Suk-Won Ahn

Reproducibility of the motor unit number index (MUNIX) in normal controls and amyotrophic lateral sclerosis patients

The motor unit number index (MUNIX) refers to an electrophysiologic technique that measures the approximate number of motor units using the surface electromyographic interference pattern (SIP) recorded during voluntary contraction. This study was done to assess the reproducibility of MUNIX performed on hypothenar muscles in 62 normal controls and 22 amyotrophic lateral sclerosis (ALS) patients. Inter‐ and intraoperator correlation coefficients for MUNIX were 0.74 and 0.86, respectively, in normal controls, and 0.95 and 0.93, respectively, in ALS patients (P < 0.01 in all). Inter‐ and intraoperator coefficients of variation for MUNIX measurements were 17.5% and 15.3%, respectively, in normal controls, and 23.7% and 24.0%, respectively, in ALS patients. This study shows a good correlation for MUNIX between intra‐ and interoperator results in both normal controls and ALS patients. The test–retest variability seems to be greater in ALS patients compared with normal controls, but this will need to be confirmed in future studies. Sources of variability should be identified and corrected for clinical use. Muscle Nerve 42: 808–813, 2010

Brain abnormalities in neuromyelitis optica

BACKGROUND Differentiating neuromyelitis optica (NMO) from multiple sclerosis (MS) is a real challenge in the clinical field. In the past, NMO (not MS), was inferred when abnormality was not detected in the brain magnetic resonance imaging (MRI). Recently, some studies have reported abnormalities in the brain MRIs of NMO, but only few among the Asian population. The aim of this study was to evaluate the frequency of brain MRI among Korean NMO patients and characterize findings that might be helpful to distinguish NMO from MS. METHODS Medical records, NMO-IgG, and brain MRI of 17 patients diagnosed with NMO by the revised diagnostic criteria of Wingerchuk et al. (2006) [6] from 2008 to 2010, were reviewed. RESULTS 11 out of 17 patients (64.7%) had abnormal MRI findings. More than two lesions were detected in most patients. The majority of patients with brain MRI abnormality showed nonspecific (5 patients) or atypical (6 patients) findings. Cerebral white matter was most frequently involved (58.8%). 3 patients (17.6%) involved corpus callosum, 4 (23.5%) with internal capsule, 2 (11.8%) with cerebellum, and 3 (17.6%) with brainstem. There were 5 (29.4%) patients who met the Paty et al. criteria (1988) [15] and 3 patients (35.3%) who met the multiple sclerosis (MS) spatial distribution diagnostic criteria of Barkhof et al. (1997) [14] in their brain MRI. CONCLUSIONS Brain abnormalities have been frequently found among Korean NMO patients and the frequencies have been reported to be higher than that of Caucasians. Current MS spatial distribution criteria, such as Paty et al. (1988) [15] or Barkhof et al. (1997) [14], are not sufficient to discriminate NMO from MS in brain MRI findings. Our results will provide valuable information that would be useful in establishing future revising criteria for NMO.

Potential Effect of S-Nitrosylated Protein Disulfide Isomerase on Mutant SOD1 Aggregation and Neuronal Cell Death in Amyotrophic Lateral Sclerosis

Aggregation of misfolded protein and resultant intracellular inclusion body formation are common hallmarks of mutant superoxide dismutase (mSOD1)-linked familial amyotrophic lateral sclerosis (FALS) and have been associated with the selective neuronal death. Protein disulfide isomerase (PDI) represents a family of enzymatic chaperones that can fold nascent and aberrant proteins in the endoplasmic reticulum (ER) lumen. Recently, our group found that S-nitrosylated PDI could contribute to protein misfolding and subsequent neuronal cell death. However, the exact role of PDI in the pathogenesis of ALS remains unclear. In this study, we propose that PDI attenuates aggregation of mutant/misfolded SOD1 and resultant neurotoxicity associated with ER stress. ER stress resulting in PDI dysfunction therefore provides a mechanistic link between deficits in molecular chaperones, accumulation of misfolded proteins, and neuronal death in neurodegenerative diseases. In contrast, S-nitrosylation of PDI inhibits its activity, increases mSOD1 aggregation, and increases neuronal cell death. Specifically, our data show that S-nitrosylation abrogates PDI-mediated attenuation of neuronal cell death triggered by thapsigargin. Biotin switch assays demonstrate S-nitrosylated PDI both in the spinal cords of SOD1 (G93A) mice and human patients with sporadic ALS. Therefore, denitrosylation of PDI may have therapeutic implications. Taken together, our results suggest a novel strategy involving PDI as a therapy to prevent mSOD1 aggregation and neuronal degeneration. Moreover, the data demonstrate that inactivation of PDI by S-nitrosylation occurs in both mSOD1-linked and sporadic forms of ALS in humans as well as mice.

25-Hydroxyvitamin D Status Is Associated With Chronic Cerebral Small Vessel Disease

Background and Purpose— The aim of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) and neuroimaging correlates of cerebral small vessel disease. Methods— We identified 759 consecutive patients with acute ischemic stroke or transient ischemic attack. Lacunes, white matter hyperintensity, and cerebral microbleed (CMB) were assessed using MR images. Deep CMB was defined as the presence of CMB in basal ganglia, thalamus, or brain stem. The association between 25(OH)D and small vessel disease was tested using linear and logistic regression analyses. Results— Mean age was 68 (±13) years. Mean level of 25(OH)D was 34.1±17.8 nmol/L. On bivariate analysis, a 25-nmol/L decrease in 25(OH)D was associated with lacunes (regression coefficient, 0.23; 95% confidence interval [CI], 0.02–0.45), severe white matter hyperintensity (odds ratio, 2.05; 95% CI, 1.41–3.08), and deep CMB (odds ratio, 1.28; 95% CI, 1.01–1.63). Also, 25(OH)D deficiency (⩽25 nmol/L) was associated with lacunes (regression coefficient, 0.5; 95% CI, 0.04–0.95), severe white matter hyperintensity (odds ratio, 2.74; 95% CI, 1.31–6.45), and deep CMB (odds ratio, 1.68; 95% CI, 1.03–2.78). The association remained significant even after multivariable adjustment and in the subgroup of previously healthy patients. Conclusions— 25(OH)D is inversely associated with lacunes, white matter hyperintensity, and deep CMB. Our findings suggest that 25(OH)D is linked to small vessel disease, and in future trials it should be tested whether 25(OH)D supplementation can prevent small vessel disease.

Frontal Assessment Battery to Evaluate Frontal Lobe Dysfunction in ALS Patients

BACKGROUND Assessment of frontal lobe impairment in amyotrophic lateral sclerosis (ALS) is a matter of great importance, since it often causes ALS patients to decrease medication and nursing compliance, thus shortening their survival time. METHODS The frontal assessment battery (FAB) is a short and rapid method for assessing frontal executive functions. We investigated the applicability of the FAB as a screening method for assessing cognitive impairments in 61 ALS patients. Depending on the results of the FAB, we classified patients into two subgroups: FAB-normal and FAB-abnormal. We then performed additional evaluations of cognitive function using the Korean version of the mini-mental state examination (K-MMSE), a verbal fluency test (COWAT), and a neuropsychiatric inventory (NPI). Results of these tests were compared between the two groups using Mann-Whitney U-tests, and Spearman correlation analyses were used to investigate the relationships between FAB score and disease duration and severity. RESULTS Of the 61 sporadic ALS patients included in this study, 14 were classified as FAB-abnormal and 47 were classified as FAB-normal. The FAB-normal and FAB-abnormal patients performed significantly differently in all domains of the COWAT. There was no difference in behavioral disturbance, as assessed by the NPI, between the two groups. The FAB scores were found to significantly correlate with both disease duration and severity. CONCLUSIONS The FAB shows promise as a method of screening for frontal lobe dysfunction in ALS, as it is not only quick and easy, but also reliable. Additional studies should examine how FAB performance changes as ALS progresses.

The neuroprotective effect of the GSK-3β inhibitor and influence on the extrinsic apoptosis in the ALS transgenic mice

BACKGROUND Glycogen synthase kinase-3β (GSK-3β) activity plays a central role in motor neuron degeneration. We hypothesized that GSK-3β inhibitor would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS). METHODS A total of 40 transgenic mice harboring the human G93A mutated SOD1 gene and 14 wild type mice were used following confirmation of their genotype. The 40 transgenic mice were divided into 2 groups; ALS transgenic mice_control and ALS transgenic mice_GSK-3β inhibitor treatment. The clinical status, rotarod test and survival of the transgenic ALS mice and wild-type mice were evaluated. Additionally, motor neuron counting, GSK-3β activity and extrinsic apoptotic signals in spinal cord were also investigated. RESULTS The treatment with GSK-3β inhibitor showed excellent motor ability and delay of the symptom onset and survival in the ALS transgenic mice. However, after clinical symptoms developed, the neuroprotective effect of GSK-3β inhibitor was not significant. And the biochemical results revealed the weakly increased extrinsic apoptotic signals in the ALS transgenic mice by GSK-3β inhibitor treatment. CONCLUSION The present study suggests that GSK-3β inhibitor would be a novel promising therapeutic strategy in ALS; however neuroprotective effect of GSK-3β inhibitor may be reduced via extrinsic apoptosis or non-neuronal patho-mechanism in late-stage of disease.

A voxel-based morphometric study of cortical gray matter volume changes in Alzheimer's disease with white matter hyperintensities.

White matter hyperintensity (WMH) is commonly detected in patients with Alzheimers disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p<0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p<0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.

Pattern difference of dissociated hand muscle atrophy in amyotrophic lateral sclerosis and variants

Introduction: Split hand is considered to be a specific feature of amyotrophic lateral sclerosis (ALS). Methods: We evaluated the pattern difference of intrinsic hand muscles of upper limb‐onset ALS (UL‐ALS), upper limb‐onset progressive muscular atrophy (UL‐PMA), brachial amyotrophic diplegia (BAD), and Hirayama disease (HD) by measuring objective electrophysiological markers. Results: The abductor digiti minimi (ADM)/abductor pollicis brevis (APB) compound muscle action potential (CMAP) amplitude ratio was significantly higher in UL‐ALS than other variants, but a considerable proportion of UL‐ALS cases had an amplitude ratio in the range of other variants. Absent APB CMAP and abnormally high ADM/APB CMAP amplitude ratio (≥4) occurred only with UL‐ALS. Conversely, an absent ADM CMAP was identified only in UL‐PMA and BAD. Conclusions: The absolute ADM/APB CMAP amplitude ratio was not specific for ALS; however, several findings from simple electrophysiological measurements may help predict prognosis in patients with motor neuron diseases and may be early diagnostic markers for ALS. Muscle Nerve 51: 333–337, 2015

Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice.

Background Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained) can affect the loss of motor neurons or cognitive function in an in vivo model of ALS. Objective To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice. Methods Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation. Results Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation. Conclusions Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.

Motor Unit Number Estimation in Evaluating Disease Progression in Patients with Amyotrophic Lateral Sclerosis

We investigated the availability of motor unit number estimation (MUNE) as a quantitative method to assess the severity and clinical progression of amyotrophic lateral sclerosis (ALS). The 143 ALS patients were evaluated by statistical MUNE and the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). By using mean values of MUNE according to disease duration, regression equation between mean MUNE and disease duration was presented as a formula. The individual MUNE ratio was calculated by dividing individual MUNE value by mean MUNE value. All patients were classified into 2 groups (MUNE ratio <1 vs. MUNE ratio ≥1) according to the MUNE ratio. Comparison between the 2 groups revealed that the patients in MUNE ratio <1 group or MUNE ratio ≥1 group were respectively assigned to rapid progression or slow progression. We recommended informative mean values of MUNE and best regression equation in ALS patients according to disease duration. These values allow us to evaluate the severity and rapidity of progression in ALS.