Takashi Haraguchi

Lead content of brain tissue in diffuse neurofibrillary tangles with calcification (DNTC): the possibility of lead neurotoxicity.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of presenile dementia, characterized pathologically by fronto-temporal atrophy with neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification, in which no senile plaques are observed. As already noted, chronic exposure to lead (Pb) might be one of the etiological factors of Fahr-type calcification. Until now, there have been no reports in which Pb concentration has been quantified in DNTC brains. We examined the concentration of Pb in fresh-frozen brain tissue and in 10% formalin-fixed brain tissue from six cases of DNTC, four cases of Alzheimers disease, and in nine non-demented elderly controls by flameless atomic absorption spectrometry, and demonstrated a high concentration of Pb in DNTC brains. Although it remains unclear how these findings are related to the formation of NFTs, they suggest that Pb neurotoxicity may be involved in the pathogenesis of DNTC.

Coexistence of Creutzfeldt-Jakob disease, Lewy body disease, and Alzheimer's disease pathology : An autopsy case showing typical clinical features of Creutzfeldt-Jakob disease

We report here an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) without hereditary burden and with a clinical course typical of sporadic CJD. A 77‐year old man developed memory disturbance, followed by gait disturbance and myoclonus. He died of bronchopneumonia 5 months after the disease onset. Post‐mortem examination revealed neuronal loss, astrocytosis, and patchy spongiosis in the cerebral cortex and lenticular nuclei. Synaptic‐type deposits of prion protein were present in the cerebral cortex. Additionally, Lewy bodies were observed in the cerebral cortex and substantia nigra. Furthermore, senile plaques compatible with definite Alzheimers disease according to Consortium to Establish a Registry for Alzheimers disease criteria and neurofibrillary changes of the limbic system consistent with Braak stage IV were found. Based on a review of the published literature, this autopsy case is very rare, and we suppose that the incidence of CJD accompanied by Lewy body disease and Alzheimers disease is very low.

Tau pathology in diffuse neurofibrillary tangles with calcification (DNTC): Biochemical and immunohistochemical investigation

Diffuse neurofibrillary tangles with calcification (DNTC) represents a primary and sporadic presenile dementia that is characterized by temporal or fronto-temporal atrophy with diffuse neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification without senile plaques. We examined the tau pathology in five autopsy cases of DNTC by immunoblotting and immunohistochemistry using phosphorylation-dependent and -independent anti-tau antibodies. The pattern of staining for different epitopes of β-amyloid (Aβ) was also investigated. NFTs were immunopositive with all the anti-tau antibodies used in this study. On the immunoblots, sarkosyl-insoluble tau appeared as three major bands of 60, 64 and 68 kDa, and as a minor band at 72 kDa. The majority of extracellular NFTs were weakly immunopositive only with the antibody recognizing the 40 carboxyl-terminal of Aβ in DNTC. These results suggest that Alzheimers disease-like tau pathology could exist independently of Aβ deposits in DNTC.

An autopsy case of postencephalitic parkinsonism of von Economo type: Some new observations concerning neurofibrillary tangles and astrocytic tangles

An autopsied case of postencephalitic parkinsonism of von Economo type with a 71‐year duration is reported. Several cases of postencephalitic parkinsonism of von Economo type have been reported in Japan but this is the first reported case from western Japan. The patient was a Japanese man who was 74 years of age at the time of death. He developed encephalitis of unknown etiology at the age of 3 years. The first symptom was antisocial behavior, which developed at 30 years of age. At the age of 40 years, the patient showed progressive parkinsonism. Neuropathological findings disclosed marked neuronal loss with gliosis in the substantia nigra, locus ceruleus, and raphe nuclei, as well as the appearance of neurofibrillary tangles in the aforementioned areas. There were also widespread tuft‐shaped astrocytes (Tu‐SA) in the central nervous system, including the thalamus. Tuft‐shaped astrocytes are considered to represent non‐reactive astrocytes because the distributions of neurofibrillary tangles (NFT) and Tu‐SA are clearly different. Therefore, the primary astrocytic lesions in postencephalitic parkinsonism of von Economo type may be more widespread. Ultrastructurally, the Tu‐SA consisted of straight filaments, 15 nm in width, which formed tight bundles. Ultrastructurally, NFT in this case revealed paired helical filaments but straight filaments, 15 nm in width, which were also found in the neurons of the substantia nigra.

Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia.

We report an autopsy case of progressive supranuclear palsy (PSP) that clinically showed only slowly progressive and symmetric upper motor neuron syndrome over a disease course of 12 years. A female patient initially exhibited dysarthria at the age of 65, followed by gait disturbance and dysphagia. Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs. However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course. She was clinically diagnosed as having motor neuron disease consistent with so-called primary lateral sclerosis. Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a lesser degree, in the basal ganglia and brain stem nuclei. In addition, severe fibrillary gliosis was noted in the precentral gyrus and corticospinal tract, being consistent with upper motor neuron syndrome observed in this case. No TAR-DNA binding protein 43-positive lesion, FUS pathology, Bunina body, or Lewy body-like hyaline inclusion was noted in the motor cortex or lower motor neurons. These findings suggest that when tau pathology is prominent in the motor cortex but is minimal in the basal ganglia and brain stem nuclei, a PSP case can lack all classic clinical features of PSP and show only slowly progressive upper motor syndrome, consistent with clinical picture of primary lateral sclerosis.

Tau-negative astrocytic star-like inclusions and coiled bodies in dementia with Lewy bodies.

Abstract To evaluate glial lesions in cases of dementia with Lewy bodies (DLB), we studied the brains of four patients with DLB. Astrocytic star-like inclusions, which resembled tufted astrocytic fibrillary tangles in shape, were found in the cortex of two of these cases. In addition, coiled bodies were found in the white matter of the cerebrum in two cases. The astrocytic star-like inclusions were immunohistochemically negative for tau protein, ubiquitin and α-synuclein. The coiled bodies were immunohistochemically negative for tau protein but immunopositive for ubiquitin and α-synuclein. These results suggest that in DLB a primary degenerative process takes place in both glial cells and neurons.

Diffuse neurofibrillary tangles with calcification (a form of dementia): X-ray spectrometric evidence of lead accumulation in calcified regions.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of slowly progressive dementia in which no senile plaques are observed. The calcification is one of the most characteristic features of DNTC. We examined the elemental content of certain mineral deposits (lead, magnesium, phosphorus, calcium, iron, copper and zinc) in the calcified and non-calcified regions of eight cases of DNTC, five cases of Alzheimers disease (AD) and in eight non-demented elderly controls. The study was performed using a combination of scanning electron microscopy and X-ray spectrometry on 10% formalin-fixed brain tissue. A marked abundance of calcium and phosphorus was observed in the calcified regions of DNTC and non-DNTC brains. Although no lead was observed in the non-calcified regions of DNTC and in non-DNTC brains, traces of lead were detected exclusively in the calcified regions of DNTC brains. The implications and possible significance of the lead accumulation in DNTC brains are discussed.

Coexistence of TDP‐43 and tau pathology in neurodegeneration with brain iron accumulation type 1 (NBIA‐1, formerly Hallervorden‐Spatz syndrome)

We report here an autopsy case of sporadic adult‐onset Hallervorden‐Spatz syndrome, also known as neurodegeneration with brain iron accumulation type 1 (NBIA1), without hereditary burden. A 49‐year‐old woman died after a 27‐year disease course. At the age of 22, she suffered from akinesia, resting tremor, and rigidity. At the age of 28, she was admitted to our hospital because of worsening parkinsonism and dementia. Within several years, she developed akinetic mutism. At the age of 49, she died of bleeding from a tracheostomy. Autopsy revealed a severely atrophic brain weighing 460 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids in the subthalamic nuclei. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia, and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which are immunolabeled by anti‐α‐synuclein, were absent. We also observed the presence of TDP‐43‐positive neuronal perinuclear cytoplasmic inclusions, with variable frequency in the dentate gyrus granular cells, frontal and temporal cortices, and basal ganglia. TDP‐43‐positive glial cytoplasmic inclusions were also found with variable frequency in the frontal and temporal lobes and basal ganglia. The present case was diagnosed with adult‐onset NBIA‐1 with typical histological findings in the basal ganglia and brainstem. However, in this case, tau and TDP‐43 pathology was exceedingly more abundant than α‐synuclein pathology. This case contributes to the increasing evidence for the heterogeneity of NBIA‐1.

Diffuse Neurofibrillary Tangles with Calcification

Diffuse neurofibrillary tangles with calcification (DNTC) is a primary and sporadic presenile dementia that is characterized by temporal and/or frontal atrophy with diffuse neurofibrillary tangles (NFTs) and Fahr-type calcification without senile plaques (SPs).

Frontotemporal dementia: Pick type

The status of Picks disease within the concept of frontotemporal dementia (FTD) is unclear. Some researchers have defined Picks disease as FTD with Pick bodies. Alternatively, the confusion may be clarified by using the term Pick body dementia (PBD) rather than by using the term Picks disease in a narrow sense. Pick body dementia is characterized by a prominent frontotemporal lobar atrophy, gliosis, severe neuronal loss, ballooned neurons, and the presence of neuronal inclusions called Pick bodies. In recent years, studies of Pick body dementia have advanced from the standpoint of the tau pathology. Tau‐positive glial inclusions as well as neuronal inclusions have been observed in PBD and its related disorders. Various forms of FTD have been proposed based on the presence of neuronal or glial inclusions. We propose a new variant of FTD termed ‘glial tangle‐predominant type’. More research is required to understand the tau abnormalities in the various forms of FTD.