[Autopsy case of frontotemporal lobar degeneration with motor neuron disease associated with numerous diffuse plaques, pretangles and neuropil threads].

We report an autopsy case of dementia associated with amyotrophic lateral sclerosis (ALS) in a 73-year-old female. She developed memory impairment at the age of 68 years. Atrophy of her hand muscles was noted at the age of 71 years. She was not aware of her memory impairment or muscle weakness, and was loquacious and euphoric. She was clinically diagnosed as having Alzheimer disease (AD) complicated by ALS with dementia/frontotemporal lobar degeneration with motor neuron disease (ALS-D/FTLD-MND). A neuropathological study confirmed the presence of features of sporadic ALS. Furthermore, severe neuronal loss involving the subiculum and the rostral portion of the medial side of the temporal pole cortex was detected, and TAR DNA-binding protein-43-positive-neuronal cytoplasmic inclusions were identified in the granule cells of the dentate gyrus. These findings were compatible with the pathological features of ALS-D/FTLD-MND. Although many pretangles, neuropil threads and senile plaques were revealed in the degenerated areas, there were few neurofibrillary tangles and typical plaques (Braak stage III, C). Further discussion is required to determine whether AD with ALS-D/FTLD-MND is different from typical AD. This case might be helpful for diagnosing similar cases in the future.

A Japanese patient with familial ALS and a p.K510M mutation in the gene for FUS (FUS) resulting in the totally locked-in state.

We describe a Japanese patient with familial amyotrophic lateral sclerosis (ALS) and a p.K510M mutation in the fused in sarcoma gene (FUS). The patient's condition was characterized clinically by an early onset and rapid progression. The patient eventually required mechanical ventilation and progressed to the totally locked-in state. Neuropathologically, multiple system degeneration with many FUS-immunoreactive structures was observed. The involvement of the globus pallidus, subthalamic nucleus, substantia nigra, cerebellar efferent system, and both upper and lower motor neurons in the present patient was comparable to that described for ALS patients with different mutations in FUS, all of whom progressed to the totally locked-in state. However, the patient also exhibited degeneration of the cerebellar afferent system and posterior column. Furthermore, the appearance of non-compact FUS-immunoreactive neuronal cytoplasmic inclusions and many FUS-immunoreactive glial cytoplasmic inclusions were unique to the present patient. These features suggest that the morphological characteristics of the FUS-immunoreactive structures and distribution of the lesions vary with the diversity of mutations in FUS.

[Rapid progressive focal myositis of the head and neck region: a case report].

A 46-year-old woman noticed a painful lump in the neck following fluctuating multiple arthralgia in the previous 3 months. The neck nodule grew rapidly, and was associated with an elevation of the serum creatine kinase activity. Under a diagnosis of focal myositis, corticosteroids were introduced, soon resulting in an amelioration of the symptoms. A biopsy from the neck nodule revealed a muscle tissue with scattered foci of densely packed inflammatory cells. Some of the cells had features similar to the granuloma, which were compact collection of cells and partial tendency of the cell fusion. These findings suggest a close relation between some cases focal myositis and granulomatous myopathy.

Frontotemporal lobar degeneration with writing disturbance mainly consisting of omission of kana letters.

A right-handed woman developed pseudobulbar palsy and a particular writing disturbance mainly composed of omission of kana letters (OKL) at the age of 79, followed by gradual progression of generalized motor disturbance and mutism. She died at the age of 88. Postmortem examination revealed frontotemporal lobar degeneration. The precentral cortex and premotor area were the most severely degenerated among the affected frontal, parietal, and temporal lobes. The omission of kana letters has been recently reported as a characteristic feature of writing disturbance in Japanese amyotrophic lateral sclerosis (ALS). Our case indicates that OKL is not specific to ALS, and that the prefrontal and precentral cortices, common lesions between our case and ALS, are responsible for OKL. This case also shows that OKL can be caused by a pathomechanism independent from other types of writing error. The neurolinguistic analysis of our case suggests the disturbance of the moraic frame of words in the transcription process of morae into kana letters or kana-letter cards.

Lateralized cortical involvement and contralateral parkinsonism without basal ganglia involvement in two autopsy cases of corticobasal syndrome-Alzheimer's disease.

Corticobasal syndrome (CBS) is characterized by lateralized motor disturbance due to levodopa nonresponsive parkinsonism and progressive apraxia. Although CBS is neuropathologically heterogeneous, it remains unclear whether the clinical features of all CBS cases are the same. We report two autopsy cases diagnosed clinically as CBS and pathologically as Alzheimer's disease characterized by lateralized cerebral cortical degeneration and absence of significant nigrostriatial lesions. Cerebral cortical degeneration in both cases was contralateral to their motor disturbances. Thus, nigrostriatial lesions and contralateral cerebral cortical lesions can cause motor disturbances in CBS, necessitating the need for bedside examination in patients with CBS.

[An autopsy case of corticobasal degeneration with notable early onset apraxia: a case report and literature review focused on apraxia].

We report the autopsy case of a 74-year-old woman. Onset of gait disturbance and left-side dominant bilateral motor disturbance in the patient led to bilateral progressive apraxia. This was associated with a decline in motor imagery, right-side dominant atrophy of the central sulcus region, and a decrease in cerebral blood flow during illness. She died of respiratory failure that had progressively worsened over a 9-year period. Pathologically, she exhibited right-side dominant cerebral atrophy; neuronal loss, gliosis, and astrocytic plaques were mainly present in the frontal lobe. She was subsequently diagnosed with corticobasal degeneration (CBD). The premotor and primary motor areas revealed marked degeneration; in addition, severe myelin pallor was observed in these regions, and it was suggested that such pathological features were responsible for the apraxia. We believe the present case is valuable since very few reports have provided a detailed description of clinicopathological apraxia in association with CBD.

[Communication disorder in amyotrophic lateral sclerosis after ventilation--a proposal of staging and a study of predictive factor].

ALS patients supported by a ventilator often suffered from difficulty in communicating with others. We herein proposed a new classification of clinical stages of advanced ALS focusing on the degree of communication disturbance. We analyzed the relationship between clinical findings and the prognosis for communication disturbance. Twenty-nine ALS patients without dementia were enrolled in the study. The proposed classification consisted of five stages. Stage I: communicate in sentences, stage II: communicate with one word answers only, stage III: communicate with nonverbal yes/no response only, stage IV: cannot communicate occasionally due to uncertain yes/no responses, stage V: cannot communicate by any means. Clinical analysis showed that patients who reached stage V had begun to use the ventilator significantly earlier than patients with the final stages of IV or less. In addition, patients in stage V frequently had a family history of ALS. Rapid disease progression before ventilator use in patients with a family history might predict a poor long-term prognosis for communication disorder after using the ventilator.

Primary progressive apraxia of speech (AOS) in a patient with Pick's disease with Pick bodies: a neuropsychological and anatomical study and review of literatures.

A 56-year-old right-handed man suffered from progressive apraxia of speech (AOS), characterized by agrammatism and buccofacial apraxia. He also became mute at the later stages of the disease progression. At autopsy, the left precentral gyrus, pars opercularis, and hippocampus showed severe atrophy. Pick bodies and Pick cells were observed. In this report, we also review previous case reports of AOS. Pick's disease is among the most commonly associated of the major diseases. Brain lesions associated with AOS may be found in regions such as the precentral gyrus and the pars opercularis in the left hemisphere.

Familial ALS with FUS P525L mutation: two Japanese sisters with multiple systems involvement.

We evaluated the clinicopathological features of familial amyotrophic lateral sclerosis (ALS) with the fused in sarcoma (FUS) P525L mutation. Two sisters and their mother had a similar clinical course, which was characterized by the development of limb weakness at a young age with rapid disease progression. An elder sister, patient 1, progressed into a totally locked-in state requiring mechanical ventilation and died 26 years after the onset of the disease. In contrast, the younger sister, patient 2, died in the early stages of the disease. The patients had neuropathological findings that indicated a very active degeneration of motor neurons and multiple system degeneration, which led to marked brain and spinal cord atrophy in the long term clinical outcome. The multiple system degeneration included the frontal lobe, the basal ganglia and substantia nigra, cerebellum and related area. Compared with previously reported ALS cases, the severe degeneration of the frontal lobe and the striatum were the characteristic features in the patient 1 in this case study. The degeneration spread over multiple systems might be caused not only by the appearance of the FUS immunoreactive neuronal cytoplasmic inclusions but also by the degeneration of neuronal connections from the primary motor cortex and related areas.

Novel G37V mutation of SOD1 gene in autopsied patient with familial amyotrophic lateral sclerosis.

We report a novel missense mutation (G37V) in exon 2 of the superoxide dismutase-1 gene in a 63-years-old Japanese male with purely lower motor neuron disease. His disease duration was 14 months, and he died of respiratory failure. The disease in this patient with the G37V mutation showed a rapid progression, although patients with G37R mutation are known to have a long survival.

[Eye movement disturbance in multiple system atrophy: chronological study of 50 patients].

To clarify the features of the eye movement disturbance in the patients with multiple system atrophy (MSA), we retrospectively examined chronological changes of 9 oculomotor parameters as described below in 50 MSA patients including 12 autopsied cases. Patients with MSA were consisted of 35 patients with cerebellar ataxia-preceding type and 15 patients with parkinsonism-preceding type. Nine parameters include saccade test, eye tracking test, positioning/positional/gaze/caloric nystagmus tests, and visual suppression test. Each parameter was evaluated by three categories; normal and the two abnormal findings according to their characteristic features. In all of the 9 parameters, no significant differences were found between the cerebellar ataxia- and the parkinsonism-preceding types of MSA both in the early (disease duration less than 3 years) and in the advanced stages (duration between 8 to 11 years). From the chronological analysis, 9 oculomotor parameters could be divided into three groups: the first group with the higher frequency of the abnormality from the early stage, the second with gradual increase of the frequency, and the third with less increased frequency even in the advanced stage. We here focused on the three representatives corresponding with the above-described each group; positioning nystagmus test mainly showing downbeat nystagmus as a first group, visual suppression test showing a qualitative change from depressed into increased response as the second, and the caloric nystagmus test showing decreased response as the third. Based on these chronological changes of the oculomotor parameters, we supposed that in MSA the dorsal vermis is involved at first, followed by the flocculus in the cerebellum, and then the degenerative lesions might expand to the vestibular nucleus, and the cerebral cortex including the vestibular cortex.

[Headache as a manifestation of SAPHO syndrome with a lesion extending to the dura mater, parietal bone, and temporal muscle].

A 50-year-old woman with a history of palmoplantar pustulosis, femur osteomyelitis, and sterno-costo-clavicular hyperostosis presented with a chronic severe left temporal headache that had progressed during the previous year. Her CRP level was elevated. Cranial images showed Gadolinium-enhancement of the left temporal muscle, left parietal bone and dura mater. (99m)Tc-HMDP scintigram showed increased uptake in the left parietal bone, left sterno-costo-clavicular joint, right femoral head and intervertebral joints. Biopsy of the lesion demonstrated 1) proliferation of connective tissue in both perimysium and endomysium of the temporal muscle with mild inflammatory cell infiltration within the interstitium, 2) marked infiltration of granulocytes to the bone marrow of the parietal bone, 3) necrosis and moderate fibrosis in the interstitium with inflammatory cell infiltration in the parietal bone, and 4) moderate fibrosis and slight infiltration of inflammatory cells in the dura mater. The patient was diagnosed with a cranial lesion of synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. There was a moderate response to treatment with intravenous steroid pulse therapy and subsequent methotrexate. In a case of headache accompanied by inflammatory response, palmoplantar pustulosis and joint lesions such as hyperostosis, the possibility of a rare cranial manifestation of SAPHO syndrome should be considered.

Phosphorylated α-synuclein immunoreactivity in the posterior pituitary lobe.

Parkinson's disease is now recognized as a major form of α-synucleinopathy involving both the central and peripheral nervous systems. However, no research has focused on the posterior pituitary lobe (PPL), despite the fact that this organ also plays an important role in systemic homeostasis. In the present study, we aimed to distinguish phosphorylated α-synuclein (pαSyn)-positive deposits in the PPL, as is observed in Lewy body- and non-Lewy body-related disorders. PαSyn deposits were immunohistochemically analyzed using formalin-fixed, paraffin-embedded PPL specimens obtained from 60 autopsy cases. Among the cases with Lewy body-related disorders, PPL pαSyn deposits were observed in almost all cases of Parkinson's disease (22/23), and in one case of dementia with Lewy bodies (1/1). On the other hand, only 3/36 cases of non-Lewy body-related disorders had pαSyn immunoreactivity in the PPL. The present study confirms the presence of pαSyn-positive deposits, as demonstrated by high specificity (97.1%) and sensitivity (88.5%), in both Parkinson's disease and dementia with Lewy bodies, suggesting that this finding can be a useful hallmark of Lewy body-related disorders.

Supranuclear ophthalmoparesis and vacuolar degeneration of the cerebral white matter in amyotrophic lateral sclerosis: a clinicopathological study.

Possible clinicopathological relationship between vacuolar degeneration of cerebral white matter and clinical manifestation, especially of supranuclear ophthalmoparesis, both infrequent in amyotrophic lateral sclerosis (ALS) patients, was tested. Of 104 ALS sequential series, cases with vacuolar degeneration of the cerebral white matter were selected to yield 14 cases pathologically surveyed in this study. Clinical features were retrospectively assessed in their clinical records. Microscopic examination clarified vacuolar changes with fibrous gliosis, infiltration of macrophages, axonal degeneration with segmental dilatation and partial loss of myelin on electron microscopy. This histological change was extended into the cerebral white matter just under the cortices but sometimes accentuated as restricted areas along the pyramidal tract and precentral regions. In a patient with the most extensive focal lesion, these white matter vacuolar changes were detected with magnetic resonance imaging. The clinical manifestations linked to this focal vacuolar degeneration were disturbance of vertical ocular movements and shorter duration of the illness, compared with patients without vacuolar degeneration. In conclusion, histological demonstration of characteristic vacuolar degeneration in the white matter of ALS and its focal accentuation along precentral-pyramidal tracts are mutually related and possibly linked to clinical manifestations such as supranuclear ophthalmoparesis, an exceptional but possible manifestation of ALS.

Proportional neuronal loss between the primary motor and sensory cortex in amyotrophic lateral sclerosis.

The number of neurons in the primary motor cortex (MI) and the primary somatosensory cortex (SI) were estimated in the same locations of brains from sporadic amyotrophic lateral sclerosis (ALS) cases and controls. The number of MI and SI neurons and Betz cells were significantly decreased in the ALS cases as compared to the controls. The number of neurons in MI and SI was independent of age at death or duration of disease. Moreover, the number of neurons in MI and SI was significantly correlated, suggesting that the neurons in both sites might be interdependent and might decrease proportionally.

A morphometric study of the vagus nerve in amyotropic lateral sclerosis with circulatory collapse.

Amyotrophic lateral sclerosis (ALS) shows peculiar abnormalities of the autonomic nervous system, including sympathetic hyperactivity, which might result in sudden death. In general, the sympathetic hyperactivity could be caused by disruption of vagal inhibition. Our objective was to evaluate the vagus nerve morphometrically in autopsy cases of ALS with sympathetic hyperactivity and circulatory collapse (CC). We investigated 10 autopsied ALS patients, six of whom had exhibited autonomic storms or CC. We also examined 10 patients without ALS as controls, and one patient with Guillain-Barré syndrome (GBS) who died from CC, for comparison. After obtaining the visceral branch of the left vagus nerve at necropsy, we analyzed the density of the myelinated and unmyelinated fibers, and the fiber diameter distribution for each fiber. Results showed that the densities of both myelinated and unmyelinated fibers in ALS patients with or without CC were not significantly different from those in control patients. In contrast, the GBS patient showed marked reduction in the whole myelinated and large unmyelinated fiber density. In conclusion, the autonomic storms or CC due to sympathetic hyperactivity in ALS could not be ascribed to the deafferentation of the baroreflex, and more central neural pathophysiology should be investigated.

Survival motor neuron (SMN) protein in the spinal anterior horn cells of patients with sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving mainly the upper and lower motor neurons of adult humans. With regard to the pathomechanism of spinal anterior horn cell (AHC) degeneration in ALS, copy number abnormalities of the survival motor neuron (SMN) genes have been reported in sporadic (s) ALS. SMN protein is the protein responsible for the pathogenesis of spinal muscular atrophy (SMA), an autosomal recessive disease characterized by lower motor neuron loss and muscle atrophy. The disease is caused by deficiency of SMN protein induced by mutation of one of the SMA-associated genes, SMN1. To clarify the role of SMN protein in the degeneration of spinal AHCs in sALS, we examined the amount of cytoplasmic SMN protein in individual AHCs using cytofluorophotometry in 9 patients with sALS and 10 control subjects. It was found that: 1) SMN protein was present in the cytoplasm, nucleus and nucleolus of AHCs and in the nucleus of glial cells, 2) expression of SMN protein in AHCs was significantly associated with cell size in both sALS patients and controls, 3) expression of SMN protein per unit area in AHCs was similar in sALS patients and controls. These findings suggest that: 1) the amount of SMN protein in the cytoplasm of AHCs is strictly controlled in accordance with cell size, in both sALS patients and controls, 2) the amount of SMN protein in the AHCs of sALS patients may be reduced when the AHCs are atrophic, and 3) decrease of SMN protein in the AHCs of sALS patients may be a secondary, and not primary, phenomenon according to their sizes.