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.

Alzheimer's disease or Alzheimer's syndrome?: a longitudinal computed tomography neuroradiological follow-up study of 56 cases diagnosed clinically as Alzheimer's disease.

BACKGROUND: Some 200 patients, including those with Alzheimer's disease and other types of dementia, stay year-round in Yokohama - Houyuu Hospital. They undergo computed tomography (CT) neuroradiological examination at least once or twice a year. For this study, the accumulative data, including clinical and neuroradiological, were analyzed. METHODS: Differential diagnoses of Alzheimer's disease were performed in accordance with the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. The 56 patients (15 men, 41 women) included in this study underwent in-hospital observation on average for 4.4 years (range: 1-10 years). The patients were classified into four groups according to the age of disease onset. The CT findings were summarized for each group and then compared among the groups to determine if there were any differences related to age of onset and, if so, to identify and analyze them. RESULTS: (1) The duration of deceased cases' total clinical course (in years) compared among the four groups. In general, the degree of dementia was more severe among those with earlier disease onset. (2) In cases admitted within 2 years from onset (n =14), the suspected initiating focus of cortical atrophy occurred in the frontal lobe (n = 6), the temporal lobe (n = 6), or the fronto-temporal lobes (n = 2). (3) Although CT findings generally showed that the more severe cases had earlier onset, serial CT examinations in each case showed widely different pathologies in degree, nature and manner of progression, regardless of group classification. (4) The earliest sites of brain atrophy, sites of its severest involvement within the brain, and neuroradiological development of the cerebral cortex pathology in combination with hemispheric white matter, lateral ventricles, and third ventricles varied among the four groups and between case within each group. Alzheimer's disease could not be subclassified simply by the age of clinical onset. CONCLUSION: Cases of so-called Alzheimer's disease, as observed through continued clinical follow-up and serial CT examinations, appear so diverse in symptomatology and radiological pathomorphology that it is difficult to consider them a single nosological entity. The pathology of Alzheimer's disease has to be reconsidered in accordance with the variety observed in the sequential development of neuroradiological findings. The pathology must be reconstructed in terms of topographical dimensions and chronological developments. The diagnosis of Alzheimer's disease appears to be not so simple based on any conventional diagnostic operational standards.

Temporal trends in antipsychotic prescriptions for pediatric patients using an administrative hospital database in Japan: a retrospective study.

BACKGROUND: Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, and other symptoms. Although treatment guidelines for schizophrenia have been established in Japan, drugs are not recommended for pediatric schizophrenia. Additionally, the temporal trends in prescribing antipsychotics for pediatric patients with schizophrenia are unclear. Therefore, we aimed to clarify the trends in antipsychotic prescriptions for Japanese pediatric outpatients from 2015 to 2022. METHODS: Administrative data (as of November 2023) of Japanese pediatric outpatients with schizophrenia aged 0-18 years who visited acute-care diagnosis procedure combination hospitals between January 1, 2015, and December 31, 2022, were included in this study. The target drugs for schizophrenia were all indicated for treating schizophrenia and marketed in Japan as of December 2022. Annual prescription trends for antipsychotics during this period were calculated based on their proportions. The Cochran-Armitage trend test was used to evaluate the proportion of prescriptions for each antipsychotic. RESULTS: The main drugs prescribed for these patients were aripiprazole and risperidone. Among male patients, the proportion of prescriptions for aripiprazole increased significantly from 21.2% in 2015 to 35.9% in 2022, whereas that for risperidone decreased significantly from 47.9% in 2015 to 36.7% in 2022 (both P < 0.001). Among female patients, the proportion of prescriptions for aripiprazole increased significantly from 21.6% in 2015 to 35.6% in 2022, whereas that for risperidone decreased significantly from 38.6% in 2015 to 24.8% in 2022 (both P < 0.001). CONCLUSIONS: Aripiprazole and risperidone were primarily prescribed for pediatric schizophrenia in Japan during the study period. Additionally, the proportion of aripiprazole prescriptions increased over time.

Trends in Anti-Influenza Drug Prescription and Adverse Drug Reaction Reporting After the Lifting of Oseltamivir Prescribing Restrictions in Pediatric Outpatients: An Ecological Study Using the MDV Analyzer® And the Japanese Adverse Drug Event Report Database.

BACKGROUND: Abnormal behavior after oseltamivir administration has been reported in the media; in 2007, the package insert for oseltamivir phosphate was revised to restrict its administration to individuals aged over 10 years. However, in 2018, the age limitation specified in the package insert was removed. Here, we evaluated the trends in anti-influenza drug prescription and adverse drug reactions (ADRs) reported in pediatric outpatients after revising the oseltamivir package insert as an ecological study. METHODS: Anti-influenza drug prescriptions for pediatric outpatients with influenza aged 0-19 years were downloaded from the acute Diagnosis Procedure Combination hospital databases using the MDV analyzer®. ADR reports on anti-influenza drug prescription among patients aged 0-20 years in the Japanese Adverse Drug Event Report database were downloaded from the Pharmaceutical and Medical Devices Agency website. Data were collected during the 2016/2017 and 2019/2020 influenza seasons. RESULTS: During the influenza epidemic season (January-March), the percentage of oseltamivir prescriptions for patients with influenza aged 10-19 years tripled after the revision of the oseltamivir package insert (9.3% during the 2016/2017 season and 29.2% during the 2019/2020 season); however, reports of abnormal behavior did not increase (two during the 2016/2017 season and none during the 2019/2020 season). CONCLUSIONS: The number of oseltamivir-related ADR reports among minors over 10 years of age did not increase although the proportion of oseltamivir prescriptions increased after the revision of the oseltamivir package insert.

Trends in prescription of anti-seizure medicines for Japanese pediatric outpatients during 2013-2019.

Temporal trends in prescriptions of anti-seizure medicines (ASMs) for children, including newer ASMs, are unclear. We investigated ASM prescription trends for pediatric outpatients in Japan. The MDV analyzer® was used to analyze the MDV database containing de-identified hospital administrative data. Administrative data as of June 2021 including pediatric outpatients (0-17 years) with epilepsy, visiting 123 acute diagnostic procedure combination hospitals during 2013-2019, were used. Annual ASMs prescription trends were calculated, based on proportions. The Cochran-Armitage trend test evaluated the proportion of prescriptions for each ASM. ASMs most often prescribed were valproic acid, carbamazepine, and levetiracetam, regardless of sex. In girls, the proportion of valproic acid and carbamazepine prescriptions decreased from 37.93% to 26.84%, and from 24.80% to 15.78%, respectively (p < 0.0001). Conversely, the proportion of levetiracetam prescriptions increased from 6.40% to 28.18% (p < 0.0001). In boys, the proportion of valproic acid and carbamazepine prescriptions decreased, from 36.58% to 32.20% and from 26.42% to 16.85%, respectively (p < 0.0001). The proportion of levetiracetam prescriptions increased from 5.64% to 23.02% (p < 0.0001). Overall, the proportion of valproic acid and carbamazepine prescriptions declined, whereas levetiracetam prescriptions increased. Trends in ASM prescriptions among pediatric outpatients with epilepsy in Japan have shifted towards more recently available ASMs.

Drug prescription for attention deficit hyperactivity disorder drugs in pediatric outpatients: A retrospective survey of Japanese administrative data (2012-2018).

We aimed to clarify the prescription trend of ADHD drugs in Japanese pediatric outpatients. From January 2012 to December 2018, we evaluated the trends of prescribing methylphenidate-osmotic-controlled release oral delivery system (OROS), atomoxetine, and guanfacine as monotherapy. In boys, methylphenidate-OROS and atomoxetine prescriptions decreased from 46.5 % to 37.2 % and 18.6 % to 15.6 %, respectively. Prescriptions of guanfacine increased from 0.0 % to 12.3 %. In girls, the methylphenidate-OROS prescriptions was not significantly different (37.0 % to 26.4 %); however, atomoxetine decreased from 23.1 % to 16.3 %, and guanfacine increased from 0.0 % to 12.8 %. Methylphenidate-OROS and atomoxetine prescriptions changed to guanfacine between 2012 and 2018.

Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease.

Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease and are also associated with diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We used immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. The immunoreactivity of LRRK2 was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions, or TAR-DNA-binding protein-43-positive inclusions. The immunoreactivity of LRRK2 frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala, and entorhinal cortex in patients with Parkinson disease or dementia with LBs. The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in dementia with LBs brains compared with age-matched control brains (p < 0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, the lysosomal-associated membrane protein 2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.

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.

[A Japanese family with familial Alzheimer's disease associated with presenilin 1 mutation: relationship between younger age of onset and ApoE gene polymorphism].

We previously reported a Japanese family with early-onset familial Alzheimer's disease associated with G 209 R presenilin 1(PS 1) mutation. There have been six patients across three generations in this family. In the present report, we described the clinical course, findings with neuroimaging and results of genetic examination of PS 1 and apolipoprotein E(ApoE) in three of six patients(II-1, III-1 and 2). The clinical course was common to all three patients. Memory disturbance, disorientation, amnestic aphasia, personality changes and perseveration appeared at early stages, whereas Gerstmann's syndrome, myoclonus and general convulsion were recognized at advanced stages. CT disclosed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the fronto--temporal lobes at advanced stages. SPECT exhibited hypoperfusion in the fronto-temporal areas at early stages and hypoperfusion in the fronto-temporal and parieto-occipital areas at advanced stages. The age of onset in six patients demonstrated two clusters at age 53-55(I-1, II-1, 2 and 5) and age 46-48(III-1 and 2). PS 1 genotyping demonstrated that the heterozygous exonic missense mutation G 209 R was confirmed in all three patients. Regarding the ApoE genotyping, II-1(mother) was epsilon 3/epsilon 3, whereas III-1 and 2(children) were epsilon 3/epsilon 4. These findings suggest the possibility that there might be a gene dose effect, since the age of onset ranged from 5 to 7 years younger in patients who received epsilon 4 alleles from the father.

[A case with late-onset MELAS with hallucination and delusion].

We report a 53-year-old male patient with late onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes(MELAS) with hallucination and delusion. The patient manifested various neurological symptoms including perceptive deafness, muscle weakness of limbs with loss of consciousness, sensory abnormalities in hands, feet and a face, abnormal sense of taste, tremor, palsy of upward eye movement and weak deep tendon reflexes prior to the psychotic episode. He was diagnosed as MELAS, because of high serum lactic acid and pyruvic acid, and the point mutation in the mitochondrial DNA 3243. SPECT imaging showed decreased perfusion in occipital cortex and thalamus. These SPECT changes improved after disappearing visual hallucination. Hallucination might be caused by delirium due to stroke-like episode. Dysfunction in the occipital cortex and thalamus might be involved with this perfusion change.

Neuropathological investigation of hypocretin expression in brains of dementia with Lewy bodies.

Hypocretin (Hcrt) is a neuropeptide synthesized in the lateral hypothalamus (LHT) that plays a key role in maintaining arousal state. In Parkinson's disease (PD), a narcolepsy-like syndrome is commonly seen, and a previous study showed substantial Hcrt neuronal loss in accordance with PD severity. In the present study, we quantitatively examined Hcrt immunoreactivity and α-synuclein and tau pathologies in the LHT and locus coeruleus (LC) in dementia with Lewy bodies (DLB) (n=15), Alzheimer's disease (AD) (n=14), and controls (n=7). In the LHT, substantial Hcrt-positive neurons were detected in controls. In contrast, in DLB and AD, the numbers of both total neurons and Hcrt-positive neurons were significantly reduced. The reduction of the latter was significantly severer in DLB than in AD. In the LC of controls, many Hcrt-positive axonal terminals were found. In contrast, the amount of Hcrt immunoreactivity was significantly reduced both in DLB and AD. In DLB, some Lewy body (LB)-bearing neurons were detected in the LHT, but the Hcrt-positive neurons did not have any LBs. Meanwhile, some tau-positive neurofibrillary tangle (NFT)-bearing neurons were detected in the LHT, and Hcrt-positive neurons occasionally contained NFTs. We observed a significant negative correlation between the number of Hcrt-positive neurons in the LHT and the neurofibrillary stage (r=-0.67, p=0.0067), whereas no significant correlation was found between the number of Hcrt-positive neurons and the Lewy stage (r=-0.47, p=0.077). This is the first report clarifying the substantial loss of Hcrt neurons in the LHT and of Hcrt axonal terminals in the LC in DLB and the correlation between the severity of Hcrt neuronal loss and progression of neurofibrillary pathology.

Neuropathological investigation of the hypometabolic regions on positron emission tomography with [18F] fluorodeoxyglucose in patients with dementia with Lewy bodies.

We performed a quantitative neuropathological examination of the hypometabolic regions on FDG PET in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and control cases. When the DLB cases were divided into two groups according to concomitant AD pathology (ADP), neuronal loss in the temporo-parietal association area was milder in the DLB groups than in the AD group, although there were no differences between the two DLB groups. Tau and Aß immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aß immunoreactivities as well as numbers of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) were more common in the AD group than in the DLB group with ADP. There was no difference in neuronal loss in the occipital area among the three groups. α-Synuclein immunoreactivity was observed in the DLB groups but not in the AD group. There were no differences in α-synuclein immunoreactivity and number of Lewy bodies (LBs) between the two DLB groups. These findings indicate that the neuropathological bases of the hypometabolic regions in the temporo-parietal association and occipital area in DLB may be AD pathology and Lewy pathology, respectively.

Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies.

There is emerging evidence implicating a role for the autophagy-lysosome pathway in the pathogenesis of Lewy body disease. We investigated potential neuropathologic and biochemical alterations of autophagy-lysosome pathway-related proteins in the brains of patients with dementia with Lewy bodies (DLB), Alzheimer disease (AD), and control subjects using antibodies against Ras-related protein Rab-7B (Rab7B), lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1A/1B light chain 3 (LC3). In DLB, but not in control brains, there were large Rab7B-immunoreactive endosomal granules. LC3 immunoreactivity was increased in vulnerable areas of DLB brains relative to that in control brains; computerized cell counting analysis revealed that LC3 levels were greater in the entorhinal cortex and amygdala of DLB brains than in controls. Rab7B levels were increased, and LAMP2 levels were decreased in the entorhinal cortex of DLB brains. In contrast, only a decrease in LAMP2 levels versus controls was found in AD brains. LC3 widely colocalized with several types of Lewy pathology; LAMP2 localized to the periphery or outside of brainstem-type Lewy bodies; Rab7B did not colocalize with Lewy pathology. Immunoblot analysis demonstrated specific accumulation of the autophagosomal LC3-II isoform in detergent-insoluble fractions from DLB brains. These results support apotential role for the autophagy-lysosome pathway in the pathogenesis of DLB.

[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.

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.

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.

Degeneration of Pick bodies visualized by methenamine-silver staining and immunohistochemistry.

The degeneration process of Pick's bodies (PB) was investigated using methenamine-silver (MS) staining and immunohistochemistry. Methenamine-silver staining sensitively detected extracellular PB as well as intracellular PB in the granular cell layer of the dentate gyrus. Extracellular PB appeared as granular masses with ill-defined boundaries in the neuropil. For MS electron microscopy, the extracellular PB were composed of randomly oriented fibrillary components measuring 9-12 nm in diameter with astroglial processes and degenerated organelles. Tau immunoreactivity of extracellular PB was reduced or abolished. These findings indicate that MS staining is a convenient method for detecting extracellular PB. In addition, it was shown that microglial involvement was associated with PB-bearing neurons at the late stage of the degeneration process and that extracellular PB remained in the neuropil with astroglial reaction.

Clinicopathological study of two subtypes of Pick's disease in Japan.

We examined the clinical and neuropathological findings in 3 cases of Pick's disease with Pick bodies (PiD) and 7 cases of atypical Pick's disease without Pick bodies (aPiD). PiD and aPiD cases corresponded clinically to frontotemporal dementia and semantic dementia, respectively, based on the clinical diagnostic criteria of frontotemporal lobar degeneration. Brain CT showed that cerebral atrophy was accentuated at an early stage of the illness in the anterior portion of the frontal lobes in PiD cases and in the anterior portion of the temporal lobes in aPiD cases. Neuropathologically, PiD cases showed more circumscribed lobar atrophy than aPiD cases. Both PiD and aPiD cases revealed moderate to severe degeneration with neuronal loss and gliosis in the affected cerebral cortex and subcortical nuclei, but only aPiD cases had pyramidal tract degeneration. Immunohistochemical analyses demonstrated that tauopathy with phosphorylated tau accumulation in the Pick bodies in PiD cases, while aPiD cases showed ubiquitinopathy with ubiquitin accumulation in the intraneuronal and dendritic inclusions. These findings suggested that two subtypes of Pick's disease in Japan can be distinguished not only neuropathologically but also clinically based on differences in pathogenesis.