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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons in the brainstem and spinal cord. Clinical studies have indicated that there is a distinct region-dependent difference in the vulnerability of motor neurons. For example, the motor neurons in the facial and hypoglossal nuclei are more susceptible to neuronal death than those in the oculomotor nucleus. To understand the mechanism underlying the differential susceptibility to cell death of the neurons in different motor nuclei, we compared the effects of chemical anoxia on the membrane currents and postsynaptic currents in different motor nuclei. The membrane currents were recorded from neurons in the oculomotor, facial and hypoglossal nuclei in brain slices of juvenile Wistar rats by using whole-cell recording in the presence of tetrodotoxin that prevents action potential-dependent synaptic transmission. NaCN consistently induced an inward current and a significant increase in the frequency of spontaneous synaptic inputs in neurons from these three nuclei. However, this increase in the synaptic input frequency was abolished by strychnine, a glycine receptor antagonist, but not by picrotoxin in neurons from the hypoglossal and facial nuclei, whereas that in neurons from the oculomotor nucleus was abolished by picrotoxin, but not by strychnine. Blocking ionotropic glutamate receptors did not significantly affect the NaCN-induced release facilitation in any of the three motor nuclei. These results suggest that anoxia selectively facilitates glycine release in the hypoglossal and facial nuclei and GABA release in the oculomotor nucleus. The region-dependent differences in the neurotransmitters involved in the anoxia-triggered release facilitation might provide a basis for the selective vulnerability of motor neurons in the neurodegeneration associated with ALS.

Background Precise associations between clinical characteristics of transient ischemic attack (TIA) patients and diffusion-weighted imaging (DWI) positivity are still controversial. Thus, the purposes of this were to investigate the clinical characteristics associated with DWI positivity in patients with TIA and to develop a risk score for the prediction of DWI positivity in TIA. Methods Between April 2008 and June 2011, we retrospectively enrolled consecutive patients, who were admitted to our hospital with TIA and underwent DWI within 24 hours of admission. Patients were divided into a DWI-positive or DWI-negative group. The clinical characteristics of the 2 groups were compared, and a DWI positivity score was determined for each patient. We calculated the DWI positivity score by assigning a point value of 1 to the following factors: blood urea nitrogen to serum creatinine (BUN/Cr) ratio greater than 17.5, glucose greater than 161 mg/dL, and brain natriuretic peptide (BNP) greater than 55.4 pg/dL. Values below these cutoffs were given a value of 0, and the 3 point values were summed to obtain the final DWI positivity score (from 0 to 3). Results A total of 41 patients (median age = 62 years; 8 women) were enrolled in this study. There were 14 (35%) patients with DWI positivity. The median of the BUN/Cr ratio, blood glucose, and BNP were significantly higher in the DWI-positive than that in the DWI-negative group. As the DWI positivity score increased, there was an increased rate of DWI positivity. Conclusions Our data indicate that seminal scores that included BUN/Cr ratio, glucose, and BNP contributed to DWI positivity in TIA patients.

We herein report that the clinical, laboratory, and radiographic features and positron emission tomography (PET) imaging may provide valuable clues to the pathogenesis of cerebral amyloid angiopathy (CAA)-associated encephalopathy, which currently remains unclear. We herein describe two cases of encephalopathy with CAA, with an emphasis on PET imaging with (11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-fluorodeoxyglucose ((18)F-FDG). One case of Alzheimer's disease for which a brain biopsy was performed showed CAA-related inflammation. Another case that had developed sudden sensory aphasia presented with posterior reversible encephalopathy syndrome-like vasogenic edema in the left temporal region with (11)C-PiB uptake and microhemorrhages. (11)C-PiB and (18)F-FDG PET are useful for detecting CAA-associated encephalopathy, including atypical CAA cases.

We report a 51-year-old man with myopathy and dementia probably caused by a novel mutation of the valosin-containing protein (VCP) gene, in the form of a p.Ala439Pro substitution. At 43 years old, he presented at least 2-year history of weakness of right ankle dorsiflexion. Findings from muscle biopsy suggested distal myopathy with rimmed vacuoles. However, no mutation in the GNE gene was identified. He complained of giving way of the knee, and muscle imaging study showed adipose tissue infiltration in the quadriceps. Ten years later, he was confined to a wheelchair and became reticent and antisocial with slightly impaired memory. A muscle CT revealed atrophy or replacement by adipose tissue in the muscles of neck, trunks and extremities muscles with laterality and variation of the degree. The magnetic resonance imaging of the brain showed bilateral frontal and temporal lobe atrophy with left dominance. Findings were compatible with inclusion body myopathy with Paget's disease of bone and frontotemporal dementia.

A 54-year-old-woman with sarcoidosis presented with progressive symmetric, predominantly distal weakness and sensory dysfunction with areflexia in all four limbs. Nerve conduction studies showed multifocal conduction blocks in several nerves. Oral steroids were ineffective; however, intravenous immunoglobulin (IVIG) therapy rapidly and repeatedly improved the patient's neurologic symptoms with a resolution of the conduction blocks. Multifocal conduction blocks are not frequently reported in patients with sarcoid neuropathy, but they may respond to early treatment with IVIG.

Background and purpose Hyperglycemia (HG) is associated with infarct volume expansion in acute ischaemic stroke patients. However, collateral circulation can sustain the ischaemic penumbra and limit the growth of infarct volume. The aim of this study was to determine whether the association between HG and infarct volume expansion is dependent on collateral circulation. Methods We performed a retrospective analysis of 93 acute ischaemic stroke patients with internal carotid artery or middle cerebral artery occlusion within 24 h of onset were retrospectively studied. HG was diagnosed in patients with an admitting blood glucose value ≥140 mg/dl. Angiographic collateral grade 0–1 was designated as poor collateral circulation and grade 2–4 as good collateral circulation. Infarct volume was measured at admission and at again within 7 days using diffusion-weighted magnetic resonance images. Results Among 34 patients with poor collateral grade, the change in infarct volume was significantly greater in the HG group than in the non-HG group (106.0 ml vs. 22.7 ml, P = 0.002). Among the 59 patients with good collateral circulation, the change in infarct volume was greater in the HG group than in the non-HG group (53.3 ml vs. 10.9 ml, P = 0.047). Multiple regression analysis indicated that admission HG (P = 0.004), baseline National Institutes of Health Stroke Scale score (P = 0.018), and poor collateral circulation (P = 0.040) were independently associated with infarct volume expansion. Conclusions Infarct volume expansion was greater in individuals with HG on admission regardless of collateral circulation status.

The fibers of corticospinal tract (CST), which control fine motor function, predominantly project to the contralateral spinal cord, not recross to the ipsilateral side. Ephrin-B3, which is expressed in the midline of the spinal cord, and its receptor, EphA4, are crucial for preventing CST fibers from recrossing the midline in the developing spinal cord. However, these fibers can cross the midline to the denervated side after a unilateral CST or cortical injury. We determined the reason CST fibers can cross the midline after a cortical injury and the changes in ephrin-B3-EphA4 signaling associated with such a crossing. We first examined axonal sprouting from CST fibers after unilateral ablation of the motor cortex in postnatal and adult mice. CST fibers crossed the midline of the spinal cord after cortical ablation, especially when conducted during the early postnatal period. These fibers were well associated with functional recovery after the injury. We next assessed the mRNA expression of ephrin-B3 and EphA4 before and after the ablation. Surprisingly, no changes were detected in the expression patterns. We found, however, that ephrin-B3 expression in the ventral part of the midline disappeared after postnatal day 9 (P9), but was pronounced along the entire midline before P6. Most of the CST fibers crossed the midline through the ventral region, where ephrin-B3 expression was absent. Our results suggest that ephrin-B3 is not expressed along the entire midline of the spinal cord, and sprouting axons can cross the midline at ephrin-B3-negative areas.

Background: Clinical symptoms of Parkinson’s disease (PD) include not only motor distress, but also autonomic dysfunction. Objective: To study the characteristics of subclinical autonomic nervous dysfunction in de novo PD without orthostatic hypotension (OH). Methods: Autonomic nervous function including cardiac sympathetic gain was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure in 20 patients with de novo PD without OH. Results: Decreased cardiac MIBG uptake was found even in patients with PD without OH. Hemodynamic studies using the Valsalva maneuver revealed that patients with PD without OH had preserved baroreceptor reflex sensitivity in phase II and phase IV. Blood pressures normally responded in early and late phase II, but not in phase IV. Blood pressure recovery time was slightly reduced in patients with PD without OH when compared with the value in controls. The low frequency component of the RR interval and systolic blood pressure and the ratio of RR-LF to RR-HF in de novo PD without OH were significantly reduced when compared with the control values, whereas the high frequency component of the RR interval did not differ significantly. Conclusion: These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension.

The rewiring of neural networks is a fundamental step in recovering behavioral functions after brain injury. However, there is limited potential for axonal plasticity in the adult CNS. The myelin-associated proteins Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are known to inhibit axonal plasticity, and thus targeting the inhibitory pathways they participate in is a potential means of promoting plasticity and functional recovery. Each of Nogo, MAG, and OMgp interacts with both the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Here, we determined whether blocking PirB activity enhances axonal reorganization and functional recovery after cortical injury. We found that axons of the contralesional corticospinal tract sprouted into the denervated side of the cervical spinal cord after unilateral injury of the motor cortex. The extent to which this axonal reorganization occurred was far greater in mice lesioned during early postnatal days than in mice lesioned at an age when myelin had begun to form. This suggests that myelin-associated proteins might limit axonal remodelingin vivo. However, the number of sprouting fibers within either the corticospinal or corticorubral tract was not enhanced in PirB−/−mice. Blocking PirB signaling also failed to enhance functional recovery with three motor tests. Our results suggest that blocking the function of PirB is not sufficient to promote axonal reorganization or functional recovery after cortical injury.

To investigate the influence of diabetes mellitus on higher cognitive functions electrophysiologically, we studied auditory P300 event-related potentials (P300) in 40 NIDDM patients, taking into account wave I-V latencies (I-V) in auditory brainstem evoked potentials, clinical parameters and head MRI findings. Compared with 20 controls, diabetics had significantly longer P300 and I-V latencies. P300 latencies in diabetics correlated with neither I-V, HbA 1 , blood glucose levels, nor disease duration. Of the 13 diabetics investigated neuroradiologically, four had lacunar infarcts with prolonged electrophysiological values. The remaining nine had normal MRI scans, but their physiological parameters were still significantly longer than those of controls. These findings suggest that NIDDM can independently alter higher cognitive and the central auditory pathway functions. Our data also suggest that these alterations occur regardless of the recent metabolic derangement and disease duration. Cerebrovascular ischemia, if present, also appears to contribute in part to cognitive alterations.

Clinical symptoms of Parkinson's disease (PD) include not only motor distress but also autonomic dysfunction. Orthostatic hypotension (OH) occurs in one-fifth to one-half of all patients with PD. We examined the relation of this type of hypotension to clinical features and cardiovascular parameters such as cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake, changes on the Valsalva maneuver, and plasma norepinephrine concentrations on head-up tilt-table testing (HUT). We performed HUT in 55 patients with PD and divided them into two groups according to the presence or absence of OH, defined as a drop in systolic blood pressure (SBP mmHg) by 20 mmHg or more on standing. We evaluated cardiac sympathetic function by 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in all subjects. We also performed HUT, 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in 20 controls. The results of HUT showed that 20 patients had OH and 35 did not. The hypotension was associated with gender, older age, longer disease duration, posture and gait instability phenotype, low mini-mental state examination scores and visual hallucinations. Cardiac 123I-MIBG uptakes were lower in patients with OH. SBP fell further during early second phase in patients with OH than in patients without the condition and their increase in SBP during the late second phase and the overshoot of SBP during the fourth phase were lower. The blood pressure recovery time during the fourth phase on the Valsalva maneuver was longer in patients with OH than in those without OH. There was, however, no association between the fall in SBP on HUT and baroreflex sensitivity or the plasma norepinephrine concentrations, adjusted by age, disease duration, disease severity and dopaminergic medication using multiple regression analyses. Patients without OH already had impaired cardiac sympathetic and baroreceptor reflex functions as early abnormalities of cardiovascular autonomic control. Our results suggest that pronounced vasomotor and cardiac sympathetic dysfunction is the primary cause of OH in PD, although baroreceptor reflex failure may also make a minor contribution. It was unclear whether vasomotor and cardiac sympathetic dysfunction in patients with PD was caused primarily by the impairment of preganglionic or postganglionic lesions.

Objective We estimated the extent and pattern of cardiovascular autonomic dysfunction in dementia with Lewy bodies (DLB) as compared with that in Parkinson's disease (PD). Methods We performed meta -iodobenzylguanidine ( 123 I-MIBG) scintigraphy of the heart and hemodynamic autonomic function testing using the Valsalva maneuver in 27 patients with DLB, 46 with PD, and 20 controls. Results 123 I-MIBG uptakes in DLB were reduced as compared with those in control and PD. Hemodynamic studies revealed that DLB had decreased baroreceptor reflex and reduced responses of SBP in phases II and IV as compared with PD and control. SBP responses on standing and the difference in plasma norepinephrine (NE) concentrations between supine and standing positions were reduced in PD as compared with those in control. Furthermore, SBP responses on standing, plasma NE concentrations in supine and standing positions, and the difference in plasma NE concentrations between these positions were significantly lower in DLB than in PD and control. Plasma NE concentrations in DLB with orthostatic hypotension (OH) were lower than that in DLB without OH, although some patients who had DLB with orthostatic hypotension had relatively normal plasma NE levels. Conclusion Cardiovascular autonomic dysfunction is more severe in DLB than in PD and is usually caused by the loss of postganglionic sympathetic nervous function, although dysautonomia in some patients with DLB may result from preganglionic dysfunction.

Objective: To study the ability of patients with semantic dementia to understand actions, in order to examine the contribution of semantic memory to action comprehension. Methods: The ability to comprehend symbolic and instrumental actions was assessed in 6 patients with semantic dementia and 10 healthy controls. The patients were also given the imitation test of meaningful and meaningless actions. Results: In all patients with semantic dementia, comprehension of both symbolic and instrumental actions was defective. The comprehension of symbolic actions was more impaired than that of instrumental actions. Their ability to imitate other’s actions was well preserved. Conclusion: This study showed that comprehension of action was impaired in semantic dementia, suggesting that semantic memory has an important role in comprehension of human action.

Objectives – To determine whether Parkinson's disease (PD) can be distinguished from multiple system atrophy (MSA) on the basis of the assessment of iodine-123 meta-iodobenzylguanidine (123I-MIBG) radioactivity in heart and cardiovascular autonomic function. Patients and methods – Seventeen patients with MSA, 39 with PD, and 25 healthy volunteers underwent 123I-MIBG scintigraphy and hemodynamic autonomic function tests using Valsalva maneuver (VM). Baroreceptor reflex sensitivity (BRS) was measured using the slope of the relation between RR interval and blood pressure during the fourth phase. Results – 123I-MIBG radioactivity in heart of patients with PD was lower than that of control subjects and patients with MSA, but there was some overlap between PD and MSA. BRS in patients with PD who had a 123I-MIBG radioactivity similar to that in MSA was larger than that in patients with MSA, with no overlap in any patient. Conclusion – Assessment of BRS may be useful for differentiating between MSA and PD that had a 123I-MIBG radioactivity similar to MSA.

Background Clinical symptoms of Parkinson's disease (PD) include not only motor distress, but also autonomic dysfunction. Objective To clarify the progression of autonomic nervous dysfunction in PD. Methods The subjects were 44 patients with de novo PD. Autonomic nervous function, including cardiac sympathetic gain, was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure. Results Decreased cardiac MIBG uptake was found even in patients with early stage PD. MIBG uptake gradually decreased with increased disease severity. Hemodynamic studies using the Valsalva maneuver revealed that patients with early stage PD had reduced baroreceptor reflex sensitivity (BRS) in phase II, but not phase IV. Blood pressures normally rose in phases II and IV, but the increments decreased with disease progression. In early stage PD, the low frequency power of the RR interval (RR-LF) and the ratio (LF / HF) of RR-LF to the high frequency component of the RR interval (RR-HF) were significantly lower than the respective control values, despite no significant difference in RR-HF; these variables decreased with disease progression. Conclusion Our results show that latent sympathetic nervous dysfunction without parasympathetic dysfunction, especially that involving the sinus node, is already present in early stage de novo PD. It is unclear whether the responsible lesion is central or peripheral.

The aim of this study is to investigate the efficacy of 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) on acute pain induced by intradermal capsaicin injection and to elucidate its mechanisms by single-photon emission computed tomography (SPECT). We compared time courses of a subjective scale of pain induced by intradermal capsaicin injection in seven normal subjects under three different conditions: rTMS over M1, sham stimulation, and control condition (natural course of acute pain without any stimulation). In ten normal subjects, using SPECT, we also studied differences in regional cerebral blood flow (rCBF) after capsaicin injection between two conditions: rTMS over M1 and the control condition. rTMS over M1 induced earlier recovery from acute pain compared with the sham or control conditions. Under rTMS over the right M1 condition compared with the control condition, the SPECT study demonstrated a significant relative rCBF decrease in the right medial prefrontal cortex (MPFC) corresponding to Brodmann area (BA) 9, and a significant increase in the caudal part of the right anterior cingulate cortex (ACC) corresponding to BA24 and the left premotor area (BA6). A region-of-interest analysis showed significant correlation between pain reduction and rCBF changes in both BA9 and BA24. We conclude that rTMS over M1 should have beneficial effects on acute pain, and its effects must be caused by functional changes of MPFC and caudal ACC.

A previously healthy 41-year-old woman with recurrent herpes labialis since her 20s noticed a herpes labialis lesion on the left side of the lower lip. After 2 days, she experienced the acute onset of tingling and a swollen sensation of the left side of the face, beginning at the V3 division of the trigeminal nerve and progressing to involve the V1 and V2 divisions over the course of 2 days. A dermatologist diagnosed herpes labialis and prescribed acyclovir 1,000 mg in 2 divided doses for 5 days. However, the symptoms did not improve after the lesion disappeared. The left side of the tongue perceived a bitter taste 8 days after the onset of symptoms. Examinations …

Summary Background/aims Cerebrovascular ultrasonography was useful clinically for evaluating cerebral hemodynamics rapidly and in real-time for patients with acute ischemic stroke. We analyzed if the patients had early recanalization or not using transcranial color-coded sonography (TCCS) in order to evaluate the usefulness of real-time monitoring in systemic thrombolysis. Methods Subjects were patients who had acute ischemic stroke with intravenous tissue plasminogen activator (tPA) within 3 h from onset. We evaluated occlusion of intracranial arteries from transtemporal or suboccipital window by TC-CFI with Thrombolysis in Brain Ischemia (TIBI) flow-grading system and monitored residual flow in real-time every 15 min until 120 min after the t-PA bolus. Results We could monitor residual flow in 5 patients who had good echo windows (4 male, mean age; 60.8 ± 6.4 years). Two patients had proximal occlusion of the middle cerebral artery (MCA), one patient had distal occlusion of MCA, one patient had M2 occlusion and one patient had distal occlusion of unilateral vertebral artery. Four patients had early complete recanalization within 60 min after the t-PA bolus (two patients within 60 min and other two patients within 30 min), however, occlusion persisted during 120 min monitoring in one patient with proximal occlusion of MCA. NIH Stroke Scale of two patients with very early recanalization was 0 at the end of the treatment. There was no symptomatic and asymptomatic intracranial hemorrhage in 4 patients except for the patients without recanalization. Conclusions It is anticipated that real-time ultrasound monitoring is useful for evaluating a very early thrombolytic effect of tPA connected with early clinical recovery.

Objective This study aimed to examine whether the volume of the olfactory bulbs and tracts (OB & T) on magnetic resonance imaging (MRI) is useful for differentiating Parkinson's disease (PD) from PD-related disorders. Methods The study group comprised 13 patients with PD, 11 with multiple system atrophy (MSA), five with progressive supranuclear palsy, and five with corticobasal degeneration (PSP/CBD). All patients were evaluated using the odor stick identification test for Japanese (OSIT-J), 123I-meta-iodobenzylguanidine (MIBG) scintigraphy, and brain MRI. OB & T areas on 1-mm-thick coronal images were measured and summed for volumes. We examined relationships between olfactory function and volume, and cardiovascular dysautonomia. We defined the cut-off values for OSIT-J score or MIBG uptake and OB & T volume to discriminate PD from PD-related disorders and calculated the proportional rate of PD in four categorized groups. Results OB & T volume was smaller in PD than in MSA or PSP/CBD (p

We herein report that the clinical, laboratory, and radiographic features and positron emission tomography (PET) imaging may provide valuable clues to the pathogenesis of cerebral amyloid angiopathy (CAA)-associated encephalopathy, which currently remains unclear. We herein describe two cases of encephalopathy with CAA, with an emphasis on PET imaging with (11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-fluorodeoxyglucose ((18)F-FDG). One case of Alzheimer's disease for which a brain biopsy was performed showed CAA-related inflammation. Another case that had developed sudden sensory aphasia presented with posterior reversible encephalopathy syndrome-like vasogenic edema in the left temporal region with (11)C-PiB uptake and microhemorrhages. (11)C-PiB and (18)F-FDG PET are useful for detecting CAA-associated encephalopathy, including atypical CAA cases.

Objective The usefulness of conventional magnetic resonance imaging (C-MRI) for diagnosing amyotrophic lateral sclerosis (ALS) remains controversial. The aim of this study was to investigate the utility of C-MRI in identifying ALS, specifically the association between corticospinal tract (CST) hyperintensity on C-MRI and clinical characteristics in patients with ALS. Methods Between June 2008 and April 2012, we retrospectively enrolled consecutive patients diagnosed with sporadic ALS who underwent C-MRI. Patients with ALS were classified as definite-phase ALS (D-ALS) and indefinite-phase ALS (ID-ALS). We focused on the hyperintensity of T2-weighted images in the CST in patients with ALS. Based on the MRI results, we divided patients into two groups: a positive CST group showing CST hyperintensity; and a negative CST group with no such findings. Clinical characteristics of the two groups were compared. Results Seventeen patients (median age, 62 years; 8 women, 9 men) were enrolled in this study, with D-ALS in eight (47%) and ID-ALS in nine (53%). Eight patients (47%) showed CST positivity. The rate of CST positivity was higher in patients with D-ALS (75%) than in patients with ID-ALS (22%, p = 0.03). Conclusions CST positivity appears significantly increased in D-ALS patients. C-MRI can play an important role in diagnosing ALS.

A 64-year-old man had transverse myelopathy that rapidly progressed without pain over the course of 1 day. The cerebrospinal fluid interleukin-6 (CSF IL-6) level was extremely high (1,120 pg/dl). Spinal cord magnetic resonance imaging (MRI) showed a longitudinal extensive lesion extending from Th8 to the conus medullaris. Despite treatment with steroids and cyclophosphamide, the symptoms worsened, and the range of sensory disturbance spread. MRI showed that the lesion expanded to Th3 over the course of 2 months. Neuro-Behcet disease (NBD) was diagnosed on basis of the high CSF IL-6 level and HLA-B51 positivity, and treatment with infliximab was begun. The sensory disturbance improved slightly, and the CSF IL-6 level fell to the normal range (7.0 pg/ml). It is important to include NBD, which rarely presents with extensive spinal cord lesion, in the differential diagnosis when patients present with acute transverse myelopathy without pain.

Objective Although previous randomized clinical trials established a basis for lipid guidelines worldwide, they employed fixed doses of statins throughout trials (fire-and-forget approach). In the real clinical setting, however, statin doses are titrated to achieve target low-density lipoprotein cholesterol (LDL-C) levels (treat-to-target approach). The major objective was to investigate whether intensive lipid-lowering therapy using the treat-to-target approach yielded greater regression of aortic plaques. Methods We therefore performed a prospective, randomized trial comparing the effects of standard (achieve LDL-C levels recommended by the Japanese guidelines) and intensive (achieve 30% lower LDL-C levels than standard) rosuvastatin therapy for 1 year in 60 hypercholesterolemic patients with a primary endpoint of aortic atherosclerotic plaques evaluated by non-invasive magnetic resonance imaging (MRI). Results Average doses were 2.9 ± 3.1 and 6.5 ± 5.1 mg/day for standard ( n = 29) and intensive therapy group ( n = 31), respectively. Although both therapies significantly reduced LDL-C and high-sensitivity C-reactive protein (hsCRP) levels, LDL-C reduction was significantly greater in the intensive group (−46 vs. −34%). MRI study showed that thoracic aortic plaques were significantly regressed in both groups, with greater regression of thoracic plaque in the intensive group (−9.1 vs. −3.2%, p = 0.01). Multivariate analyses revealed that thoracic plaque regression was significantly correlated with hsCRP reduction, but not with changes in serum lipids, endothelial function, or doses of rosuvastatin. Conclusion Intensive statin therapy with titration targeting lower LDL-C levels resulted in greater thoracic aortic plaque regression compared to standard therapy, which was correlated with hsCRP reduction, suggesting that intensive statin therapy could provide better clinical outcomes.

OBJECTIVE To investigate neurophysiological alterations of higher brain function in patients with NIDDM. RESEARCH DESIGN AND METHODS Auditory P300 event-related potentials were recorded in 60 NIDDM patients who had no evidence of stroke, dementia, or any other neurological illnesses. The P300 wave latencies in diabetic patients were compared with those in neurologically healthy control subjects, with consideration of clinical parameters and diabetic complications. RESULTS Diabetic patients had significantly longer P300 latencies than control subjects. Seven diabetic patients had pathologically prolonged P300 values. There was a trend toward longer P300 latencies in diabetic patients with retinopathy and in those with HbA1 of ≥10%; the differences between these diabetic subgroups and control subjects were both statistically significant. However, three of seven diabetic patients with abnormal P300 latencies had no retinal lesions, and no significant correlation was observed among diabetic patients between P300 latencies and HbA1 levels. Peripheral neuropathy, nephropathy, blood glucose levels, and disease duration appeared not to correlate with P300 alterations. CONCLUSIONS These findings suggest the presence of central nervous pathological processes in NIDDM that affect higher brain functions, as assessed by P300 latencies. Our findings also suggest that microangiopathy and metabolic derangement during the preceding 4- to 8-week period may contribute in small part to the pathophysiology of this central nervous involvement.

Cerebral microbleeds (CMBs) are recognized as a manifestation of arteriolosclerosis in cerebral small vessels. However, little is known regarding whether stroke patients with CMBs often have systemic atherosclerosis. The aim of the present study was to elucidate this issue using the cardio-ankle vascular index (CAVI), a new index of systemic atherosclerosis, in acute ischemic stroke patients. We prospectively studied 105 patients (71 males, median age=70.0 years) with acute ischemic stroke. All of the patients were examined using T2*-weighted gradient echo magnetic resonance imaging (MRI) to look for and assess the CMBs and using fluid-attenuated inversion recovery to evaluate white matter hyperintensity (WMH). We assigned the patients into CMB and non-CMB groups and compared the clinical characteristics of these groups. The factors associated with CMBs were investigated using multivariate logistic regression analysis. T2*-weighted gradient echo MRI revealed CMBs in 47 patients (44.8%) and no CMBs in 58 patients (55.2%). The CAVI was significantly higher in the CMBs group (10.5 vs. 8.6, P

Objective: Right-to-Left shunt (RLS) detection by Transcranial Doppler is useful for diagnosis of paradoxical embolism. However, we sometimes could not monitor MCA due to insufficient temporal bone window, especially in old patients. Other insonation windows such as transorbital and suboccipital window (basilar artery) are using recently, whereas the ability to detect of intracranial arteries from these windows was not so high. We evaluated usefulness of RLS detection in intracranial vertebral artery (VA) from suboccipital approach that could be measured in almost patients. Methods: We evaluated RLS using transcranial color flow imaging (TC-CFI) in patients with ischemic stroke or transient ischemic attack who could be detected middle cerebral artery (MCA) from temporal bone window and intracranial VA from suboccipital window by TC-CFI. We monitored microembolic signal (MES) at ipsilateral MCA and VA (not hypoplastic side) for 90seconds after injection of 9ml saline agitated with 1ml of air in the right antecubital vein. The procedure was performed three times in each artery with and without Valsalva maneuver. The presence of MES was classified according to Spencer Logarithmic Scale (SLS) criteria. Results: Fifty two patients (46 male, mean age of 64.1±14.3) were included. Twelve patients were positive of MES (23.1%). VA comparison to MCA showed 10 true positive, 40 true negative, 0 false positive and 2 false negative cases (sensitivity 83.3%, specificity 100%, positive predictive value 100%, negative predictive value 95.2% and accuracy 96.2%). In 12 patients with MES, 22 of 36 examinations in MCA were positive of MES (SLS grade I was 20 examinations and grade II was 2 examinations), on the other hand, 20 of 36 examinations in VA were positive (SLS grade I was 20 examinations). The positive ratio of 36 examinations in 12 patients did not show significant difference statistically between MCA and VA. Conclusion: The evaluation of RLS in intracranial VA using TC-CFI from suboccipital window has equal diagnostic ability to MCA, and is useful for the patients with insufficient temporal bone window.

We report a 55-year-old woman with limbic encephalitis associated with leucine-rich glioma-inactivated 1 (LGI1) antibody. She first developed a generalized seizure, following by consciousness loss. Although anticonvulant was initially effective, she began to present frequently with seizure and memory impairment. After eleven months from onset, she was admitted due to generalized seizure. Neurological examination after recovering from the treatment with anesthetic agent demonstrated disorientation and memory impairment. Cerebrospinal fluid analysis was unremarkable. MR brain FLAIR imaging demonstrated high intensity lesions in the medial parts of the both temporal lobes, suggesting limbic encephalitis. There were no signs of malignant tumor detected on systemic examination. LGI1 antibody was positive in the cerebrospinal fluid and we finally diagnosed this patient as having limbic encephalitis associated with LGI1 antibody. She demonstrated a good response to steroid therapy and was discharged after one month.

We report here in a 61-year-old woman in whom sensory disturbance predominantly affecting the distal portion of the limbs progressed over the course of 1 year. Blood tests showed IgM monoclonal gammopathy as well as the presence of anti-myelin-associated glycoprotein (MAG) antibody. Nerve conduction studies revealed significant prolongation of distal latency, and sural nerve biopsy showed IgM deposition on the myelin sheath. She was diagnosed as suffering anti-MAG neuropathy. High-dose intravenous immunoglobulin therapy proved to be ineffective and her symptoms progressed. Therefore, rituximab was administered and the sensory disturbance improved. Although no detailed studies on rituximab therapy for anti-MAG neuropathy have been reported in Japan, the present findings suggest that rituximab may be more effective than immunoglobulin therapy and other conventional therapies that have been used for autoimmune neuropathies.

It remains unclear whether cardiac iodine-123-labeled metaiodobenzylguanidine ((123)I-MIBG) uptake is clinically related to autonomic dysfunction on conventional autonomic function testing in de novo Parkinson's disease (PD). We therefore studied the relation between cardiac (123)I-MIBG uptake and cardiovascular autonomic dysfunction in patients with de novo PD. The subjects were 26 patients with de novo PD. The ratio of the average pixel count in the heart to that in the mediastinum was calculated to derive the cardiac (123)I-MIBG uptake. Cardiovascular autonomic function was evaluated on the basis of cardiovascular autonomic response on the Valsalva maneuver (VM), and systolic blood pressure response (SBP) on head-up tilt-table testing (HUT). Patients with de novo PD had significantly reduced cardiac (123)I-MIBG uptake as compared with controls (1.58 ± 0.43 vs. 2.25 ± 0.34, p = 0.0001) and cardiovascular autonomic response on the VM. No significant difference in the fall in SBP on HUT was found between patients with de novo PD and the controls. Cardiac (123)I-MIBG uptake in de novo PD was not significantly related to vasomotor sympathetic function, baroreceptor reflex gain, cardiac parasympathetic function, or the changes in SBP on HUT. Cardiac (123)I-MIBG uptake was, however, significantly related to the blood pressure overshoot in phase IV of the VM (r = 0.648, p = 0.0003). Cardiac (123)I-MIBG uptake began to decrease in association with the reduction in the overshoot of phase IV on the VM. Cardiac (123)I-MIBG uptake clinically reflects cardiac sympathetic dysfunction in de novo PD.

We report a family with Boucher-Neuhauser syndrome (BNS). All 3 patients with BNS had hypersegmented neutrophils on peripheral-blood films. Our findings indicate that hypersegmented neutrophils are a characteristic of BNS. Blood films should therefore be examined in patients with a suspected diagnosis of BNS.

心電図QT時間を用いた交感神経機能評価法により慢性期の脳卒中患者の自律神経機能障害を検討した.対象と方法 : 1) 健常者602名でQT時間とR-R間隔の回帰直線を求め, 実際に測定したQT時間とその時のR-R間隔を回帰直線に代入して得られたQT時間との差ΔQTを算出し, QT時間の指標とした.2) 発症1ヵ月以降の脳卒中患者42名でΔQTを算出し, 脳卒中の病態との関連を検討した.結果 : 1) 健常者のR-R間隔 (xmsec) とQT時間 (ymsec) の回帰直線はy=0.143x+243であった.また, 健常者のΔQTは0±17msecであった.2) 脳卒中患者のΔQTの平均は+23msecでagematchした健常者42名の+9msecに比較して大きかった.3) 罹病期間が1年未満の脳卒中患者のΔQT (29msec) は1年以上の群 (17msec) に比較して大きかった.結論 : 1) 罹病期間が1年未満の脳卒中患者では交感神経機能障害が強かった.2) ΔQTは脳卒中患者の交感神経機能障害の評価に有用である.

We analyzed the serum levels of type IV collagen, a major component of the basement membrane, during various stages of sporadic amyotrophic lateral sclerosis (ALS). Serum concentrations of type IV collagen increased significantly with the duration of illness. Findings indicate that the metabolism of type IV collagen and the basement membrane may be affected in the disease process of ALS.

Several studies have reported that olfactory dysfunction is an early neuropathological manifestation of Parkinson's disease (PD). Reduced cardiac meta-iodobenzylguanidine ((123)I-MIBG) uptake may be one of the earliest signs of PD. We studied the relation of olfactory dysfunction to cardiovascular dysautonomia in patients with PD. The study group comprised 66 patients with PD (70.5 years) and 26 controls (70.3 years) for olfactory assessment, 21 controls (72.1 years) for cardiac (123)I-MIBG scintigraphy and heart rate variability (HRV), assessed using the coefficient of variation for RR intervals (HRV), and 23 controls (69.2 years) for orthostatic blood pressure response. Olfactory function was assessed by the odor stick identification test Japan (OSIT-J), and cardiovascular autonomic function was evaluated by (123)I-MIBG scintigraphy of the heart, the fall in orthostatic blood pressure, and HRV. Patients with PD had a significantly lower OSIT-J score than did the controls (4.1 +/- 3.0 vs. 9.9 +/- 1.7, p = 0.001). The OSIT-J score was unrelated to variables other than gender, including age, disease duration, motor score on the unified Parkinson's disease rating scale, score on the mini-mental state examination, motor phenotype, visual hallucinations, and dopaminergic medication on multiple regression and logistic regression analyses. The OSIT-J score was related to the heart/mediastinum ratio of cardiac (123)I-MIBG uptake, the fall in orthostatic blood pressure, and HRV, after adjustment for other clinical variables. Olfactory dysfunction in PD was, thus, significantly related to both cardiac sympathetic and parasympathetic dysfunction, as well as vascular sympathetic dysfunction. As non-motor symptoms of PD, olfactory dysfunction and autonomic network failure appear to be closely related in PD.

Morphologic characteristics and hemodynamics in the carotid artery were investigated in patients with stroke by use of Doppler color-flow analysis and three-dimensional (3D) analysis by computer graphics. The 3D imaging of the carotid bifurcation was reconstructed from a series of transverse B-mode images. Comparison of color-flow and 3D images demonstrated that wall configuration in vivo, dilation, and curvature play an important role in reversal of flow and stagnation at the carotid bifurcation. Furthermore, 3D analysis is very useful in mapping the distribution of the atheromatous plaques. The analyses suggest that it is important to investigate the wall configuration of the bifurcation in vivo on flow patterns, especially flow separation and stagnation, in relation to the development of atheromatous plaques.

Objective: To examine the relation between the results of cardiac 123 I-meta-iodobenzylguanidine (MIBG) scintigraphy and cardiovascular autonomic function in Lewy body disease (LBD). Methods: The subjects were 66 patients with LBD, 44 of whom had Parkinson disease (PD), 10 PD with dementia (PDD), and 12 dementia with Lewy bodies (DLB); 20 age-matched healthy subjects were studied as controls. Cardiovascular autonomic function was evaluated on the basis of cardiac 123 I-MIBG uptake, cardiovascular autonomic response on the Valsalva maneuver (VM), and systolic blood pressure (SBP) response on head-up tilt table (HUT) testing. Results: Patients with LBD had reduced cardiac 123 I-MIBG uptake, cardiovascular autonomic response on the VM, and SBP response on HUT testing as compared with controls. Cardiac 123 I-MIBG uptake and cardiovascular autonomic function in PDD and DLB were severely impaired as compared with those in PD. Cardiac 123 I-MIBG uptake in LDB was not significantly related to vasomotor sympathetic function, baroreceptor reflex gain, cardiac parasympathetic function, or the changes in SBP on HUT testing. Cardiac 123 I-MIBG uptake was, however, significantly related to the blood pressure overshoot in phase IV of the VM. Conclusion: Cardiac 123 I-meta-iodobenzylguanidine uptake clinically reflects cardiac sympathetic dysfunction in Lewy body disease. GLOSSARY: BRS = baroreceptor reflex sensitivity; DLB = dementia with Lewy bodies; H/M ratio = the ratio of the average pixel count in the heart to that in the mediastinum; HUT = head-up tilt table test; LBD = Lewy body disease; MIBG = 123 I-meta-iodobenzylguanidine; MMSE = Mini-Mental State Examination; PD = Parkinson disease; PDD = Parkinson disease with dementia; phase II E = systolic blood pressure decreases in early phase II; phase II L = systolic blood pressure increases in late phase II; PRT = pressure recovery time; VM = Valsalva maneuver; ROI = region of interest; SBP = systolic blood pressure; TH = tyrosine hydroxylase.

Clinical symptoms of Parkinson's disease (PD) include not only motor distress but also autonomic dysfunction. Orthostatic hypotension (OH) occurs in one-fifth to one-half of all patients with PD. We examined the relation of this type of hypotension to clinical features and cardiovascular parameters such as cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake, changes on the Valsalva maneuver, and plasma norepinephrine concentrations on head-up tilt-table testing (HUT). We performed HUT in 55 patients with PD and divided them into two groups according to the presence or absence of OH, defined as a drop in systolic blood pressure (SBP mmHg) by 20 mmHg or more on standing. We evaluated cardiac sympathetic function by 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in all subjects. We also performed HUT, 123I-MIBG scintigraphy and assessed cardiovascular autonomic function by using the Valsalva maneuver in 20 controls. The results of HUT showed that 20 patients had OH and 35 did not. The hypotension was associated with gender, older age, longer disease duration, posture and gait instability phenotype, low mini-mental state examination scores and visual hallucinations. Cardiac 123I-MIBG uptakes were lower in patients with OH. SBP fell further during early second phase in patients with OH than in patients without the condition and their increase in SBP during the late second phase and the overshoot of SBP during the fourth phase were lower. The blood pressure recovery time during the fourth phase on the Valsalva maneuver was longer in patients with OH than in those without OH. There was, however, no association between the fall in SBP on HUT and baroreflex sensitivity or the plasma norepinephrine concentrations, adjusted by age, disease duration, disease severity and dopaminergic medication using multiple regression analyses. Patients without OH already had impaired cardiac sympathetic and baroreceptor reflex functions as early abnormalities of cardiovascular autonomic control. Our results suggest that pronounced vasomotor and cardiac sympathetic dysfunction is the primary cause of OH in PD, although baroreceptor reflex failure may also make a minor contribution. It was unclear whether vasomotor and cardiac sympathetic dysfunction in patients with PD was caused primarily by the impairment of preganglionic or postganglionic lesions.

We assessed the relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with Parkinson's disease (PD). The subjects were 37 patients without VH (VH(−)) and 31 with VH (VH(+)). Autonomic function was evaluated on the basis of cardiac 123-radioiodinated metaiodobenzylguanidine (123I-MIBG) uptake and hemodynamic testing with Valsalva maneuver. Systolic blood pressure (SBP) and plasma norepinephrine concentrations (NE) were measured by tilt-table testing. 123I-MIBG uptake was lower in VH(+) than VH(−). Hemodynamic studies showed that VH(−) had only cardiac sympathetic and parasympathetic dysfunction, while VH(+) additionally had reduced vasomotor sympathetic functions. The fall in SBP during tilt-table testing was greater in VH(+) than VH(−). NE and its difference in the supine and upright positions were decreased in VH(+). We conclude that cardiac and vasomotor sympathetic dysfunction is more severe in VH(+) than in VH(−). Severe dysfunction in PD with VH is probably attributed to Lewy-body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both. © 2007 Movement Disorder Society

Background: Baroreflex sensitivity assessments have been considered to be important to evaluate cardiac autonomic neuropathy. The phenylephrine method, Valsalva maneuver or sequence method at rest caused several problems. We evaluated the usefulness of the sequence method during deep respiration. Method: Baroreflex sensitivity was evaluated in 20 normal volunteers and 50 patients with Parkinson’s disease. R–R intervals and systolic blood pressures were obtained by electrocardiogram and tonometry using a continuous blood pressure monitoring system. The sequence method is an evaluation of baroreflex sensitivity using sequences of 3 or more consecutive beats for 4 min. Baroreflex sensitivity was also assessed by the Valsalva maneuver at 5 beats before the peak systolic blood pressure of phase IV. The slope of the linear interrelationship between systolic blood pressure and the following R–R interval, i.e. baroreflex sensitivity (ms/mm Hg), was calculated with a correlation coefficient greater than 0.8. Result: The mean value of baroreflex sensitivity obtained by the Valsalva maneuver was 7.91 in normal volunteers and 5.35 in patients with Parkinson’s disease; the one obtained by the sequence method at rest was 9.10 in normal volunteers and 8.42 in patients with Parkinson’s disease, and the one obtained by the sequence method during deep respiration was 10.23 in normal volunteers and 6.73 in patients with Parkinson’s disease. In some cases with Parkinson’s disease, baroreflex sensitivities could not be found, whereas in all patients with Parkinson’s disease, the sequence method during deep respiration could be used for evaluations. Significant correlations were found among the baroreflex sensitivities obtained by the Valsalva maneuver, and the sequence method at rest or during deep respiration in normal volunteers and patients with Parkinson’s disease. Conclusions: The baroreflex sensitivity obtained by the sequence method during deep respiration could be investigated noninvasively in all cases with PD, being thus a useful method for clinical evaluation of baroreflex sensitivity.

QTc intervals were measured in 30 patients with Parkinson's disease and 30 healthy control subjects. The mean value of QTc intervals in patients with Parkinson's disease significantly exceeded that of healthy controls (418 +/- 14 ms vs. 403 +/- 18 ms). Prolongation of the QTc interval was unrelated to the administration of levodopa. The mean QTc interval in patients whose Hoehn and Yahr score was III or more was significantly greater than that of patients whose score was II or less (424 +/- 12 ms vs. 410 +/- 12 ms). A significant correlation between the QTc interval and the Valsalva ratio, as well as the overshoot, was identified. The QTc interval is closely related to autonomic nervous system dysfunction, including abnormal baroreceptor reflex function, in patients with Parkinson's disease.

We have attempted to clarify the relationships of the QT c interval to α and β sympathetic, as well as parasympathetic function tests including spectral analyses of the R-R interval and systolic blood pressure. The QT c intervals were estimated in 76 diabetic patients and 76 age-matched healthy controls whose R-R intervals were comparable to those of the diabetic patients. We also investigated the relationships of the QT c interval to various clinical features of diabetes mellitus and to autonomic function tests. The QT c interval in diabetic patients was significantly greater than that in healthy controls. The QT c intervals were unrelated to diabetic control, retinopathy and nephropathy, but were prolonged in patients with a long duration of diabetes as compared to those with a short disease duration. There were significant correlations between the QT c interval and orthostatic hypotension, R-R variation and the Valsalva maneuver. Significant correlations were observed between the QT c interval and both the low and the high frequency component of spectral analysis of the R-R interval, whereas no correlations were found with spectral analysis of systolic blood pressure. An abnormal QT c interval is an indicator of cardiac sympathetic and parasympathetic nervous dysfunction, but not vasomotor dysfunction.

Although about 5 to 10% of amyotrophic lateral sclerosis (ALS) cases are familial, the pathophysiology of ALS remians unknown. A new point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene, resulting in an amino acid substitution of leucine84 by valine (L84V), in a Japanese patient with familial ALS (FALS) was identified. This L84V substitution was not observed in 57 normal Japanese control subjects. The enzymatic activities of Cu/Zn SOD of skin fibroblasts were significantly reduced to 75% of the control level in the affected patient. The progression of the disease with this mutation is very rapid, but the age at onset varies with sex or generation within a family.

We studied autonomic nervous system function using the principle of maximum entropy (ME) to perform spectral analyses of the R-R interval and systolic blood pressure in 32 diabetic patients and 40 healthy controls. The R-R interval and systolic blood pressure were measured using a continuous, noninvasive monitoring system. The power spectra of both the R-R interval (RR) and systolic blood pressure (SYS) were obtained using ME and the areas of two frequency components were measured: a low- (LFC) and a high-frequency component (HFC). The RR-LFC, RR-HFC and SYS-LFC of diabetic patients were significantly smaller than those of healthy controls. The results of the spectral analyses in diabetic patients correlated with neither disease duration nor nephropathy, while the SYS-LFC showed significant correlations with both retinopathy and the delay in median motor nerve conduction velocity. In the mild autonomic neuropathy group, the RR-LFC and SYS-LFC were not differ from those of healthy controls or patients without autonomic neuropathy. However, the RR-HFC was significantly smaller than that of healthy controls or patients without atonomic neuropathy. In the setting of mild diabetic autonomic neuropathy, it was suggested that cardiac parasympathetic dysfunction preceded both alpha and beta sympathetic dysfunction.