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.     

Neurodegenerative disease and the evolution of art: the effects of presumed corticobasal degeneration in a professional artist.

Production of art is a complex process involving a combination of technical skill and a unique talent. Changes in artistic ability may accompany neurodegenerative disorders when they occur in an artist. The nature of these changes in the context of definable regional neuropathological disturbances may provide insight into the structural basis of the creative process. We describe a professional artist in whom presumed corticobasal degeneration (CBD) was associated with an alteration of his artistic judgement and production. Disinhibition, perseveration, and left hemispatial neglect, features of his cognitive profile were readily discernible in his work. The differences in his style are examined with respect to his main neuroanatomic abnormalities, namely right cerebral hemiatrophy as defined by magnetic resonance and single-photon emission computed tomography imaging. Cognitive deficits, including visuoconstructive and motor neglect, apathy, perseveration, and disinhibition as determined by neuropsychological testing, contributed to the dissolution of his artistic skills. Our case study adds to the growing literature on the effects of brain damage on artistic expression in the graphic arts.     

Amyotrophic lateral sclerosis with dementia showing clinical parkinsonism and severe degeneration of the substantia nigra: Report of an autopsy case

An autopsy case of amyotrophic lateral sclerosis with dementia (ALS‐D) showing clinically overt parkinsonism and severe degeneration of the substantia nigra is reported. The patient was a 78‐year‐old man who died after a 2‐year clinical course characterized by parkinsonism that was responsive to Levodopa (L‐DOPA) treatment. Motor neuron symptoms and dementia were not apparent ante‐mortem. The autopsy demonstrated the severe degeneration of the substantia nigra without α‐synucleinopathy‐related changes. Finely granular mineralization of necrotic neurons was a unique finding in the substantia nigra. The mild loss of spinal anterior horn cells, the appearance of several Bunina bodies and the degeneration of the hippocampal subiculum and temporal cortex were also noted. A small number of ubiquitinated intra‐cytoplasmic inclusions were found in neurons of the dentate fascia of the hippocampus and the temporal and frontal cortices. Although the degeneration of the substantia nigra is a common finding in ALS‐D, patients seldom develop clinically overt parkinsonism. This case indicates that patients with ALS‐D rarely present with predominantly parkinsonian clinical features and these symptoms and signs can be improved by L‐DOPA treatment.     

Seizures in corticobasal degeneration: A case report

Seizures are relatively common in Alzheimer disease (AD) and other neurodegenerative disorders. To our knowledge, however, there have been no reports of seizures associated with corticobasal degeneration (CBD). We describe a patient with brain biopsy features suggestive of CBD whose course was complicated by complex partial seizures with secondary generalization. Thus, the occurrence of seizures in a patient with dementia should not exclude the diagnosis of CBD.     

An autopsied case of corticobasal degeneration presenting with frontotemporal dementia followed by myoclonus

A Japanese woman developed frontotemporal dementia (FTD)‐like symptoms of abnormal behavior, such as stereotyped behavior and disinhibition. The patient developed these symptoms at the age of 59 years, although aphasia symptoms were not apparent at early disease stages. Progressive parkinsonism was dominant on the left side, and conspicuous myoclonus was recognized in the late disease stage. MRI indicated severe, right side‐dominant frontotemporal lobe atrophy with white matter degeneration. Brainstem and cerebellar atrophy were also observed. The patient underwent gastrostomy 7 years after the onset of her symptoms and died at the age of 70 years. Neuropathological examination showed diffuse neuron loss with gliosis and tissue rarefaction in the frontotemporal lobe, particularly in the right anterior portion of the frontal lobe. Spongiform changes and ballooned neurons were also observed in the frontotemporal cortex, particularly in the superficial layer and deeper layers, respectively. Gallyas‐Braak silver staining and anti‐phosphorylated tau immunostaining indicated numerous argyrophilic and tau‐positive structures, including pretangles, astrocytic plaques, coiled bodies and neuropil threads. We speculate that the myoclonus observed in the present case was at least partly caused by or related to the spongiform change and ballooned neurons in the cerebral cortex. The clinical phenotypes of corticobasal degeneration (CBD) vary considerably, and the clinical presentation of the present patient was compatible with frontal behavioral‐spatial syndrome in the early disease stage. However, in the later disease stages, her symptoms were reflective of corticobasal syndrome. Because it is not rare for the clinical phenotype to change along with disease progression in cases of CBD, we should consider CBD in cases presenting with FTD at symptom onset.     

Clinical features of corticobasal degeneration

Coritcobasal degeneratin (CBD) has various neurological findings, such as cortical sign, parkinsonism, supranuclear palsy, myoclonus, and dementia. This disease used to be rare, but 20 years later, many case have been reported. Corticobasal degeneration is investigated from a wide range of specific analyses. It presents with a clinical resemblance to progressive supranuclear palsy (PSP) and it is important to determine whether CBD and PSP are the same entity. I will attempt to review the difference and similarities between PSP and CBD from a clinical standpoint.     

Chameleons and mimics: Progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that show parkinsonism as their main symptom. Both PSP and CBD are sporadic tauopathies associated with hyperphosphorylated four-repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and the appearance of tufted astrocytes and globose-type neurofibrillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar dentate nuclei. Conversely, the characteristic pathologies of CBD are cortical atrophy and the appearance of astrocytic plaques and argyrophilic threads. CBD is associated with severe degeneration in the cerebral white matter, substantia nigra, and globus pallidus. Clinical symptoms depend on the topographical distribution and severity of degeneration rather than on the type of aggregated protein or inclusions. PSP and CBD present clinically differential diagnostic difficulties because of their overlapping pathological distributions.     

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     

Phosphorylated c-MYC expression in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration.

Phosphorylated c-Myc (c-Myc-P) expression has been examined by immunohistochemistry, using an antibody that recognizes phosphorylated c-Myc at Thr58 and Ser62, in the brains of Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and age-matched control cases, as well as in human medulloblastomas and central neuroblastomas. Strong c-Myc-P immunoreactivity was seen in dystrophic neurites and neurones with neurofibrillary tangles in AD, and in neurones and glial cells bearing abnormal tau deposits in PiD, PSP and CBD. Previous studies have shown active Ras and increased mitogen-activated protein kinase (MAPK/ERK) expression in neurones and glial cells with abnormal tau deposition in AD and other tauopathies. Since MAPKs phosphorylate c-Myc at Thr58 and Ser62, these observations implicate the Ras/MAP kinase pathway in c-Myc phosphorylation and accumulation in AD and other tauopathies. Previous studies have also shown activation of cell cycle associated proteins in neuronal death. The present results have shown colocalization of nuclear c-Myc-P and active, cleaved caspase-3, a major executioner of apoptosis, in medulloblastomas and central neuroblastomas, thus suggesting phosphorylated c-Myc expression in caspase-3-dependent apoptosis of tumour cells. However, no evidence of caspase-3 activation has been observed in neurones and glial cells with strong phosphorylated c-Myc immunoreactivity in AD, PiD, PSP and CBD. Therefore, it is not clear that the activation of the Ras/MAPK/c-Myc subprogramme leads to neuronal death in AD and other tauopathies.     

Apraxia of eyelid opening in a case of atypical corticobasal degeneration

Summary. Apraxia of eyelid opening (AEO) occurs in several clinical conditions, even in the absence of any other neurological sign; nonetheless, in most of the cases AEO has been reported in association with basal ganglia diseases, such as corticobasal degeneration (CBD). We describe a patient with a clinical diagnosis of frontotemporal dementia who, later, developed parkinsonian signs and AEO. We suggest that the finding of AEO in patients with a frontotemporal syndrome could be a helpful expedient for the early diagnosis of atypical clinical findings of CBD, characterised by behavioural and cognitive aspects at first.Received March 8, 2003; accepted June 11, 2003 Published online August 13, 2003     

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.     

Frontal lobe degeneration of non-Alzheimer type

Frontal lobe degenerative dementias, the second largest degenerative dementia group after Alzheimer's disease, is dominated by frontal lobe degeneration of non-Alzheimer type. It is classified in a group also containing Pick's disease, progressive aphasia and dementia in motor neuron disease. Frontal lobe degeneration of non-Alzheimer type is clinically marked by frontal lobe symptoms and frontotemporal reduction of blood flow. From a histopathological point of view it is characterized by gliosis, microvacuolation, neuronal atrophy-loss and 40–50% loss of synapses in three superficial cortical laminae of the frontal convexity and anterior temporal cortex, while the deeper laminae are little or not changed. The structural changes of Alzheimer's disease including amyloid, Levy body dementia and Pick's disease are entirely lacking. A strong heredity points to a genetic cause as yet undefined.     

Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases

Globular glial tauopathies (GGTs) are four‐repeat tauopathies characterized by the presence of two types of tau‐positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs – a 76‐year‐old woman and a 70‐year‐old man – in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray‐white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.     

Pathological heterogeneity of clinically diagnosed corticobasal degeneration

Two patients fulfilling suggested clinical diagnostic criteria for corticobasal degeneration (CBD) are presented, who were found at postmortem to have alternative pathological diagnoses not suspected during life, namely, Alzheimer's disease and Pick's disease, respectively. The nosological position of these cases is considered in light of a literature review of previous reports of clinically diagnosed corticobasal degeneration with atypical (not corticobasal degeneration) pathology. Since such phenocopies may be common, we suggest that all clinically diagnosed cases of corticobasal degeneration should initially be labelled as "corticobasal degeneration syndrome" (CBDS) to emphasize that this is a diagnosis based on clinical phenotype, with the term corticobasal degeneration being reserved for the specific neuropathological phenotype, which itself may have a variety of clinical presentations.     

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.     

Basic pathology of corticobasal degeneration

A survey of 32 clinically and pathologically evaluated cases of corticobasal degeneration (CBD) revealed three subtypes of cortical lesions. Besides the main subgroup with frontoparietal atrophy, especially with degeneration around the central sulcus, there are at least two subtypes in which the degenerating focus shifts from the central region to the frontal or superior temporal region. Such diversity of degenerating areas of the cerebrum results in the clinical heterogeneity of CBD. In contrast to the diversity of cerebral lesions, affected nuclei in the subcortical regions are rather uniform and their distribution is of diagnostic value. Cytopathologically, CBD is characterized by several types of abnormal cytoskeletal structures in both neurons and glia. They have common epitopes with hyperphosphorylated tau except for ballooned neurons, which are regarded as a pathological hallmark of this disease. Massive Gallyas/tau-positive structures consist of neurofibrillary tangles and pre-tangles in neurons as well as astrocytic plaques, coiled bodies and argyrophilic threads in glia. A part of argyrophilic threads are proved to originate from neuronal element. There is discrepancy between poor formation of solid tangles and massive appearance of Gallyas/tau-positive structures in CBD. The former is detectable by Bodian method whereas the latter is scarcely seen by conventional silver impregnations. This indicates that almost all of Gallyas/tau-positive structures have poor inclination to form solid structures in CBD. Immunohistochemical study with an antibody to the exon 3-derived epitope of tau indicates that the majority of Gallyas/tau-positive structures in CBD originate from glial cells. Differences as well as overlaps between CBD and progressive supranuclear palsy are discussed.     

Corticobasal degeneration as cause of progressive non‐fluent aphasia: Clinical,radiological and pathological study of an autopsy case

A Japanese male developed gradual loss of spontaneous speech at age 60. Three years later meaningful speech had deteriorated to the point that it had become restricted to monotonous utterances. Neuropsychological examination at age 62 showed that he had severe non‐fluent aphasia. A brain MRI demonstrated mild cortical atrophy with ischemic lesions in the cerebral white matter. He was diagnosed as having primary progressive aphasia. At age 63, he was admitted to the hospital to reevaluate the neurological condition. Neurologic examination showed severe non‐fluent aphasia, hyperreflexia, snout and sucking reflexes. No alien hand was observed. He was able to walk, dress, wash himself and use chopsticks as well as name real objects. At age 65, ^99mTc‐hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO‐SPECT) revealed diffuse cerebral hypoperfusion that was particularly prominent in the left frontal lobe. An MRI showed progressive cortical atrophy with the definite atrophy of the left paracentral gyrus. The hippocampal formation and putamen were also atrophic. He died of pneumonia at age 67. The brain weighed 810 g with atrophy of the frontal lobe, globus pallidus, enlargement of the lateral ventricles and depigmentation of the substantia nigra. Microscopic examination showed severe neuronal loss and gliosis in the cerebral cortex, globus pallidus interna and substantia nigra. Ballooned neurons were observed in the cerebral cortex. Gallyas‐Braak method revealed numerous astrocytic plaques and argentophilic threads in the cerebrum. Clinical diagnosis of corticobasal degeneration sometimes is difficult in individuals with atypical clinical presentations. More exact clinical and radiological criteria may warrant a diagnosis of corticobasal degeneration.     

An autopsied case of unclassifiable sporadic four‐repeat tauopathy presenting with parkinsonism and speech disturbances

A 48‐year‐old Japanese woman experienced slow‐onset parkinsonism and speech disturbances. Neurological examinations revealed rigidity in the trunk and extremities, bradykinesia and postural instability, although cognitive impairments and psychiatric symptoms were not apparent in the early disease stage. Neuroimaging revealed progressive bilateral frontotemporal lobe atrophy with cerebral blood flow hypoperfusion. No apparent signs of lower motor neuron involvement were observed, such as fasciculation or electromyogram findings. She eventually reached the akinetic mutism state, and gastrostomy and tracheotomy were performed at 4 years after onset. A clinical diagnosis of progressive supranuclear palsy was made prior to her death, which occurred 6 years after onset. Post mortem examinations revealed that the brain weighed 1200 g and showed atrophy of the frontotemporal lobe and brainstem. Severe neuron loss and gliosis were observed in the frontotemporal lobe. The superior and middle frontal gyri were the most severely affected and showed spongiform changes in the superficial layer. The globus pallidus, subthalamic nucleus, cerebellar dentate nucleus, substantia nigra and inferior olivary nucleus also showed neuronal loss with gliosis. Using hyperphosphorylated tau (AT‐8) immunostaining, pretangle‐like neurons, numerous short threads and glial tau pathology were extensively observed. Using Gallyas?Braak silver staining, thin and short threads were also extensively observed, but considerably fewer than those observed by AT‐8 immunostaining. Neither astrocytic plaques nor tuft‐shaped astrocytes were observed. Examination by immunoelectron microscopy showed straight fibrils approximately 15 nm in diameter in the neuronal cytoplasmic inclusions in the cerebral cortex and in the fibrillary structures in the cerebral white matter. Western blot analysis of sarkosyl‐insoluble tau revealed predominantly four‐repeat tau and a banding pattern similar to that seen in progressive supranuclear palsy. No pathogenic mutations were found during the gene analysis of microtubule‐associated protein tau. After completing our comprehensive investigation, we diagnosed this patient with unclassifiable four‐repeat tauopathy.