[show abstract][hide abstract] ABSTRACT: Patients with anti-thyroid antibodies (ATAs) present various kinds of psychiatric conditions. When these psychiatric patients with ATAs (PPATs) show responsiveness to immunotherapy, they are frequently diagnosed with a diffuse progressive type of Hashimoto's encephalopathy (HE). Anti-glutamate receptor ɛ2 subunit (GluRɛ2) antibodies have previously been reported in HE patients. However, it is unclear whether there is any relationship between PPATs, including HE patients, and anti-GluRɛ2 antibodies. We investigated anti-GluRɛ2 antibodies in the serum and cerebrospinal fluid (CSF) of 15 PPATs, and we compared the results with those of 11 patients with neuropsychiatric systemic lupus erythematosus (NPSLE), an anti-glutamate receptor antibody-related disease. We then compared the neuropsychiatric symptoms between the PPATs with and without anti-GluRɛ2 antibodies. The prevalence of anti-GluRɛ2 antibodies was significantly higher in the CSF than in the serum of PPATs (41.7% versus 6.7%; p=0.040). The prevalence of anti-GluRɛ2 antibodies was slightly higher in the CSF of PPATs than NPSLE patients. PPAT-GluR(+)s showed a significantly higher prevalence of emotional instability (100% versus 33.3%; p=0.03) and also showed a significantly lower prevalence of delusions (0% versus 100%; p=0.001) and hallucinations (17% versus 83%; p=0.038) than PPAT-GluR(-)s. Our results suggest that anti-GluRɛ2 antibodies may be associated with the neuropsychiatric manifestation of PPATs.
[show abstract][hide abstract] ABSTRACT: Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collectively referred to as FTLD-FUS. In the present study, we investigated the localization of FUS in human and mouse brains. FUS was detected by western blot as an approximately 72 kDa protein in both human and mouse brains. Immunohistochemistry using lightly fixed tissue sections of human and mouse brains revealed FUS-positive granular staining in the neuropil, in addition to nuclear staining. Such granules are abundant in the gray matter of the brainstem and spinal cord. They are not frequent in the telencephalon. At the light microscopic level, FUS-positive granules are often co-localized with synaptophysin and present in association with microtubule-associated protein 2-positive dendrites. In the synaptosomal fraction of mouse brain, FUS is detected mainly in the post-synaptic density fraction. Thus, while FUS is primarily a nuclear protein, it may also play a role in dendrites. In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases. The increase in Alzheimer's disease (AD) is less remarkable but still significant. The dendritic localization of FUS and its increase in FTLD-TDP and AD may have some implication for the pathophysiology of neurodegenerative diseases.
[show abstract][hide abstract] ABSTRACT: 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 Aβ immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aβ 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.
Journal of the neurological sciences 03/2012; 314(1-2):111-9. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Neuropathology and Experimental Neurology 03/2011; 70(4):264-80. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0-I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia.
[show abstract][hide abstract] ABSTRACT: Nasu-Hakola disease is an autosomal recessively inherited disease characterized by lipomembranous polycystic osteodysplasia and sclerosing leukoencephalopathy. While white matter lesions prominent in the brain have been reported in the literature, gray matter lesions have not received particular attention. In this study, we examined three autopsy cases of Nasu-Hakola disease in order to focus specifically on gray matter lesions. The ages at onset of the three cases were 20, 23 and 29 years, and the disease durations were 29, 19 and 8 years, respectively. In addition to characteristic degeneration in the cerebral white matter, such as demyelination with conspicuous fibrillary gliosis and axonal changes, all three cases showed overt pathology in the gray matter. Neuronal loss with gliosis in the thalamus (particularly in the dorsomedial nucleus and anterior nucleus), caudate nucleus, putamen and substantia nigra was prominent in all cases, and the severity corresponded to the disease duration. The cerebral cortices were relatively preserved in all cases. One case showed neuronal loss and gliosis in the gray matter of the hippocampus, possibly due to repeated episodes of epileptic convulsions. These gray matter pathologies are considered to be responsible for some of the clinical manifestations of the disease, including extrapyramidal symptoms.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Neuropathology and Experimental Neurology 09/2009; 68(9):994-1005. · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
We neuropathologically investigated aPiD and D-MND cases with and without semantic aphasia.
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.
Degeneration of the temporal pole is most likely to participate in the pathomechanism of SA in semantic dementia.
[show abstract][hide abstract] ABSTRACT: Adherence to antipsychotic treatment is particularly important in the long-term management of schizophrenia and other related psychotic disorders since poor adherence to medication is associated with poor health outcomes. Although the patients' subjective satisfaction with the medication is crucial for adherence to medication, few studies have examined the relationship between subjective satisfaction with antipsychotics and adherence. In this study, we investigated subjective satisfaction with antipsychotics in patients with schizophrenia by using the Treatment Satisfaction Questionnaire for Medication (TSQM), a self-reporting instrument to assess the major dimensions of patients' satisfaction with their medication. The subjects included 121 clinically stabilized outpatients who met the following criteria: 1) patients between 20 and 65 years of age, diagnosed with schizophrenia or other psychotic disorders as defined by DSM-IV, 2) patients undergoing oral antipsychotic monotherapy or taking only an antiparkinsonian agent as an adjuvant remedy, and 3) patients who had received a stable dose of an antipsychotic for more than four weeks. Patients were asked to answer the TSQM questions, and their clinical symptoms were also evaluated by the Brief Psychiatric Rating Scale (BPRS). Satisfaction with regard to side-effects (p=0.015) and global satisfaction (p=0.035) were significantly higher in patients taking second-generation antipsychotics (SGAs, n=111) than those taking first-generation antipsychotics (FGAs, n=10), whereas no significant difference was found between the two groups in clinical symptoms according to BPRS (p=0.637) or the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS, p=0.209). In addition, correlations were not significant between the subjective satisfactions and clinician-rated objective measures of the symptoms. These findings suggest that SGAs have more favorable subjective satisfaction profiles than FGAs in the treatment of schizophrenia. Since it is often difficult to detect the difference by a traditional objective assessment of the patients, it is desirable that physicians pay attention to the patients' subjective satisfaction in conjunction with their own objective clinical assessment.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2008; 32(3):755-60. · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Brain Research 01/2008; 1184:284-94. · 2.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: A number of the lysosomal storage diseases that have now been characterized are associated with intra-lysosomal accumulation of lipids, caused by defective lysosomal enzymes. We have previously reported neuronal accumulation of both alpha- and beta-synucleins in brain tissue of a GM2 gangliosidosis mouse model. Although alpha-synuclein has been implicated in several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, its functions remain largely unclear. In our present study, we have examined a cohort of human lipidosis cases, including Sandhoff disease, Tay-Sachs disease, metachromatic leukodystrophy, beta-galactosialidosis and adrenoleukodystrophy, for the expression of alpha- and beta-synucleins and the associated lipid storage levels. The accumulation of alpha-synuclein was found in brain tissue in not only cases of lysosomal storage diseases, but also in instances of adrenoleukodystrophy, which is a peroxisomal disease. alpha-synuclein was detected in both neurons and glial cells of patients with these two disorders, although its distribution was found to be disease-dependent. In addition, alpha-synuclein-positive neurons were also found to be NeuN-positive, whereas NeuN-negative neurons did not show any accumulation of this protein. By comparison, the accumulation of beta-synuclein was detectable only in the pons of Sandhoff disease cases. This differential accumulation of alpha- and beta-synucleins in human lipidoses may be related to functional differences between these two proteins. In addition, the accumulation of alpha-synuclein may also be a condition that is common to lysosomal storage diseases and adrenoleukodystrophies that show an enhanced expression of this protein upon the elevation of stored lipids.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: We investigated Lewy pathologies in the claustrum and the related cerebral cortices and subcortical nuclei of dementia with Lewy bodies (DLB) brains using alpha-synuclein-immunohistochemistry to clarify the relationship between Lewy pathology in the claustrum and visual misidentification of DLB patients. The claustrum is known to have strong reciprocal connections with the visual areas. Consequently, the claustrum demonstrated many Lewy bodies (LB) and LB-related neurites. The insular and inferior temporal cortices, amygdala, BA 18, 19, transentohrinal and cingulate cortices showed stronger or similar Lewy pathology as compared with the claustrum, while BA 17, precentral, postcentral and transverse temporal cortices showed weaker Lewy pathology. Comparing the correlation coefficient of Lewy pathology between the clausturm and other regions, BA 18 and 19 as well as the insular and transentorhinal cortices demonstrated a higher correlation coefficient. These findings suggest that Lewy pathology in the claustrum is more closely associated with that in visual areas than in auditory, somatosensory or motor areas, and that dysfunction of the visuo-claustral pathway participates in visual misidentification in addition to the visuo-amygdaloid pathway. The paralimbic cortices including the insular and transentorhinal cortices may connect visual areas with limbic areas by relay of the visuo-claustral or visuo-amygdaloid pathway.
[show abstract][hide abstract] ABSTRACT: Limbic neurofibrillary tangle dementia (LNTD) is a subset of senile dementia characterized by numerous neurofibrillary tangles (NFT) in the hippocampal area, although there is an absence or scarcity of amyloid deposits (AM) throughout the brain. In the present study, we immunohistochemically investigated regional numbers and tau isoforms of NFT in the hippocampal area of nine LNTD patients with anti-three-repeat (3R) tau-specific and anti-four-repeat (4R) tau-specific antibodies, differentiating NFT into three developmental stages of pretangles (PT), NFT and ghost tangles (GT). Consequently, most PT were 4R tau-positive, most GT were 3R tau-positive, and NFT were 3R tau-, 4R tau- or double-positive, suggesting that composition of tau isoforms may shift from a 4R tau-predominant pattern to a 3R tau-predominant pattern during the development of NFT. In addition, a large number of NFT showing different developmental stages and different rates of 3R tau- and 4R tau-positive neurons according to the region were found in the hippocampal area, suggesting that regions undergoing earlier NFT formation may show higher ratio of 3R tau-positive neurons to 4R tau-positive neurons, and that NFT formation may begin in the entorhinal and transentorhinal cortices, subsequently progress to the subiculum and CA1, and further to the CA2, amygdala and CA3-4, although progression to the neocortex is limited. Furthermore, 4R tau-positive astrocytes and grains were found in several patients, suggesting that LNTD is a form of tauopathy.
[show abstract][hide abstract] ABSTRACT: The effects of cerebrovascular lesions on DLB are not yet fully understood, whereas the development of Alzheimer's disease (AD) is known to be associated with cerebrovascular lesions. In this study, we investigated the frequency of concomitant cerebrovascular pathologies in autopsy-proven DLB cases (n = 25) in comparison with AD cases (n= 63). We also investigated the correlation between cerebrovascular pathologies and the clinical features of DLB cases. On gross inspection, five cases of DLB and seven cases of AD were complicated by cerebral hemorrhages and the difference was significant; most of the lesions in DLB were subdural hemorrhages, possibly related to trauma. Nine cases of DLB and 25 cases of AD had grossly identified infarctions, but no significant difference was observed. Three cases of DLB and four cases of AD had concomitant hemorrhages, while 10 cases of DLB and 43 cases of AD had infarcts on microscopic inspection. There was a significant difference in the frequency of microscopic infarcts between DLB and AD, whereas no significant difference was noted in the frequency of microscopic hemorrhages. In DLB cases without vascular complications, memory disturbance was common as the initial symptom, while parkinsonism was more common in those with vascular complications. However, no significant difference was observed between DLB cases with and without vascular complications with respect to the frequency of individual clinical symptoms over the whole clinical course. These findings suggest that grossly identified hemorrhages are more common in DLB because of trauma, while microinfarcts are less common in DLB than AD, although the reason remains unclear. Such vascular complications might affect the clinical manifestations, in particular, the initial symptom, of DLB.
[show abstract][hide abstract] ABSTRACT: We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmann's area 17), secondary visual pathway (pulvinar, Brodmann's areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.
Journal of the Neurological Sciences 08/2006; 246(1-2):95-101. · 2.24 Impact Factor