Constant involvement of the Betz cells and pyramidal tract in multiple system atrophy: a clinicopathological study of seven autopsy cases

We investigated clinicopathologically the pyramidal signs, including spasticity, hyperreflexia, and Babinski’s sign, and the involvement of the pyramidal tract and primary motor cortex, in seven Japanese autopsy cases of multiple system atrophy (MSA). Pyramidal signs were observed in six (86%) of the seven autopsy cases. Hyperreflexia and Babinski’s sign were each evident in five patients, but spasticity was observed in only one patient. Loss of Betz cells and presence of glial cytoplasmic inclusions in the primary motor cortex were noticed in all seven cases. Astrocytosis in the fifth layer of the primary motor cortex was noticed in five cases, but its presence was not related to the duration of the disease. Involvement of the pyramidal tract in the spinal cord, particularly of the small myelinated fibers, was observed in all seven cases, but no involvement of the pyramidal tract in the midbrain was evident in any of the six cases in which this structure was examined. In MSA, pyramidal signs were shown to be present more frequently than believed before, and the clinicopathological correlation between pyramidal signs and involvement of the pyramidal tract was obvious. Constant involvement of Betz cells in MSA has not been reported. Our clinicopathological findings may also make a contribution to the understanding of the clinicopathological hallmarks of MSA. Received: 28 June 1999 / Revised: 13 September 1999 / Accepted: 30 September 1999     

Distribution of cerebral cortical lesions in corticobasal degeneration: a clinicopathological study of five autopsy cases in Japan

We investigated five Japanese patients with autopsy-proven corticobasal degeneration (CBD) both clinically and pathologically, and examined the distribution of their cerebral cortical lesions in hemisphere specimens. The lesions were classified into three categories (slight, moderate and severe). Only two of our patients had clinical features considered to be typical of CBD. Severe lesions were present in the posterior portions of the frontal lobe, anterior to the precentral gyrus in two patients with the clinical diagnosis of CBD. By comparison, in two patients with clinically diagnosed frontal Pick’s disease, and one with the clinical diagnosis of progressive supranuclear palsy (PSP), severe lesions were seen in the anterior portions of the frontal lobe. The primary motor area of all five had mostly slight to moderate lesions. We postulate that the clinical features of CBD have a much wider spectrum than previously believed. Our data also indicate that the lesion responsible for limb-kinetic apraxia in CBD is in the premotor cortex. We suggest that when the anterior portions of the frontal lobe are damaged, the clinical picture mimics those of Pick’s disease and PSP. In addition, we consider that focal cerebral atrophy of CBD is multicentric. Received: 3 February 1997 / Revised: 14 April 1997 / Accepted: 2 May 1997     

Constant involvement of the Betz cells and pyramidal tract in amyotrophic lateral sclerosis with dementia: a clinicopathological study of eight autopsy cases

We investigated clinicopathologically pyramidal signs, including hyperreflexia, Babinski sign, and spasticity, and the involvement of the primary motor cortex and pyramidal tract, in eight Japanese autopsy cases of amyotrophic lateral sclerosis (ALS) with dementia. Pyramidal signs were observed in seven (88%) of the eight autopsy cases. Hyperreflexia and Babinski sign were evident in seven (88%) and three (38%) patients, respectively, but spasticity was not observed in any of the eight patients. Loss of Betz cells in the primary motor cortex was evident in the seven cases in which this structure was examined. Astrocytosis in the fifth layer of the primary motor cortex was noticed in three cases. In all eight cases, involvement of the pyramidal tract was obvious in the medulla oblongata, but no involvement of the pyramidal tract was found in the midbrain. Involvement of the pyramidal tract in the spinal cord, particularly of large myelinated fibers, was observed in all six cases in which the spinal cord was examined. In ALS with dementia, pyramidal signs were shown to be present more frequently than previously believed, and the clinicopathological correlation between pyramidal signs and involvement of the pyramidal tract was obvious. Constant involvement of Betz cells and the pyramidal tract in ALS with dementia has not been reported. Our clinicopathological findings may make a contribution to the understanding of the clinicopathological hallmarks of this disorder. Furthermore, we believe that this study will also contribute to the elucidation of the nosological status of ALS with dementia.     

Reversible spastic and pyramidal tract signs in a patient with parkinson's disease on L-Dopa

Zusammenfassung Eine Patientin mit Parkinson-Syndrom wird beschrieben, bei der gleichzeitig mit L-Dopa induzierten Dyskinesien reversible unilaterale spastische und Pyramidenbahnzeichen auftraten. Ein ursächlicher Zusammenhang zwischen diesen Zeichen, L-Dopa und einer latenten Läsion des zentral-motorischen Systems wird angenommen. Mit Hilfe von tierexperimentellen Befunden wird versucht, diesen Zusammenhang zu erklären.     

Creutzfeldt-Jakob disease presenting as corticobasal degeneration: a neurophysiological study

Abstract Creutzfeldt-Jakob disease (CJD) can occasionally present with a clinical picture resembling a corticobasal degeneration (CBD). Transcallosal inhibition, as tested by focal transcranial magnetic stimulation, is frequently absent or highly disrupted in CBD patients. We report a case of CJD presenting at the beginning of the disease as a CBD in which the ipsilateral silent period (iSP) was present and well detectable. This brief report shows that study of the iSP may be a useful diagnostic tool in order to differentiate CBD from syndromes presenting with similar clinical features.     

Alzheimer's disease: Report of two autopsy cases with a clinical diagnosis of corticobasal degeneration

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy‐proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8‐positive neurofibrillary tangles (NFTs) and Aβ‐positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and Aβ deposits may begin in the fronto‐parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra.     

Bilateral upper limb rehabilitation with videogame-based feedback in corticobasal degeneration: a case reports study

Corticobasal degeneration (CBD) is a neurodegenerative disorder characterized by a combination of cortical and basal ganglia signs. We reported two cases treated with a bilateral upper limb rehabilitation tool with videogame based feedback for 3 time per week for 8 weeks. Both patients showed an improvement of pinch and grasp forces and motor function. However, both of them reported an increased upper limb pain. Bilateral upper limb mechanical device with exergame feedback was effective also in the two patients suffering of CBD for limiting the effects of apraxia by performing intensive purposeful task training.     

Fragmentation of the Golgi apparatus of the ballooned neurons in patients with corticobasal degeneration and Creutzfeldt-Jakob disease

We investigated immunohistologically the Golgi apparatus (GA) and the trans-Golgi network (TGN) of the cortical ballooned neurons (BNs) in two patients with corticobasal degeneration and in five with Creutzfeldt-Jakob disease. We observed that the BNs showed fragmentation of the GA and the TGN, accompanied by a reduction in the number of fragmented Golgi elements and by a unique perinuclear distribution. This is the first report of the abnormalities of GA in cortical BNs. These findings suggests that the GA and the TGN may play some roles in the BN formation. Received: 1 September 1999 / Revised, accepted: 30 November 1999     

Paired helical filaments in corticobasal degeneration: the fine fibrillary structure with NanoVan

Paired helical filaments (PHF) composed of hyperphosphorylated tau proteins are characteristic findings in neurodegenerative disorders, including Alzheimer's disease (AD) and corticobasal degeneration (CBD). The filaments in CBD differ from those in AD by a reduced number of tau isoforms and less stable ultrastructure. To further compare the ultrastructure of both filaments, we employed a novel staining reagent, NanoVan, as well as aurothioglucose and uranyl acetate. With commonly used uranyl acetate, both kinds of filaments appeared as twisted ribbons 15–20-nm and 21–23-nm wide, respectively, without significant internal substructure. With application of aurothioglucose, only few structural details were apparent. With NanoVan, AD filaments showed similar structure to that with uranyl acetate but CBD filaments displayed a highly heterogeneous appearance consistent with the dissociation of the 20–25-nm-wide filaments along two longitudinal axes. This was evident by the presence of thinner, 12–13-nm-wide filaments and filaments that splayed into two 20–25-nm-wide components at one or both ends. Moreover, detection of a prominent, 7–8-nm-wide axial region distinguished up to four protofilaments per one filament. Each protofilament appeared to contain two 3–5-nm-wide fibrils separated by an approximately 1-nm-wide axial region. The results suggest that 3–5-nm fibrils are the smallest structural subunits of filaments in CBD and that NanoVan may be an unique reagent in detecting eight-fibril organization in these less stable filaments.     

Pallidonigroluysian degeneration with iron deposition: a study of three autopsy cases

In the basal ganglia of three autopsy cases of pallidonigroluysian degeneration, we found marked iron deposition, a finding which has not been mentioned previously in the literature. Besides severe astrogliosis and neuronal loss in the pallidum, Luysian body and nigra, granular deposits of brown pigments were found in the neuropil, microglias, oligodendrocytes and astrocytes in three such the nuclei and the striatum. These brown pigments proved histochemically to be iron. Our histochemical semiquantitative study showed a significantly stronger reation for iron in the degenerated nuclei in these three cases than in control cases comprising non-degenerative and the other degenerative diseases. Quantitative study with inductively coupled emission spectrometry also demonstrated a markedly higher iron content in the globus pallidus and the striatum in comparison with the control cases. The possibility is discussed that iron deposition plays a role in generating the lesions of pallidonigroluysian degeneration.     

Degeneration of the cerebellar dentate nucleus in corticobasal degeneration: neuropathological and morphometric investigations

To resolve the controversy regarding the involvement of the dentate nucleus in corticobasal degeneration (CBD), an entire profile of the dentate nucleus was exposed in a sagittal plane and divided into four fields, and the number of neurons in each filed was counted separately using a computer-assisted analyzer in five cases of CBD and compared to those from seven age-matched controls. The size of the nucleus and the number of neurons were significantly reduced in all five cases of CBD. The neuronal loss had a definite regional predilection, more severe in the caudolateral neodentatum than in the rostromedial palaeodentatum, and was accompanied by grumose degeneration and astrogliosis which paralleled the severity of the neuronal loss. Thus, the dentate nucleus appears to be a cardinal target in CBD. Received: 18 May 1999 / Revised, accepted: 27 July 1999     

The overlap of corticobasal degeneration and Alzheimer changes: An autopsy case

The aspects of various neurodegenerative diseases can be observed overlapping with each other during autopsy. Corticobasal degeneration (CBD) is a rare neurodegenerative disease, whereas Alzheimer disease (AD) is the most common cause of dementia. In this article, we present the combination of CBD and AD in an autopsy case. The patient, an 82‐year‐old right‐handed woman developed asymmetrical parkinsonism, visuospatial dysfunction and memory loss, as well as subsequent non‐influent aphasia over the past 10 years. The autopsy revealed characteristic CBD‐related pathology, ballooned neurons, globose tangles and astrocytic plaques, mainly in the frontal cortex and basal ganglia. The Alzheimer‐related pathology was also present concomitantly. Senile plagues deposited diffusively throughout the hippocampus and neocortices. Neurofibrillary tangles (NFTs) were more confined to the hippocampus. The autopsy demonstrated pathological overlap of CBD and AD, which therefore explained the clinical early development of dementia and parkinsonism. We should suspect the concurrence of various neurodegenerative disorders in any case with atypical or complex clinical manifestations. Tau pathology is a prominent feature in both CBD and AD. Such a combination would be a clue for the pathogenesis of various tauopathies.     

Levodopa-responsive parkinsonism in a patient with corticobasal degeneration and bilateral choroid plexus xanthogranulomas

Corticobasal degeneration (CBD) has substantial overlap of clinical features with other neurodegenerative diseases including Parkinson’s disease (PD). Its clinical diagnostic accuracy is the lowest among the common neurodegenerative diseases, and its antemortem diagnosis is more challenging when CBD is comorbid with another brain disease. We report an elderly male patient with multiple medical conditions and a family history of essential tremor. He presented with progressive tremor that was initially thought to be essential tremor and later diagnosed as PD despite head computerized tomography showing bilateral intraventricular masses and other minor changes. The clinical diagnosis of PD was supported by his responsiveness to low-dose levodopa. However, postmortem neuropathological examination revealed CBD and bilateral choroid plexus xanthogranulomas with mild ventricular enlargement and multifocal ependymal lining injury presumably due to mild hydrocephalus. CBD is typically levodopa-unresponsive, but hydrocephalus-associated parkinsonism is commonly levodopa-responsive. We raise awareness of the present comorbidity and atypical parkinsonism due to the choroid plexus xanthogranuloma-induced hydrocephalus for the clinical diagnosis and management of parkinsonism.     

Fluorodopa uptake and glucose metabolism in early stages of corticobasal degeneration

Fluorodopa (FDOPA) and fluorodeoxyglucose (FDG) PET was performed in six patients in early stages of corticobasal degeneration (CBD) and compared to Parkinson’s disease (PD) patients with a similar degree of bradykinesia and rigidity and to healthy controls. Statistical parametric mapping analysis comparing CBD to controls showed metabolic decrease in premotor, primary motor, supplementary motor, primary sensory, prefrontal, and parietal associative cortices, and in caudate and thalamus contralateral to the side of clinical signs. Except for the prefrontal regions a similar metabolic pattern was observed when CBD was compared to PD. Putamen FDOPA uptake was decreased in both CBD and PD. Caudate FDOPA uptake in CBD patients was decreased contralateral to clinical signs when compared to controls, but was higher than in PD. In early stages of CBD, FDOPA and FDG PET patterns differed from those observed in PD. In CBD the asymmetry in FDOPA uptake was less pronounced than that of clinical signs or metabolic impairment. Received: 19 January 1999 Received in revised form: 2 July 1999 Accepted: 14 July 1999     

Epitope expression and hyperphosphorylation of tau protein in corticobasal degeneration: differentiation from progressive supranuclear palsy

Corticobasal degeneration (CBD) is a rare, progressive neurological disorder characterized by widespread neuronal and glial accumulation of abnormal tau protein. Using immunohistochemistry we analyzed tau epitope expression and phosphorylation state in CBD and compared them to cytoskeletal changes in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Epitopes spanning the entire length of the tau protein were present in CBD inclusions. An antibody against the alternatively spliced exon 3 did not recognize cytoskeletal lesions in CBD, but did in AD and PSP. Tau epitopes from each region of the molecule were present in cytoskeletal inclusions in CBD, including gray matter astrocytic plaques, gray and white matter threads, and oligodendroglial inclusions. As in AD, tau from CBD was highly phosphorylated. Antibodies that recognized phosphorylated tau epitopes reacted with material from CBD in a highly phosphatase-dependent manner. Again, all types of inclusions contained phosphorylated epitopes. We conclude that abnormal tau protein in CBD comprises the entire tau molecule and is highly phosphorylated, but is distinguished from AD and PSP by the paucity of epitopes contained in the alternatively spliced exon 3.     

Basal ganglia lesions in corticobasal degeneration differ from those in Pick's disease and progressive supranuclear palsy: A topographic neuropathological study of six autopsy cases

The distribution of the lesions of the basal ganglia including the striatum, pallidum and subthalamic nucleus were investigated neuropathologically in six Japanese autopsy cases of corticobasal degeneration (CBD) using routine staining including the hematoxylin-eosin (HE) and Holzer methods. We compared the distribution of these lesions with those reported in Pick's disease and progressive supranuclear palsy (PSP). The lesions were classified as mild, moderate or severe. The extent and distribution of basal ganglia lesions in all six cases was uniform: the pallidum showed severe lesions, the striatum moderate lesions, and the subthalamic nucleus mild lesions. In CBD, the degree and distribution of the lesions within the basal ganglia differed from those reported for Pick's disease and PSP; in Pick's disease the lesions of the striatum are more prominent than that of the pallidum, and in PSP the involvement of the subthalamic nucleus is more pronounced than that of the striatum. These neuropathological findings have implications for the morphological differential diagnosis among Pick's disease, CBD, and PSP.     

Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are characterized by their unique clinical features and neuronal pathology. Although astrocytic plaques and tufts of abnormal fibers have been suggested to be specific histopathologic markers, recent studies have revealed significant clinicopathologic overlap between CBD and PSP. Based on the distinctive camera lucida profile of astrocytic inclusions on Gallyas-Braak silver staining, we found that astrocytic plaques and tufts of abnormal fibers did not coexist in the same patient among 30 cases of clinically diagnosed CBD, PSP and atypical Parkinson’s disease. Using Tau immunohistochemistry it was difficult to verify the absence of tufts of abnormal fibers. A morphometric analysis revealed that the two groups classified by the presence or absence of astrocytic plaques and tufts of abnormal fibers exhibited significant differences in the density of ballooned neurons and neurofibrillary tangles and degeneration of the subcortical nuclei. Assessment using the NINDS neuropathologic criteria revealed that the cases with astrocytic plaques and tufts of abnormal fibers closely correspond to CBD and typical PSP, respectively. In addition, the cases lacking either of these two astrocytic inclusions had atypical PSP according to the NINDS criteria, and were associated with novel tau-positive astrocytes (spiny astrocytes). We thus conclude that astrocytic plaques and tufts of abnormal fibers are highly characteristic structures for CBD and typical PSP, respectively. We emphasize the importance of strict differentiation between different astrocytic inclusions not only for diagnosis, but also for further studies for elucidation of their role in the disease mechanisms of CBD and PSP. Received: 10 December 1997 / Revised, accepted: 23 March 1998     

Ubiquitin immunoreactivity of paired helical filaments differs in Alzheimer’s disease and corticobasal degeneration

To establish whether there is a relationship between ubiquitination and ultrastructural appearance of filaments, we compared the ubiquitin immunoreactivity of paired helical filaments (PHFs) in Alzheimer’s disease (AD) and corticobasal degeneration (CBD). PHFs in these disorders share a limited similarity since filaments in CBD are wider and twisted at longer intervals than those in AD, and also display less ultrastructural stability. Preparations enriched in SDS-soluble filaments were isolated from AD and CBD brains and subjected to tau and ubiquitin immunogold labeling. Both preparations contained mostly dispersed individual PHFs, which labeled for the amino and carboxyl termini of tau. Immunolabeling of ubiquitin was variable, however, being more intense in AD than CBD samples. SDS-insoluble filaments were prepared from PHFs by boiling in the presence of SDS and 2-mercaptoethanol and collected by sedimentation. In both disorders, the pellets contained highly aggregated and bundled filaments, which were devoid of the amino but not the carboxyl terminal region of tau. Again, ubiquitin labeling was more intense in AD than CBD filaments. The present results suggest that ubiquitination has limited influence on SDS solubility, aggregation and bundling of PHFs; however, it may be one of the factors responsible for the ultrastructural variability and/or stability of filaments. Received: 6 March 1998 / Revised, accepted: 14 May 1998     

The effect of repeated administrations of granulocyte colony stimulating factor for blood stem cells mobilization in patients with progressive supranuclear palsy,corticobasal degeneration and multiple system atrophy

Granulocyte colony stimulating factor (GCSF) may boost physiological stem cell repair system in patients with cerebral lesions. Atypical parkinsonisms (PSP, CBD, MSA) are characterized by rapidly progressive course without significant benefit from current therapies.     

Alcoholic cerebellar degeneration: A clinicopathological study of six Japanese autopsy cases and proposed potential progression pattern in the cerebellar lesion

Alcoholic cerebellar degeneration (ACD) is one of the most common neurological complications in alcoholics. As far as we know, however, only four Japanese autopsy cases of ACD have been reported, and only limited clinicopathological data on this disease are now available in Japan. The aims of this study were: (i) to examine the clinicopathological correlation of six Japanese autopsy cases of ACD, including three asymptomatic cases; and (ii) to elucidate the pattern of progression of the cerebellar lesion in ACD. All six alcoholics were histopathologically diagnosed as having “pure” ACD without Wernicke’s encephalopathy. The characteristics of the topographical distribution of the cerebellar lesion were as follows. Symptomatic cases (cases 1–3) showed more severe and widespread change than asymptomatic cases (cases 4–6). Even in case 6, which had the mildest lesion, the anterior vermis developed a moderate change (Purkinje cell loss and narrowing of the molecular layer). In cases 4 and 5 with more severe and widespread lesions, the superior and posterior vermis and the adjacent regions of the superior hemisphere, including the anterior lobe and simple lobule, were involved. In all symptomatic cases, the anterior superior hemisphere had severe lesions involving the granular cell layer. In contrast to asymptomatic cases, all symptomatic cases also had severe to moderate lesions in the anterior inferior hemisphere. In cases 1 and 2 with the most severe lesions, the moderate to severe changes were distributed in the posterior and inferior portions of both the vermis and hemisphere. These findings suggest that in ACD, severe lesions successively develop: (i) in the anterior superior vermis; (ii) anterior superior hemisphere; (iii) anterior inferior hemisphere; and (iv) anterior inferior vermis. In addition, cerebellar symptoms may frequently occur if the anterior superior hemisphere and anterior inferior hemisphere, in addition to the anterior superior vermis, are involved.