Yuichi Hayashi

Glial fibrillary acidic protein mutations in adult‐onset Alexander disease: clinical features observed in 12 Japanese patients

Yoshida T, Sasayama H, Mizuta I, Okamoto Y, Yoshida M, Riku Y, Hayashi Y, Yonezu T, Takata Y, Ohnari K, Okuda S, Aiba I, Nakagawa M. Glial fibrillary acidic protein mutations in adult‐onset Alexander disease: clinical features observed in 12 Japanese patients. u2028Acta Neurol Scand: 2011: 124: 104–108.u2028© 2010 John Wiley & Sons A/S.

Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of 99mTc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt–Jakob disease

We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT.

Reduction in the numbers of drugs administered to elderly in-patients with polypharmacy by a multidisciplinary review of medication using electronic medical records.

Polypharmacy is a major problem for elderly patients in developed countries. We investigated whether a multidisciplinary medication review using electronic medical records could reduce the number of drugs administered to elderly patients receiving polypharmacy.

An autopsy-verified case of FTLD-TDP type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease

ABSTRACT Here we report an autopsy-verified case of frontotemporal lobar degeneration (FTLD)-transactivation responsive region (TAR) DNA binding protein (TDP) type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD). A 69-year-old woman presented with an 11-month history of progressive dementia, irritability, insomnia, and gait disturbance without a family history of dementia or prion disease. Neurological examination revealed severe dementia, frontal signs, and exaggerated bilateral tendon reflexes. Periodic sharp-wave complexes were not observed on the electroencephalogram. Brain diffusion MRI did not reveal abnormal changes. An easy Z score (eZIS) analysis for 99mTc-ECD-single photon emission computed tomography (99mTc-ECD-SPECT) revealed a bilateral decrease in thalamic regional cerebral blood flow (rCBF). PRNP gene analysis demonstrated methionine homozygosity at codon 129 without mutation. Cerebrospinal fluid (CSF) analysis showed normal levels of both 14-3-3 and total tau proteins. Conversely, prion protein was slowly amplified in the CSF by a real-time quaking-induced conversion assay. Her symptoms deteriorated to a state of akinetic mutism, and she died of sudden cardiac arrest, one year after symptom onset. u2003Despite the SPECT results supporting a clinical diagnosis of MM2-thalamic-type sCJD, a postmortem assessment revealed that this was a case of FTLD-TDP type A, and excluded prion disease. Thus, this case indicates that whereas a bilateral decreasing thalamic rCBF detected by 99mTc-ECD-SPECT can be useful for diagnosing MM2-thalamic-type sCJD, it is not sufficiently specific. Postmortem diagnosis remains the gold standard for the diagnosis of this condition.

B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) levels in cerebrospinal fluid of patients with meningoencephalitis

The B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) are important factors for the survival of transitional and mature B cells. High levels of BAFF and APRIL are present in adults with several autoimmune diseases. However, there are few reports about BAFF and APRIL levels in the cerebrospinal fluid (CSF) of patients with meningoencephalitis. We evaluated BAFF and APRIL levels in CSF samples from patients with viral meningitis (VM) (28 patients), autoimmune encephalitis (AE) associated with antineuronal antibodies (15 patients), idiopathic normal pressure hydrocephalus (iNPH) (11 patients), herpes simplex encephalitis (HSE) (9 patients), bacterial meningitis (BM) (6 patients), and cryptococcal meningitis (CM) (4 patients). The CSF BAFF levels were significantly higher in patients with HSE, BM, or VM than AE or iNPH, and significantly higher in patients with CM than iNPH. The CSF APRIL levels were significantly higher in patients with HSE or BM than AE, VM, or iNPH. Although this is a preliminary report due to within-group variation and small sample size, the data suggest that CSF BAFF and APRIL levels are increased in HSE and BM, but not AE.

Association between naturally occurring anti-amyloid β autoantibodies and medial temporal lobe atrophy in Alzheimer's disease

Background Naturally occurring autoantibodies against amyloid β (Aβ) peptide exist in the serum and cerebrospinal fluid (CSF) of healthy individuals. Recently, it was reported that administration of intravenous immunoglobulin at the mild cognitive impairment (MCI) stage of Alzheimers disease (AD) reduces brain atrophy. Objective To examine the association between naturally occurring anti-Aβ autoantibodies and brain atrophy in patients with cognitive impairment. Methods Serum and CSF levels of anti-Aβ autoantibodies and CSF biomarkers were evaluated in 68 patients with cognitive impairment, comprising 44 patients with AD, 19 patients with amnestic MCI and five patients with non-Alzheimers dementia. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volume of interest (VOI) in medial temporal structures, including the whole hippocampus, entorhinal cortex and amygdala. Results CSF levels of anti-Aβ autoantibodies were inversely correlated with the extent and severity of VOI atrophy, and the ratio of VOI/grey matter atrophy in patients with AD, but not in MCI or non-AD patients. Serum levels of anti-Aβ autoantibodies were not associated with these parameters in any of the patient groups. Conclusions These results indicate that CSF levels of naturally occurring anti-Aβ autoantibodies are inversely associated with the degree of the VOI atrophy in patients with AD. Although the mechanism is unclear, CSF levels of naturally occurring anti-Aβ autoantibodies may be implicated in the progression of atrophy of the whole hippocampus, entorhinal cortex and amygdala, in AD.

Preserved regional cerebral blood flow in the occipital cortices, brainstem, and cerebellum of patients with V180I-129M genetic Creutzfeldt-Jakob disease in serial SPECT studies

Creutzfeldt-Jakob disease (CJD) with a causative point mutation of valine to isoleucine at codon 180 (V180I) is one of the major types of genetic CJD (gCJD) in Japan. V180I gCJD is rarely accompanied by a family history, and its clinical characteristics include late-onset, long disease duration, and edematous cortical hyperintensity in diffusion, fluid attenuate inversion and T2-weighted MRI. We performed serial imaging with single-photon emission computed tomography (SPECT) and MRI in three V180I gCJD cases over long-term observation. All cases were characterized by progressive dementia, parkinsonism, and the absence of cerebellar signs or cortical visual dysfunction in their clinical courses. Moreover, during the end-stage, SPECT findings showed preserved regional cerebral blood flow (rCBF) in the occipital cortices, brainstem, and cerebellum. Similarly, no apparent atrophy or increased signal intensities were observed in MRI images of the occipital and cerebellar regions. In conclusion, we report a decrease in rCBF predominantly in the frontal and temporal cortices during the early-stage, which became more widespread as the disease progressed. Importantly, rCBF was preserved in the occipital cortices, brainstem, and cerebellar regions until the end-stage, which may be distinct to V180I gCJD cases.

Improvement of memory recall by quercetin in rodent contextual fear conditioning and human early-stage Alzheimer's disease patients.

Patients with Alzheimer’s disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion ‘Quergold’) powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion (‘Mashiro’ white onion) powder. These results indicate that quercetin might influence memory recall.

Identification of target antigens of naturally occurring autoantibodies in cerebrospinal fluid

UNLABELLEDnNaturally occurring autoantibodies have natural physiologic functions related to normal cell processes. However, the repertoire of naturally occurring autoantibodies against neuronal antigens in CSF is unclear. The purpose of this study was to identify naturally occurring autoantibodies against neuronal antigens in CSF from patients with various neurologic diseases by proteomics-based analysis. The CSF samples were collected from 77 patients with various neurologic disorders. The antigen source for 2-dimensional immunoblotting was the SH-SY5Y human neuroblastoma cell line. There were 8 spots recognized in CSF from more than one-fourth of the 77 patients including all patient groups and these spots were recognized in intravenous immunoglobulin preparations. These antigen spots were identified as heat shock 105-kDa/110-kDa protein 1, isoform CRA_b, 78-kDa glucose-regulated protein, heat shock cognate 71-kDa protein, tubulin beta chain, vimentin (2 spots), and 60-kDa heat shock protein, mitochondrial; we could not identify the protein name corresponding to 1 of the 8 spots. In summary, there were 6 proteins identified that were main target antigens that reacted with naturally occurring autoantibodies in CSF from patients with varied neurologic disorders; the functions of autoantibodies against the identified antigens are unknown and may be clarified with further studies.nnnBIOLOGICAL SIGNIFICANCEnNaturally occurring autoantibodies may have important functions in tissue homeostasis. In this study, we identified 6 common target antigens that reacted with autoantibodies in cerebrospinal fluid (CSF) from patients, independent of disease type. These findings may clarify the importance of naturally occurring autoantibodies in CSF and the use of these antibodies potentially may be a novel therapy for various neurologic disorders.

A multidisciplinary medical network approach is crucial for increasing the number of autopsies for prion disease [Reply to: How can we increase the numbers of autopsies for prion disease? A model system in Japan]

We readwith great interest the recent publication by Takao et al. [1], which presented a newmodel system for increasing the number of autopsies for prion disease in Japan. Their model system has directly increased the number of autopsies performed for prion disease in their area. A neuropathological diagnosis for prion disease is still the gold standard for diagnosis, especially in cases with an atypical course or symptoms [2], and it is necessary for accurate prion disease surveillance. However, even in university hospitals, autopsies for prion disease are frequently refused because of the fear of disease transmission. In Japan, some neuropathological centers can perform autopsies for prion disease; however, they are not always located close to hospitals or nursing homes. Usually, the diagnosis of prion disease is made in an acute hospital; subsequent long-term follow-up depends on the countrys permanent care hospital or nursing homes [1]. Moreover, in our experience, more than 50% of patients with prion disease refuse at least once to transfer to such a chronic hospital or nursing home after diagnosis. This high refusal rate reflects the reality that many hospitals hesitate to care for patients with prion disease because hospital staffs often lack correct information, and there is a fear of disease transmission even if routine care is followed. In 2006, we established a medical network for prion disease and neurodegenerative disease follow-up with social workers comprising our department, a permanent care hospital, and a neuropathological center. We visit some permanent care hospitals or nursing homes repeatedly for patient follow-up, and we have increased the number of autopsies for prion disease in our area. We have previously published some articles related to prion disease based on this medical network [2–5]. Before we transfer a patient with prion disease, we have a conference with the staff of the hospital or nursing home in order to provide correct information on prion disease, includingpractice guidelines for prion disease. This practice has resulted in the development of a trusting relationship between the patients family and the medical staff. Because pathologists and technicians have avoided autopsies for patients suspected to have prion disease, it is necessary to