Yoshiki Niimi

Behavioral changes in early ALS correlate with voxel-based morphometry and diffusion tensor imaging.

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with impairment of frontotemporal functions such as cognition and behavior, but the behavioral changes associated with ALS are not well defined. METHODS Twenty-one consecutive patients with sporadic ALS and 21 control subjects participated in the study. The Frontal System Behavior Scale (FrSBe) was used to assess behavioral change. Voxel-based morphometry (VBM) and voxel-based analysis of diffusion tensor images (DTI) were performed to explore the associations of brain degeneration with behavior. All patients were evaluated before the notification of ALS. RESULTS FrSBe scores of ALS patients before notification were significantly increased compared to those of control subjects. Moreover, the FrSBe Apathy score of ALS patients significantly changed from pre- to post-illness (P<0.001). The severity of apathy was significantly correlated with atrophy in the prefrontal cortex, especially in the orbitofrontal (P=0.006) and dorsolateral prefrontal (P=0.006) cortices in VBM, and in the right frontal gyrus (P<0.001) in DTI. CONCLUSIONS ALS patients exhibited apathy during the early course of the illness, the severity of which was significantly associated with frontal lobe involvement. These findings support the view that a continuum exits between ALS and frontotemporal dementia.

Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson’s disease☆

BACKGROUND Oxidative stress is causally associated with the pathogenesis of Parkinsons disease (PD). Oxygen generates a large amount of reactive oxygen species (ROS). ROS including hydroxyl radicals and H(2)O(2) react with guanine residues in DNA and produce 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG serves as a biomarker for oxidative stress in various diseases. METHOD We investigated urinary 8-OHdG levels in 61 PD patients and 28 normal subjects to evaluate the correlation with various clinical features. We quantified disease severity using the Unified Parkinsons Disease Rating Scale for motor symptoms (UPDRS part 3), the Mini-Mental State Examination (MMSE) for mental function, and the Tottori University Hallucination Rating Scale (TUHARS) for quantifying hallucinations. RESULTS There were significant correlations between 8-OHdG and all the examined parameters, but the partial correlation coefficients excluding contributions of all the other parameters showed that only TUHARS and UPDRS part 3 are significantly related to 8-OHdG. In particular, TUHARS correlates best with urinary 8-OHdG levels. CONCLUSION The significant correlation between urinary 8-OHdG levels and hallucinations but not with dementia suggests that hallucinations are likely to have unique but unidentified mechanisms that lead to excessive production of 8-OHdG.

Anti-neutral glycolipid antibodies in encephalomyeloradiculoneuropathy

Objective: The aim of this study was to review 4 patients with encephalomyeloradiculoneuropathy (EMRN) and assess for autoantibodies against neutral glycolipids. Methods: We studied the progression of clinical, radiologic, neurophysiologic, and CSF findings, as well as anti-neutral glycolipid antibodies in sera. Results: All patients developed acute or subacute motor weakness and impaired consciousness. Their CSF showed pleocytosis and high immunoglobulin G concentrations. MRI revealed lesions in the brain and spinal cord. Neurophysiologic examinations indicated dysfunction of the spinal cord, nerve roots, and peripheral nerves. Steroid pulsed immunotherapy and/or high dose of IV immunoglobulin replacement therapy resulted in clear and often dramatic clinical improvements. Reactivity to anti-neutral glycolipid antibodies was positive in all patients with acute EMRN but not in the recovery phase. Forty-seven age-matched patients with other neurologic disorders and 28 age-matched healthy volunteers tested negative for reactivity to anti-neutral glycolipid antibodies. Conclusion: The resolution of radiologic and neurologic abnormalities and altered autoantibody titers against neutral glycolipids after immunotherapy suggest that EMRN is caused by an immune-mediated mechanism. These autoantibodies may be useful biomarkers for EMRN.

MM2‐cortical‐type sporadic Creutzfeldt‐Jakob disease with early stage cerebral cortical pathology presenting with a rapidly progressive clinical course

We report the case of a 67‐year‐old man with MM2‐cortical‐type sporadic Creutzfeldt‐Jakob disease (sCJD) with a rapidly progressive clinical course of 5 months. Initial symptoms were progressive memory disturbance and dementia. MRI revealed high signal‐intensity lesions on diffusion‐weighted images in the bilateral frontal and occipital cortices. Myoclonus and periodic sharp‐wave complexes on the electroencephalogram were observed in the early disease stage. The clinical diagnosis was typical sCJD. Neuropathologic examination at autopsy showed widespread, characteristic cerebral neocortical involvement with large confluent vacuole‐type spongiform change. Spongiform degeneration was also evident in the striatum and medial thalamus. In the cerebellar cortex, slight depletion of Purkinje neurons was evident without spongiform change in the molecular layer or apparent neuron loss in the granule cell layer. The inferior olivary nucleus showed slight hypertrophic astrocytosis without neuron loss. Prion protein (PrP) immunostaining showed widespread, characteristic perivacuolar‐type PrP deposits with irregular plaque‐like PrP deposits in the cerebral neocortex, striatum and medial thalamus. We believe this patient showed early‐stage cerebral cortical pathology of MM2‐cortical‐type sCJD, which may provide clues regarding the pathologic progression of this rare sCJD subtype. Although MM2‐cortical‐type sCJD generally shows slow progression without myoclonus or periodic sharp‐wave complexes, the present patient showed a rapidly progressive clinical course similar to that of MM1‐type sCJD.

Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke

BACKGROUND Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

Clinical and radiological impact of liver transplantation for brain in cirrhosis patients without hepatic encephalopathy

OBJECTIVE To elucidate the effect of liver transplantation (LT) on brain dysfunctions in cirrhotic patients who had no clinical evidence of hepatic encephalopathy (HE), we performed a prospective study of voxel-based diffusion tensor imaging (DTI) and detailed cognitive examination. METHODS We assessed 12 consecutive patients as transplant candidates by DTI, with neurological and cognitive examinations just before and at 6 months after LT. RESULTS After LT, cirrhotic patients showed significant improvement in visual reproduction, digit symbol, digit span, Stroop test, and Trail-making test scores, suggesting recovery of frontal-temporal function. As for voxel-based DTI, increased mean diffusivity (MD) and reduced fractional anisotropy (FA) values were found before LT in the frontal and temporal lobes of cirrhotic patients. After LT, the unusual FA and MD values observed in the frontal and temporal lobes preoperatively were significantly reduced. CONCLUSION End-stage cirrhotic patients without clinical evidence of HE showed increased MD and decreased FA values in both frontal and temporal lobes. These parameters improved after LT, in line with cognitive function. MD and FA values might be of value as a biomarker in end-stage cirrhotic patients for investigating brain tissue dysfunctions and evaluating the efficacy of LT.

Usefulness of combining 123I-FP-CIT-SPECT striatal asymmetry index and cardiac 123I-metaiodobenzylguanidine scintigraphy examinations for diagnosis of parkinsonisms

BACKGROUND Although single-photon emission computerized tomography of the dopamine transporter (DAT-SPECT) is useful for diagnosing parkinsonian syndrome, its applicability toward the early phase of Parkinsons disease remains unknown. METHODS We enrolled 32 patients showing parkinsonism with normal cardiac 123I-metaiodobenzylguanidine (MIBG) uptake and abnormal DAT-SPECT findings among 84 consecutive patients with parkinsonism. We divided these patients into two groups (group 1: Parkinsons disease, group 2: corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy), and compared their clinical characteristics, specific binding ratios, and striatal asymmetry indexes on DAT-SPECT examinations. RESULTS The striatal asymmetry indexes were significantly lower in group 1 than in group 2 (p<0.05), but there were no differences in the specific binding ratios between the two groups. CONCLUSION The combined use of striatal asymmetry index on DAT-SPECT and cardiac MIBG scintigraphy might offer useful clues for the differential diagnosis of the early phase Parkinsons disease from other parkinsonian syndromes.

Cutaneous arteritis associated with peripheral neuropathy: two case reports.

Dear Editor, Primary vasculitis confined to a single organ without systemic manifestation is referred to as single organ vasculitis (SOV). SOV that affects the skins or peripheral nerves has been named cutaneous arteritis or non-systemic vasculitic neuropathy (NSVN), respectively. These isolated vasculitides predominantly affect middleor small-sized vessels within the lower dermis or epineurium and show relatively benign prognosis obtained by immunosuppressive therapies. We describe two cases of necrotizing vasculitis confined to the skin and peripheral nerves and discuss pathogenetic relationship between these isolated vasculitides. Case 1 was a 24-year-old woman who presented with sensory disturbance, progressive weakness, and pain in her hands and feet, which had started 3 months prior. Chemical exposure, daily alcohol consumption and a history of diabetes mellitus were absent. On admission, the skin of the lower extremities demonstrated multiple livedo reticularis, purpura and tenderness (Fig. 1a–b). The weakness and sensory disturbance showed a pattern of mononeuritis multiplex predominantly in her left foot, which was supported by electrophysiological studies. Other constitutional symptoms were absent. Routine examinations of blood chemistry, urine and cerebrospinal fluid were normal. Tests for eosinophil count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), thiamine, anti-immunoglobulin (Ig)G cardiolipin, anti-IgG prothrombin, anti-SS-A/B, anti-DNA, anti-Sm, antineutrophil cytoplasmic antibodies, lupus anticoagulants, cryoglobulins,

Anti-GM1 ganglioside antibodies modulate membrane-associated sphingomyelin metabolism by altering neutral sphingomyelinase activity

ABSTRACT Previous studies have shown that patients with Guillain‐Barré syndrome express autoantibodies against ganglioside GM1 (GM1), although its pathogenic significance for the development of the disease remains to be elucidated. nSMase2 is the best characterized neutral sphingomyelinase (nSMase) found in neuronal cells. Activation of this enzyme leads to ceramide production, which is a known second messenger of the cell‐death program in neuronal cells. We have explored the effects of anti‐GM1 antibodies on sphingomyelin metabolism of PC12 cells stably transfected with human trk cDNA (PCtrk cells) by determining their effects on nSMase2 activity. The data we present here strongly suggest that anti‐GM1 caused a significant change in sphingomyelin content of the membrane fraction in PCtrk cells. Both nSMase2 activity and the level of nSMase2 protein were significantly decreased by anti‐GM1 treatment of PCtrk cells, while acidic SMase activities remained unchanged. Our results indicate, for the first time, that anti‐GM1 may produce profound impacts on lipid metabolism in neuronal cell membranes. HighlightsAnti‐GM1 antibodies are often found in patients with Guillain‐Barré syndrome.Anti‐GM1 antibodies inhibit membrane neutral sphingomyelinase activity.It in turn caused significant change of membrane sphingomyelin contents.It also inhibit exosome secretion into culture medium.Thus, this study revealed new aspect of the autoantibody to neuronal cells.

Changes in Serial D-Dimer Levels Predict the Prognoses of Trousseau's Syndrome Patients

Background: The development of acute multiple embolic infarctions (AMEI) resulting from cancer is known as Trousseaus syndrome (TS). At present, however, there is no good marker for predicting the prognosis of TS patients. In the present study, we evaluated the use of serial D-dimer levels as a prognostic marker for TS. Methods: This retrospective cohort study included 1,409 consecutive acute ischemic stroke patients. We selected a group of patients with TS showing AMEI (n = 38; TS group) and a group of patients with atrial fibrillation (Af) and AMEI (n = 35; Af group) as controls. Serial D-dimer levels were measured between days 7 and 28 after stroke (sub-acute phase) in 21 patients of the TS group and 24 patients of the Af group. Results: D-dimer levels at onset (acute phase) were significantly higher in the TS group (8.45 ± 1.79 μg/mL, n = 38) compared with the Af group (1.14 ± 0.14 μg/mL, n = 35) (p < 0.0001). In patients for whom serial D-dimer measurements were made, D-dimer levels measured at the sub-acute phase decreased to 0.48 ± 0.12 μg/mL (n = 24) in the Af group, but remained elevated in the TS group during the sub-acute phase (11.20 ± 2.77 μg/mL, n = 21) (p < 0.0001). In all TS patients in whom serial D-dimer measurements were made, D-dimer levels in 17 patients who died within 500 days (13.31 ± 3.23 μg/mL) were significantly higher than those of the four surviving patients (2.23 ± 0.38 μg/mL) (cut-off D-dimer level = 3.0 μg/mL) during this period. Moreover, serial D-dimer levels of 10 patients who died within 90 days (17.78 ± 4.60 μg/mL) were significantly higher than those of the 11 patients who survived up to 90 days (5.21 ± 2.12 μg/mL) (p < 0.05). Conclusions: Serial D-dimer levels may be a good biomarker for TS as well as a useful predictor of the prognosis of TS patients.