Akihide Mochizuki

Identification of amino‐terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated tau with four microtubule‐binding repeats. Although PSP and CBD have distinctive pathological features, no biochemical difference in aggregated tau has been identified. In this study, we examined the brains of eight patients with PSP, six patients with CBD, and one atypical case with pathological features of both CBD and PSP. On immunoblots of sarkosyl‐insoluble brain extracts, a 33kDa band predominated in the low molecular weight tau fragments in PSP, whereas two closely related bands of approximately 37kDa predominated in CBD. Immunoblots of the atypical case showed both the 33kDa band and the 37kDa doublet. Protein sequencing and immunochemical analyses showed that the 33kDa band and the 37kDa doublet consisted of the carboxyl half of tau with different amino termini. These results suggest that, despite the identical composition of tau isoforms, different proteolytic processing of abnormal tau takes place in these two diseases. Such a biochemical divergence may be related to the neuropathological features of these diseases.

Aβ42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease

Immunohistochemistry with end-specific antibodies against C-termini of Aβ40 and Aβ42 in Alzheimers disease showed that Aβ42 immunoreactivity was localised intracellularly in subpopulations of neurons of patients with Alzheimers disease.

Clinicopathological characterization of Pick’s disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions

Although frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions (FTLD-TDP) and Pick’s disease are common pathological substrates in sporadic FTLD, clinical differentiation of these diseases is difficult. We performed a retrospective review of medical records and semiquantitative examination of neuronal loss of 20 sporadic FTLD-TDP and 19 Pick’s disease cases. Semantic dementia as the first syndrome developed only in FTLD-TDP patients. Impaired speech output in the early stage was five times more frequent in Pick’s disease than in FTLD-TDP. The total frequency of asymmetric motor disturbances (e.g., parkinsonism, pyramidal signs, and contracture) during the course was significantly more frequent in FTLD-TDP (78%) than in Pick’s disease cases (14%). Asymmetric pyramidal signs were found in 7 of 13 FTLD-TDP cases with corticospinal tract degeneration similar to primary lateral sclerosis. Frontotemporal dementia as the first syndrome was noted in both FTLD-TDP (28%) and Pick’s disease cases (64%); however, only FTLD-TDP cases subsequently developed asymmetric motor disturbances, and some of the cases further exhibited hemineglect. Concordant with these clinical findings, degeneration in the temporal cortex, caudate nucleus, putamen, globus pallidus, substantia nigra, and corticospinal tract was significantly more severe in FTLD-TDP, and degeneration in the frontal cortex tended to be more severe in Pick’s disease. Given these findings, the initial impairment of semantic memory or comprehension and subsequent asymmetric motor disturbances in sporadic FTLD patients predict sporadic FTLD-TDP rather than Pick’s disease, while initial behavioral symptoms or non-fluent aphasia without subsequent asymmetric motor disturbances predict Pick’s disease rather than sporadic FTLD-TDP.

Steroid-responsive Devic’s variant in Sjögren’s syndrome

Sjogren’s syndrome is a chronic autoimmune disorder characterized by mononuclear infiltrates in the exocrine glands and various complications involving the peripheral and central nervous systems.1 Optic neuropathy is associated with this disease far less often than it is with other autoimmune vasculitic disorders such as systemic lupus erythematosus (SLE) and giant cell arteritis,2,3 and its mechanism has not been determined. We describe a patient with serologic and biopsy-confirmed Sjogren’s syndrome who had both a corticosteroid-responsive myelopathy and later an optic neuropathy. Additionally, a brain CT showed a swollen intraorbital optic nerve. At 58 years of age, a woman was admitted to the hospital because of the rapid onset of a visual field defect in her left eye. She had a history of a dry sensation in her mouth from her childhood. At age 51, she developed weakness in her arms and legs, had difficulty in walking, and was first admitted to the hospital. Neurologic examination on admission showed tetraparesis, sensory disturbance below the Th6 …

Frontotemporal dementia with ubiquitinated neuronal inclusions presenting with primary lateral sclerosis and parkinsonism: clinicopathological report of an autopsy case

We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.

Association of Lewy bodies and glial cytoplasmic inclusions in the brain of Parkinson's disease.

Abstract. We report the histopathological and immunohistochemical findings from the brain of an elderly patient diagnosed with Parkinsons disease (PD). Neuropathological examination revealed moderate neuronal cell loss and astrocytosis in the substantia nigra. Lewy bodies were found in many sites characteristic for PD, including the substantia nigra, locus coeruleus, hypothalamus, substantia innominata, pontine raphe nucleus, and dorsal motor vagal nucleus, cingulate and insular cortices. Furthermore, argyrophilic glial intracytoplasmic inclusions were found predominantly in the ventral pons, cerebellar white matter, precentral and frontal white matter, internal and external capsule, claustrum, and putamen. Inclusions were triangular in shape, and immunopositive for ubiquitin and α-synuclein. In view of these histopathological and immunohistochemical findings and patterns of distribution, the inclusions were suggested to be glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). These findings suggested that our case might have experienced two pathological processes; PD and the early stage of MSA (striatonigral degeneration) that had not progressed to striatal involvement. Alternatively a common pathological background including abnormal processing of α-synuclein could contribute to widespread accumulation of Lewy bodies and GCIs in a single condition accompanied by nigral degeneration.

Exacerbation of myasthenia gravis in a patient after interferon-β treatment for chronic active hepatitis C

We report the case of a 53-year-old female patient, who developed bilateral blepharoptosis, limb weakness, dysphagia, and dyspnea several days after human natural interferon-beta (IFN-beta) treatment for chronic active hepatitis C. A positive edrophonium test, an elevated anti-acetylcholine receptor antibody titer, and decrements in the amplitude of muscle action potentials evoked by repetitive stimulation confirmed the diagnosis of myasthenia gravis (MG). Since she had been suffering from drooping of her right eyelid, fluctuating diplopia and easy fatiguability of limbs before receiving IFN-beta, her symptoms of MG were considered to be exacerbated by IFN-beta. It is recommended that IFN-beta should be used with particular care in patients with known MG or its compatible symptoms.

Pathological Heterogeneity of the Precentral Gyrus in Pick’s Disease: A Study of 16 Autopsy Cases

This report concerns the upper motor neuron involvement in 16 autopsy cases of Pick disease with Pick bodies, including 11 cases reported by us previously. Prominent, circumscribed atrophy of the precentral gyrus, conspicuously in the lower portion, was noted in one case. Loss of Betz cells and astrocytosis of the precentral gyrus layer V were encountered in 15 cases (94%) and eight cases (50%), respectively. Appearance of Pick bodies and ballooned neurons in the precentral gyrus layer V was confirmed in seven cases (44%). Degeneration of the pyramidal tract in the medulla oblongata was noted in all 15 cases in which this structure was examined. Pyramidal signs were observed in four (67%) of the six cases that were neurologically sufficiently examined: hyperreflexia in four cases (67%), spasticity in one case (17%). Babinski sign was not encountered in any of the six cases. In all four cases having pyramidal signs, degeneration of the pyramidal tract was observed. In contrast, two cases having degeneration of the pyramidal tract did not develop pyramidal signs. In Pick’s disease with Pick bodies, obvious involvement of the precentral gyrus and pyramidal tract was not previously noticed. Furthermore, we suggest that pyramidal signs in Pick’s disease with Pick bodies have been underestimated.

Cheiro-Oral Syndrome with Internuclear Ophthalmoplegia and Cerebellar Ataxia following Midbrain Infarction

Cheiro-Oral Syndrome with Internuclear Ophthalmoplegia and Cerebellar Ataxia following Midbrain Infarction Akihide Mochizuki, MD, Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305 (Japan) The cheiro-oral syndrome (COS) is a unilateral sensory disturbance that is limited to the hand and the ipsilateral perioral region. Lesions have also been reported in the parietal cortex [1], corona radiata [2], thalamus [3], and pons [4]. Except for one case of a small midbrain hemorrhage [5], midbrain lesions have not been reported. We describe the first case of a small midbrain infarct leading to COS with the rare combination of internuclear ophthalmoplegia and cerebellar ataxia. A 52-year-old man suddenly developed dizziness with left-sided dysesthesia, at the corner of the mouth, tip of the tongue, and the first 3 fingers on the left hand. He experienced double vision and was admitted to the hospital on the same day. On admission, he was alert and cooperative but his speech was slow and slurred. Isocoria was evident in the pupils and the light reflex was normal. The horizontal gaze to the left showed paresis of adduction of the right eye and coarse horizontal nystagmus of the abducting left eye. Convergence was incomplete. Dysesthesia was evident around the left corner of the mouth, the left side of the tip of the tongue, and the first 3 fingers of the left hand. Muscle power was essentially normal. Deep tendon reflexes were normal and plantar responses were flexor. Slight dysmetria was noted in the limbs on the left. The gait was slightly wide-based and unsteady. A cranial CT revealed no abnormalities. The adduction paresis of the right eye and nystagmus of the abducting left eye disappeared on the second hospital day. The sensory disturbances and cerebellar signs gradually improved. MRI performed 40 days after onset revealed a small lesion of low intensity on a Tl-weighted image, and of high intensity on a T2-weighted image in the

Horner's syndrome associated with mononeuritis multiplex due to cytomegalovirus as the initial manifestation in a patient with AIDS

We report on a 60-year-old male with AIDS who presented Horners syndrome that was associated with mononeuritis multiplex due to cytomegalovirus (CMV) infection. This is the first case who presented Homers syndrome in the course of AIDS. Horners syndrome associated with mononeuritis multiplex in this patient was the initial manifestation without any opportunistic infections. Since Horners syndrome and mononeuritis multiplex in the present case were both improved by ganciclovir, it is important to consider CMV infection when Horners syndrome or mononeuritis multiplex is observed in immunocompromised patients, such as those with HIV-1 infection or AIDS, even if they do not show any other opportunistic infections.