Takashi Oide

Anti-neuronal autoantibody in Hashimoto's encephalopathy: neuropathological, immunohistochemical, and biochemical analysis of two patients

Hashimotos encephalopathy (HE) is thought to be caused by disorders of immune mechanisms. Although immunologically mediated central nervous system vasculitis or unidentified anti-neuronal autoantibodies have been suspected of causing HE, its pathogenesis is still unclear. For the study presented here, two patients with typical clinical and laboratory/electrophysiological findings of HE were analyzed to clarify the role of anti-neuronal autoantibodies in the pathogenesis of HE. The autopsied brain of one of the patients was histopathologically examined. For Western blotting analysis and immunohistochemistry, serum and purified immunoglobulin G obtained from the other patient were used. Autopsy revealed no evidence of central nervous system vasculitis or other abnormal findings in the brain. The patients serum contained an anti-neuronal autoantibody that immunohistochemically labeled neurons of mouse and human cerebral cortices and reacted with the 36-kDa antigenic protein present in a soluble fraction obtained from human cerebral cortex. Our results indicate that anti-neuronal autoantibodies may be associated with the pathogenesis of HE.

Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia

Aceruloplasminemia (ACP) is an inherited disorder of iron metabolism caused by the lack of ceruloplasmin activity; the neuropathological hallmarks are excessive iron deposition, neuronal loss, bizarrely deformed astrocytes, and numerous ‘grumose or foamy spheroid bodies (GFSBs)’. We histopathologically examined two autopsied ACP brains, and observed for the first time that GFSBs form in clusters at the ends of perivascular astrocytic foot processes. Both the deformed astrocytes and the GFSBs contained ferric iron and were intensely immunolabelled with antibodies against the antioxidant proteins ferritin and manganese superoxide dismutase (Mn SOD). Ceruloplasmin is largely produced by perivascular astrocytes in the central nervous system and exhibits a ferroxidase activity that inhibits iron‐associated lipid peroxidation and hydroxyl radical formation; therefore, the lack of ceruloplasmin causes direct oxidative stress on astrocytes. The intense immunolabelling of ferritin and Mn SOD most likely reflects a defensive response to iron‐mediated oxidative stress. This study suggests that astrocytes play key roles in iron trafficking and the detoxification of iron‐mediated free radicals at the blood–brain barrier and in the parenchyma in ACP brain. The antioxidative ability of astrocytes is one of their essential neuroprotective effects, and the decompensation of this ability may lead to secondary neuronal cell death in ACP.

Extensive loss of arterial medial smooth muscle cells and mural extracellular matrix in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a distinctive clinicopathologic entity characterized by young adult‐onset non‐hypertensive vasculopathic encephalopathy accompanied by alopecia and disco‐vertebral degeneration. CARASIL arteriopathy is histopathologically characterized by intense arteriosclerosis without the deposition of granular osmiophilic materials. Until now, the obliterative arteriosclerosis is the presumptive cause of subcortical ischemia in CARASIL; however, a detailed vascular pathology leading to diffuse leukoencephalopathy remains unclear. In this study, we examined two autopsied CARASIL brains in comparison with an autopsy case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Intensity of arterial sclerotic changes of CARASIL was evaluated by sclerotic index analysis. Immunohistochemical investigations were performed using a battery of primary antibodies, which recognized vascular cellular and extracellular components. As a result, sclerotic changes were disclosed to be mild and infrequent in CARASIL, in contrast to CADASIL that showed severe obliterative arterial changes. In CARASIL, conversely, most of the arteries were centrifugally enlarged and some were collapsed. We further revealed that arterial medial smooth muscle cells (SMCs) in patients with CARASIL were extensively lost, even in arteries without sclerotic changes. Arterial adventitia in CARASIL was conspicuously thin and immunoreactivities for type I, III, and VI collagens and fibronectin were appreciably weak in this region, indicating a reduction in the mural extracellular matrix (ECM). Because of the medial and adventitial degeneration, CARASIL brains likely receive marked fluctuations in blood flow because of deviations in the structural and functional basis of autoregulation mechanisms. We thus consider that diffuse leukoencephalopathy in CARASIL may be caused by arterial medial SMC loss with mural ECM reduction. We speculate that the abnormalities in the ECM are causatively related to the SMC degeneration, since the ECM is a crucial signal determining the biophysiological properties of arterial SMCs.

Chronic exercise accelerates the degeneration–regeneration cycle and downregulates insulin-like growth factor-1 in muscle of mdx mice

The aim of this study was to examine the effects of chronic running exercise on degenerative–regenerative processes in the hindlimb muscles of dystrophin‐deficient mdx mice. The number of large‐sized degenerative–regenerative groups (DRGs) was markedly decreased, whereas that of small‐sized DRGs was unchanged by exercise. Expression of insulin‐like growth factor‐1 (Igf1), as well as a myogenic factor MyoD (Myod1), was downregulated in mdx muscles by exercise. The downregulation of Igf1 may well correlate with the decrease in the population of early regenerating fibers, which existed predominantly in DRGs, because IGF‐1 was mainly localized in these fibers. Our data indicate that chronic exercise may accelerate the active cycle of degeneration–regeneration in mdx skeletal muscles. This means that mdx skeletal muscles can temporarily cope with work‐induced injury by enhancing muscle regeneration and repair, but we speculate that an early decline of IGF‐1 will accelerate age‐dependent muscle wasting and weakness in the later stage of life in mdx mice. Muscle Nerve, 2005

Relationship between lobar intracerebral hemorrhage and leukoencephalopathy associated with cerebral amyloid angiopathy: clinicopathological study of 64 Japanese patients.

Cerebral amyloid angiopathy (CAA) has two major clinical manifestations: intrucerebral hemorrhages and is chemic lesions. Among these, the lobar fype of intracerebral hemorrhage (ICH) is a well-known clinical manyestation, while the CAA-related diffuse deep white matter degeneration known as leukoencephalopathy is thought to be rare. The characteristics of CAA-related leukoencephalopathy are still incompletely understood, and the relationship between lobar ICH and leukoencephalopathy in patients with CAA has not been properly clarified. The main purpose of this study is to elucidate the clinical and histopathological features of CAA-related lobar ICH and leukoencephalopathy in order to determine whether the degree of deep white matter degeneration parallels the severity of CAA-associated vasculopathies that lead to vascular wall rupture. We studied 64 Japanese patients with histopathologi-cally proven amyloid beta protein (AP) type CAA presenting with lobar ICH (52 biopsy and 12 autopsy). In this study, a lotal of 106 hematomas were observed C.4A-related cerebrul hemorrhages tend to occur recurrently and multocaly. Multiple simultaneous lobur hemorrhages occasionally developed (9.4%). CAA-related ICH in the sixth decade was not rare (14.1%). Although most patients suffered relapsing and/or multiple severe ICH, no patient in our series presented with diffuse leukoencephalopathy. In conclusion, Aβ type cerebrovascular amyloid deposition causes recurrent, multifocal, and open multiple simultaneous ICH even in relatively younger elderly patients, but rarely produces diffuse leukoencephalopathy. This suggests that CAA-associated vasculopathies that cause vascular wall rupture do not always lead to is chemic deep white matter degeneration, and that there may be another unknown pathogenetic mechanism producing the latter CAA-related white matter lesion.

Serial CT and MRI findings in a patient with isolated angiitis of the central nervous system associated with cerebral amyloid angiopathy

We report serial CT and MRI findings in a biopsy-proven case of cerebral amyloid angiopathy (CAA) with isolated angiitis of the central nervous system (CNS). A 69-year-old man had developed dizziness, dementia, and generalized seizure during the preceding 4 years. An initial examination by brain CT and MRI showed bilateral symmetrical periventricular lesions closely resembling those of Binswangers disease. Subsequently, the lesions expanded slowly, involving a large area of the right cerebral hemisphere with an obvious mass effect. Since a primary brain tumor was suspected, a brain biopsy was performed, and histopathological examination revealed amyloid beta protein CAA within the meningocortical vessels associated with perivascular monocytic cuffing, indicating the presence of isolated angiitis of the CNS. Multinucleated giant cells containing intracytoplasmic beta protein amyloid around a heavily amyloid-laden cortical vessel were also observed. This is the first case report to show sequential radiographical studies of the leukoencephalopathy associated with CAA and isolated angiitis of the CNS.

An autopsy case of chronic inflammatory demyelinating polyradiculoneuropathy with respiratory failure

An 85‐year‐old Japanese woman presented with progressive symmetrical proximal and distal muscle weakness, numbness in the distal extremities, and sudden onset of hemifacial weakness. The results of laboratory studies fulfilled the American Academy of Neurology criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). She died of respiratory failure after two courses of intravenous immunoglobulin treatment, each resulting in transient improvement in strength and sensory symptoms. Autopsy revealed multifocal demyelinative or axonal lesions of varying severity affecting the cranial and peripheral nerves and including the phrenic nerve. These findings suggest that the clinical phenotype of CIDP depend on distribution and severity of the anatomical lesions. Muscle Nerve 30:382–387, 2004

A clinical and neuropathological study of an unusual case of sporadic tauopathy. A variant of corticobasal degeneration

We report a sporadic case of tauopathy with unusual clinical and neuropathological features. The patient presented with progressive symmetric rigid-akinetic parkinsonism and dementia of the subcortical type. Magnetic resonance imaging of the brain revealed atrophy resembling multiple system atrophy. The level of cerebrospinal fluid tau protein phosphorylated at serine 199 was markedly elevated. The autopsy revealed more glial than neuronal tauopathy, with much heavier involvement of subcortical white matter and the brainstem than of the cerebral cortex. Analysis of dephosphorylated tau revealed that hyperphosphorylated four-repeat tau isoforms were deposited in the brain of the patient. Despite morphological and biochemical resemblance to a certain form of familial fronto-temporal dementia, no mutation of the tau gene including exon 10 could be found. Our findings, taken together with those in previous similar case reports, indicate that the case represents an atypical form of corticobasal degeneration or a new variant of sporadic tauopathy.

Paraneoplastic Sensorimotor Neuropathy and Encephalopathy Associated with Anti-α-Enolase Antibody in a Case of Gastric Adenocarcinoma

Paraneoplastic Sensorimotor Neuropathy and Encephalopathy Associated with Anti-·-Enolase Antibody in a Case of Gastric Adenocarcinoma Kana Tojo a, Takahiko Tokuda a, b, Masahide Yazaki a, Takashi Oide a, Akihiro Nakamura c, Shigeaki Mitsuhashi a, Kazuma Kaneko a, Keiko Maruyamad, Fuyuki Kametani e, Keiichi Higuchi c, Shu-ichi Ikeda a aThird Department of Internal Medicine, Departments of bNeuroplasticity and c Aging Angiology, Shinshu University School of Medicine, Matsumoto, d Department of Neurology, Suwa Red Cross Hospital, and eDepartment of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo, Japan