Argyrophilic grain disease presenting with frontotemporal dementia: A neuropsychological and pathological study of an autopsied case with presenile onset

A right‐handed Japanese man with no consanguinity exhibited personality changes, speech disorder and abnormal behaviors, such as stereotypical, running‐away, environment‐dependent, and going‐my‐way behaviors, since the age of 49 years. At age 52 years, neuropsychological examination revealed frontal lobe dysfunctions, mild memory impairment, and transcortical sensory aphasia. MRI showed symmetrical severe atrophy of the anterior part of the temporal and frontal lobes. The clinical diagnosis was FTD. He died at age 54 years after a clinical illness of approximately 5 years. Numerous argyrophilic grains were observed throughout the limbic system, temporal lobe, frontal lobe and brainstem. In addition, there were many tau‐positive neurons and glial cells. These findings are all compatible with argyrophilic grain disease (AGD). Our case, however, is atypical AGD because of the young age of onset of the disease and sharply circumscribed cortical atrophy exhibiting severe neuronal loss and gliosis. Our case, together with some other similar cases of atypical AGD, gives rise to the possibility that this type of AGD would constitute a part of pathological background of FTD.     

Ubiquitin and ubiquitin‐related proteins in the brains of patients with atypical Pick's disease without Pick bodies and dementia with motor neuron disease

Nine cases of atypical Pick's disease without Pick bodies (aPiD) and seven cases of dementia with motor neuron diseases (D‐MND) were compared using immunohistochemistry of ubiquitin (ub) and ub‐related proteins. All cases showed rostral‐dominant atrophy in the temporal and frontal lobes, although the degree of atrophy with neuronal loss was much more severe in the aPiD cases. In both aPiD and D‐MND cases, ub‐positive and tau‐negative structures were found mainly in the hippocampal dentate gyrus and cerebral cortex. Granular cells of the dentate gyrus showed similar ub‐positive intraneuronal inclusions in both cases. In the aPiD cases, most of the ub‐positive cortical structures were ub‐positive dendrites in layers II‐IIIab and layers V‐VI, although some neurons also showed diffuse ub‐positive staining in the cytoplasm. In the D‐MND cases, some neurons showed ub‐positive inclusions in layers II‐IIIab, and ub‐positive dendrites were unremarkable. The number of ub‐positive neurons and dendrites in relation to the degree of neuronal loss in the cerebral cortex were then evaluated. The number of ub‐positive neurons in the regions showing very mild to mild neuronal loss was significantly greater in the D‐MND cases than in the aPiD cases. However, in the aPiD cases, the number of ub‐positive neurons was significantly greater in the regions showing moderate neuronal loss. When double‐immunostained, almost all ub‐positive structures were positive for ub‐binding protein p62. Some ub‐positive or negative neurons in the cerebral cortex were immunostained with anti‐ub ligase (Parkin) and anti‐ub C‐terminal hydrolase (UCH‐L1) antibodies. Granular cells of the dentate gyrus were weakly positive for UCH‐L1. There could be some differences in the mechanism by which neurons in the cerebral cortex accumulate ub between aPiD and D‐MND.     

Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis

K. Soma, Y.‐J. Fu, K. Wakabayashi, O. Onodera, A. Kakita and H. Takahashi (2012) Neuropathology and Applied Neurobiology 38, 54–60 Co‐occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis Aims: Phosphorylated TDP‐43 (pTDP‐43) is the pathological protein responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Recently, it has been reported that accumulation of pTDP‐43 can occur in the brains of patients with argyrophilic grain disease (AGD), in which phosphorylated 4‐repeat tau is the pathological protein. To elucidate the association of ALS with AGD, we examined the brains from 37 consecutively autopsied patients with sporadic ALS (age range 45–84 years, mean 71.5 ± 9.0 years). Methods: Sections from the frontotemporal lobe were stained with the Gallyas‐Braak method and also immunostained with antibodies against phosphorylated tau, 4‐repeat tau and pTDP‐43. Results: Fourteen (38%) of the 37 ALS patients were found to have AGD. With regard to staging, 5 of these 14 cases were rated as I, 4 as II and 5 as III. pTDP‐43 immunohistochemistry revealed the presence of positive neuronal and glial cytoplasmic inclusions in the affected medial temporal lobe in many cases (93% and 64%, respectively). On the other hand, pTDP‐43‐positive small structures corresponding to argyrophilic grains were observed only in one case. A significant correlation was found between AGD and the Braak stage for neurofibrillary pathology (stage range 0–V, mean 2.1). However, there were no significant correlations between AGD and any other clinicopathological features, including dementia. Conclusions: The present findings suggest that co‐occurrence of AGD in ALS is not uncommon, and in fact comparable with that in a number of diseases belonging to the tauopathies or α‐synucleinopathies.     

Sporadic amyotrophic lateral sclerosis with circumscribed temporal atrophy: A report of an autopsy case without dementia and with ubiquitinated intraneuronal inclusions

This report concerns an autopsy case of amyotrophic lateral sclerosis (ALS) with circumscribed temporal atrophy. The patient was a Japanese woman without hereditary burden who was 71‐year‐old at the time of death. She developed dysarthria and gait disturbance at age 69, followed by dysphagia. A neurological examination about 1 year 11 months after the onset of the disease revealed absence of character change and of dementia. Neuroradiological examination disclosed circumscribed atrophy of the anterior part of the right temporal lobe. The patient died of respiratory failure 2 years after the disease onset. No respirator administration was performed throughout the clinical course. Macroscopically, neuropathological examination showed circumscribed atrophy of the right first temporal gyrus. Histologically, there was neuronal loss in the cerebral cortex, including the first temporal gyrus, the parahippocampal gyrus, subiculum, amygdala, substantia nigra, brain stem motor nuclei, and anterior horns of the spinal cord, in addition to loss of Betz cells, obvious degeneration of the pyramidal tracts, and the presence of Bunina bodies. Ubiquitin‐immunoreactive intraneuronal inclusions were present in the hippocampal dentate granular cells, frontotemporal cortical layer II neurons, and motor neurons in the brain stem and spinal cord. Based on these clinicopathological findings and a review of the literature, we concluded that our case was atypical ALS without dementia, showing temporal lobe atrophy macroscopically, in addition to pathological hallmarks compatible with ALS with dementia. We also note the possibility that there is a forme fruste of ALS with dementia showing no overt dementia clinically.     

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.     

Pick’s disease with Pick bodies combined with progressive supranuclear palsy without tuft‐shaped astrocytes: A clinical,neuroradiologic and pathological study of an autopsied case

We report clinical, neuroradiologic features, and neuropathologic findings of a 76‐year‐old man with coexistent Pick’s disease and progressive supranuclear palsy. The patient presented with loss of recent memory, abnormal behavior and change in personality at the age of 60. The symptoms were progressive. Three years later, repetitive or compulsive behavior became prominent. About 9 years after onset, he had difficulty moving and became bed‐ridden because of a fracture of his left leg. His condition gradually deteriorated and he developed mutism and became vegetative. The patient died from pneumonia 16 years after the onset of symptoms. Serial MRI scans showed progressive cortex atrophy, especially in the bilateral frontal and temporal lobes. Macroscopic inspection showed severe atrophy of the whole brain, including cerebrum, brainstem and cerebellum. Microscopic observations showed extensive superficial spongiosis and severe neuronal loss with gliosis in the second and third cortical layers in the frontal, temporal and parietal cortex. There were Pick cells and argyrophilic Pick bodies, which were tau‐ and ubiquitin‐positive in neurons of layers II–III of the above‐mentioned cortex. Numerous argyrophilic Pick bodies were observed in the hippocampus, especially in the dentate fascia. In addition, moderate to severe loss of neurons was found with gliosis and a lot of Gallyas/tau‐positive globus neurofibrillary tangles in the caudate nucleus, globus pallidus, thalamus, substantia nigra, locus coeruleus and dentate nucleus. Numerous thorned‐astrocytes and coiled bodies but no‐tuft shaped astrocytes were noted in the basal ganglion, brainstem and cerebellar white matter. In conclusion, these histopathological features were compatible with classical Pick’s disease and coexistence with progressive supranuclear palsy without tuft‐shaped astrocytes.     

Amyotrophic lateral sclerosis with dementia: The clinicopathological spectrum

Amyotrophic lateral sclerosis with dementia (ALS‐D) is a non‐Alzheimer‐type dementia characterized by both frontotemporal degeneration and motor neuron disease and marked by ubiquitin‐positive, tau‐ and α‐synuclein‐negative intraneuronal inclusions and dystrophic neurites. New neuropathological diagnostic criteria for ALS‐D are proposed on the basis of the present investigation of 28 autopsy cases. Clinical features included those of typical ALS‐D, primary lateral sclerosis, atypical ALS with frontotemporal atrophy and atypical Pick's disease without Pick's bodies. Macroscopically anterior frontotemporal atrophy was observed involving or not involving the precentral gyrus. Microscopically non‐specific neuronal loss and gliosis with spongiosis were seen, particularly in superficial layers II and III of the frontotemporal cortices. Diffuse fibrous gliosis was seen in the frontotemporal white matter. The substantia nigra and amygdala showed neuronal loss and gliosis. In all 28 cases, degeneration of both the lower and upper motor neuron systems, consistent with classic sporadic ALS, was present. The distribution and degree of degenerative frontotemporal lesions and motor neuron disturbance were of various patterns. Ubiquitin‐positive and tau‐ and α‐synuclein negative intraneuronal inclusions and dystrophic neurites in extramotor cortices were observed in all cases. Furthermore, ubiquitin‐positive inclusions in lower motor neurons were found in all cases. The distribution pattern and density differed between neuronal inclusions and dystrophic neurites and correlated with clinicopathological phenotypes. Therefore, the ALS‐D spectrum may be broader than that previously recognized, extending to primary lateral sclerosis, atypical ALS and to atypical Pick's disease without Pick bodies. Further investigation is needed to determine the characteristics of the ubiquitinated component in ALS‐D.     

Frontotemporal and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS

We present the case of a patient who had clinical frontal lobe dementia without apparent motor neurone disease (MND), with pathologic findings not typical of any single currently classified frontotemporal degeneration (FTD). At autopsy, the brain had frontal and temporal atrophy with neuronal loss, gliosis, and superficial spongiosis, typical of all FTDs. There were at least three different morphologic types of intracytoplasmic neuronal inclusions in a variety of brain and brainstem regions, including the hippocampal dentate gyrus and pyramidal neurones, the neocortex (in particular, the motor cortex), basal ganglia, thalamus, subthalamic nucleus, basis pontis, and inferior olivary nuclei. Inclusions had the morphologies of Pick-like bodies, pleomorphic inclusions, and hyaline conglomerate (HC)-like inclusions. None of these were positive with tau immunostains. Pick-like bodies in the dentate gyrus were labelled with ubiquitin. The pleomorphic inclusions in the neocortex and dentate gyrus and the HC-like inclusions in the motor and parietal cortex were strongly positive with immunostains for neurofilament. We discuss the differential diagnosis and compare this case with those disorders to which it is most similar. In particular, we compare the unique neurofilament-positive inclusions to the inclusions of FTD-MND, to Pick bodies, and to the basophilic and HC inclusions that are occasionally seen in amytrophic lateral sclerosis (ALS). Although FTD-MND may be found in ALS, the findings in this case may have additional implications for a link between FTD and ALS.     

Severe involvement of the ambient gyrus in a case of dementia with argyrophilic grain disease

We report here the severe involvement of the ambient gyrus in a case of argyrophilic grain (AG) dementia (AGD). The patient was a 78-year-old man who was first presented with prosopagnosia (agnosia of the face) at age 68, which was followed by progressive mental decline and the patient's death in a state of tetraplegia. The postmortem study showed severe atrophy of the medial temporal lobe with anterior gradient, most prominent in the ambient gyrus. Histologically, numerous AGs, pretangles and coiled bodies were detected by Gallyas-Braak (G-B) silver staining and also by immunostaining with various anti-tau antibodies in the affected area. Tau-immunoreactive ballooned neurons were also present. Neuronal loss and gliosis with laminar sponginess were evident in the ambient gyrus. Diffuse plaques were seen in the neocortex and frequently associated with clusters of AGs, which were morphologically distinct from neuritic plaques. Neurofibrillary tangles were localized in the entorhinal area. Vascular lesions were very scanty. Thus, this case fulfilled the morphological criteria of AGD.It is still unclear whether AG itself causes neuronal degeneration leading to dementia. The present case may reflect the importance of the ambient gyrus in the center of neuronal degeneration in AGD.     

Autopsy findings in the early stage of amyotrophic lateral sclerosis with “dropped head” syndrome

Dropped head syndrome (DHS) has been rarely observed in amyotrophic lateral sclerosis (ALS), and the neuropathological findings of this condition have almost never been described. The identification of transactivation response DNA‐binding protein 43 kDa (TDP‐43), which binds to RNA/DNA has provided a new method for studying ALS and frontotemporal lobar degeneration (FTLD). Post‐mortem examination of an adult sudden death case of a 71‐year‐old patient who complained of DHS exhibited severe loss of anterior motor neurons in the cervical cord (C4‐6). Loss of nerve fibers of the anterior roots was striking compared with posterior roots, together with marked neurogenic atrophy of posterior muscles semispinalis cervicis. Bunina bodies were found in large neurons of Betz giant cells, but not in the motor neurons of spinal cords, or neurons of bulbar regions. Phosphorylated TDP‐43 (p‐TDP‐43)‐positive structures were detected in the residual neurons of the cervical, thoracic and lumber cords, hypoglossal nucleus, cerebellar dentate nucleus and parahippocampal cortex, together with ubiquitin‐positive inclusions. Phosphorylated Tau positive structures in neuronal cytoplasm were found in the amygdala, entorhinal cortex and parahippocampal cortex, some of which co‐expressed p‐TDP‐43. The medial zone of cervical cords may be the first onset site, and that is the cause of head drop in the early stage of ALS. In spite of detailed examination, the direct cause of sudden death was not verified. This autopsy report revealed the relation of DHS which is a rare clinical manifestation of ALS, and neuropathological findings.     

An autopsy case of neuronal intermediate filament inclusion disease with regard to immunophenotypic and topographical analysis of the neuronal inclusions

We report an autopsy case of neuronal intermediate filament inclusion disease (NIFID), in which pyramidal motor dysfunction preceded cognitive disturbance for 3 years from the onset. A 41‐year‐old Japanese man presented progressive spastic tetraparesis followed by cognitive impairment. His neurological symptoms gradually deteriorated and he died of pneumonia 16 years from the onset. His brain showed severe generalized atrophy with enlargement of ventricles. The microscopic examination revealed severe neuronal loss with gliosis and sponginess predominantly in the fronto‐temporal cortices, caudate and putamen. Many hyaline conglomerate inclusions (HC) without immunoreactivity for ‘fused in sarcoma’ protein (FUS) and some granular and small round FUS‐immunoreactive (FUS‐ir) neuronal cytoplasmic inclusions (NCI) were observed in the remaining neurons. Some neurons with HC had small basophilic inclusions which showed positive FUS‐ir, attached to HC in the cytoplasm. Otherwise, FUS‐ir large compact inclusions (so‐called Pick‐like) were also observed but were scarce. In the cerebral cortex and the neostriatum, frequency of the inclusions was well correlated with neuronal loss. In the brainstem, neuronal loss was mild and FUS‐ir inclusions dominated. In the subthalamic nucleus and red nucleus, there was no HC but there were many FUS‐ir inclusions without neuronal loss. The above findings suggest that cytoplasmic mislocalization and aggregation of FUS appear at the early stage of the disease, and the FUS aggregate process may not be a direct precedent structure of HC.     

“Forme fruste” of amyotrophic lateral sclerosis with dementia: A report of five autopsy cases without dementia and with ubiquitinated intraneuronal inclusions

We clinicopathologically investigated five autopsy cases of ALS without dementia and with ubiquitinated intraneuronal inclusions. The age at onset of symptoms ranged from 52 to 81 years and the duration of the disease was from 10 months to 3 years, 3 months. All five patients initially developed lower motor neuron signs, including bulbar signs, and upper motor neuron signs were found in the middle to late clinical stages, but dementia was not observed in all five cases. Thus, the clinical diagnoses of all five patients were ALS without dementia. Neuropathological examination of all five cases revealed not only obvious degeneration of upper motor neurons with neuronal loss of Betz cells, but also lower motor neuron involvement associated with Bunina bodies. In addition, ubiquitin‐immunoreactive intraneuronal inclusions in the hippocampal dentate granular cells and degeneration of the substantia nigra were observed in all five cases. Furthermore, neuronal loss with astrocytosis in the dorsomedial portion of the anterior first temporal gyrus was observed in all three cases in which this structure was examined. Neuronal loss with astrocytosis in the subiculum was found in four cases. Neuronal loss of the parahippocampal gyrus was observed in three of the five autopsy cases, and amygdala involvement was encountered in three of four cases in which this structure was investigated. Based on these clinicopathological findings and a review of the published literature, we concluded that our five cases were ALS without dementia, but with pathological hallmarks compatible with ALS with dementia. We also concluded that there is a “forme fruste” of ALS with dementia showing no overt dementia clinically.     

Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia)

Frontotemporal dementia (FTD) with motor neuron disease means amyotrophic lateral sclerosis (ALS) with dementia. In the cerebrum of this condition, the medial cortex of the rostral temporal lobe is constantly and most remarkably involved. Another constant and quite characteristic lesion is neuronal loss localized to the CA1‐subiculum transitional area at the level of the pes hippocampi. The rostral portion of the parahippocampal gyrus, and the amygdaloid nucleus are also involved. Ubiquitinated intracytoplasmic inclusions are seen in the dentate granule cells and parahippocampal gyrus neurons. Some cases of ALS without dementia show the identical temporal lobe degeneration as well as the cortical ubiquitinated inclusions, thus raising the possibility of overlooked dementia or premature death of the patients. Similarly, recently proposed motor neuron disease‐inclusion dementia may be a forme fruste of ALS with dementia.     

Ubiquitin and ubiquitin‐related proteins in neurons and dendrites of brains of atypical Pick's disease without Pick bodies

Nine cases of atypical Pick's disease without Pick bodies were investigated immunohistochemically. Ubiquitin (ub)‐positive and tau‐negative structures were mainly found in the cerebral cortex and hippocampal dentate gyrus. In the cerebral cortex, most of the ub‐positive structures had ub‐positive dendrites in the neuropil, although some also showed diffuse ub‐positive staining in the neuronal cytoplasm. These ub‐positive structures were distributed throughout layers II‐IIIab and layers V‐VI. Granular cells of the dentate gyrus had ub‐positive intraneuronal inclusions. When the numbers of ub‐positive neurons and dendrites were evaluated in relation to the degree of neuronal loss in the cerebral cortex, the number of ub‐positive neurons was significantly lower in regions showing very mild neuronal loss and higher in regions showing moderate neuronal loss. In contrast, ub‐positive dendrites were detected even in cortical regions showing very mild neuronal loss. Immunoelectron‐microscopically, ub‐positive structures contained ub‐positive ribosome‐like granular components in the neuronal cytoplasm and dendrites, which were occasionally related to the rough endoplasmic reticulum and accompanied by a few filamentous components. Almost all ub‐positive structures were positive for ub‐binding protein p62 in double‐immunostaining method. Some ub‐positive or negative neurons in the cerebral cortex were positively immunolabeled with anti‐ub ligase (Parkin) and anti‐ub C‐terminal hydrolase antibodies, whereas dendrites were not labeled by these antibodies. From the present study, it is suggested that in the cerebral cortex, these ubiquitinated proteins may firstly accumulate in the dendrites at the onset of neuronal degeneration, then appear in the neuronal cytoplasm before finally disappearing with neuronal loss.     

An autopsied case of sporadic adult‐onset amyotrophic lateral sclerosis with FUS‐positive basophilic inclusions

Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA‐binding protein 43 (TDP‐43), have been identified in patients with juvenile‐onset amyotrophic lateral sclerosis (ALS) and adult‐onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin‐positive and tau‐negative inclusions (aFTLD‐U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult‐onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP‐43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein‐like inclusions, or Lewy‐like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified.     

Progressive nonfluent aphasia: A rare clinical subtype of FTLD‐TDP in Japan

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD‐tau) and FTLD with TDP‐43 accumulation (FTLD‐TDP) both cause PNFA. We reviewed clinical records of 29 FTLD‐TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81‐year‐old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP‐43‐immunoreactive neuronal cytoplasmic inclusions and round or irregular‐shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD‐TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.     

Argyrophilic grain disease mimicking temporal Pick's disease: a clinical, radiological, and pathological study of an autopsy case with a clinical course of 15 years

This report concerns an autopsy case of argyrophilic grain disease (AGD) mimicking temporal Pick's disease. The patient was a Japanese woman without hereditary burden who was 89 years old at the time of death. She developed memory impairment and began wandering at the age of 74, followed by prominent character changes about 6 years after disease onset. A neurological examination 5 months before her death revealed poor rapport, unconcern, severe dementia, and double incontinence, without aphasia or muscle rigidity. Serial neuroradiological examination revealed progressive enlargement of the bilateral inferior horns of the lateral ventricle, reflecting progressive atrophy of the medial temporal lobes. Macroscopically, neuropathological examination showed circumscribed atrophy of the bilateral amygdalae, hippocampi, parahippocampal gyri, and lateral occipitotemporal gyri. Histologically, there was neuronal loss in the areas mentioned above, the caudate nucleus, putamen, thalamus, substantia nigra, and locus ceruleus, with ballooned neurons in the cerebral cortex and amygdala. Numerous argyrophilic grains with coiled bodies were present not only in the limbic system, but also in the affected cerebrum. Rare neurofibrillary changes were present in the limbic areas, consistent with Braak stage II, with no senile plaques. Based on these findings and a review of the literature, we note that AGD is clinicopathologically similar not only to mesolimbocortical dementia, but also to atypical senile dementia of Alzheimer type. This report may contribute to the elucidation of the clinicopathological hallmarks of AGD.     

Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation

We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.     

Anti-tau phospho-specific Ser262 antibody recognizes a variety of abnormal hyper-phosphorylated tau deposits in tauopathies including Pick bodies and argyrophilic grains

The rabbit polyclonal anti-tau phospho-specific Ser262 antibody (577814 Calbiochem) recognizes disease-specific band patterns on Western blots of sarkosyl-insoluble fractions in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD) and Pick's disease (PiD): four bands of 74/72, 68, 64 and 60 kDa in AD, two bands of 68 and 64 kDa in PSP, CBD and AGD, and two bands of 64 and 60 kDa in PiD. Moreover, anti-tau phospho-specific Ser262 decorates neurons with neurofibrillary tangles, neurons with pre-tangles, dystrophic neurites of senile plaques, neuropil threads, Pick bodies, argyrophilic grains, and coiled bodies. Achromatic neurons in CBD, ballooned neurons in AGD, tufted astrocytes in PSP, astrocytic plaques in CBD and tau-containing astrocytes in AGD are not immunostained with the anti-tau phospho-specific Ser262 antibody. The lack of phospho-specific Ser262 immunoreactivity in tau-containing inclusions in astrocytes suggests different kinase equipment and activation in comparing neurons and astrocytes in tauopathies. Pick bodies in PiD and grains in AGD are weakly, or not all, immunostained in tissue samples with long post-mortem delays, although Ser262 is preserved in brain homogenates corresponding to the same time points processed for Western blot. This indicates postmortem modifications of tau in Pick bodies and argyrophilic grains, but not in other tau-containing inclusions, including paired helical filaments and coiled bodies, and suggests differences in tau conformation, particularly that involving phospho-tau Ser262 among tauopathies. However, it is important to note that phosphorylation of tau at Ser262 does occur in Pick bodies and argyrophilic grains, and this may have important consequences in reducing the capacity of binding phospho-tau to microtubules in these inclusions.     

Familial parkinsonism and dementia with ballooned neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles, tau-negative astrocytic fibrillary tangles, and Lewy bodies

We report four patients with a new type of familial parkinsonism and dementia consisting of an autosomal dominant inheritance, dopa-responsive parkinsonism, severe dementia, variable myoclonus and autonomic disturbances. Autopsy of two patients revealed symmetrical cerebral atrophy with fronto-temporal dominant distribution, and marked depigmentation in the substantia nigra and locus ceruleus. Neuronal loss and gliosis were observed in the deep cerebral cortex and amygdala as well as in the areas vulnerable to Parkinson’s disease. In the cerebral cortex, swollen neurons with frequent granulovacuolar changes were observed, consisting of ballooned neurons and those with argyrophilic intracytoplasmic inclusions, in addition to neuropil threads. Atypical neurofibrillary tangles, which barely stained with tau antibodies, were numerous in the upper cortical layers, consisting of 15-nm straight tubules. In addition, tau-negative astrocytic fibrillary tangles were also frequent. Electron microscopically, the ballooned neurons and argyrophilic neuronal inclusions contained filamentous structures coated with fuzzy electron-dense deposits. The inclusions showed immunohistochemical features different from those of cortical Lewy bodies and Pick bodies. Occasional Lewy bodies were present in the brain stem lesions of both patients. In two of our patients, the pathology in the brain stem was similar to that of Parkinson’s disease, whereas their cerebral pathology was unusual and has not been reported previously. Received: 11 April 1997 / Revised, accepted: 17 August 1997