An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years.

The patient was a 72-year-old Japanese woman. At the age of 57, she started having difficulty performing daily work and developed agraphia. She also exhibited restlessness and loss of interest, and began to speak less. Thereafter, stereotypical behavior, gait disturbance and dysphagia were noted. CT scan demonstrated left-dominant frontal and temporal lobe atrophy. She died at the age of 72, about 16 years after the onset of symptoms. Neuropathologically, the brain weighed 867 g, and showed remarkable cerebral atrophy with degeneration of the white matter, predominantly in the left dorsal frontal lobe and anterior temporal lobe. Microscopically, severe neuronal loss and gliosis with rarefaction were found in the cerebral cortex, and severe destruction of myelin and axons was observed in the cerebral white matter. Moderate neuronal loss with gliosis was also found in the pallidum and substantia nigra. Gallyas-Braak staining and tau immunostaining revealed pretangle neurons, NFTs, ballooned neurons and astrocytic plaques in the cerebral cortex, subcortical nuclei and brainstem, and argyrophilic threads and coiled bodies in the subcortical white matter. Tau isoform-specific immunostaining revealed that most tau-immunoreactive structures were positive for 4-repeat (4R) tau, but some of the NFTs were positive for 3-repeat (3R) tau in the cerebral neocortex. Immunoblotting demonstrated an accumulation of 4R tau in the cerebral cortex and subcortical white matter. The patient was pathologically diagnosed as having corticobasal degeneration. Her long survival course likely accounts for the severe white matter degeneration and accumulation of 3R tau in NFTs.

Neuropathological investigation of regions responsible for semantic aphasia in frontotemporal lobar degeneration.

BACKGROUND/AIMS: Semantic dementia is a subtype of frontotemporal lobar degeneration, of which an initial symptom is semantic aphasia. Semantic dementia pathologically corresponds to atypical Pick's disease (aPiD), showing ubiq- uitin-positive inclusions similar to those in dementia with motor neuron disease (D-MND). Previous studies have not clarified the regions responsible for semantic aphasia in aPiD, and there have been no reported neuropathological studies concerning its pathomechanism. METHODS: We neuropathologically investigated aPiD and D-MND cases with and without semantic aphasia. RESULTS: We determined that the regions involved in the early stage of the disease course of semantic dementia were more restricted to the anterior and inferior portion of the temporal lobe on the side of the dominant hemisphere. CONCLUSION: Degeneration of the temporal pole is most likely to participate in the pathomechanism of SA in semantic dementia.

Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies.

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.

Appearance pattern of TDP-43 in Japanese frontotemporal lobar degeneration with ubiquitin-positive inclusions.

TAR-DNA-binding protein 43 (TDP-43) was identified as a major component of ubiquitin-positive intracellular inclusions from brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Here, we immunohistochemically investigated the appearance pattern of TDP-43 to compare the distribution of TDP-43-positive structures with that of ubiquitin-positive structures in brains of seven patients with Japanese FTLD-U, five of atypical Pick's disease (aPiD) and two of dementia with motor neuron disease (D-MND), as well as two patients with PiD as control. TDP-43-immunoreactivity generally colocalized to ubiquitin-immunoreactivity in both neuronal cytoplasmic inclusions and neurites in FTLD-U brains, but TDP-43-immunoreactivity alone or ubiquitin-immunoreactivity alone was also observed. In five aPiD cases, double-immunostaining with TDP-43 and ubiquitin demonstrated that diffuse neuronal cytoplasmic immunostaining for ubiquitin did not always display TDP-43-immunoreactivity. In contrast, ubiquitin-positive neuronal cytoplasmic inclusions usually displayed TDP-43-immunoreactivity in two D-MND cases, although most glial inclusions in one of two cases were immunostained only for TDP-43. TDP-43-positive structures were not detected in two PiD cases. Thus, the ratio in the appearance pattern of TDP-43 and ubiquitin was different between aPiD and D-MND, leading to the hypothesis that this difference may be associated with the two pathogenic variants related to clinical and pathological heterogeneity in FTLD-U.

[Clinico-pathological investigation of two patients with dementia with motor neuron disease].

Dementia with motor neuron disease (D-MND) is characterized clinically by frontal and neurological signs, and pathologically by localized atrophy of the fronto-temporal lobes and neuronal ubiquitin(Ub)-positive inclusions. In this study, we compared the clinico-pathological findings of two patients with D-MND. Case 1 (55-year-old male): At the age of 51, he developed personality change and disinhibition, lacking neurological signs. Brain MRI exhibited localized atrophy of the frontal lobes. At the age of 54, he showed dysphagia and died after a disease duration of 4 years. Neuropathologically, the cerebrum showed localized atrophy of the dorsal area of the frontal lobes. The atrophied cerebral cortex demonstrated moderate neuronal loss with spongy change and gliosis in the superficial layers. The brainstem and spinal cord revealed moderate neuronal loss in the substantia nigra, severe neuronal loss with Bunina bodies in the hypoglossal nucleus, and moderate neuronal loss in the cervical anterior horn. There were some Ub-positive neuronal inclusions in the atrophied cortex and many in the dentate gyrus. Case 2 (68-year-old female): At the age of 64, she developed personality change, and then gait disturbance and dysarthria. Brain MRI exhibited localized atrophy of the fronto-temporal lobes. At the age of 67, she showed dysphagia with Babinski signs and died after a disease duration of 4 years. Neuropathologically, the cerebrum showed localized atrophy of the basal area of the temporal lobes, especially on the right side. The atrophied cerebral cortex demonstrated moderated neuronal loss with spongy change and gliosis in the superficial layers. The pre-central cortex revealed severe loss of Betz cells. The brainstem and spinal cord showed mild neuronal loss without Bunina bodies in the hypoglossal nucleus and cervical anterior horn, accompanied by severe degeneration of the bilateral pyramidal tracts. There were many Ub-positive neuronal inclusions with a few neurites in the atrophied cortex and some in the dentate gyrus. Cases 1 and 2 were clinically diagnosed as Pick's disease (PiD) and D-MND, respectively, although pathological diagnoses were both D-MND. Case 1 showed neuropathological findings typical to D-MND, whereas case 2 showed neuropathological findings common to atypical Pick's disease (aPiD). D-MND and aPiD are should be clinico-pathologically differentiated, although they are included in the frontotemporal lobar degeneration with motor neuron disease-type inclusions.