Atypical late-onset dementia characterized by limbic degeneration with coiled bodies and argyrophilic threads.

This report concerns an autopsy case of late-onset dementia with atypical neuropathological features. The patient was a Japanese man who was 83 years old at the age of death. At 73 years, he developed behavioral disorders, including emotional changes, and dementia. He died at the age of 83. A neuropathological study revealed largely confined involvement of the limbic regions, characterized by degeneration consisting of neuronal loss with a spongy state and gliosis. Massive tau-positive oligodendroglial coiled bodies and argyrophilic threads were also observed mainly in these regions. Although the clinicopathological findings of the present case showed some similarities to those of a unique subtype of frontotemporal dementia, including mesolimbocortical dementia, argyrophilic grain disease, corticobasal degeneration and dementia with tangles, there seems to be no suitable category of neurodegenerative disease into which our case can be classified. Further study is needed to determine whether the present case could be classified as an atypical case of these diseases or represents a new entity.

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.

Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients.

Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.

Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases.

We investigated five Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), both clinically and pathologically, and examined the degree and distribution of the basal ganglia lesions, especially in the amygdala, striatum, pallidum, and substantia nigra. The lesions in the amygdala, striatum, and pallidum were classified into three categories (mild, moderate, and severe). The lesions in the substantia nigra were qualitatively judged, compared with normal controls. Severe dementia was observed in four cases neuropathologically showing pronounced neuronal loss in the cerebral cortex, but one case without neuronal loss in the cerebral cortex showed mild memory disturbance. Extrapyramidal signs were evident in three cases. Obvious neuronal loss in the substantia nigra with the presence of Lewy bodies was noticed in four cases. Basal ganglia lesions in all five cases were uniform: the amygdala showed severe to moderate lesions, the caudate nucleus moderate to slight lesions, and the putamen and pallidum slight lesions to normal. Furthermore, the lesions in the amygdala were more prominent in the basolateral group than in the corticomedial group, inconsistent with those in the amygdala of Alzheimer's disease. Moderate lesions were evident in the basolateral group of the amygdala in the case without neuronal loss in the cerebral cortex. In DNTC, the degree and distribution of the basal ganglia lesions, except for nigral lesions, were analogous to those found in Pick's disease with Pick bodies. These clinicopathological findings may contribute to the elucidation of the clinicopathological hallmarks in this disorder.

Relationship of calbindin D28K-immunoreactive cells and neuropathological changes in the hippocampal formation of Alzheimer's disease.

Previous studies have reported that calcium binding proteins, which have important functions in regulating the intracellular ion concentration, may influence the vulnerability of neurons in neurodegenerative disease. It has been observed that the neurons containing calbindin D28K (CB) may in certain circumstances be more resistant to excitotoxic and ischemic injury. In the present study the susceptibility of hippocampal neurons containing CB to develop NFT was studied, and the distribution of CB cells was compared with hippocampal plaque density in the Alzheimer's disease (AD) brain. Interestingly CB-positive hippocampal neurons did not contain tangles and could be seen next to degenerating tau-positive pyramidal cells. Comparison of the hippocampal plaque distribution with that of CB neurons showed that in general CB-positive neurons were found in areas with a low plaque burden. Further comparison of cases with differing degrees of severity indicated that CB-positive neurons were relatively preserved in cases with moderate plaque and tangle content but that in severe cases the CB-positive pyramidal cells were lost. These findings indicate that CB cells may be protected in the earlier stages of the disease but that this resistance ability is lost in the late stages of AD. The observation that CB-positive pyramidal cells do not accumulate NFT suggests that proteolysis of tau differs in CB-negative and CB-positive cells.

Cognitive decline in schizophrenics with Alzheimer's disease: a mini-review of neuropsychological and neuropathological studies.

Cognitive decline in elderly schizophrenic patients is an important clinical symptom, but it is often difficult to analyze in detail due to the patient's original residual psychotic symptoms. In this article, the authors provide neuropsychological and neuropathological research information about cognitive decline in elderly schizophrenic patients, especially with reference to Alzheimer's disease (AD). Neuropsychological and neuropathological reports about cognitive impairments are reviewed. The effect of long-term antipsychotic medication upon cognitive function is also discussed. As a result, it is apparent that elderly schizophrenic patients often show cognitive impairments, however, such impairments do not have the characteristics of progressive degenerative illnesses such as AD, and the speed of their progress is very slow. Neuropathological studies have shown that AD brain pathology appears no more frequently among schizophrenic patients than in the normal population. Since making a diagnosis of AD means that the progressive deterioration not only of cognitive function, but also of physical ability, paralleling the degeneration of the central nervous system, can be expected within a few years and appropriate care will be required. One should be very cautious in adding a diagnosis of AD to elderly schizophrenic patients with cognitive impairments.

[An autopsied case of presenile dementia with tangles].

We report an autopsied case of presenile dementia showing neuropathologically abundant neurofibrillary tangles(NFT) without senile plaques(tangle only dementia). A Japanese woman developed memory disturbance when she was 60 years old. At age of 65, her ability to understand deteriorated and euphoria and wandering manifested but neither psychotic symptoms, including hallucination and delusion nor a change in character were observed. The patient was hospitalized at age 66 and a cranial CT scan revealed bilateral moderate atrophy of the cortex and moderate enlargement of the lateral ventricle, especially in the inferior horn. No lobar atrophy was detected. She exhibited an oral tendency and became appallic at her final stage and died at the age of 75. Autopsy showed that her brain weighed 850 g and neuropathological study showed numerous NFT mainly in the entorhinal (trans-entorhinal) region, subiculum, CA1-CA4, dentate gyrus, amygdara, subthalamic nucleus, basal nucleus of Meynert, substantia nigra and locus coeruleus. Severe neuronal loss with gliosis was noted in the temporal lobes including the hippocampal region. No senile plaque was detected in any of the brain regions. There have been some recent reports of patients with abundant NFT with the predominant involvement of the allocortex but no or very little senile plaque. All the patients in the reported cases were very elderly at onset(over 80 years of age). In our case, the onset was presenile and we could exclude any other diseases, that usually present with NFT, and to our knowledge, this is the first report of a presenile dementia with tangles.

Astroglial function of schizophrenic brain: a study using lobotomized brain.

The neurodevelopmental hypothesis is now being recognized as one of the most useful hypothesis for schizophrenia, and by using it, abnormalities in protein associated with neuron growth or neuronal migration have been reported. From neuron-glia interrelations in the neural development, it is important to study the function of astroglia in the schizophrenic brain. In this study, we examined the neuropathological reaction of astroglia using lobotomized brains, and a significant decrease of astroglia after artificial histological damage was observed in schizophrenic brains. We speculated that this may be due to the latent vulnerability of the dynamic function of astroglia in schizophrenia. Astroglia plays a guidance role on migration and if astroglia has latent vulnerability, we speculate that younger neurons may not sufficiently migrate during development. In further investigation of the neurodevelopmental hypothesis of schizophrenia, it will be necessary to examine the function of astroglia.

A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients.

The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels.

Morphological changes in neuropeptide Y-positive fiber in the hippocampal formation of schizophrenics.

1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration.

The distribution of neuropeptide Y and brain-derived neurotrophic factor immunoreactivity in hippocampal formation of the monkey and rat.

The distribution of neuropeptide Y (NPY) and Brain-Derived Neurotrophic Factor (BDNF) in the hippocampal formation of monkey and rat brains was studied immunohistochemically. The NPY-neuronal system is more highly developed in the monkey compared to that in the rat. The distribution of NPY-positive products was coincident with that of abundant BDNF-positive deposits. These observations suggest that the role of BDNF and the interaction of BDNF-NPY may differ between species.

Argyrophilic glial inclusions in the midbrain of patients with Parkinson's disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein.

Argyrophilic glial inclusions occur in the midbrain of patients with Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). These inclusions are immunohistochemically positive for NACP/alpha-synuclein but negative for tau protein. The results of the present study suggest that a primary degenerative process involves NACP/alpha-synuclein in PD and DLBD and that the process takes place not only in neurons but also in glial cells. Argyrophilic cytoplasmic inclusions, both glial and neuronal, in a variety of degenerative diseases may be grouped into two major categories; one related to aggregates of abnormally phosphorylated tau protein and the other to unusual accumulations of NACP/alpha-synuclein.

Autopsy study of Alzheimer's disease brain pathology in schizophrenia.

The brains of 125 schizophrenic patients (DSM-IV criteria) without other major diseases likely to affect brain morphology were examined at autopsy in our hospital for an evaluation of the number of neurofibrillary tangles (NFT) and senile plaques (SP) as indicators of the incidence of Alzheimer's disease (AD) brain pathology. The clinical degree of dementia and the presence or absence of delirium and Parkinsonism were determined in a review of the patients' charts. No significant difference in the degree of AD brain pathology between the 12 schizophrenics more than 75 years old and 12 age-matched normal controls was present. We conclude that AD pathology seems to be no more frequent among schizophrenic patients than in the normal population, and that the severe cognitive impairment observed in schizophrenics is based on neither neuronal degeneration nor neuronal loss like that occurring in AD. We believe that future morphological studies of cognitive impairments in schizophrenics will require a more detailed investigation at the receptor level.

[An elderly patient with progressive supranuclear palsy without neurological signs].

We report an elderly patient with progressive supranuclear palsy (PSP) who showed no neurological signs clinically. A 70-year-old man presented with irritation and poor hygiene, thereafter he showed excitement and violence. A cranial CT scan revealed bilateral moderate atrophy of the temporal lobes and slight enlargement of the lateral ventricle. The brain stem was slightly atrophic. Although he died at the age of 80 years, he had no neurological signs throughout the clinical course. Neuropathological study showed typical findings of PSP, neuronal loss with gliosis and neurofibrillary tangles in the basal ganglia, amygdala, midbrain, pons, dentate nucleus and inferior olivary nucleus. Staining by Gallyas-Braak methods revealed argyrophilic and tau-positive glial fibrillary tangles in the cerebral cortex. Neurofibrillary tangles showed greater frequency than usual for the physiological level in that age group in the hippocampus regions as well as in the amygdala. The possibility that the psychotic symptoms, mainly personality change, are connected with the degeneration of limbic system is indicated. Since there have not been any previous reports of PSP without neurological signs, this case represents an important in terms of clinico-pathological variation of PSP. We suggest that there is discrepancy between symptomatic and neuropathological aspects in elderly patients with PSP.

Pick's disease with amyotrophic lateral sclerosis (ALS): report of two autopsy cases and literature review.

We report the findings in two autopsy cases of Pick's disease with amyotrophic lateral sclerosis (ALS). Both presented severe cortical degeneration and subcortical gliosis of temporal lobes, as well as the neuropathological characteristics of ALS. As such cases are rare, we present the clinical and pathological findings in detail and a review the relevant literature.

Corticobasal degeneration with primary progressive aphasia and accentuated cortical lesion in superior temporal gyrus: case report and review.

A 57-year-old woman showed progressive sensory aphasia as an initial symptom, and then developed total aphasia within 6 years and, finally, severe dementia. Neuropathologically, the cerebral cortex was most severely affected in the superior and transverse temporal gyri, and subsequently in the inferior frontal gyrus, especially in the pars opercularis. The degeneration in the subcortical grey matter was most severe in the substantia nigra, and it was moderate to mild in the ventral part of thalamus, globus pallidus and striatum. Cytopathologically, in addition to achromatic ballooned neurons, massive taupositive types of cytosekeletal abnormalities were observed both in neurons and glia, mainly in the degenerating region. This cytoskeletal pathology coincided with that reported in corticobasal degeneration (CBD). On Bodian staining, only a few neurofibrillary tangles were found in the entorhinal pre-alpha layer and substantia nigra. Pick's bodies and senile plaques could not be found. This case is thought to represent a type of CBD, but with its cortical lesion focus located in the speech area instead of the frontoparietal region. A survey of 28 pathologically evaluated cases of CBD revealed two similar cases, both of which began with progressive aphasia and presented cortical degeneration in the superior temporal gyrus. An overview of CBD cases clarified the features in another group of cases, in which the cerebral accentuated focus was shifted forward from the central region, clinically resembling Pick's disease. The clinical manifestations in CBD seem to be the expression of these diverse cortical lesions. Primary progressive aphasia may include cases of CBD with involvement of the language center.

Long-term antipsychotic medication of schizophrenics does not promote the development of Alzheimer's disease brain pathology.

The present autopsy study was performed to examine whether long-term antipsychotic medication of schizophrenics promoted pathologic transition to Alzheimer's disease (AD) of the brain. Immunohistological staining of the hippocampal region with anti-human tau antibody was used to examine the degree of AD pathology in seven schizophrenic patients who had received long-term antipsychotic medication and in seven controls. The schizophrenic patients showed no significant difference from the controls for the number of tau-positive neurons. Additionally, the total amount of antipsychotic drugs for schizophrenic patients was calculated by using of chlorpromazine equivalents. No significant correlation between the total amount of antipsychotic drugs and the degree of AD pathology was observed. The long-term antipsychotic medication of these schizophrenics did not promote the development of AD pathology in the brain.