Association of cerebral spinal fluid copper imbalance in amyotrophic lateral sclerosis.

A plethora of environmental risk factors has been persistently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), including metal/metalloids. This study aimed to examine potential associations between cerebral spinal fluid (CSF) metal/metalloids and ALS risks. CSF concentrations of copper (Cu), nickel (Ni), mercury (Hg), arsenic (As), manganese (Mn), and iron (Fe) in ALS (spinal- and bulbar-onset) patients and controls were measured using inductively coupled plasma mass spectrometry (ICP-MS). Results from this study revealed marked differences between control, spinal-onset, and bulbar-onset groups. We report that Cu levels were lower in the ALS and spinal-onset groups compared to the control group. Ni level were higher in the spinal-onset group compared to the control and bulbar-onset groups. In addition, associations between CSF metal/metalloid levels with disease severity, sex, and serum triglycerides were also examined to broach the potential relevance of neurotoxic metal/metalloids in ALS disease heterogeneity.

Acute nitrous oxide-induced neuropathy mimicking Guillain-Barré syndrome.

The early clinical features of nitrous oxide (N2 O)-induced neuropathy were mimicking that of Guillain-Barré syndrome (GBS). We aimed to explore clinical and laboratory characteristics of N2 O-induced neuropathy in comparison with GBS. We retrospectively reviewed data of 15 patients with N2 O-induced neuropathy and compared them with 15 GBS patients. The age of the N2 O-induced neuropathy group was significantly younger than that in the GBS group (22 ± 5 vs 45 ± 17). Paresthesia was more common in N2 O-induced neuropathy group (100% vs 53.3%). The proportion of distal upper limbs weakness was lower than that in GBS group (20.0% vs 93.3%). There was no significant difference in the distal weakness of the lower limbs (100% vs 80.0%). The incidence of motor conduction block and compound muscle action potential amplitude reduction in upper limbs was lower than that in GBS group (6.7% vs 60.0%; 26.7% vs 80.0%). The sensory nerve action potential amplitude drop in the lower limbs was more severe than that in GBS group (53.3% vs 0). The increase of Mean corpuscular volume (MCV) was more pronounced compared to GBS group (96.97 ± 6.00 vs 88.55 ± 5.41). High homocysteine levels were more common in N2 O-related group [29.80(11.60, 70.50) vs 14.35(9.22, 19.30)]. Typical clinical features of the acute N2 O neuropathy appears to be a myeloneuropathy, affecting the lower limbs more than the upper limbs, mixed axonal-demyelinating electrophysiological performance, higher homocysteine level, and larger MCV and common posterior spinal cord involvement in cervical segment.

Comparative assessment of blood Metal/metalloid levels, clinical heterogeneity, and disease severity in amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis is an unremitting neurodegenerative (ND) disease characterized by progressive and fatal loss of motor neuron function. While underlying mechanisms for ALS susceptibility are complex, current understanding suggests that interactions between age, genetic, and environmental factors may be the key. Environmental exposure to metal/metalloids has been implicated in various ND diseases including ALS, Alzheimer's Disease (AD), and Parkinson's Disease (PD). However, most of currently available population-based ALS studies in relation to metal exposure are based on individuals from European ancestry, while East Asian populations, especially cohorts from China, are less well-characterized. This study aims to examine the association between metal/metalloid levels and ALS onset by evaluating blood cadmium (Cd), lead (Pb), Cu, Zn, calcium (Ca), magnesium (Mg), and iron (Fe) levels in controls and sporadic ALS patients from North Western China. We report that Cu and Fe levels are found at higher levels in ALS patients compared to the controls. Spinal and bulbar onset patients show significant difference in Ca levels. Moreover, Cd, Pb, Cu, and Ca levels are positively correlated with high disease severity. Results from this study may provide new insights for understanding not only the role of metal/metalloids in ALS susceptibility, but also progression and forms of onset.

Characteristics of serum metabolites in sporadic amyotrophic lateral sclerosis patients based on gas chromatography-mass spectrometry.

To identify differential metabolites and metabolic pathways and provide guidance for the novel biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis (ALS). ALS patients and people without nervous diseases were recruited. Metabolomic analysis was performed using gas chromatography-mass spectrometry (GC/MS). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used to identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst were used to identify metabolic pathways. 75 metabolites were detected and aligned. The OPLS-DA showed the metabolomic profile of ALS patients and those in the fast-progression and slow-progression ALS groups differed from that of CTRL (p < 0.05). The levels of maltose, glyceric acid, lactic acid, beta-alanine, phosphoric acid, glutamic acid, ethanolamine and glycine in ALS were significantly higher, while 2,4,6-tri-tert-butylbenzenethiol was lower. Glycine, serine and threonine metabolism, D-glutamine and D-glutamate metabolism, alanine, aspartate, and glutamate metabolism, beta-alanine metabolism, and pyruvate metabolism were significantly altered metabolic pathways in ALS. ROC was used to discriminate ALS from CTRL with an AUC of 0.898 (p < 0.001) using 2,4,6-tri-tert-butylbenzenethiol, beta-alanine, glycine, and ethanolamine. The serum metabolites and metabolic pathways in ALS patients are significantly altered compared with CTRL. These findings may contribute to the early diagnosis of ALS.

Brainstem Involvement in Amyotrophic Lateral Sclerosis: A Combined Structural and Diffusion Tensor MRI Analysis.

INTRODUCTION: The brainstem is an important component in the pathology of amyotrophic lateral sclerosis (ALS). Although neuroimaging studies have shown multiple structural changes in ALS patients, few studies have investigated structural alterations in the brainstem. Herein, we compared the brainstem structure between patients with ALS and healthy controls. METHODS: A total of 33 patients with ALS and 33 healthy controls were recruited in this study. T1-weighted and diffusion tensor imaging (DTI) were acquired on a 3 Tesla magnetic resonance imaging (3T MRI) scanner. Volumetric and vertex-wised approaches were implemented to assess the differences in the brainstem's morphological features between the two groups. An atlas-based region of interest (ROI) analysis was performed to compare the white matter integrity of the brainstem between the two groups. Additionally, a correlation analysis was used to evaluate the relationship between ALS clinical characteristics and structural features. RESULTS: Volumetric analyses showed no significant difference in the subregion volume of the brainstem between ALS patients and healthy controls. In the shape analyses, ALS patients had a local abnormal surface contraction in the ventral medulla oblongata and ventral pons. Compared with healthy controls, ALS patients showed significantly lower fractional anisotropy (FA) in the left corticospinal tract (CST) and bilateral frontopontine tracts (FPT) at the brainstem level, and higher radial diffusivity (RD) in bilateral CST and left FPT at the brainstem level by ROI analysis in DTI. Correlation analysis showed that disease severity was positively associated with FA in left CST and left FPT. CONCLUSION: These findings suggest that the brainstem in ALS suffers atrophy, and degenerative processes in the brainstem may reflect disease severity in ALS. These findings may be helpful for further understanding of potential neural mechanisms in ALS.

The degeneration of upper and lower motor neuron from the perspective of clinical neurological examination and MRI-electromyography manifold detection in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to explore the upper motor neurons (UMN) and lower motor neurons (LMN) degeneration in amyotrophic lateral sclerosis (ALS) from the perspective of the clinical neurological examination and MRI-electromyography manifold detection, respectively. METHODS: The clinical data, cortical thickness of corresponding areas in different body regions in MRI and electromyography data were collected from 108 classical ALS patients. RESULTS: The kappa value of UMN and LMN involvement signs in the bulbar region (0.31) was higher than that of the left upper limb (-0.13), right upper limb (-0.27), left lower limb (-0.05) and right lower limb (-0.08). The cortical thickness in the positive LMN damage group was thinner than that of the negative LMN damage group in the left head-face area (P < 0.05; Cohen's d = 0.84); however, cortical thickness showed no significant differences in the right head-face, bilateral tongue-larynx, upper-limb, trunk and lower-limb areas between LMN-damage-positive and LMN-damage-negative groups. CONCLUSION: The degeneration of motor neuron could be independent through UMN and LMN levels. The degenerative process was not only confined to UMN and LMN levels but can also expand to white matter fiber tracts. Thus, the degeneration of UMN and LMN might be independent of the motor system's three-dimensional anatomy.

Dominant Heterogeneity of Upper and Lower Motor Neuron Degeneration to Motor Manifestation of Involved Region in Amyotrophic Lateral Sclerosis.

The aim of this study was to localize the anatomic distribution of upper motor neuron (UMN) loss through examining cortical thickness at the clinical onset of amyotrophic lateral sclerosis (ALS) and explore motor manifestation in functionally impaired body region attribute to impairment of lower motor neuron (LMN) or UMN or mixed LMN and UMN? The clinical features, cortical thickness of corresponding areas from different body regions in MRI and electromyography (EMG) data were collected from 108 classical ALS patients. The cortical thickness was thinner in ALS group than control group in bilateral head-face and upper-limb areas (p < 0.05). In head-face area, the cortical thickness of bulbar-onset group was significantly lower than that of control groups (p < 0.05). In upper-limb areas, the cortical thickness of cervical-onset group was significantly thinner than that of control group. Notably, the bulbar ALSFRS-R subscore was correlated with cortical thickness in bilateral head-face areas (p < 0.05). The bulbar ALSFRS-R subscore of the positive LMN damage group was lower compared to that of the negative LMN damage group (P < 0.001). The limb ALSFRS-R subscore correlated with compound muscle action potential (CMAP) amplitudes of median, ulnar, peroneal, and tibial nerves (P < 0.001), but was not related to cortical thickness. In conclusion, the UMN degeneration in ALS was derived from focal initiation, bulbar- and cervical-onset may date from head-face and upper-limb areas in motor homunculus cortex, respectively. The bulbar dysfunction was resulted from the mixed UMN and LMN impairment, while limb dysfunction derived mostly from LMN loss.

Dissociated lower limb muscle involvement in amyotrophic lateral sclerosis and its differential diagnosis value.

To explore differential diagnosis value of dissociated lower-limb muscle impairment, we performed a retrospective analysis of clinical and electrophysiological features in 141 lower-limb involved ALS patients, 218 normal controls, 67 disease controls, and 32 lumbar spondylosis disease patients. The dissociated lower-limb muscle impairment was quantified by plantar flexion and dorsiflexion strength, compound muscle action potentials ratio of peroneal and tibial nerves (split index, SI) and semi-quantitative scoring scale of denervation potential. Clinical features: the proportion of decreased dorsiflexion was higher than decreased planter flexor strength in lower-limb involved ALS (77.2%vs 38.3%). Electrophysiological features: (1) SI in ALS was the lowest among four groups (Test statistic = 40.57, p < 0.001). (2) Percentage of positive denervation potential was higher in tibialis anterior than gastrocnemius muscle (χ2 = 87.12, p < 0.001). ROC curve: the SI cutoff was 0.52 and 0.33 respectively to differentiate ALS from lumbar spondylosis disease and peripheral neuropathy. Lower-limb involved ALS patients exhibited "split leg" phenomenon. The SI value could be used as an electrophysiological marker to differentiate ALS from lumbar spondylosis disease and peripheral neuropathy.

Decremental Responses to Repetitive Nerve Stimulation in Amyotrophic Lateral Sclerosis.

INTRODUCTION: To illuminate the mechanism of neuromuscular junction involvement by analyzing the features of a slow-rate repetitive nerve simulation (RNS) and EMG in amyotrophic lateral sclerosis (ALS) patients. METHODS: We retrospectively analyzed relationship between clinical features and the decremental response in RNS in 184 sporadic ALS patients. RESULTS: (1) 44.3 and 43.5% of compound muscle action potentials (CMAP) decrement were more than -10% in deltoid muscle (Del) and Trap; (2) ALS patients were divided into RNS positive (RNS+) and RNS negative (RNS-) group according to decremental percentage of RNS greater or less than -10%. The diagnostic delay time was shorter and ALSFRS-r score was lower in RNS+ than RNS- group (p < 0.05), progression rate had no difference. The incidence of RNS+ decrement was higher in cervical enlargement onset and definite diagnostic degrees (p < 0.05); (3) In EMG+ group, the CMAP amplitude was lower (Axillary: 3.1 ± 1.91 vs. 5.92 ± 2.896, p = 0.000; Accessory: 2.68 ± 1.349 vs. 3.65 ± 1.53, p = 0.002), decremental percentage of RNS was higher (Axillary: -10.85 ± 7.508 vs. -5.43 ± 8.425, p = 0.000; Accessory: -13.11 ± 7.539 vs. -8.03 ± 5.999, p = 0.000) compared with needle EMG- group whether in Del or Trap; (4) Decremental response of RNS was positively correlated with the CMAP amplitude in Axillary and Accessory nerves (R = 0.201, p < 0.0001; R = 0.103, p < 0.0001). CONCLUSIONS: Our clinical results support the mechanism of decremental phenomenon of RNS is immature sprouts and unstable conduction by the degenerating axons in ALS patients. The more serious the axon damage, the more significant the RNS decremental response. But decremental response dose not effect disease progression.

Very Early Neurophysiological Study in Guillain-Barre Syndrome.

PURPOSE: The diagnosis of Guillain-Barre syndrome (GBS) in the very early stage may be challenging. Our aim was to report the neurophysiological abnormalities in GBS within 4 days of clinical onset. We expected that GBS will be diagnosed by the assistance of neurophysiological study in the very early stage. METHODS: We prospectively recruited patients with a diagnosis of GBS discharged from First Affiliated Hospital of Xi'an Jiaotong University and Xi Jing Hospital. Patients were classified into 3 groups according to the onset of symptoms to electromyography examination interval (OEI). The neurophysiological findings were carried out using standard procedures. All patients were examined by the same experienced neurophysiologist. RESULTS: There were not significant group differences in abnormal rate, distal motor latency (DML), motor nerve conduction velocity (MNCV), F response (FR), compound muscle action potential (CMAP), conduction block (CB), sensory nerve action potential (SNAP), and sensory nerve conduction velocity among OEI ≤4 days, 4< OEI ≤10 days, and OEI > 10 days groups. Motor nerves were more affected than sensory nerves in neurophysiological presentation in very early stage patients. The difference of motor nerves and sensory nerves was statistically significant in lower limbs, but was not in upper limbs. In motor nerve conduction studies, the abnormal rate of DML, MNCV, FR, CB was more common seen in ulnar and peroneal nerve than median and tibial nerve, the abnormal rate of CMAP was the same in ulnar, median, peroneal and tibial nerve. In sensory nerve conduction studies, the abnormal rate of ulnar nerve and median nerve was higher than the superficial peroneal nerve and sural nerve. The OEI was not correlated with the SNAP decrease rate of median (r = 0.10, p = 0.23) and ulnar (r = 0.26, p = 0.06) but was statistically correlated with sural SNAP decrease rate (r = 0.29, p = 0.04). The sural-sparing pattern phenomenon was the most commonly discovered phenomenon in very early stage patients (OEI ≤4 days), followed by patients with 4< OEI ≤10 days, ultimately found in patients with OEI > 10 days. CONCLUSIONS: We suggest performing neurophysiological examination as soon as possible for suspected GBS patients, particularly focusing on multi-spots inspection of ulnar and peroneal nerves, and paying close attention to sural-sparing patterns.

Measuring the validation of assessing the non-dominant-hand function by ALSFRS-r in Chinese ALS patients.

ALSFRS-r is a widely accepted rating scale for measuring the global function of Amyotrophic Lateral Sclerosis (ALS) patients, but we found some limitations of ALSFRS-r in assessing the function of non-dominant hand in Chinese ALS patients. We reviewed 95 ALS patients who expressed upper-limb symptoms at first visit and analyzed the ALSFRS-r score and subscale. In both upper limb involved patients, the ALSFRS-r had no difference between dominant-hand and non-dominant-hand onset groups (39.15±5.55 vs 38.0±5.91, p=0.477). But in only one upper limb involved patients, the ALSFRS-r score in non-dominant-hand onset patients was higher than dominant-hand onset patients (43.94±3.44 vs 40.87±4.42, p<0.05), especially in item of handwriting, cutting food and handing utensils (3.56±0.89 vs 2.2±1.27 p=0.001, 3.44±1.03 vs 1.8±1.21 p=0.000). When the item of cutting food and handing utensils was replaced by using food bowl and chopsticks to assess the function of non-dominant-hand, the modified ALSFRS-r score was significantly lower than original ALSFRS-r (43.94±3.44 vs 42.88±3.07 p=0.001), the progression rate was slower (0.81±0.63 vs 0.64±0.63, p=0.001). So, for Chinese ALS patients, using food bowl and chopsticks should replace the item of cutting food and handling utensils to assess the non-dominant-hand function, especially in non-dominant-hand onset patients.

Long Exercise Test in the Interattack Period of Periodic Paralysis: A Useful and Sensitive Diagnostic Tool.

PURPOSE: The reference values of long exercise test are inconsistent in previous studies. Our research aims to determine the reference values and improve diagnostic efficiency of long exercise test in periodic paralysis. METHODS: In this study, 100 healthy controls, 35 non-periodic paralysis patients, and 47 patients with periodic paralysis were recruited. The procedures of long exercise test were conducted following McMannis(1986) method. RESULTS: The decrease rate in compound muscle action potential amplitudes was correlated with gender, and it was not influenced by age, height, weight, and exercise. After analyzing receiver operating characteristic curves, the compound muscle action potential amplitude decrease rate was stratified by sex. The mean area under the curve, sensitivity, and specificity were higher in male and female than all pooled subjects. The reference values of compound muscle action potential amplitude decrease rate were 46.8% in male and 26.9% in female, respectively. CONCLUSIONS: The long exercise test is a useful and sensitive diagnostic tool for primary periodic paralysis and thyrotoxic periodic paralysis. However, the reference values should be set by sex, which has better diagnostic performance, sensitivity, and specificity.

Urinary Extracellular Domain of Neurotrophin Receptor p75 as a Biomarker for Amyotrophic Lateral Sclerosis in a Chinese cohort.

To comprehensively assess whether p75ECD in urine could be a candidate biomarker for ALS evaluation. Urine samples were collected from 101 ALS patients, 108 patients with other neurological disease (OND) and 97 healthy controls. 61 ALS patients were followed up with clinical data including ALSFRS-r every 6 to 12 months, 23 ALS patients died and 17 ALS patients lost touch during follow up period. Enzyme-linked immunoassay was employed to determine urine p75ECD concentration. The ALSFRS-r was employed to assess the severity of ALS. The concentration of p75ECD in ALS was significantly higher than that of OND and CTRL (p < 0.001). Additionally, urine p75ECD concentrations in ALS-definite grade patients were significantly higher than that in ALS-probable grade and ALS-possible grade patients (p < 0.001). Higher urine p75ECD concentrations were correlated with increased clinical stage (p = 0.0309); urine p75ECD concentrations and ALSFRS-r were negatively correlated (p = 0.022); and urine p75ECD concentration in the fast-progressing ALS group was significantly higher than that in slow-progression (p = 0.0026). Our finding indicates that urine p75ECD concentration provides additional evidence for patients with clinically suspected ALS, and can be employed to evaluate ALS-severity.

Hyperintensity of the corticospinal tract on FLAIR: A simple and sensitive objective upper motor neuron degeneration marker in clinically verified amyotrophic lateral sclerosis.

OBJECTIVE: The involvement of upper motor neuron (UMN) degeneration is crucial to the diagnosis of amyotrophic lateral sclerosis (ALS). However, it is difficult to detect in the early stages, and particularly with predominantly lower motor neuron (LMN) dysfunction. Thus, objective and sensitive UMN degeneration markers are needed for an accurate and early diagnosis. Several studies have investigated the abnormal signal changes in brain MRI for patients with ALS, so we hope to develop a neuroimaging diagnosis method in brain MRI that can evaluate UMN degeneration. MATERIALS AND METHODS: We investigated corticospinal tract (CST) hyperintensity on MRI-fluid attenuated inversion recovery (FLAIR) images for 82 clinically verified ALS patients and 38 age-and gender-matched control subjects. Visual evaluation of the FLAIR images was analyzed independently by 3 observers. The clinical examination was implemented by an experienced neurological physician. RESULTS: The three observers' views were identical regarding CST hyperintensity on FLAIR images in subcortical precentral gyrus, centrum emiovale, internal capsule, and cerebral peduncles levels (p>0.05). The frequency of CST hyperintensity is significantly higher for the ALS group than the control group in subcortical precentral gyrus, centrum semiovale, posterior limbs of internal capsule and cerebral peduncles levels. (p<0.01). The mean areas under the receiver operating characteristic curves (AUC) values were not different among clinical examinations, CST hyperintensity and mixed-examination (CST hyperintensity and clinical examination groups) in subcortical precentral gyrus, centrum semiovale, internal capsule, and cerebral peduncles levels (p>0.05), although AUC values of CST hyperintensity was slightly higher than clinical examination in centrum semiovale level. There was no statistically significant correlation between CST hyperintensity and age of onset, gender, disease duration, region of onset, and clinical UMN manifestation. (p>0.05). CONCLUSION: CST hyperintensity was found more frequently in patients with ALS compared to the matched control group. It can be used to evaluate UMN degeneration effectively in subcortical precentral gyrus, centrum semiovale and cerebral peduncles levels. Combining CST hyperintensity and clinical examination can improve the sensitivity of diagnostic performance for UMN degeneration in ALS.

Spread Direction and Prognostic Factors in Limb-Onset Sporadic Amyotrophic Lateral Sclerosis.

OBJECTIVE: To investigate the spread direction and prognostic factors in limb-onset sporadic amyotrophic lateral sclerosis (sALS). METHODS: Medical records of 128 patients with sALS were reviewed. Variables studied were age at symptom onset, gender, region and lateralization of onset, onset to diagnosis interval (ODI), progression direction, bulbar-involved, time from onset to bulbar-involved, ALSFRS-r, upper motor neuron (UMN) signs and progression rate. RESULTS: First, the horizontal and vertical directions are major spreading directions in limb-onset sALS. Second, in crossed and interposed groups, while ODI is shorter, the progression rate is faster and UMN signs are more pronounced (p < 0.05). Third, ALSFRS-r, UMN signs and progression rate have significant differences between with-bulbar-involved and without-bulbar-involved (p < 0.05). The progression rate is related to the time from onset symptoms to bulbar-involved (correlation coefficient -0.535, p = 0.00). Fourth, in multivariate regression analysis, progression rate could respectively increase by about 1.14 and 3.89 times with shorter ODI and bulbar-involved in limb-onset sALS patients. CONCLUSIONS: The horizontal and vertical directions are the major spread directions in limb-onset sALS. Except for ALSFRS-r and ODI, bulbar-involved is an adverse factor for ALS progression, and progression rate is related to the time from onset symptoms to bulbar-involved.

Sympathetic Skin Response in Amyotrophic Lateral Sclerosis.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons, but it is increasingly recognized to be a more disseminated disease. The literature on the involvement of the sympathetic skin response (SSR) in ALS is few. METHODS: We reviewed the literature with specific emphasis on SSR in ALS and investigated SSR in 120 patients with sporadic ALS and in 130 age-matched healthy subjects to determine the effects of SSR in ALS patients. The SSR was conducted in all ALS patients and healthy subjects. RESULTS: We found prolonged mean SSR latency in ALS patients, and the mean SSR amplitude is reduced compared with that of control subjects, especially in their low extremities (P < 0.05). The disease duration seems to have little impact on the SSR latency and amplitude (P > 0.05). Yet, whichever arm or leg involved, the overall difference in lower extremity SSR measurements between the two groups is significant (P < 0.05). And there is no correlation between initial manifestation of autonomic nervous impairment and amplitude and latency of SSR (P > 0.05). CONCLUSIONS: The SSR impairment occurs mainly in lower extremities, which is earlier than clinical manifestation of autonomic nervous impairment in ALS. This may be a subclinical manifestation of ALS. We hypothesize that these results are caused by damage to the unmyelinated postganglionic fibers in ALS patients.

Side of limb-onset predicts laterality of gray matter loss in amyotrophic lateral sclerosis.

Conflicting findings have been reported regarding the lateralized brain abnormality in patients with amyotrophic lateral sclerosis (ALS). In this study, we aimed to investigate the probable lateralization of gray matter (GM) atrophy in ALS patients. We focused on the relationship between the asymmetry in decreased GM volume and the side of disease onset in patients with limb-onset. Structural imaging evaluation of normalized atrophy (SIENAX) and voxel-based morphometry (VBM) were used to assess differences in global and local brain regions in patients with heterogeneous body onset and subgroups with different side of limb-onset. We found global brain atrophy and GM losses in the frontal and parietal areas in each patient group as well as left predominant GM losses in the total cohort. The intriguing findings in subgroup analyses demonstrated that the motor cortex in the contralateral hemisphere of the initially involved limb was most affected. We also found that regional brain atrophy was related to disease progression rate. Our observations suggested that side of limb-onset can predict laterality of GM loss in ALS patients and disease progression correlates with the extent of cortical abnormality.