Search

Highlights • We investigated trends in ASM prescriptions with children in Japan during 2013–2019. • Valproic acid, carbamazepine, and levetiracetam were most commonly prescribed. • A decline in valproic acid and carbamazepine prescriptions was observed. • An increase in levetiracetam prescriptions was observed. • ASM prescription in Japan has shifted toward the use of recently available ASMs., 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

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.

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.

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.

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.

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.

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.

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.

Background: Binswanger's disease is a special type of vascular dementia, which requires further reappraisal and redefinition. In a geriatric psychiatry hospital (with 207 beds), we treated several patients who probably had this disease, and tried to establish a basis for making a clinical diagnosis. Methods: From 2001 to 2005, we treated seven inpatients with noteworthy symptoms, who had been under observation in hospital wards for between 4 and 19 months. Here, for these patients, we examine the history of the illness, the condition of the patients at admission, the clinical course, and serial computed tomography (CT) findings. Results: Characteristic features of the clinical courses and symptoms of these patients were: (i) onset occurred late in life (patients were aged in their 70s and 80s); (ii) vascular events were atypical and transient, leaving few permanent neurological sequelae; (iii) progression of dementia and other somatic or neurologic symptoms was continuous and fast in four patients, and rather gradual in three patients; (iv) there was an alternating or changing pattern in all patients’ state of consciousness, mood, behavior, or manner of respiration; symptoms such as mutism, lack of facial expression, and apparent indifference were counterbalanced with such behaviors as occasional unexpected smiles, pertinent verbal responses, and sincere gazes; (v) significant negative symptoms were a lack of dysarthria, lack of dysphagia, lack of involuntary movement, and occasional lack of muscle rigidity. The primary CT findings were: (i) moderate to severe generalized (involving whole of centrum semiovale), diffuse and homogeneous (except one patient) leukoaraiosis of the hemispheric white matter, including the temporal lobe (except one patient), all (except one patient) frontal and parietal dominant, with the corpus callosum involved in one case; (ii) diffuse and generalized atrophy of the pallium, most marked in the frontal and parietal lobes, restricted to the frontal and parietal lobes in three patients, and to the frontal, parietal and temporal lobes in four patients; (iii) atrophy of the medial temporal lobe was inconstant and, when present, ambiguous in degree; (iv) slight to moderate enlargement of the bilateral lateral and third ventricles; (v) a few small lacunae in the basal ganglia and thalamus in one patient, inhomogeneous macular changes of density in the basal ganglia and thalamus in two patients, and no such findings in the remaining four patients. Conclusion: We have described a group of patients with dementia characterized by a clinical course with episodes of rather transient vascular intervention, psychopathology characteristic of organic dementia, fluctuating psychotic symptoms in combination, and intensive extensive homogeneous leukoaraiosis of the hemispheric white matter on CT. These clinical and CT neuroradiological findings seem to warrant the clinical diagnosis of Binswanger's disease, which should be reconfirmed at autopsy. Early research on this disease by Binswanger, Alzheimer, Nissl and others is reviewed. Some points of differential diagnosis in serial neuroradiology are discussed in relation to multilacunar dementia.

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.

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.

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.

We report a 62-year-old Japanese man with familial frontotemporal dementia and a novel missense mutation (N296H) in exon 10 of the tau gene. The patient presented with frontal signs followed by temporal signs and parkinsonism. The brain showed localized frontotemporal lobe atrophy including the precentral gyrus and discoloration of the substantia nigra, and revealed severe neuronal loss with proliferation of tau-positive protoplasmic astroglia in the affected cerebral cortex, tau-positive coiled bodies and threads in the subcortical white matter, and tau-positive pretangle neurons in the subcortical and brain stem nuclei. There were no tau-positive neurofibrillary tangles, Pick bodies, tuft-shaped astrocytes or astrocytic plaques in the cerebral cortex. Immunoelectron microscopically, phosphorylated tau accumulated in both neurons and glial cells in different modalities, such as glial filaments in protoplasmic astroglia, straight tubules in coiled bodies, and free ribosomes in pretangle neurons. These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17. Immunoblotting of sarkosyl-insoluble tau exhibited accumulation of four-repeat tau isoforms in the brain. The N296H mutation may interfere with the ability of mutated tau to bind with microtubules and lead to tau aggregation. Further study is necessary to determine whether this mutation can account for the characteristic tau pathology of this case.

Six cases of atypical Pick's disease (PD) without Pick bodies (PB) were examined immunohistochemically. These cases showed severe neuronal loss with gliosis predominantly in the temporal cortices. Ubiquitin immunohistochemistry revealed ubiquitin-positive intraneuronal inclusions in the dentate gyrus and ubiquitin-positive neurites in the cerebral cortex. In the dentate gyrus, the dendrites in the stratum moleculare as well as the intraneuronal inclusions in the granular cells were positively stained. Both structures were composed of ubiquitin-positive ribosome-like granular components and a few filamentous components immunoelectron-microscopically. In the cerebral cortex, ubiquitin-positive neurites were distributed in layers II-IIIab and layers V-VI, and were considered to be the distal dendrites from the small neurons. The dendrites and perikarya of these neurons contained ubiquitin-positive components similar to those in the dentate gyrus. Some ubiquitin-positive neurites were also found in the hippocampal subiculum, amygdala and striatum. The results of this study suggest that the granular cells in the dentate gyrus and the small neurons in the cerebral cortex share common ubiquitin-related and ribosome-associated abnormalities in both the perikarya and dendrites, that the degeneration of the perforant pathway caused by the parahippocampal lesion participates in the ubiquitin related abnormalities in the granular cells, and that PD cases with and without PB have common affected neurons, as shown immunohistochemically.

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.

Unsymmetrical phthalocyanine analogues with three 15-crown-5 ether voids at the 3,4-positions (MtNIL, MtBZ, MtNAP) (Mt = Zn, Cu) have been synthesized and characterized. Their dimerization is induced by addition of some cations, particularly Rb2+ and K+. Cofacial dimer formation in the presence of these cations proceeds in a two-step three-stage process, as indicated by absorption and emission spectroscopy. These cofacial species have a highly specific C2v eclipsed configuration providing well-defined dimeric species for spectroscopic analysis. The ESR spectra of the cation-induced dimeric copper derivatives show axial symmetry and may be analyzed in terms of interplanar separation of 4.2 A. CuNAP alone forms a cofacial dimer even in the presence of Na+ or Cs+, and the estimated interplanar distances are 4.1−4.2 A without depending on the size of cations. The 1H NMR spectra of zinc dimers are consistent with a cofacial configuration. Magnetic circular dichroism (MCD) spectra of C2v type monomers can be in...

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.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.(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.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.

A monomer and sandwich dimer (so-called “blue form”) of lutetium tetra-tert-butylpyrazinoporphyrazine have been synthesized and characterized by electronic absorption and magnetic circular dichroism spectroscopy (MCD), together with cyclic- and differential-pulse-voltammetry. A-term MCD dispersions appear in the Q and B bands, especially corresponding in each of the split Q bands of the dimer. The potential difference between the 1st-oxidation and -reduction of the monomer is 1.98 V and that between the 1st- and 2nd-reduction is 0.72 V in o-dichlorobenzene (DCB). The dimer shows 7 redox couples.

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.

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.

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.

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.

Background: Atypical Pick’s disease without Pick bodies is a type of frontotemporal dementia characterised by semantic dementia and temporal dominant lobar atrophy with ubiquitinopathy. No neurochemical analyses have ever been reported in this condition. Objective: To investigate muscarinic acetylcholine receptors (mAchR) and their subtypes (M1–M4) in atypical Pick’s disease. Subjects: Five cases of atypical Pick’s disease were studied. They were compared with nine control cases, 11 cases of Alzheimer’s disease, and seven cases of dementia with Lewy bodies. Methods: A [ 3 H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation assay using subtype specific antisera were used. Results: The total amount of mAchR in the temporal cortex was lower in atypical Pick’s disease than in controls or Alzheimer’s disease cases, but there were no significant differences between the three groups in the frontal cortex. In the temporal cortex, there was a smaller proportion of M1 receptors in atypical Pick’s disease than in the controls or in the patients with Alzheimer’s disease and dementia with Lewy bodies. In contrast, the proportion of M2 receptor was higher in atypical Pick’s disease than in the other three groups. Conclusions: Depletion of postsynaptic cholinoreceptive neurones in the temporal cortex is more severe in atypical Pick’s disease than in other neurodegenerative dementing disorders.

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.

Of the five subtypes (m1-m5) of muscarinic acetylcholine receptors (mAChR), the m1 subtype is the most abundant in the human cerebral cortex and hippocampus. Impairment of the muscarinic cholinergic system in the brain may cause cognitive dysfunction in patients with Alzheimer's disease (AD), and choline esterase inhibitors (ChE-I) are used to improve cognitive dysfunction. Severe impairment of the cholinergic system has also been reported in the brains of subjects with dementia with Lewy bodies (DLB). There have been a few reports about the distribution of mAChR subtypes in the human brain. In the present study, we investigated the distribution of m1 mAChR in the human hippocampus using an antibody against the m1 subtype. In the control brains, m1 immunoreactivity was observed in the apical dendrites and cell bodies of granular neurons of the dentate gyrus and pyramidal neurons of CA1-3 and the subiculum. The dendrites and the cell bodies of the pyramidal neurons in layers III and V of the parahippocampal cortex and other temporal cortices were also positive for m1 immunoreactivity. This m1 immunoreactivity was markedly reduced in AD and DLB brains.

We investigated immunohistochemically the localization of type 1 plasminogen activator inhibitor (PAI-1) in rat and human brain tissues. In rat, neurons and astrocytes were stained positively for PAI-1 after colchicine treatment. In post-mortem human brain, neurons were stained for PAI-1 but the number of positive neurons varied greatly from case to case. PAI-1 positive astrocytes occurred in the white matter lesions of some patients. In Alzheimer's disease, weak PAI-1 labeling was seen in association with senile plaques and ghost tangles. The present results support a notion that PAI-1 and its target proteases such as plasminogen activators and thrombin are involved in a variety of physiological and pathological processes in brain.

Telencephalin (TLN) is a cell adhesion molecule expressed in the telencephalon of the mammalian central nervous system. We have investigated immunohistochemically the expression of TLN in human brain tissue from control subjects and patients with Alzheimer's disease (AD). In control brain, neuropil of the gray matter was stained diffusely with the anti-TLN antibody. TLN immunoreactivity was markedly decreased in the brain of AD patients, particularly in the hippocampal formation.

cis-Platinum complexes of aromatic amines were synthesized in water or at the interfacial layer between water and an organic solvent. The position of substitution of aniline derivatives had a marked effect on the synthesis of the complexes. The coordination of 2-substituted anilines needed a long time and the yields were low. That of 3- or 4-substituted anilines was fast, and the yields were high. Disubstituted or N-substituted anilines needed fairly long reaction times and the yields were lower than those of monosubstituted anilines; sometimes unidentified complexes were obtained or no reaction product was formed.Six synthesized cis-dichloro platinum(II) complexes which coordinate bis(4-aminophenol), bis(3-toluidine), bis(2-aminobiphenyl), bis(4-sulfamidoaniline), bis(1-naphthylamine) and bis(4-phenylazo-1-naphthylamine) had high antitumor activities against Sarcoma 180 ascites in female ICR/JCL mice. The dose of platinum of these effective complexes given to the mice was in the range of 7.37-105.76 mg/kg (26.44%-39.96%). This result suggests that the toxicity of the platinum complexes might depend on their carrier ligands.

Host–guest complexation between γ-cyclodextrin (γ-CD, cyclo-octa-amylose) and pyrene has been studied in detail by fluorescene and induced circular dichroism (i.c.d.) spectra. γ-CD forms complexes with pyrene with 1 : 1, 1 : 2, 2 : 1, and 2 : 2 stoicheiometries at ambient temperature. The inclusion of pyrene by γ-CD proceeds stepwise; γ-CD including only one pyrene molecule can accommodate a second pyrene molecule to produce a 1 : 2 and/or 2 : 2 complex. Both in a monomolecularly dispersed pyrene solution and in a suspended pyrene solution, several hours are required for γ-CD to include two pyrene molecules. The configuration of two pyrenes included is an S-helix. At temperatures above ca. 85 °C, a 1 : 1 complex alone is formed mainly, where a pyrene molecule is accommodated with its long axis parallel to the axis of γ-CD. The data are compared with those of the systems containing β-CD (cyclohepta-amylose) in place of γ-CD.

A kinetic study of Pt-blue complex formation was carried out in a solution containing [Pt (NH3)2 (H2O)2]2+ and uracil under oxygen bubbling, with monitoring by means of an oxygen analyzer and visible spectrometer. The rate of oxygen consumption was first-order with respect to concentration of [Pt (NH3)2 (H2O)2]2+, uracil, or oxygen. A correlation was found between the decrease of oxygen consumption in the solution and the increase of the absorbance at 640 nm, namely formation of the blue complex. The formation mechanism of the blue complex is considered to be 1) first the equilibrium reaction of the coordination of uracil to Pt, 2) next the oxidation of the Pt-uracil complex with oxygen, and 3) finally a follow-up reaction presumably via formation of polynuclear complexes. Eight other blue complexes were formed by the use of N-aromatic base ligands possessing an amide linkage. The oxygen consumption rates of these complexes were found to be large in the case of the ligands which form many structurally isomeric complexes.

Enamine annulation between 3,4-dihydro-1-methyl-β-carboline (4) and dimethyl 3-methoxyallylidenemalonate (5) yielded 2-(2,2-dimethoxyethyl)-2,3,4,6,7,12-hexahydro-3-methoxycarbonyl-4-oxoindolo [2,3-a]quinolizine (6), which was transformed into (±)-dihydrocorynantheol (1). (±)-Corynantheal (19), which is convertible into (±)-corynantheine (2) and (±)-ajmalicine (3), was stereoselectively synthesised from (6)via empimerisations at the angular position using Adams catalyst.

cis-Dichloroplatinum complexes of nitrogen cyclic compounds and sulfur-containing compounds were synthesized through the reaction of K2PtCl4 with the corresponding ligands in water or an interfacial layer between water and an organic solvent. The effect of substituents of pyridine derivatives on the synthesis of the cis-platinum complexes depended greatly on their position. The coordination of 2-substituted pyridines required a long reaction time and the yields were low. That of 3- or 4-substituted pyridines proceeded smoothly in high yields. The complexes coordinating dimethyl- or trimethyl-substituted pyridines were obtained in low yields, but a methyl group at the para position increased the coordination activity of pyridines. The reactivity of other nitrogen cyclic compounds depended greatly on their structures and no clear correlation between structure and reactivity was observed. In some cases, polynuclear or unidentified complexes were formed. Sulfurcontaining compounds reacted smoothly in high yields.Three synthesized cis-dichloroplatinum(II) complexes coordinating di(3-methylpyridine), di(quinoline) and di(isoquinoline) and a polynuclear platinum piperidine complex (Pt4Cl5(OH)3-(C5H11N)6·3H2O) had high antitumor activities against Sarcoma 180 ascites in female ICR/CRJ mice. The required platinum weight of these effective complexes for antitumor activity was in the range of 23-94 mg/kg in mice compared with 5 mg/kg in the case of cis-dichlorodiammineplatinum.

cis-Dichloroplatinum complexes of nitrogen cyclic compounds and sulfur-containing compounds were synthesized through the reaction of K2PtCl4 with the corresponding ligands in water or an interfacial layer between water and an organic solvent. The effect of substituents of pyridine derivatives on the synthesis of the cis-platinum complexes depended greatly on their position. The coordination of 2-substituted pyridines required a long reaction time and the yields were low. That of 3- or 4-substituted pyridines proceeded smoothly in high yields. The complexes coordinating dimethyl- or trimethyl-substituted pyridines were obtained in low yields, but a methyl group at the para position increased the coordination activity of pyridines. The reactivity of other nitrogen cyclic compounds depended greatly on their structures and no clear correlation between structure and reactivity was observed. In some cases, polynuclear or unidentified complexes were formed. Sulfurcontaining compounds reacted smoothly in high yields.Three synthesized cis-dichloroplatinum(II) complexes coordinating di(3-methylpyridine), di(quinoline) and di(isoquinoline) and a polynuclear platinum piperidine complex (Pt4Cl5(OH)3-(C5H11N)6·3H2O) had high antitumor activities against Sarcoma 180 ascites in female ICR/CRJ mice. The required platinum weight of these effective complexes for antitumor activity was in the range of 23-94 mg/kg in mice compared with 5 mg/kg in the case of cis-dichlorodiammineplatinum.

cis-Platinum complexes of aromatic amines were synthesized in water or at the interfacial layer between water and an organic solvent. The position of substitution of aniline derivatives had a marked effect on the synthesis of the complexes. The coordination of 2-substituted anilines needed a long time and the yields were low. That of 3- or 4-substituted anilines was fast, and the yields were high. Disubstituted or N-substituted anilines needed fairly long reaction times and the yields were lower than those of monosubstituted anilines; sometimes unidentified complexes were obtained or no reaction product was formed.Six synthesized cis-dichloro platinum(II) complexes which coordinate bis(4-aminophenol), bis(3-toluidine), bis(2-aminobiphenyl), bis(4-sulfamidoaniline), bis(1-naphthylamine) and bis(4-phenylazo-1-naphthylamine) had high antitumor activities against Sarcoma 180 ascites in female ICR/JCL mice. The dose of platinum of these effective complexes given to the mice was in the range of 7.37-105.76 mg/kg (26.44%-39.96%). This result suggests that the toxicity of the platinum complexes might depend on their carrier ligands.

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.