Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

Impact of individual factors and personality trait on psychological problems of family members living with staff of a COVID-19 frontline hospital: A cross-sectional self-administered anonymous questionnaire survey.

Aim: This study aims to evaluate the association between individual factors/personality traits and depression and anxiety in family members living with staff working on the frontline of COVID-19 care. Methods: The subjects were family members over the age of 15 years living with staff members of a COVID-19 frontline hospital. Between March 27 and April 11, 2021, 204 self-administered anonymous questionnaires were distributed, and 149 responses were received. Symptoms of depression and anxiety were assessed using the Hospital Anxiety and Depression Scale (HADS). Personality trait was assessed using the Big Five personality traits, and fear of COVID-19 was assessed using the Fear of COVID-19 Scale. We examined associations between HADS depression or anxiety scores with individual background factors, scores of Big Five personality traits, and Fear of COVID-19 Scale. Results: The participants with anxiety had significantly higher scores for neuroticism and for the Fear of COVID-19 Scale. The participants with depression had significantly lower scores for extraversion and higher scores for the Fear of COVID-19 Scale. No individual background factors were significantly associated with HADS depression or anxiety scores. Conclusion: Among family members of staff of a COVID-19 frontline hospital, lower extraversion, higher neuroticism, and fear of COVID-19 were associated with anxiety and depression. This questionnaire survey was conducted before wide-spread rollout of COVID-19 vaccination, so the findings of this study are expected to be applicable to other future novel infectious outbreaks.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

The Big Five personality traits and the fear of COVID-19 in predicting depression and anxiety among Japanese nurses caring for COVID-19 patients: A cross-sectional study in Wakayama prefecture.

Recent studies have found a relationship between fear of COVID-19 and mental health problems. Medical workers caring for COVID-19 patients tend to suffer from mental health problems; however, the impact of their personality traits, in the form of mental problems like depression and anxiety in Japan is unclear. In this study, we investigated the risk of nurses' depression and anxiety, predicted by the fear of COVID-19 and the Big Five personality traits. A total of 417 nurses working in hospitals providing care to COVID-19 patients in Wakayama prefecture of the Kansai region participated in this study. The questionnaires comprised items on nurses' basic characteristics and three scales: the Fear of COVID-19 Scale 2020, the Big-Five Scale, and the Japanese version of the Hospital Anxiety and Depression Scale (HADS). Depression and anxiety in the HADS were set as dependent variables, and basic attributes, fear, and personality traits as independent variables; multivariate logistic regression analyses were conducted. The questionnaire, with no missing items was distributed from February to March 2021. Neuroticism (OR = 1.06, 95%CI = 1.03-1.09) was the only significant factor associated with the depression symptom, and both FCV-19S scores (OR = 1.16, 95%CI = 1.09-1.23) and neuroticism (OR = 1.09, 95%CI = 1.06-1.13) were the significant factors associated with anxiety. The Nagelkerke's R squared was 0.171 in the depression model and 0.366 in the anxiety model. Thus, it was found that it is necessary to support nurses' mental health by developing methods suitable to their personalities.

Risk Factors for Therapeutic Intervention of Remdesivir in Mild to Moderate COVID-19-A Single-Center Retrospective Study of the COVID-19 Fourth Pandemic Period in Wakayama, Japan.

Background and Objectives: The incidence of coronavirus disease 2019 (COVID-19) has increased in Wakayama, Japan, due to the spread of the highly infectious B.1.1.7 variant. Before this event, the medical systems were almost unaffected. We aimed to assess the clinical characteristics of patients hospitalized with COVID-19 and the risk factors for therapeutic intervention of remdesivir during the fourth pandemic period in Wakayama, Japan. Materials and Methods: This single-center retrospective study enrolled 185 patients with mild to moderate COVID-19 hospitalized in our hospital without intensive care between 14 March and 31 May 2021. Results: In this period, 125 (67.6%) of the 185 patients had the B.1.1.7 variant. Sixty-three patients (34.1%) required remdesivir treatment. Age upon admission and length of hospitalization were significantly different between remdesivir treatment and careful observation groups (mean (standard deviation); 59.6 (14.7) versus 45.3 (20.6) years; p < 0.001 and median (interquartile range); 10 (9-12) versus 9 (8-10) years; p < 0.001). One patient was transferred to another hospital because of disease progression. At hospital admission, age ≥60 years (odds ratio (OR) 6.90, p < 0.001), a previous history of diabetes mellitus (OR 20.9, p = 0.002), B.1.1.7 variant (OR 5.30; p = 0.005), lower respiratory symptoms (OR 3.13, p = 0.011), headache (OR 3.82, p = 0.011), and fever ≥37.5 °C (OR 4.55, p = 0.001) were independent risk factors to require remdesivir treatment during the admission. Conclusions: Many patients with mild to moderate COVID-19 required the therapeutic intervention of remdesivir during the fourth pandemic period in Wakayama, Japan. From the clinical data obtained at admission, these risk factors could contribute to a prediction regarding the requirement of remdesivir treatment in cases of mild to moderate COVID-19.

Association between oxidative stress and microRNA expression pattern of ALS patients in the high-incidence area of the Kii Peninsula.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of the upper and lower motor neuron systems. The high incidence of ALS in the southern part of the Kii Peninsula of Japan (K-ALS) was reported in the 1960s, but it has gradually decreased to the worldwide average. Although causes of the high incidence of ALS in this area are unknown, our previous studies suggested that environmental factors, including essential mineral deficiency and increased metal-induced oxidative stress, play a role in its development. Recently, it has been reported that microRNAs (miRNA) contribute to the degeneration of nervous system such as ALS. The aim of this study is to explore specific miRNAs in K-ALS and evaluate relationships between oxidative stress. We comprehensively analyzed serum miRNAs and examined urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), serum Cu/Zn superoxide dismutase (SOD) and serum Nɛ-hexanoyl lysin (HEL) as oxidative stress markers in the patients with K-ALS, sporadic ALS (S-ALS), residents in this area (K-residents) and controls from another area. The expression levels of miR-92a-3p and miR-486-5p in the patients with K-ALS were significantly higher than those in controls. The HEL levels were significantly higher in the patients with K-ALS than in those with S-ALS and controls. The expression levels of miR-92a-3p and miR-486-5p were not correlated with the levels of HEL. A set of high levels of miR-92a-3p, miR-486-5p and serum HEL may be a useful biomarker for K-ALS in the Kii Peninsula. The findings should be further studied by a large number of subjects.

Increased large-scale inter-network connectivity in relation to impulsivity in Parkinson's disease.

Impulsivity is a neuropsychiatric feature of Parkinson's disease (PD). We investigated the pathophysiology of impulsivity in PD using resting-state functional magnetic resonance imaging (rs-fMRI). We investigated 45 patients with idiopathic PD and 21 healthy controls. Based on Barratt Impulsiveness Scale (BIS-11) score, PD patients were classified as higher (PD-HI) or lower impulsivity (PD-LI). Functional connectivity (FC) between various large-scale brain networks were analysed using the CONN toolbox. FC between the right frontoparietal network (FPN) and medial visual network (MVN) was significantly higher in PD-HI patients than PD-LI patients (false discovery rate [FDR]-adjusted p = 0.0315). FC between the right FPN and MVN had a significant positive correlation with total BIS-11 score (FDR-adjusted p = 0.010) and the attentional impulsivity (FDR-adjusted p = 0.046) and non-planning impulsivity subscale scores (FDR-adjusted p = 0.018). On the other hand, motor impulsivity subscale score had a significant negative correlation with the FC between the default-mode and salience networks (right supramarginal gyrus, FDR-adjusted p = 0.018; anterior cingulate cortex, FDR-adjusted p = 0.027); this trend was observed in healthy controls. The attentional and non-planning impulsivity, regarded as 'cognitive' impulsivity, may be associated with dysfunction in integration of perceptual information and flexible cognitive control in PD.

Superficial siderosis associated with duplicated dura mater detected by CISS reverse MRI.

Superficial siderosis (SS) of the central nervous system is a rare disease caused by chronic or repeated hemorrhages in the subarachnoid space. Closure of dural defects is an effective therapy for SS. Conventional magnetic resonance imaging (MRI), however, cannot sufficiently detect dural tears. To better detect these defects, we analyzed the clinical data of consecutive patients admitted to our department with SS and performed constructive interference in steady-state (CISS) reverse MRI of the brain and spinal cord. CISS reverse method emphasizes the contrast between the dura and cerebrospinal fluid, enabling detection of dural defects better than usual T2-weighted MRI. CISS reverse MRI detected fluid-filled collections in five of the seven SS patients we studied. These images showed that the fluid-filled collections were packed within duplicated dura mater. In three of the five, dural defects were confirmed intraoperatively. We postulate that fluid-filled collections are actually derived from dissection of the dura mater. In accordance with the Monro-Kellie hypothesis, we propose that CSF transferal into the fluid-filled collections via dural defects induces an increase in blood volume and promotes the exudation of blood from engorged vessels. In patients with SS, it is very important to repair dural defects to prevent further associated neurological impairment. CISS reverse MRI is useful for detecting such dural defects.

[Neuromyelitis optica following thymectomy with severe spinal cord atrophy after frequent relapses for 30 years].

A 60-year-old woman had frequent relapses of neuromyelitis optica (NMO) for 30 years despite receiving steroid and azathioprine therapy. She developed MGFA Class IIIb type of myasthenia gravis (MG) at the age of 23, and thymectomy resulted in complete remission of MG. The initial symptoms of NMO, including headache, high fever, retrobulbar optic neuritis, and neurogenic bladder, appeared at the age of 30. Two years later, paraplegia also developed. Although she received oral administration of steroids or azathioprine and intravenous steroid pulse therapy for treatment of NMO for over 30 years, she experienced frequent relapses. The examination at the ages of 58 and 60 years showed that anti-aquaporin-4 antibody was absent. Intravenous immunoglobulin therapy administered in January and June 2009 was effective, and she had 2 years of remission of NMO attack. Spinal MRI after frequent NMO attacks for 30 years revealed an extended spinal cord atrophy involving the lower cervical region and the entire thoracic region. We describe and discuss the prognosis of NMO and the effectiveness of therapies in an NMO patient who underwent thymectomy for MG.

Transcranial sonography of the substantia nigra and MIBG myocardial scintigraphy: complementary role in the diagnosis of Parkinson's disease.

Both transcranial sonography (TCS) of the substantia nigra (SN) and metaiodobenzylguanidine (MIBG) myocardial scintigraphy have been determined to be useful for the diagnosis of Parkinson's disease (PD). In the present study, we performed both tests in 65 consecutive Japanese patients with idiopathic PD. In 30 PD patients (46.2%), the midbrain was adequately displayed by TCS allowing quantitative measurements of SN hyperechogenic areas. No significant correlation was found between the area of SN echogenicity and the reduction of myocardial uptake of MIBG. However, if the cut-off value was appropriately set, 29 patients (97%) were identified as abnormal by combined TCS and MIBG myocardial scintigraphy. Since TCS and MIBG myocardial scintigraphy can distinctively detect PD-related pathological phenomenon, it is expected that the combination of these tests could contribute to an accurate diagnosis of PD.

[How Parkinson's disease patients recognize Parkinson's disease therapeutic guideline?].

The "Parkinson's disease (PD) therapeutic guideline 2002 (PGL)" was published by Societas Neurologica Japonica in Japan. The guideline, which is based on evidence-based medicine (EBM), is a good reference for making medical decisions. Although physicians recognize the usefulness of the guideline, it is unclear whether PD patients know of the its existence. We performed a survey of 42 PD patients to evaluate their thoughts on the guideline. Sixty-seven percent of the patients had no knowledge of the existence of the PGL. However, after informing them of the existence of the PGL, 93% of the patients welcomed its publication. Forty-three percent of the patients wanted to read the PGL, although they expressed reservation that the PGL might be difficult to understand. Ninety-five percent of the patients answered that they would read the PGL if an easy-to read explanation manual were provided. However, none of the patients wanted an excessively strict obedience to the PGL. Eighty-three percent of the patients wanted a flexible application of the PGL to their own therapy. The PGL seems to have been accepted by the patients. A plain-language explanation manual of the PGL for PD patients, if published, would be helpful to the patients' understanding of PD therapy and to building cooperation between patients and physicians.

Nuclear localization of glyceraldehyde-3-phosphate dehydrogenase is not involved in the initiation of apoptosis induced by 1-Methyl-4-phenyl-pyridium iodide (MPP+).

Nuclear localization of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is implicated in the process of apoptosis. To study the function of GAPDH, we expressed GAPDH C-terminally fused with or without nuclear localization signal (NLS) in SH-SY5Y and NB41A3 cells using a retrovirus expression system. GAPDH carrying NLS (GAPDH-NLS) was expressed mainly in the nucleus. However, expression of GAPDH-NLS did not cause any difference in cell survival rate as compared to that of the vector alone or GAPDH without NLS. Treatment with 1-Methyl-4-phenyl-pyridium iodide (MPP+) caused no difference in the cell survival rate or in the pattern or extent of apoptosis among the three transductants. In the cells expressing GAPDH without NLS, MPP+ did not cause visible translocation of GAPDH into nucleus before the onset of apoptosis. Since GAPDH is known to comprise a CRM1-mediated nuclear export signal, we blocked the nuclear export of GAPDH by treatment with leptomycin B, an inhibitor of CRM1-mediated nuclear export. The treatment did not cause any difference in apoptosis among the three transductants. An additional treatment with MPP+ induced no apoptotic difference in these cells. Thus, we have concluded that a simple nuclear localization of GAPDH does not induce apoptosis, and that MPP+-induced apoptosis is not caused by nuclear translocation of GAPDH.

Changes in the incidence of amyotrophic lateral sclerosis in Wakayama, Japan.

In the 1960s, the incidence of amyotrophic lateral sclerosis (ALS) in the Kozagawa and Koza areas in Wakayama prefecture was much higher than that in other areas of the world. However, between 1980 and 1993, a gradual decrease in the incidence of the disease in these areas was reported. To ascertain whether the decreased incidence has persisted, we conducted a retrospective epidemiological study, and determined the average annual incidence of ALS in Wakayama prefecture from 1998 to 2002. The number of ALS cases encountered during the period was 134 (male 79, female 55). The crude average annual incidence in Wakayama prefecture in total was 2.50 (male 3.08, female 1.99) per 100,000. In the Kozagawa and Koza areas in Wakayama prefecture, where the senility rate rapidly increased in recent years, the average annual incidence of ALS in the present research was 10.56 (male 14.14, female 7.66). When the crude rate was standardized for both age and sex to the Japanese population in 1990, the expected value was 5.24 (male 7.34, female 3.18), which was lower than that of our previous survey. The prevalence in Wakayama prefecture at 31 December 2002 was 11.31 (male 14.40, female 8.53). In Kozagawa and Koza areas, the crude prevalence was 52.81 (male 70.70, female 38.28). These results indicated that the incidence of ALS in Wakayama prefecture, especially for females, steadily decreased compared to that in previous reports. However, a high incidence of ALS persisted among males in Wakayama prefecture, especially in the Kozagawa and Koza areas. Some environmental factors and gender specificity may be related to the decreased incidence of ALS in focus areas.

[MELAS-like episodes in an adult case with cytochrome c oxidase deficiency].

A 30-year-old man was hospitalized with dysarthria and weakness of his right arm and leg. Three months previously, he had noticed numbness and weakness of his right shoulder, which spread to involve his left leg but which improved after 8 months. On admission, neurological examination revealed limb kinetic apraxia and constructive apraxia of the right hand, motor aphasia, dysarthria, and spastic quadriplegia. Sensory examination revealed hyperalgesia and dysesthesia in the right arm and left leg. Deep tendon reflexes were hyperactive in all four extremities. And he had bilateral Babinski signs. Laboratory examination revealed pH 7.38, PCO2 46.1 Torr, PO2 93.4 Torr, BE 1.7, and blood lactate, 9.0 mg/dl (normal 5-20 mg/dl). Cerebrospinal fluid lactate level was 20.0 mg/dl. pyruvate 1.34 mg/dl. and protein 83 mg/dl. Blood lactate and pyruvate values were markedly elevated after aerobic exercise. T2WI brain MRI showed scattered high signal lesions in the left precentral and postcentral gyrus, right paracentral lobes, both superior frontal gyri, and right superior temporal gyrus. Right biceps brachi biopsy showed almost complete cytochrome c oxidase (COX) deficiency. There were no ragged-red fibers. There was marked decrease of COX activity: 2.7 nmol/min/mg-mitochondrial protein (normal range: 33.0 +/- 16.1, n = 7) in the biopsied muscle. Open brain biopsy (after permission from the patient and his family) revealed gliosis and perivascular infiltration of lymphocytes and macrophages without vascular proliferation. There was no mitochondrial DNA mutations, deletion or duplication, including tRNA-Leu 3243, 8993, 3271, 9176, 3291, and tRNA-Lys 8344, 8356, and 8363. From these findings, a diagnosis of COX deficiency presenting as MELAS-like episodes was done. His mother also showed abnormality on aerobic exercise test, but she had no episode of stroke or neurological dysfunction. Six months later, his aphasia and apraxia of the right hand had resolved, and at discharge he was able to ambulate with a cane. Ten months later, he returned to his work. There has been no recurrence of neurologic symptoms over the next 3 years and 10 months. This patient appears to represent a rare case of adult onset COX deficiency presenting as MELAS-like episodes.

[A patient with multiple system atrophy presenting prolonged levodopa-responsive parkinsonism and off-dystonia of the trunk].

A 46-year-old man had a 7-year history of dopa-responsive parkinsonism. Four years after starting levodopa, he had typical motor complications such as wearing-off and peak dose as well as off-period dystonia of his trunk. Brain MRI showed marked atrophy of the brainstem and cerebellum, and the cross sign was present in the pontine base. There was neither abnormal signal intensity nor atrophy in the basal ganglia. Then, he was suspected as having multiple system atrophy (MSA). It is not easy to differentiate MSA from Parkinson diseases, particularly when the patient shows good response to levodopa and motor complications like those seen in Parkinson's disease. If the striatal pathology was not severe and nigral degeneration was prominent, presynaptic parkinsonism might occur in MSA, and putaminal preservation might account for good response to levodopa therapy. In patients with MSA, disproportionate antecollis is common before levodopa treatment, and levodopa induced off-dystonia of his trunk is very rare.

["Stunned myocardium" on echo cardiogram in myotonic dystrophy: a case report].

A 56-year-old woman with a 23 year-history of myotonic dystrophy was admitted to our hospital because of dysphagia and aspiration pneumonia. On admission, patient's ECG showed Ist degree of atrioventricular block and elongation of QRS (133 msec.). On the third hospital day, abnormal Q wave abruptly appeared in aVL associated with elevation of ST segment in V2 and V3, reverse T wave in I, II, III, aVF and V 2-6 leads on ECG. Echo cardiogram demonstrated asynergy at the apex and septal wall. Coronary angiography was normal. Left ventricular ejection fraction determined by left ventriculography decreased to 47.4%. Based on these findings, we thought "stunned myocardium" had developed. Biopsied myocardium from the apex, septum, and free wall showed non-specific findings including mild fibrosis and lymphocytic infiltration. Although overt myocardial disease is rare in myotonic dystrophy, myocardiac disease such as "stunned myocardium" not due to arrhythmia or coronary angiopathy may develop under severe infection, stress, and/or respiratory distress.

[Isolated finger flexion caused by continuous muscle fiber activity].

We report two patients who presented with progressive involuntary flexion of fingers. Both of them were women (Case 1 and 2 were 23 year old and 86 year old, respectively), and developed involuntary finger flexions, particularly of the ring and little fingers, following a localized pain of their hands and forearms. The other neurological findings were not present. There was no abnormal finding in their serum, and anti-voltage-gated potassium channel antibodies were negative. Nerve conduction velocity studies revealed no obvious peripheral neuropathy or conduction block. EMG studies revealed continuous muscle fiber activities only in the flexor digitorum superficialis muscles in both patients. Additionally, in Case 1, neuromyotonic discharges at frequencies of 100-200 Hz were recorded only from the flexor digitorum superficialis muscle. The present findings are likely to be similar to those of a novel form of focal neuromytonia reported recently as 'isolated finger flexion'.

[Benefit of L-DOPA-without-DCI (decarboxylase inhibitor) therapy on wearing-off phenomenon in advanced stages of Parkinson's disease patients].

Motor fluctuation is the most annoying complication experienced by patients in the advanced stages of Parkinson's disease. A Combination therapy of a dopamine receptor agonist and levodopa/DCI(DOPA-decarboxylase inhibitor) is commonly used to control the complication. Although administration of levodopa/DCI is useful in minimizing peripheral side effects of levodopa, it increases the incidence of motor complications due to the marked fluctuation of plasma levodopa level. The use of levodopa without DCI might be an option for controlling motor fluctuation, because the extent of plasma levodopa level fluctuation is smaller when levodopa is administered without DCI than with DCI. Six patients with Parkinson's disease who had troublesome motor complications under levodopa/DCI and DA agonist combination therapy were compared in terms of the extent of motor complications and their satisfaction after changing their therapy from levodopa/DCI to levodopa without DCI. The change from levodopa/DCI to levodopa(without DCI) was carried out all at once, and the levodopa/DCI to levodopa dose ratio was started at 1:4. The dose of levodopa(without DCI) was then increased gradually until motor complications improved or side effects were observed in patients. Except two patients who voluntarily quitted levodopa and restarted DOPA/DCI before the dose of levodopa fixed, all cases showed improvement of wearing-off phenomenon. No adverse event was observed. Levodopa-without-DCI-therapy was effective for controlling motor fluctuation in patients of Parkinson's disease in advanced stages.

FKBP12 immunoreactivity in the human spinal cord of motor neuron disease patients.

We investigated the FKBP12 immunoreactivity in the spinal cord of neurological controls and motor neuron disease (MND) patients. In the neurological controls, the spinal neurons were markedly stained with antihuman FKBP12 (N-19 and C-19) antibodies. FKBP12 immunoreactivity was associated with lipofuscin in formalin-fixed paraffin-embedded samples. In an electron microscopic view, the 10-nm colloidal gold particles labeled by the anti-FKBP12 (N-19) antibody were present on the lipofuscin of the spinal anterior horn neurons. In the MND cases, atrophic neurons with an abundance of lipofuscin granules in the anterior horns of the spinal cord were mildly stained with the anti-FKBP12 (N-19 and C-19) antibodies. Normal-appearing neurons, inclusion-laden neurons and chromatolytic neurons of MND cases were weak or negatively stained with anti-FKBP12 (N-19) antibodies. These findings suggest that FKBP12 (N-19) may decrease in the early stages of degeneration in MND. Complexes of FKBP12 and ligands were reported to have neuroprotective and/or neuroregenerative properties. It is speculated that the decrease in FKBP12 (N-19) plays some causative role in the development of neurodegeneration in MND. Further investigation of FKBP12 and ligands may help elucidate the pathogenesis of MND.