver cirrhosis may develop diffuse white matter lesions.