Stratifying disease stages with different progression rates determined by electrophysiological tests in patients with amyotrophic lateral sclerosis

By determining the usefulness of motor unit number estimate (MUNE) and compound muscle action potential (CMAP) amplitude in patients with amyotrophic lateral sclerosis (ALS), we tried to find an effective way to stratify the disease stages. In all, 112 consecutive ALS patients were enrolled, among whom 73 were elicited in a longitudinal study. MUNE by the standard incremental technique, the average CMAP amplitude, total Medical Research Council (MRC) score, ALS‐functional rating score (ALS‐FRS), Appel ALS rating scale (AARS), and forced vital capacity (FVC) were performed at baseline and months 3, 6, and 12 after study entry. We found MUNE correlated with CMAP amplitude (P < 0.01) as well as MRC score (P < 0.01) in regionally concordant distal muscles. Both MUNE and CMAP amplitude correlated significantly with ALS‐FRS (P < 0.05) and AARS (P < 0.01). A MUNE decrease was observed at months 3, 6, and 12 compared with baseline, and the rate of change at month 3 was 50.47%. The decrease in MUNE over the first 3 months was significantly greater than other measurements. We arbitrarily divided the patients into three stages: (1) rapid progression: the rate of change of MUNE and CMAP amplitude during the first 3 months exceeded 50%; (2) moderate progression: the rate of change of MUNE was greater than 50% but CMAP amplitude was less than 50%; (3) slow progression: the rate of change of both MUNE and CMAP amplitude were less than 50%. Comparing the rate of ALS‐FRS descent per year using one‐way ANOVA showed a significant difference among the three groups (P < 0.01). Muscle Nerve 39: 304–309, 2009     

Motor unit number estimation,isometric strength,and electromyographic measures in amyotrophic lateral sclerosis

Pathologic progression in amyotrophic lateral sclerosis (ALS) results from motor neuron death, while the clinical expression also reflects the compensatory effects of collateral reinnervation consequent to lower motor neuron loss. In a cross-sectional study of ALS subjects, we made comparisons between motor unit number estimation (MUNE) values and several measures reflecting collateral reinnervation, including isometric strength, compound muscle action potential (CMAP) amplitude, surface motor unit action potential (S-MUAP) amplitude, fiber density (FD), macro-EMG potential amplitude, turns-to-amplitude (T/A) ratio, and amplitude and recruitment pattern of low threshold voluntary motor units in elbow flexor muscles. Before comparisons were made, testretest reproducibility of these measures was assessed in ALS subjects, and is highest for isometric strength, and lower but similar for EMG measures. When the effects of multiple comparisons are considered, borderline significant correlations are found between MUNE values and isometric strength. Neither MUNE values nor isometric strength are significantly correlated with macro-EMG amplitude, FD, T/A ratio, or amplitude and recruitment rate of low threshold voluntary motor units. There are significant correlations of CMAP and S-MUAP with MUNE values, but these are statistical artifacts with no independent interpretation. We conclude that collateral reinnervation prevents isometric strength and EMG measures from accurately reflecting lower motor neuron death in ALS. MUNE measurements are better suited to provide insight into the true natural history of the disease process and may be clinically useful to follow progression and response in drug trials. © 1993 John Wiley & Sons, Inc.     

Electrical impedance myography correlates with standard measures of Als severity

Introduction: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. Methods: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale‐Revised (ALSFRS‐R) score, and motor unit number estimation (MUNE). Results: Moderate strength correlations between EIM parameters and HHD were observed for both whole‐body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS‐R upper and lower extremity subscores, but not total ALSFRS‐R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. Conclusions: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS. Muscle Nerve 49 :441–443, 2014     

Multipoint incremental motor unit number estimation versus amyotrophic lateral sclerosis functional rating scale and the medical research council sum score as an outcome measure in amyotrophic lateral sclerosis

Introduction:

Monitoring the disease progression in amyotrophic lateral sclerosis (ALS) is a challenge due to different rates of progression between patients. Besides clinical methods to monitor disease progression, such as the ALS functional rating scale (ALSFRS) and the medical research council (MRC) sum score, quantitative methods like motor unit number estimation (MUNE) are of interest.

Objective:

The objective of the present study is to evaluate the rate of progression in ALS using multipoint incremental MUNE and to compare MUNE, ALSFRS and MRC sum score at baseline and at 6 months for progression of the disease.

Materials and Methods:

Multipoint incremental MUNE using median nerve, ALS-FRS and MRC sum score was carried out in 29 ALS patients at baseline and then at 6 months.

Results:

Of the 29 ALS patients studied, the mean MUNE at baseline was 21.80 (standard deviation [SD]: 19.46, range 4-73), 15.9 in the spinal onset group (SD: 14.60) and 30.16 (SD: 22.89) in the bulbar onset group. Spinal onset patients had 74.02% of baseline MUNE value while bulbar onset patients had only 24.74% baseline value MUNE at 6 months follow-up (Unpaired t-test, P = 0.001). ALSFRS and MRC sum score showed statistically significant decline (P < 0.001) at 6 months follow-up. MUNE had the highest sensitivity for progression of the disease when compared to the ALS FRS and MRC sum score.

Conclusion:

Multipoint incremental MUNE is a valuable tool for outcome measure in ALS and other diseases characterized by motor unit loss. The rate of decline of multipoint incremental MUNE is more sensitive than that of MRC sum score and ALSFRS-R, when expressed as the percentage change from baseline.     

Repeater F-waves in amyotrophic lateral sclerosis: Electrophysiologic indicators of upper or lower motor neuron involvement?

ObjectiveTo extract insight about the mechanism of repeater F-waves (Frep) by exploring their correlation with electrophysiologic markers of upper and lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS).MethodsThe correlations of Frep parameters with clinical scores and the results of neurophysiological index (NI), MScanfit MUNE, F/M amplitude ratio (F/M%), single and paired-pulse transcranial magnetic stimulation (TMS), and triple stimulation technique (TST) studies, recorded from abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles of 35 patients with ALS were investigated.ResultsFrep parameters were correlated with NI and MScanfit MUNE in ADM muscle and F/M% in both muscles. None of the Frep parameters were correlated with clinical scores or TST and TMS measures. While the CMAP amplitudes were similar in the two recording muscles, there was a more pronounced decrease of F-wave persistence in APB, probably heralding the subsequent split hand phenomenon.ConclusionOur findings suggest that the presence and density of Freps are primarily related to the degree of lower motor neuron loss and show no correlation with any of the relatively extensive set of parameters for upper motor neuron dysfunction.SignificanceFreps are primarily related to lower motor neuron loss in ALS.     

Motor unit number index (MUNIX) versus motor unit number estimation (MUNE): a direct comparison in a longitudinal study of ALS patients

ObjectiveTo evaluate how the motor unit number index (MUNIX) is related to high-density motor unit number estimation (HD-MUNE) in healthy controls and patients with amyotrophic lateral sclerosis (ALS).MethodsBoth MUNIX and HD-MUNE were performed on the thenar muscles in 18 ALS patients and 24 healthy controls. Patients were measured at baseline, within 2 weeks, and after 4 and 8 months. Clinical evaluation included Medical Research Council (MRC) scale and the ALS functional rating scale (ALSFRS).ResultsThere was a significant positive correlation between MUNE and MUNIX values in ALS patients (r = 0.49 at baseline; r = 0.56 at 4 months; r = 0.56 at 8 months, all p < 0.05), but not in healthy controls. After 8 months, both MUNE and MUNIX values of the ALS patients decreased significantly more compared to MRC scale, ALS functional rating scale (ALSFRS) and compound muscle action potential (CMAP) (p < 0.05). There was no significant difference in relative decline of MUNIX and HD-MUNE values.ConclusionsIn ALS patients, MUNIX and HD-MUNE are significantly correlated. MUNIX has an almost equivalent potential in detecting motor neuron loss compared to HD-MUNE.SignificanceMUNIX could serve as a reliable and sensitive marker for monitoring disease progression in ALS.     

Age‐related changes in motor unit number estimates in adult patients with Charcot–Marie–Tooth type 1A

Background: Charcot–Marie–Tooth disease type 1A (CMT1A) is known as a demyelinating hereditary neuropathy. Secondary axonal dysfunction is the most important determinant of disease severity. In adult patients, clinical progression may be because of further axonal deterioration as was shown with compound muscle action potential (CMAP) amplitude reductions over time. The motor unit number estimation (MUNE) technique may be more accurate to determine the number of axons as it is not disturbed by the effect of reinnervation. The purpose of this study was to investigate the number and size of motor units in relation to age in patients and controls. Methods: In a cross‐sectional design, we assessed arm and hand strength and performed electrophysiological examinations, including CMAP amplitudes and MUNE of the thenar muscles using high‐density surface EMG in 69 adult patients with CMT1A and 55 age‐matched healthy controls. Results: In patients, lower CMAP amplitudes and MUNE values were related to hand weakness. The CMAP amplitude and MUNE value of the thenar muscles were significantly lower in patients than in controls. CMAP amplitudes declined with age in controls, but not in patients. MUNE values declined with age in both patients and controls. Conclusions: The age‐dependent decrease in the number of motor units was not significantly different between patients with CMT1A and controls, indicating that loss of motor units in adult patients is limited.     

Sensitivity of electrophysiological tests for upper and lower motor neuron dysfunction in ALS: A six‐month longitudinal study

By following a group of amyotrophic lateral sclerosis (ALS) patients longitudinally using lower motor neuron (LMN) and upper motor neuron (UMN) markers of dysfunction it may be possible to better understand the functional relationships between these motor systems in this disease. We used neurophysiological techniques to follow UMN and LMN dysfunction in a group of 28 patients with ALS, in comparison with the ALS functional rating scale (ALS‐FRS) score and the forced vital capacity (FVC). We used motor unit number estimation (MUNE), compound muscle action potential (CMAP) amplitude, and the Neurophysiological Index (NI) to quantify the LMN disorder, and transcranial motor stimulation to study cortical motor threshold, motor‐evoked response amplitude, central motor conduction time, and cortical silent period (CSP). The patients were studied shortly after diagnosis and then 6 months later, using both abductor digiti minimi muscles (ADM); ADM strength was initially >MRC 3 (Medical Research Council, UK). The NI and MUNE changed more than any other variable. CSP increased by about 30%, a change more marked than the slight increase observed in the cortical motor threshold (9%). The normal increase of CSP after acute muscle fatigue was preserved during disease progression. The CSP increase correlated with the MUNE rate of decay but not to the NI reduction, perhaps because NI includes F‐wave frequency in itscalculation. There was no definite correlation between UMN and LMNdysfunction or progression, but there was a link between CSP and LMN changes in ALS. The CSP may be a useful variable in following UMN dysfunction in clinical practice and in clinical trials. Muscle Nerve, 2010     

Revised statistical motor unit number estimation in the Celecoxib/ALS trial

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. As amyotrophic lateral sclerosis (ALS) is characterized by progressive motor unit loss, this disease offers an ideal setting for the use of MUNE. Statistical MUNE was employed in a recent multicenter trial of creatine in ALS, and was shown to be reliable, reproducible, and to decline with disease progression. However, motor unit amplitude stayed constant over 7 months, a finding believed to reflect an artifact of the method. The statistical method was revised to reflect more accurately the presence of larger motor units and employed in a 12-month study of Celecoxib in ALS. MUNE declined by 49% in 12 months; however, motor unit amplitude again stayed constant over the same period. Statistical MUNE estimates motor unit number based on the variability of response to a repeated stimulus of constant strength, with an underlying assumption that this variability is due solely to the number of motor units responding in an intermittent manner. Based on studies showing that single motor units in ALS display excessive amplitude variability when stimulated repeatedly, we show that response variability in ALS patients is in large part due to single unit changes. Thus, we conclude that the statistical method is not an appropriate measure of motor unit number in any disease associated with motor unit instability.     

Motor unit number index and neurophysiological index as candidate biomarkers of presymptomatic motor neuron loss in amyotrophic lateral sclerosis

Introduction: Our objective was to determine the utility of motor unit number index (MUNIX) and neurophysiological index (NI) as surrogate biomarkers of disease progression in limbs without clinical signs of lower motor neuron (LMN) involvement from patients with slowly progressive amyotrophic lateral sclerosis (ALS). Methods: Patients with slowly progressive ALS and at least 1 clinically unaffected limb were prospectively enrolled. Clinical signs of LMN loss and results from hand‐held dynamometer (HHD), revised ALS Functional Rating Scale (ALSFRS‐R), mean‐MUNIX (from 3 different muscles), and NI were longitudinally recorded. Results: Eighteen patients with 43 presymptomatic muscles were evaluated. Twenty‐seven muscles remained clinically unaffected during study, with stable ALSFRS‐R subscores and HHD measures. However, a significant decline in mean‐MUNIX and NI was detected. Discussion: Mean‐MUNIX and NI were more sensitive than clinical measures at detecting LMN loss in presymptomatic limbs from patients with slowly progressive ALS. Therefore, these electrophysiological biomarkers should be included in early study phases as meaningful outcome measures. Muscle Nerve 58 : 204–212, 2018     

Motor unit number index and compound muscle action potential amplitude

ObjectivesMUNIX (motor unit number index), derived from the compound muscle action potential (CMAP) and surface EMG interference pattern (SIP) has become popular as a substitute for motor unit number estimation (MUNE). This study was undertaken to determine why, in recent recordings from amyotrophic lateral sclerosis (ALS) patients and healthy controls, we found that MUNIX values resembled CMAP amplitudes more closely than MUNE values.MethodsThe relationship between MUNIX and CMAP and SIP amplitudes was investigated by a theoretical analysis and by reanalysing the data from the previous study.ResultsTheory indicates that when motor unit potentials overlap extensively, information about motor unit size and number is lost, and MUNIX depends only on CMAP area and power. Accordingly, MUNIX values were found to be sensitive to changes in CMAP amplitude but insensitive to changes in SIP amplitude. The reproducibility of MUNIX measurements in healthy controls was found to depend almost entirely on correlation with CMAP properties.ConclusionsMUNIX gives misleading information about motor unit numbers in healthy controls, and provides little information about loss of motor units in ALS patients beyond that given by simple CMAP amplitude measurements.SignificanceMUNIX should not be interpreted as a MUNE method.     

Reductions in motor unit number estimates (MUNE) precede motor neuron loss in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice

The potential of MUNE as a unique electrophysiological tool to detect early motor unit abnormalities during a clinically silent period was investigated in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice. There was a significant reduction in MUNE in the PMCA2-heterozygous mice as compared to the wild type littermates at two months of age. In contrast, the compound motor action potential (CMAP) was not altered. The conduction velocity (CV) of the sensory nerve and sensory nerve action potentials (SNAP) were not modified indicating lack of major sensory deficits. Interestingly, despite a decline in MUNE at this age, no changes were detected in choline acetyl transferase (ChAT) positive motor neuron number in the ventral horn of the lumbar spinal cord. Hindlimb grip strength, a test that evaluates clinical dysfunction, was also similar to that of the wild type controls. However, motor neuron number significantly decreased by five months suggesting that a drop in MUNE preceded motor neuron loss. In the two-month-old PMCA2-null mice, reduced MUNE measurements coincided with lower motor neuron number and decreased hindlimb grip strength. The fall in motor neuron number was already detectable at three weeks, the earliest time studied, and became more pronounced by five months. Our results show that even partial reductions in PMCA2 levels are sufficient to cause delayed death of motor neurons and that MUNE may be a reliable and sensitive approach to detect pathology prior to cell loss and in the absence of overt clinical signs.     

The motor neuron response to SMN1 deficiency in spinal muscular atrophy

Introduction: The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). Methods: Sixty‐two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. Results: Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (?6.32 μV/year, P = 0.10), and stable CMAP amplitude. Conclusions: The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. Muscle Nerve 49 : 636–644, 2014     

ALS功能评分和CMAP波幅对MND患者预后评估的研究

目的探讨MND患者ALSFRS与运动传导改变的相关性及其对预后评估的价值。方法2007年8月～2008年7月间符合Escorial诊断标准不同确定性水平的MND患者40例,健康志愿者102名为对照组。对所有患者均进行ALSFRS,并分别测量尺神经（腕部）-小指展肌以及胫神经（踝部）-[足母]展肌的复合肌肉动作电位（CMAP）波幅和末端运动潜伏期（DML）,分析ALSFRS与运动传导参数的关系。结果（1）肯定型ALS20例,拟诊型ALS10例,可能型ALS4例,进行性脊肌萎缩6例;（2）与对照组比较,患者组小指展肌和[足母]展肌CMAP波幅（mV）减低,尺神经DML延长（P〈0．01）;（3）ALSFRS与小指展肌和[足母]展肌CMAP波幅以及尺神经DML均呈显著相关（r分别为0．653,0．446和-0．592;P分别为0．000、0．004和0．000）;ALSFRS％30分的9例（100％）患者CMAP波幅均异常减低,31例ALSFRS≥30分的患者有17例（54．8％）的CMAP波幅异常减低（Х^2=6．25,P=0．012）;（4）随访的8例患者中6例ALSFRS在30分以下;与首次就诊相比,随访的8例患者其ALSFRS以及小指展肌CMAP波幅均减低（P〈0．05）。随访者的ALSFRS与小指展肌及[足母]展肌CMAP波幅均呈正相关（r分别为0．836和0．822;P分别为0．01和0．012）,与DML无相关（P〉0．05）。结论MND患者可出现CMAP波幅减低及DML延长;ALSFRS与CMAP波幅显著相关,二者同时减低提示预后差,可作为客观反映MND患者严重程度的可靠指标。     

Motor unit number estimate of distal and proximal muscles in Charcot-Marie-Tooth disease

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot-Marie-Tooth (CMT) disease (29 patients with CMT-1A, 13 with CMT-X, and 12 with CMT-2) by using spike-triggered averaging (STA) of the ulnar-innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo-cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length-dependent fashion. The reduction in ADM-MUNE strongly correlated with clinical weakness in the hand. Both the ADM-MUNE and BB-MUNE were abnormal more often than CMAP amplitude, probably reflecting extensive motor unit reconfiguration and enlargement that maintains CMAP amplitude despite severe motor unit loss. This study suggests that MUNE can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude. The STA technique of MUNE may be useful in longitudinal studies of proximal and distal motor unit changes in CMT.     

Proposed modification to data analysis for statistical motor unit number estimate

Motor unit number estimation (MUNE) is an important electrophysiological technique for quantitative measurement of motor neuron loss. Although commonly used, there is no consensus concerning the optimal procedure for statistical MUNE, particularly regarding several operator-dependent variables. To assess the variables, we analyzed 500 sequential, submaximal compound muscle action potential (CMAP) responses at three or four stimulus intensities in 10 controls and 10 patients with amyotrophic lateral sclerosis (ALS). In both controls and ALS patients, we found that posttest filtering data based on 20% or 25% windows or 2, 2.5, or 3 SD excludes <5% of data. Windows of 10% or 15% excluded <5% of data in controls but not in ALS patients. Excluding data based on +/-2 SD, the coefficient of variation for final MUNE was 12% in controls and 6% in ALS patients. Group sizes of 30 or 50 and sample sizes of 300 to 500 sequential CMAP responses per run yielded the lowest coefficient of variation. We propose that statistical MUNE data should be analyzed based on excluding data >2 SD from the mean, because this is operator independent, includes the majority of data, effectively excludes clearly outlying data, such as fasciculations or movement artifact, and has a reasonable coefficient of variation.     

Magnetoencephalographic evidence of abnormal auditory processing in amyotrophic lateral sclerosis with bulbar signs.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron damage that gives rise to muscle denervation. Besides motor neuron damage, conscious auditory processing appears to be impaired in ALS, whereas it has remained ambiguous whether preceding automatic auditory processing is abnormal in ALS and specifically in ALS with bulbar signs. METHODS: Auditory evoked fields (AEFs) to monaurally presented frequent and infrequent tones with stimulus intervals of 500 and 2500 ms were recorded with magnetoencephalography (MEG) from 10 ALS patients having bulbar signs and from 10 age-matched healthy subjects. RESULTS: The amplitudes of the P50m and N100m responses, which index automatic auditory processing underlying stimulus detection, were significantly increased and P50m latency was shortened in ALS patients. MMNm, which reflects memory-based auditory comparison process, was increased in amplitude in the patient group, whereas the MMNm latency was similar in both groups. AEF latency and amplitude values failed to correlate with the severity of ALS as measured by ALS Functional Rating Scale (ALSFRS). CONCLUSIONS: The present results suggest that auditory processing underlying stimulus detection, and subsequent memory-based comparison processes are abnormal in ALS patients with severe bulbar signs. This might be due to cortical overactivity of excitatory neurotransmitter glutamate observed in ALS.     

Sources of error in the spike-triggered averaging method of motor unit number estimation (MUNE)

Motor unit number estimation (MUNE) is an electrophysical technique to estimate the number of motor units innervating a muscle or muscle group. MUNE may be useful as a measure of progression of lower motor neuron loss in amyotrophic lateral sclerosis (ALS). Several methods of MUNE have been developed. The spike-triggered averaging method can be readily performed on EMG machines with signal averaging capabilities and is suitable for estimating the number of motor neurons innervating proximal muscles. We have used MUNE as a measure of disease state in a drug efficacy trial for ALS. From our experience with this method we have identified sources of error which can affect MUNE accuracy. We have investigated these sources and report their effect on MUNE.© 1995 John Wiley & Sons, Inc.     

The use of statistical MUNE in a multicenter clinical trial

Techniques to estimate motor unit number (MUNE) measure the number of functioning motor units in a muscle. In diseases characterized by progressive motor unit loss, such as amyotrophic lateral sclerosis (ALS), MUNE may be useful to monitor disease progression or beneficial response to treatment. As part of a multicenter, placebo-controlled, randomized, double-blind clinical trial testing the efficacy of creatine in patients with ALS, statistical MUNE was measured in 104 patients tested monthly for 6 months. The objective was to determine whether MUNE was a reliable and sensitive outcome measure in the context of a multicenter trial. Formal training and reliability testing was required for all MUNE evaluators. Testing of normal controls showed a high degree of test-retest reliability. All patient data were combined as the experimental treatment showed no efficacy. There was a 23% decline in MUNE over 6 months. The technique as employed in this trial overemphasized the presence of small motor units; this problem was partially addressed by poststudy data monitoring and censuring. Thus, MUNE can be used reliably as an outcome measure in multicenter clinical trials; specific remedies are suggested for the difficulties encountered in this study.     

Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations.

BACKGROUND: Mice with trangenes that express mutations in the gene for cytosolic copper/zinc superoxide dismutase (SOD1) develop motor neuron degeneration resembling human ALS. Neurophilin ligands are small molecules that promote neurite outgrowth. OBJECTIVE: To test the hypothesis that treatment with two neurophilin ligands increases survival in these ALS mice by slowing the loss of motor neurons and increasing the sizes of motor units. METHODS: Transgenic mice hemizygous for the G93A mutation were untreated or treated from 30 days of age with one of two doses of two neurophilin ligands (V-13,670; V-10,367, Vertex Pharmaceuticals, Boston, MA). Onset of behavioral abnormalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days. RESULTS: In control animals, disease onset occurred at 77.0 days of age and death occurred at 137 days of age. Neither neurophilin ligand affected the disease course. In control animals, MUNE declined with time beginning before behavioral abnormalities were noted, and motor unit size increased concomitantly. There was no effect of drug on motor unit loss as assessed by MUNE; however, motor unit size increased more rapidly and to a greater degree in animals treated with V-13,670. CONCLUSION: As in human ALS, the transgenic ALS mice show physiologic changes in the motor unit prior to the development of clinical signs: MUNE declines as motor unit size increases. Although neither neurophilin ligand significantly affected survival, one produced an increase in motor unit size. The fact that survival was not altered by the increase in motor unit size may reflect the rapid disease course in this animal model.