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Neutron reflectometry (NR) has been utilized to study the electric double layer (EDL) of ionic liquids (ILs), however, further improvement of the sensitivity toward interfacial structure would be desirable. We recently proposed two ways to improve the NR sensitivity toward the EDL structure at the IL/electrode interface (J. Phys. Chem. C, 123 (2019) 9223). First, as the electrode, a thin film of metal (Nb) was used with the scattering length density (SLD) and thickness controlled to sensitively analyze the potential dependent EDL structure. Second, the IL cation and anion were chosen so that they have large size and large SLD difference, both of which also increase the sensitivity. In the present study, we have further explored this rational material design for the sensitivity enhancement, by changing the film metal from Nb to Bi whose SLD is closer to those for two bulk materials: Si and the IL used, trihexyltetradecylphosphonium bis(nonafluorobutanesulfonyl)amide. We successfully observed not only the first ionic layer in the EDL but also the overlayers, revealing that the IL cation is specifically adsorbed on the electrode and that the cation-rich first layer induces overscreening in the overlayers up to the third ionic layer.

A neutron spin echo experiment for tiny samples with high energy resolution can be realized by combining modulated intensity by zero effort (MIEZE) technique and ellipsoidal neutron focusing supermirrors. We observed TOF–MIEZE (the time-of-flight method with MIEZE) signals with an effective frequency of 108 kHz with focusing beam. The Fourier time range 0.48–5.3 ns was covered at once by using TOF technique with neutron wavelength 0.65–1.45 nm. The contrasts of TOF–MIEZE signal were 0.62 ± 0.02 and 0.50 ± 0.05 with each neutron wavelength of 0.68 nm and 1.35 nm, respectively.

We report on first experimental tests of a neutron magnetic spin resonator at a very cold neutron beam port of the high flux reactor at the ILL Grenoble. When placed between two supermirror neutron polarizers and operated in a pulsed traveling-wave mode it allows to decouple its time- and wavelength-resolution and can therefore be used simultaneously as electronically tunable monochromator and fast beam chopper. As a first ‘real’ scientific application we intend its implementation in the PERC (p roton and e lectron r adiation c hannel) project related to high-precision experiments in neutron beta decay.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a total upending of our daily lives. While anxiety and depression were frequently reported among the general population, the pandemic’s impact on patients with mental health problems remains unknown. Methods: A cross-sectional questionnaire survey involving 1,166 patients was conducted at one psychiatric hospital and one mental health clinic. Results: Symptom deterioration was reported in 23% to 34% of the patients and 9% to 20% reported increase in drug dosage. No significant differences were reported in these items among diagnostic categories. Patients with F3 (mood disorders) reported more psychological stress during the pandemic’s beginning and during the emergency. Patients with F2 (schizophrenia, schizotypal, and delusional disorders) did online shopping and meetings less frequently, and reported poorer adherence of 3C’s, while mask management was stricter in patients with F4 (neurotic, stress-related, and somatoform disorders). Symptom deterioration was significantly associated with increase in drug dosage, new physical symptoms, anxiety unrelated to COVID-19, stress at the beginning of pandemic, stress during the ‘state of emergency’, poor adaptability to environmental change, daily life changes, decrease in sleeping time, and decrease in time spent outside. Conclusion: One third of patients reported symptom deterioration during the pandemic, which was associated with stress and daily life changes. Patients with good adaptability to environmental changes might resilient against symptom deterioration. Providing continuous support to help patients manage their daily life in this COVID-19 era may minimize the risk of symptom deterioration.

The mesolimbic dopamine (DA) system has been associated with the pathogenesis of schizophrenia. Here, we show DA-containing neuronal structures of the ventral tegmental area (VTA) of an autopsy case of disorganized type of schizophrenia (75 year-old female), using tyrosine hydroxylase (TH) immunohistochemistry. A free floating method using 50-\(\mu\)m cryostat sections and three-dimensional imaging analyzer AvioVision were applied to observe wide range structures of TH-immunoreactive (-ir) neurons. TH-ir neuronal cell bodies in the VTA of the present case varied in shape and size, and TH-ir neuronal processes had irregular thickness, straightened shape, or curved shape having many corners, when compared with a control autopsy case with no detectable neurological and psychiatric diseases (64 year-old male). Mean volume of the nerve cells is diminished in the VTA of drug-naive schizophrenia. The mechanisms underlying the morphological characteristics of DA neurons of the brains with schizophrenia should further be elucidated epigenetically as well as genetically.

The neutron spin-echo spectroscopy technique involving pulsed beams can be used to effectively access a wide range of space-time correlations of condensed matter. In this study, the features of this technique, in particular, the modulation of the intensity with zero effort (MIEZE) by using pulsed beams, which is based on the quantum-state manipulation of the neutron spin and energy, are comprehensively examined. A formulation of the MIEZE combined with the time of flight method (TOF MIEZE) is established by considering the characteristics of the pulsed neutron beams. Moreover, a parameter, namely, the detuning parameter, is introduced as a measure of the magnitude of detuning from the optimized instrumental state, known as the spin-echo condition. The phase and frequency shifts of the neutron intensity signals resulting from the TOF MIEZE under various configurations are investigated systematically. It is found that the detuning parameter equals the derivative of phase with respect to the TOF, whose zero-point corresponds to the spin-echo condition. The theoretical predictions on phase and frequency shifts by the established formulation are well validated by the experiments using an intense pulsed neutron source. The detuning parameter helps clarify the principle of the TOF MIEZE technique and can provide practical guidance regarding the implementation and optimization of spectrometers.

We are developing a neutron polarizer with polarized $^3$He gas, referred to as a $^3$He spin filter, based on the Spin Exchange Optical Pumping (SEOP) for polarized neutron scattering experiments at Materials and Life Science Experimental Facility (MLF) of Japan Proton Accelerator Research Complex (J-PARC). A $^3$He gas-filling station was constructed at J-PARC, and several $^3$He cells with long spin relaxation times have been fabricated using the gas-filling station. A laboratory has been prepared in the MLF beam hall for polarizing $^3$He cells, and compact pumping systems with laser powers of 30~W and 110~W, which can be installed onto a neutron beamline, have been developed. A $^3$He polarization of 85% was achieved at a neutron beamline by using the pumping system with the 110~W laser. Recently, the first user experiment utilizing the $^3$He spin filter was conducted, and there have been several more since then. The development and utilization of $^3$He spin filters at MLF of J-PARC are reported., Comment: 9 pages, 15 figures

Neutron reflectometry (NR) has been performed at the electrochemical interface between a Nb film and an ionic liquid, trihexyltetradecylphosphonium tetrakis(pentafluorophenyl)borate ([THTDP+][PFPB–...

Neutron spin echo technique is essential for high resolution inelastic and quasi-elastic neutron scattering experiments. We have developed a neutron resonance spin echo (NRSE) spectrometer at BL06 in Materials and Life Science Experimental Facility (MLF), Japan Proton Accelerator Research Complex (J-PARC), and installed a pair of 900 mm long ellipsoidal focusing m = 5 supermirrors with 2.5 m focal length. In this manuscript, we report the first result of time-of-flight neutron spin echo signals by the NRSE instrument.

In this study, we propose a phase correction method for a type of neutron spin echo spectroscopy, known as modulation of intensity with zero effort using a time-of-flight method (TOF-MIEZE). The phase of the MIEZE signal sensitively varies with the neutron flight path lengths. The geometrical lengths from the sample position to the flat detector plane differ depending on the positions on the detector plane. Integrating the phase-shifted signals may decrease the signal contrast solely through the geometrical path-length deviations. To measure the decrement of contrast accurately, which corresponds to the intermediate scattering function, the position-dependent phase shifts must be corrected. The data correction is performed by shifting the MIEZE signal in time depending on path-length deviations, the MIEZE frequency, and neutron wavelengths. In the calculation of path-length deviations, the sample is assumed to be a point scatterer while a detector inclination is taken into account. We also discuss the relation between the frequency shift of TOF-MIEZE signal and path-length deviation, which is helpful to quantify phase shifts larger than 2 π . The presented phase correction method is demonstrated with a 32 × 32 cm 2 area detector for a 200 kHz TOF-MIEZE signal scattered from an elastic sample.

A neutron guide system for neutron resonance spin echo spectrometers has been constructed at BL06 of the Japan Proton Accelerator Research Complex, Materials and Life Science Experimental Facility....

We report the first experimental test of TOF-MIEZE technique using very cold neutrons (VCNs) towards high-resolution quasi-elastic neutron scattering spectroscopy . TOF-MIEZE is a type of neutron resonance spin echo spectroscopy with a combination of the time-of-flight (TOF) method and modulation of intensity by zero effort (MIEZE). A compact MIEZE instrument was constructed at the VCN beam port at the High Flux Reactor at the Institut Laue Langevin. By accumulating individual oscillations of raw data, we observed a TOF-MIEZE signal with an effective frequency of 50 kHz in a wavelength band of 4–6 nm. The signal contrasts were 0.59 ± 0.04 and 0.29 ± 0.03 for wavelengths of 4 nm and 6 nm, respectively. The Fourier time was estimated to be 70 ns with 6 nm VCNs in the experimental set-up.

This paper reports imaging of objects with slow neutrons, specifically very cold neutrons and cold neutrons, at Institut Laue Langevin, using novel, permanent magnet (Nd2Fe14B) compound refractive lenses (MCRL) with a large 2.5 cm bore diameter. The MCRL focuses and images spin-up neutrons and defocuses spin-down neutrons via a large, radial magnetic field gradient. A single lens neutron microscope, composed of an MCRL objective lens with 2-fold magnification, was tested using very cold (slow) neutrons at 45 A wavelength. One-to-one imaging was obtained using 16.7 A polarized neutrons. The magnetic field gradient of the MCRL was measured by raster-scanned pencil beams on D33. Finally, a compound neutron microscope was realized using an MCRL condenser lens, which provided increased illumination of objects, and an MCRL as objective lens to produce 3.5-fold magnification.

Neutron spin phase correction is an essential technique for achieving a high energy resolution in neutron spin-echo experiments. We propose a double-focusing geometry in which two identical ellipsoidal mirrors are arranged in series. This arrangement enables us to correct the path length differences for large divergent beams using a complete ellipsoidal focusing mirror. In this study, we evaluated the effectiveness of this geometry both analytically and numerically. A Fourier time of 1 μ s is achievable using this geometry.

We describe a film coating facility for the development of multilayer mirrors for use in neutron optical devices that handle slow neutron beams. Recently, we succeeded in fabricating a large neutron supermirror with high reflectivity using an ion beam sputtering system (KUR-IBS), as well as all neutron supermirrors in two neutron guide tubes at BL06 at J-PARC/MLF. We also realized a large flexible self-standing m =5 NiC/Ti supermirror and very small d -spacing ( d =1.65 nm) multilayer sheets. In this paper, we present an overview of the performance and utility of non-magnetic neutron multilayer mirrors fabricated with the KUR-IBS

A modulated intensity by zero effort (MIEZE) spectrometer is a type of neutron-resonance spin-echo spectrometer and can be used to analyze the slow dynamics of condensed matter by measuring the intermediate scattering function I(Q,τ). A crucial feature of a MIEZE spectrometer is it leaves completely free the space between the sample and the detector because the sample is placed after the neutron-spin analyzer. Measuring the magnetic dynamics with a conventional neutron-spin-echo spectrometer is difficult, but with a MIEZE spectrometer such a measurement may be done simply by introducing a second analyzer after the sample. Measuring the magnetic dynamics with high precision requires the background to be reduced to a minimum and is a job for which a 3He neutron-spin filter (3He-NSF) is a promising candidate as a second analyzer. However, one difficulty with this approach is the diffusion of 3He gas from the 3He-NSF, which may be measured and interpreted as dynamics. Therefore, we investigate herein whether the dynamics of gas diffusion is detected when using a 3He-NSF as second analyzer in a MIEZE spectrometer. Toward this end, we experimented with the MIEZE spectrometer installed at beamline 06 (BL06) at the Materials and Life Science Experimental Facility at Japan Proton Accelerator Research Complex (J-PARC MLF). The results confirm that the gas-diffusion dynamics of the 3He-NSF are not detected, and that the 3He-NSF, therefore, can be used as a second analyzer in this MIEZE spectrometer.

A new beam line for neutron resonance spin echo spectrometers is under construction at BL06 in the Materials and Life Science Facility (MLF) of the Japan Proton Accelerator Research Complex (J-PARC). To design the radiation shielding in the setup for commissioning experiments we have performed the neutron beam transport calculation and dose evaluation via Monte Carlo method in the three-dimensional geometry. The radiation dose rates were kept below about 6 μSv/h outside of the thickness of 30 cm concrete shield surrounding the experimental area. We propose the conceptual design of radiation shielding of the beam line and simulation result playing an important role in determining engineering design and starting the construction.

By inserting two-dimensional (2D) elliptical focusing mirrors between each pair of RSFs in neutron resonance spin echo spectrometer, the flight path lengths between the pair of RSFs can be made equal even for any divergent beam. We investigate numerically the feasibility of using polygonal 2D elliptical focusing mirrors as beam correction devices, and we show the relation of the energy resolution and the neutron intensity including effect of gravity.

We propose a basic formula and demonstration for a high-resolution quasi-elastic neutron scattering (QENS) by combining the time-of-flight (TOF) method with Modulation of Intensity by Zero Effort (MIEZE) type neutron spin echo spectroscopy. The MIEZE technique has the potential to develop a unique approach to study on slow dynamics of condensed matter; however, the energy resolution is limited owing to the hypersensitivity of the MIEZE signal contrast to the echo condition, which is strongly affected by the alignment of the instruments and the sample. The narrow allowance of the optimal alignment is a major obstacle to the wide use of this technique. Combining the TOF method with MIEZE (TOF-MIEZE), the hypersensitivity of MIEZE signals is significantly alleviated with a short pulsed beam. This robustness is very useful to optimize experimental alignments and enables accurate measurements of QENS. The experimental results demonstrate the characteristic of the TOF-MIEZE technique and are well described by the formula presented in this study.

Results of this study demonstrated that electroless nickel-phosphorus (NiP) plated metal substrate is an excellent material for producing large aspherical neutron-focusing supermirrors. A large plano-elliptical neutron-focusing supermirror comprising two metallic segments was fabricated using single-point diamond cutting, precision polishing and supermirror coating. The average surface roughness of the metallic substrates was approximately 0.3 nm rms. For evaluation, the focusing supermirror was installed at the SOFIA neutron reflectometer, showing high neutron reflectivity and giving minimal beam width of 0.34 mm in FWHM. Because of the large beam divergence accepted by the mirror, the count rate with the focusing mirror was 3.3 times higher than that obtained using conventional two-slit collimation.

Novel horizontal-type time-of-flight neutron reflectometer SOFIA (SOFt Interface Analyzer) was installed in BL 16 of Materials and Life Science Experimental Facility at the Japan Proton Accelerator Research Complex (J-PARC). The design and performance of SOFIA reflectometer was described based on the preliminary results of the neutron reflectivity (NR) measurements of deuterated polystyrene (d-PS) thin films, Langmuir–Blodgett film and at deuterium oxide/ polymer brush interfaces. Time-resolved in-situ NR measurement at 1-min intervals was also demonstrated to observe interfacial mixing of d-PS on the PS brush surface during annealing.

No clear clinical syndrome for argyrophilic grain disease (AGD) has yet been identified. Previous studies have documented its clinical features, namely, personality changes characterized by emotional disorder involving aggression or ill temper and relatively well-preserved cognitive function, but the clinical manifestations of delusions and hallucinations as they appear in AGD have not been thoroughly described. Here, we report on a 72-year-old Japanese AGD patient who showed psychiatric symptoms, memory impairment and emotional change. He perceived and described a person who was not present and tried to grasp things on the floor though nothing was there. He also insisted that somebody was watching him and consequently always kept his curtains closed. These psychiatric symptoms were observed at an early stage in the patient's disease course. Serial neuroradiological examination showed progressive atrophy of the bilateral temporal lobes. The patient died at 79 years-of-age. Microscopic neuropathological examination showed transactivation responsive region (TAR)-DNA-binding protein of 43 kDa (TDP-43) positive structures in addition to widespread argyrophilic grains and coiled bodies. According to recent recommendations for pathological diagnosis, this case corresponds to AGD with limbic TDP-43 pathology. This case shows that patients with AGD that is eventually confirmed through autopsy can present with delusions and hallucinations early in the course of their disease. The clinical significance of TDP-43 pathology in the brains of patients with AGD remains uncertain.

Aim: The aim of the present study was to evaluate the relationship between aging and the behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer’s disease (AD). Methods: Eligible subjects were consecutively referred AD patients with BPSD. According to patient age at the time of the test, the AD patient group (n = 79, whole AD group (WADG)) was divided into two groups: a relative older group (OG) in the whole AD group (WAD) (age at the time of test was 81 years or more, n = 40) and a relative younger group (YG) in the WAD (age at the time of test was below 81 years, n = 39). A comparison was made of the demographic data (sex difference, educational level and severity of dementia), cognitive functions and BPSD between the groups. BPSD was evaluated using the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). The factor analysis of BPSD was conducted in the WADG as well as in the OG and YG. Results: Sex difference, educational level, severity of dementia and cognitive functions were not different; however, the total score of the BEHAVE-AD symptom domain in diurnal rhythm was significantly higher in the OG than in the YG (Student’s t-test: P < 0.05). Factor analysis showed that psychosis was the first factor in the OG, but was the third factor in the YG and that the psychotic symptoms were caused by anxieties and phobias in the OG. Conclusion: From these results, we found that the effects of aging on the BPSD in AD were characterized by diurnal rhythm disturbance and psychosis.

Objective TAR DNA-binding protein of 43kDa (TDP-43) is deposited as cytoplasmic and intranuclear inclusions in brains of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Previous studies reported that abnormal phosphorylation takes place in deposited TDP-43. The aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance of phosphorylation of TDP-43. Methods We generated multiple antibodies specific to phosphorylated TDP-43 by immunizing phosphopeptides of TDP-43, and analyzed FTLD-U and ALS brains by immunohistochemistry, immunoelectron microscopy, and immunoblots. In addition, we performed investigations aimed at identifying the responsible kinases, and we assessed the effects of phosphorylation on TDP-43 oligomerization and fibrillization. Results We identified multiple phosphorylation sites in carboxyl-terminal regions of deposited TDP-43. Phosphorylation-specific antibodies stained more inclusions than antibodies to ubiquitin and, unlike existing commercially available anti–TDP-43 antibodies, did not stain normal nuclei. Ultrastructurally, these antibodies labeled abnormal fibers of 15nm diameter and on immunoblots recognized hyperphosphorylated TDP-43 at 45kDa, with additional 18 to 26kDa fragments in sarkosyl-insoluble fractions from FTLD-U and ALS brains. The phosphorylated epitopes were generated by casein kinase-1 and -2, and phosphorylation led to increased oligomerization and fibrillization of TDP-43. Interpretation These results suggest that phosphorylated TDP-43 is a major component of the inclusions, and that abnormal phosphorylation of TDP-43 is a critical step in the pathogenesis of FTLD-U and ALS. Phosphorylation-specific antibodies will be powerful tools for the investigation of these disorders. Ann Neurol 2008

Aims: It clarifies a difference between early acute phase and late acute phase in medication. Methods: The present report describes three patients with schizophrenia who presented with restlessness and excitement requiring hospitalization. Results: Treatment with risperidone solution orally or parenteral haloperidol until the day after admission, followed by olanzapine, successfully improved the clinical condition of the patients. In the early stage of hospitalization, selection of fast-acting drugs that can be administered to uncooperative patients is considered preferable, focusing on rapid control of symptoms and behavioral disorders, whereas after this early stage, olanzapine is preferable for improving patient compliance in addition to stabilizing symptoms. Conclusions: Because the target symptoms differ between the early and late acute phases, the term ‘acute phase’ used in the broad sense should be divided into two units, each requiring a different therapeutic strategy, and independent clinical approaches should be considered in order to provide more suitable treatment.

Tau-negative and ubiquitin-positive inclusions (UPI) are the pathological hallmarks of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, TDP-43, a heterogeneous nuclear ribonucleoprotein was identified as a component of these UPI. However, it remains to be determined whether TDP-43 is the major component of UPI, because only antibodies recognizing both normal and abnormal TDP-43 have been available. We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43. Of the generated antibodies, pS379, pS403/404, pS409, pS410 and pS409/410 clearly labeled UPI and glial cytoplasmic inclusions but not the nuclei. Immunoblot analyses of sarkosyl insoluble fractions demonstrated that the phosphorylation-specific antibodies recognized TDP-43 at -45 kDa, smearing substances and the -25 kDa fragment, all of which were present in the brains of FTLD-U and ALS but not controls. These antibodies did not recognize normal TDP-43 at 43 kDa. These results clearly indicate that abnormally phosphorylated full-length TDP-43 and the C-terminal fragments are the major component of UPI in FTLD-U and ALS. These findings together with recent discovery of mutations in the TDP-43 gene in ALS strongly suggest that TDP-43 is the

Reported herein is a case of methamphetamine psychosis in which tardive dystonia was treated successfully with clonazepam. The patient was a 69-year-old man who had taken methamphetamine habitually for approximately 40 years. Auditory hallucinations had developed 25 years previously, for which haloperidol had been prescribed. Tardive dystonia had developed in December 2005. Haloperidol was withdrawn and risperidone or olanzapine alone had been administered, but neither had improved the dystonic posture. However, when clonazepam was added, a gradual improvement in the dystonic posture became evident. Tardive dystonia is currently treated on a trial-and-error basis. Accumulation of further cases similar to the present one is very important for establishing an effective treatment.

A patient with progressive anomia and alexia with agraphia for kanji (Japanese morphograms) is described. The patient showed a deficit in single-word comprehension and on-reading (a type of reading that conveys phonetic value) dominance in kanji reading, i.e. on-preceding (pronouncing first with on-reading, irrespective of its preferred reading) and kun-deletion (inability to recall and recognize kun-reading [another type of reading that conveys meaning]) when reading a single-character kanji. These features were due to loss of lexico-semantic information and thus the patient was regarded as having progressive Gogi (word-meaning) aphasia by Imura, a Japanese manifestation of semantic dementia. Macroscopically, neuropathological examination disclosed atrophy of the left frontotemporal lobe with accentuation in the anterior portion of the temporal lobe. Histologically, there was neuronal loss in the cerebral cortex, hippocampus, parahippocampal gyrus, amygdala, caudate nucleus, and putamen. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells. This case demonstrates that progressive Gogi aphasia is semiologically identical to semantic dementia, and our patient clinicopathologically resembled those of Rossor et al. [Rossor, M.N., Revesz, T., Lantos, P.L., Warrington, E.K. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123: 267-76.] and Hodges et al. [Hodges, J.R., Davies, R.R., Xuereb, J.H., Casey, B., Broe, M., Bak, T.H., et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56: 399-406.].

Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.

We evaluated dementia symptoms to clarify the character of dementia with Alzheimer's disease (AD) observed in the oldest old patients and that of dementia with early-onset AD. Subjects were consecutive AD inpatients admitted for the first time at age of 90 years and over because of behavioral symptoms (demented nonagenarian group: D90G; n=18) and those with 24 consecutive inpatients with AD with early-onset (EOG). The Gottfries, Brane and Steen's scale and the Dementia Behavior Disturbance scale were used to evaluate the symptoms and troublesome behaviors. The scores of these scales in D90G and in EOG were compared with those of 26 sex distribution-, severity of dementia-, and disease duration-matched inpatients with AD with late-onset (LOG). Compared with LOG, wakefulness was more impaired and waking up at night was more frequent in D90G, while memory, orientation and inappropriate behaviors were more severe in EOG. These results suggest that the clinical features of dementia in EOG were quantitatively different from those of LOG. In contrast, the clinical feature of dementia of D90G were sleep-wake pattern disturbance and were qualitatively different from those of LOG.

This report concerns a clinicopathological study of two autopsied patients with spinocerebellar ataxia 6 (SCA6), and a statistical analysis between neuronal loss of the inferior olive and disease duration of 15 SCA6 autopsy cases reported to date, including the two cases reported in this study. Cases 1 and 2 came from independent Japanese families. Case 1 developed gait disturbance at age 35 years and died at age 78 years; she had a CAG-repeat expansion of the SCA6 gene (25/13). Case 2 presented with gait disturbance at age 68 years and died at age 78 years; he had an expanded CAG-repeat of the SCA6 gene (22/13). Neuropathological examination of both cases disclosed not only neuronal loss of the Purkinje cells and inferior olive, but also some unnoticed features, including cactus-like expansion of the dendrite of Purkinje cells and relative preservation of Golgi cells in the granular layer of the cerebellum. Exploratory statistical analysis between 11 SCA6 autopsy cases with neuronal loss in the inferior olive (average disease duration: 27 years) and four SCA6 autopsy cases without neuronal loss in the olive (average disease duration: 14.5 years) was investigated by Kaplan-Meier estimates of survival and log-rank test, retrospectively. Kaplan-Meier estimates of survival revealed an obvious difference between the two groups. Survival of 10 years after the disease onset was 90.9% in the former 11 SCA6 autopsy cases, but was 50% in the latter four SCA6 autopsy cases. Furthermore, a log-rank test on the two groups disclosed a significant difference (P=0.0450). We postulate that the neuronal loss of the inferior olive in SCA6 may depend on disease duration.

This report concerns a clinicopathological study of three additional patients with corticobasal degeneration (CBD), described here for the first time, and a clinicopathological correlation between pyramidal signs and upper motor neuron involvement, in ten autopsy cases of CBD, including seven cases reported by us previously. We investigated pyramidal signs, including hyperreflexia, Babinski sign, and spasticity, and involvement of the primary motor cortex and pyramidal tract, focusing on the astrocytosis of the fifth layer of the primary motor cortex. Pyramidal signs were observed in six (60%) of the ten cases. Hyperreflexia was evident in six patients (60%), with spasticity being observed in three patients (30%). Loss of Betz cells associated with prominent astrocytosis and presence of ballooned neurons in the fifth layer of the primary motor cortex was observed in all ten cases. In all cases, involvement of the pyramidal tract was obvious in the medulla oblongata, without involvement of the pyramidal tract in the midbrain. Constant and severe involvement of the fifth layer of the primary motor cortex, including the Betz cells, has not previously been reported in CBD. We suggest that the pyramidal signs in CBD have been disregarded.

We investigated postmortem human brain tissues to determine whether systemic inflammation causes activation of vascular endothelial cells and perivascular cells. In some cases, we used serum concentrations of an acute-phase reactant, C-reactive protein (CRP), as an index of systemic inflammation. Since the serum concentration of CRP at the agonal stage was available only in a limited number of patients, we estimated the degree of systemic inflammation by the intensity of immunohistochemical staining of the residual blood in brain tissue for CRP. Expressions of intercellular adhesion molecule (ICAM)-1, CD40 and cyclooxygenase (COX)-2 were used as markers for activation of vascular endothelial cells. Activation of perivascular cells was estimated by the occurrence of HLA-DR- and CD68-positive perivascular cells. In cases without brain lesions, activation of vascular endothelial cells and perivascular cells was related to the degree of systemic inflammation. In cases with brain lesions, these cells are often activated even in the absence of systemic inflammation. We suggest that inflammatory stimuli derived from the peripheral blood and the brain parenchyma adjunctly activate vascular cells. Under such circumstances, low-grade inflammation in the pre-existing brain lesions might enhance inflammatory signaling to the brain parenchyma from the periphery. The results of this study could explain the vulnerability of neurological patients to delirium caused by systemic inflammatory conditions.

The human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic l-amino acid decarboxylase (AADC, the second-step monoamine synthesizing enzyme, =DDC: dopa decarboxylase), but not for tyrosine hydroxylase (TH, the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH, the first-step serotonin synthesizing enzyme) (Neurosci Lett 232 (1997) 111–114). These AADC (+)/TH (−)/TPH (−) neurons are named as D-neurons (Jaeger CB, Ruggiero DA, Albert VR, Joh TH, Reis DJ. Immunocytochemical localization of aromatic-l-amino acid decarboxylase. In: Bjorklund A, Hokfelt T, editors. Classical transmission in the CNS, Part I, Handbook of chemical neuroanatomy, vol. 2. Amsterdam: Elsevier, 1984. pp. 387–418). The nucleus accumbens is one of the brain regions that is involved in the pathogenesis of schizophrenia. We examined the distribution of striatal D-neurons using AADC immunohistochemistry and postmortem brains obtained by legal and pathological autopsies (nine controls (27–75 years old) and nine schizophrenics (32–78 years old), postmortem interval to fixation (PMI): 2–30 h). Because the number of AADC-positive neurons per section had a tendency to reduce in the case with longer PMI, we analyzed specimens of five controls (27–64 years old) and six schizophrenics (51–78 years old) in which the PMI was less than 8 h. The number of AADC-positive neurons was reduced in the striatum of schizophrenics compared to that of controls. The reduction was significant in the nucleus accumbens ( P t -test). D-Neurons might be involved in the pathogenesis of schizophrenia. Further studies using sex-, age- and PMI-matched controls are essential.

The microtubule-associated protein tau accumulates as cytoplasmic inclusions in Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We investigated the immunoreactivity of tau-positive structures using a panel of antibodies to epitopes spanning the entire length of the tau molecule. In ethanol-fixed brain tissues, most antibodies to the microtubule-binding domain (MBD) required formic acid (FA) treatment to stain tau inclusions in PSP and CBD. This is in contrast with the intense labeling of neurofibrillary tangles in AD without FA treatment. Pick bodies (PiB) in PiD showed an intermediate pattern with respect to the immunoreactivity of the MBD because accumulated tau in PiB mostly lacks the insertion of exon 10, and the proportion of tau phosphorylated at Ser262 is smaller than in other abnormal tau structures. Such immunohistochemical profiles appeared to correlate with the occurrence of the smeared tau on immunoblot analysis of brain homogenate. The smeared tau was more abundant in AD and PiD than in PSP and CBD. Since the smeared tau was N-terminally truncated and was characteristic of advanced forms of modified tau, these findings suggest that tau accumulated in AD and PiD was processed more markedly than that in PSP and CBD. The MBD of tau may be masked in the presence of the intact N terminus and require FA treatment for antibody recognition in tissue sections. Advanced modification may expose the MBD in brain tissues of AD and PiD. It is suggested that the processing of abnormally accumulated tau characterizes the pathophysiology of each tauopathy.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated tau with four microtubule-binding repeats. Although PSP and CBD have distinctive pathological features, no biochemical difference in aggregated tau has been identified. In this study, we examined the brains of eight patients with PSP, six patients with CBD, and one atypical case with pathological features of both CBD and PSP. On immunoblots of sarkosyl-insoluble brain extracts, a 33kDa band predominated in the low molecular weight tau fragments in PSP, whereas two closely related bands of approximately 37kDa predominated in CBD. Immunoblots of the atypical case showed both the 33kDa band and the 37kDa doublet. Protein sequencing and immunochemical analyses showed that the 33kDa band and the 37kDa doublet consisted of the carboxyl half of tau with different amino termini. These results suggest that, despite the identical composition of tau isoforms, different proteolytic processing of abnormal tau takes place in these two diseases. Such a biochemical divergence may be related to the neuropathological features of these diseases.

We investigated the occurrence of T cells in the brain parenchyma of Alzheimer's disease (AD), non-AD degenerative dementias and controls by semi-quantitative analysis of immunohistochemically stained tissue sections. In all cases, we found at least some T cells. The number of T cells was increased in the majority of AD cases compared with other cases. The phenotype of T cells in the AD brain indicates that they are activated but are not fully differentiated. Antigen-triggered clonal expansion is not likely to take place. Local inflammatory conditions might cause accumulation and activation of T cells in the AD brain.

Background: As wandering in the demented is difficult to define qualitatively, we tride to define it quantitatively. We investigated the relationship between wandering and rhythm abnormalities. Methods: In order to study the pacing rhythms of wanderers observed in a subgroup of demented inpatients (dementia due to Alzheimer's disease and vascular dementia), we assessed 1 15 inpatients in terms of steps during four parts of a day and total daily steps using a pedometer. As the mean+2 S.D. of total daily steps in the nondemented was 9,979, we defined 10,000 steps in a day as the cut off for defining demented wanderers versus nonwanderers. Then, the pacing rhythms (nadir part and amplitude) were compared among demented wanderers, demented nonwanderers and nondemented subjects. Results: That there were no statistically significant differences among the three groups. But wandering groups defined by pedometer exhibited many of the same characteristics in wanderers observed in other studies. Conclusion: The quantification of steps might provide a good hallmark of wandering behaviors in the demented, and these results might indicate hyperpacing rather than rhythm dysfunctions to be essential to wandering behavior.

To clarify different features of cytoskeletal pathology in neocortical neurons between corticobasal degeneration (CBD) and Alzheimer's disease (AD), the relationship between neurofibrillary tangles (NFTs), which are defined as a fibrillary structure stained by the Bodian method, and tau-immunopositive neurons in layers II-III of the premotor cortex was assessed by sequential staining for tau immunohistochemistry followed by the Bodian method on the same section. In AD brains, tau-like immunoreactivity in neurons was uniformly colocalized with Bodian-positive NFTs. In CBD brains, however, tau-immunopositive neurons could be classified into three different types: (1) those not stained at all by the Bodian method (diffuse cytoplasmic type), which represented the majority of these immunopositive neurons, (2) some partly stained by the Bodian method (mixed type), and (3) a few for which argyrophilia demonstrated by the Bodian method was completely colocalized with immunoreactivity (NFT type). This discrepancy between tau-like immunoreactivity and Bodian method is characteristic of CBD and suggests that the tau molecule is less liable to form argyrophilic fibrils in neocortical neurons of CBD.

Spinocerebellar ataxia type 6 (SCA6) is caused by small CAG repeat expansion in the gene encoding the alpha1A-voltage-dependent-calcium channel subunit (CACNLIA4) on chromosome 19p13, and is a subgroup of the late-onset pure cerebellar ataxia (ADCA III). To investigate the prevalence of SCA6 in the Japanese, we analyzed this mutation in 23 families and 12 probands with ADCA III. The specificity and stability of the CAG repeat were examined in additional individuals and families with other miscellaneous dominant SCAs. The CAG expansion of SCA6 gene was exclusively observed in 12 of 23 families (52%) and 12 proband cases with ADCA III, but not in others. The CAG repeat was 21-33 in the disease-associated alleles (n=56), and 4-18 in normal alleles (n=1148). Expanded alleles were stable during transmission, and a significant inverse correlation for CAG repeat number with age at onset was noted. Our results indicate that SCA6 shares approximately half of the ADCA III in the Japanese, and that gene mutations causing the remaining, have yet to be identified.