Kang Zhang

Excessive daytime sleepiness in Chinese patients with sporadic amyotrophic lateral sclerosis and its association with cognitive and behavioural impairments

Objective To examine the frequency and clinical features of excessive daytime sleepiness (EDS) and its association with cognitive and behavioural impairments in patients with amyotrophic lateral sclerosis (ALS). Methods We conducted a cross-sectional investigation to explore the frequency and clinical features of EDS in a group of 121 Chinese patients with ALS compared with 121 age-matched and sex-matched healthy subjects. EDS was diagnosed using the Epworth Sleepiness Scale (ESS). Other characteristics of patients with ALS including sleep quality, REM sleep behaviour disorder (RBD), restless legs syndrome (RLS), cognition, behaviour, depression and anxiety were also evaluated. Results EDS was significantly more frequent in patients with ALS than in controls (26.4% vs 8.3%; p<0.05). Patients with ALS with EDS scored lower scores on the revised ALS Functional Rating Scale (ALSFRS-R), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and MMSE and MoCA delayed memory subitems and higher on the Frontal Behavioural Inventory (FBI) than patients with ALS without EDS. ESS scores correlated with global ALSFRS-R, FBI, MMSE and MoCA scores and MMSE and MoCA delayed memory scores. RLS and global ALSFRS-R scores were independently associated with EDS in patients with ALS. Conclusions We identified a high frequency of EDS symptoms in Chinese patients with ALS, and these patients might have more serious physical, cognitive and frontal behaviour impairment. Patients with ALS might improve quality of life from the timely recognition and optimised management of EDS symptoms. Our results further suggest that ALS is a heterogeneous disease that might exhibit abnormal sleep-wake patterns.

Correlation of Creatine Kinase Levels with Clinical Features and Survival in Amyotrophic Lateral Sclerosis

Objective To evaluate serum creatine kinase (CK) levels of amyotrophic lateral sclerosis (ALS) patients and to explore the relationship between CK levels and the clinical characteristics and survival prognosis of ALS patients. Methods We analyzed the CK levels of 185 ALS patients who underwent long-term follow-up. The relationship between CK levels and clinical features including sex, age, disease duration, site of onset, body mass index (BMI), serum creatinine (Cr), and spontaneous electromyographic activity was analyzed by univariate analysis and multiple linear regression. Kaplan–Meier and Cox proportional hazards models were used to explore whether CK levels were independently correlated with survival prognosis of ALS. Results Baseline serum CK was raised in 43% of participants. The median CK level was 160u2009U/L (range: 20–2,574u2009U/L), and 99% of patients had a baseline serum CK level less than 1,000u2009U/L. CK levels were significantly higher in male patients than in female patients [204 (169) versus 117 (111)u2009U/L, pu2009<u20090.001] and in patients with limb onset ALS than with bulbar onset ALS (pu2009<u20090.001). CK levels were also correlated with serum Cr (pu2009=u20090.011) and the spontaneous potential score of electromyography (EMG) (pu2009=u20090.037) but not correlated with age (pu2009=u20090.883), disease duration (pu2009=u20090.116), or BMI (pu2009=u20090.481). Log CK was independently correlated with survival of ALS patients (HRu2009=u20090.457, 95% confidence interval 0.221–0.947, pu2009=u20090.035) after adjusting for age, sex, site of onset, serum Cr, and BMI. Conclusion Serum CK levels of ALS patients were correlated with sex, site of onsite, serum Cr, and spontaneous activity in EMG. Serum CK could be an independent prognostic factor for survival of ALS patients.

ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia

Objective To investigate the genetic contribution of ANXA11, a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia. Methods Sequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR. Results We identified 6 nonsynonymous heterozygous mutations (5 novel and 1 recurrent), 1 splice site mutation, and 1 deletion of 10 amino acids (not accounted in the mutant frequency) in 11 unrelated patients, accounting for a mutant frequency of 5.6% (1/18) in FALS, 2.3% (8/353) in SALS, and 8.3% (1/12) in ALS-FTD. The deletion of 10 amino acids was detected in 1 clinically undetermined male with an ALS family history who had atrophy in hand muscles and myotonic discharges revealed by EMG. The novel p. P36R mutation was identified in 1 FALS index, 1 patient with SALS, and 1 ALS-FTD. The splicing mutation (c.174-2A>G) caused in-frame skipping of the entire exon 6. The rest missense mutations including p.D40G, p.V128M, p.S229R, p.R302C and p.G491R were found in 6 unrelated patients with SALS. Conclusions The ANXA11 gene is one of the most frequently mutated genes in Chinese patients with SALS. A canonical splice site mutation leading to skipping of the entire exon 6 further supports the loss-of-function mechanism. In addition, the study findings further expand the ANXA11 phenotype, first highlighting its pathogenic role in ALS-FTD.

Genetic analysis of TIA1 gene in Chinese patients with amyotrophic lateral sclerosis

Mutations in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1) was recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in non-Hispanic white populations. We sequenced the TIA1 exons 11-13 encoding LCD in a series of 588 Chinese ALS/ALS-FTD patients (Familial ALSxa0= 29; Sporadic ALSxa0= 546; ALS-FTDxa0= 13) and 500 neurologically normal control subjects. We found a novel heterozygous missense mutation (c.973A>G, p.N325D) in a sporadic ALS patient, which suggests that TIA1 LCD mutations are not common in Chinese ALS/ALS-FTD.

Mutation analysis of KIF5A in Chinese amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is an age-related fatal neurodegenerative orphan disorder that is characterized by progressive injury of both the upper and lower motor neurons. Recently, loss-of-function mutations predominately disrupting the C-terminal amino acid sequence of KIF5A via aberrant exon 27 splicing have been reported in European ALS cohorts. However, the contributions of KIF5A mutations in Asian patients with ALS remain unclear. KIF5A sequences, including exons 26 and 27, were analyzed in a large Chinese ALS cohort comprising 33 unrelated familial ALS probands, 645 sporadic ALS (SALS) patients, 15 ALS patients presenting with concomitant frontotemporal dementia, 400 in-house controls, and 12,951 East Asian individuals from the Exome Aggregation Consortium and Genome Aggregation Database databases. As a result, the previously reported canonical splicing site mutation c.2993-1G>A was found in 1 SALS patient, while no mutations were detected in familial ALS case or ALS patients presenting with concomitant frontotemporal dementia. The frequency of KIF5A mutations accounts for 0.16% (1/645) of Chinese SALS patients, implying that it is an uncommon genetic determinant of ALS in Chinese patients.

Restless Legs Syndrome in Chinese Patients With Sporadic Amyotrophic Lateral Sclerosis

Objective: To evaluate the frequency and clinical features of restless legs syndrome (RLS) in a group of Chinese patients with amyotrophic lateral sclerosis (ALS). Methods: 109 Patients included in this study fulfilled the revised El Escorial diagnostic criteria for clinically definite, probable and lab-supported probable ALS, and a group of 109 control subjects was matched for age and sex to the ALS group. Disease severity was assessed by the revised ALS functional rating scale (ALSFRS-R). The diagnosis of RLS was made according to the criteria of the International RLS Study Group. Other characteristics including sleep quality, excessive daytime sleepiness (EDS), REM sleep behavior disorder (RBD), depression and anxiety were also evaluated in ALS patients. Results: RLS was significantly more frequent in ALS patients than in control subjects (14.6 vs. 0.9%; P < 0.05). Compared to those without RLS, ALS patients with RLS reported a higher frequency of anxiety and EDS. ALS patients with RLS showed more severe legs dysfunction. EDS and legs function scores of the ALSFRS-R were independent factors significantly associated with RLS in ALS patients. Conclusions: Our findings suggest that Chinese ALS patients exhibit a high frequency of RLS symptoms and that these patients may benefit from recognition of the condition and optimized management of its symptoms. Moreover, ALS patients might cause circadian rhythms disturbance and our study further supports that ALS is a heterogeneous disorder involving multiple systems; further studies are needed to confirm these preliminary findings.

Brain Structural and Perfusion Signature of Amyotrophic Lateral Sclerosis With Varying Levels of Cognitive Deficit

Objective To characterize the patterns of brain atrophy and perfusion as measured by arterial spin labeling (ASL)-MRI, in amyotrophic lateral sclerosis (ALS) patients with varying levels of cognitive deficit, including ALS with frontotemporal dementia (FTD). Methods A total of 55 ALS patients and 20 healthy controls (HCs) were included, and all participants underwent neuropsychological assessments and MRI scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, nu2009=u200927), ALS with cognitive impairment (ALS-Ci, nu2009=u200917), and ALS-FTD (nu2009=u200911). Voxel-based comparisons of gray matter (GM) changes and cerebral blood flow (CBF) were conducted among the subgroups. Results The whole-brain comparisons of GM changes and CBF among ALS-Ci, ALS-Cn, and HCs were not significantly different. However, the ALS-FTD patients demonstrated a similar pattern of GM loss and hypoperfusion with more significant alterations in the left frontal and temporal lobe compared with the HCs, ALS-Cn, and ALS-Ci patients. Decreased CBF was found in many of the same brain areas wherein structural alterations occurred, although isolated GM loss and hypoperfusion were also observed. In addition, for both GM and CBF abnormalities, a similar pattern of changes was found in the comparisons of ALS-FTD vs. ALS-Ci, ALS-FTD vs. ALS-Cn, and ALS-FTD vs. HCs, with the differences being most significant between ALS-FTD and HCs. Conclusion The cognitive status of ALS patients is associated with different patterns of GM changes and cerebral perfusion. ASL-MRI might be a useful tool with which to investigate the pathological burden of ALS and to disclose the early signature of possible cognitive impairment.

Creatine kinase level and its relationship with quantitative electromyographic characteristics in amyotrophic lateral sclerosis

OBJECTIVEnTo explore the relationship between serum creatine kinase (CK) level and electromyographic characteristics in patients with amyotrophic lateral sclerosis (ALS).nnnMETHODSnTwo hundred thirty-eight consecutive ALS patients were enrolled. All patients underwent electrophysiological study with a consistent approach. We calculated a compound muscle action potential (CMAP) sum score, and spontaneous potentials were graded from 0 to 4 depending on their density and distribution. We tested for any independent correlation of the CK levels with CMAP sum score, mean spontaneous potential (MSP) score, F wave persistence or conduction velocity.nnnRESULTSnThe median serum CK level was 151 U/L. Log CK was independently correlated with MSP score (βu202f=u202f0.07, 95% CI: 0.01-0.14, pu202f=u202f0.032) and F persistence (βu202f=u202f-0.0013, 95% CI: -0.00251 to -0.0002, pu202f=u202f0.02) but not with CMAP sum score or F wave conduction velocity. When stratified by sex, the correlation of log CK with MSP score and F persistence was significant in male but not female patients.nnnCONCLUSIONSnThe results support that lower motor neuron loss and muscle denervation are associated with elevated CK levels of ALS patients.nnnSIGNIFICANCEnThe severity of lower motor neuron loss and denervation might be involved in pathophysiological mechanisms of CK elevation in ALS patients.

F49. Creatine kinase level and its relationship with quantitative electromyographic characteristics in ALS

Introduction Creatine Kinase (CK) level has been reported to be mildly to moderately elevated in some amyotrophic lateral sclerosis (ALS) patients. The mechanism of CK elevation is still not well understood, and to date, the main hypothesizes include up-regulated CK expression and increased muscle membrane permeability due to muscle denervation. Objective To explore the relationship between serum CK level and electromyographic characteristics in patients with ALS. Methods Two hundred thirty-eight consecutive ALS patients were enrolled. All patients underwent CK level test and electrophysiological study with a consistent approach. We calculated a compound muscle action potential (CMAP) sum score and spontaneous potentials were graded from 0 to 4 depending on their density and distribution. We tested for any independent correlation between CK levels and CMAP sum score, mean spontaneous potential (MSP) score, F wave persistence or conduction velocity. Results The median serum CK level was 151u202fU/L. Log CK was independently correlated with MSP score ( β u202f=u202f0.07, 95% CI: 0.01–0.14, pu202f=u202f0.032) and F persistence ( β u202f=u202f−0.0013, 95% CI: −0.00251 to −0.0002, pu202f=u202f0.02) but not with CMAP sum score or F wave conduction velocity. When stratified by sex, the correlation between log CK and MSP score and F persistence was significant in male patients but not in female patients. Conclusion The results supported an effect of functional lower motor neuron loss and muscle denervation associated with CK levels of ALS patients. The severity of lower motor neuron loss and denervation may be implicated in pathophysiological mechanisms of CK elevation in ALS patients.

BS04. Characteristics of respiratory dysfunction in amyotrophic lateral sclerosis: A clinical study in 159 cases

Introduction Amyotrophic lateral sclerosis(ALS) is a neurodegenerative disorder involving both upper and lower motor neurons with an average survival time of 3–5u202fyears. Respiratory deterioration is the main cause of ALS and affects almost all ALS patients in different courses. Currently, it is still controversial of the characteristics of respiratory deterioration in ALS patients, including the effect of the type of disease onset, as well as the progression rates. Methods We performed a retrospective cohort study including 159 ALS patients at Peking Union Medical College Hospital from June 2014 to April 2017. Age at symptom onset, sex, time form onset to PFT, ALSFRS-R score, onset and area involved were recorded. All patients were followed in March 2016 and Jun 2017 separately. Depending on the pattern of onset, patents were subdivided into two groups. One included patients with bulbar-onset ALS and the other included those with limb-onset. Results The mean age at symptom onset of 159 cases included was 52.9u202f±u202f10.1u202fyears old; the male: female ratio was 1.24:1. Bulbar-onset of symptoms was seen in 17.0% patients, while 81.6% presented with limb-onset. The time from symptom onset to PFT was shorter in the bulbar-onset group (7.0 vs. 11.5u202fm, pu202f=u202f0.004), as well as the time from symptom onset to diagnosis (8.0 vs. 12.0u202fm, pu202f=u202f0.027). Significant differences were showed of the age at symptom onset (pu202f=u202f0.025), time form symptom onset to diagnosis (pu202f=u202f0.026) and ALSFRS-R scores (pu202f=u202f0.004) between the two groups. The PFT parameters revealed a main characteristic restrictive type of dysfunction. Only 26.0% patients of respiratory dysfunction from PFT parameters had respiratory complaints. Mean FVC% and FEV1%value was 86.7%u202f±u202f22.2%, 85.6%u202f±u202f19.2% respectively. After adjusting for sex, ALSFRS-R score, time from symptom onset to diagnosis, BMI and age at symptom onset, no significant difference was observed for patients with time form symptom onset to PFT less than 14 mouths. In contrast, for those with time more than 14 mouth, bulbar-onset group showed worse PFT values than the limb-onset group, with differences was 27.5% (95%CI: 4.3%, 50.7%), 24.7% (95%CI: 4.3%, 45.2%) and 42.0% (95%CI: 17.7%, 66.4%) separately. The decline rates for FVC% and FEV1% were 0.7% per mouth and 0.8% per mouth. No difference was found between the two groups. Δ FVC% and Δ FEV1% of patients in bulbar-involved group were 1.5% (95%CI: 0.0–18.5%) and 1.4% (95%CI: 0.0–9.8%), which were significantly higher than those in limb-involved group of 0.2% (95%CI: 0.0–10.4) and 0.5%(95%CI: 0.0–8.0%) (pu202f Conclusion The main type of pulmonary dysfunction was restrictive pattern. Bulbar involvement predicted poorer respiratory function in ALS patients compared with limb-only involvement, no matter whether the involvement was the onset symptom.The progression rate was higher in the bulbar involved patients than those with limb-only involvement.