Lactate stress testing in sporadic amyotrophic lateral sclerosis

Mitochondrial dysfunction is frequently observed in ALS. Mitochondrial dysfunction may result in increased serum lactate at rest or low levels of exercise, being used for diagnostic purposes. The study investigated if resting-lactate-determination is superior to lactate-stress-testing (LST) in demonstrating mitochondrial dysfunction in ALS. Included were 15 ALS patients, 4 women, 11 men, aged 37-72. Severity of the disease was assessed by the Norris-score. The control group comprised 66 healthy subjects, 40 women, 26 men, aged 36-76. Serum lactate was determined before, three times during, and once after a constant workload with 30 W on a bicycle ergometer. According to the EIEscorial criteria 8 patients had definite, 4 probable, 3 possible ALS. Resting lactate was increased in 2 patients, 1 with definite and 1 with possible ALS. The LST was abnormal in 5 patients with definite, 1 with probable and 1 with possible ALS. The mean Norris-score was 67.8 in patients with abnormal LST and 74.6 in patients with normal LST. In conclusion, the LST is more suitable than resting-lactate-determination in demonstrating mitochondrial dysfunction in ALS. The LST suggests mitochondrial dysfunction in half of the ALS patients. Mitochondrial dysfunction in ALS is related to the clinical severity of the disease.     

Stress lactate in mitochondrial myopathy under constant, unadjusted workload

As it is under debate if determination of lactate during cycle ergometry (lactate stress testing, LST) under a continuous, unadjusted, low workload is a valuable diagnostic tool for mitochondrial myopathy (MMP), the present study aimed to investigate how sensitive the LST is in a large cohort of patients with indications for MMP (MMP patients). Serum lactate was determined once before, three times during, and once after a 15-min, constant 30 W-workload on a bicycle ergometer in 115 healthy controls, 166 patients with neurological disorders other than MMP, and 291 MMP patients. Serum lactate's upper reference limit at rest, 5, 10, 15 min after starting, and 15 min after finishing the exercise was 2.0, 2.0, 2.1, 2.0 and 1.7 mmol/l, respectively. Resting lactate was increased in 75 MMP patients (26%). The specificity of resting lactate determination was 84%. The sensitivity of the LST was 66% and the specificity 84%. Among the 192 MMP patients with abnormal LST, 120 (63%) had a normal resting lactate. The LST is abnormal in two thirds of the MMP patients. The sensitivity of the LST is higher than that of resting lactate determination. The LST is a simple and cheap but effective and reliable screening method for detecting the impaired oxidative metabolism in MMP.     

Spasms in children with definite and probable mitochondrial disease.

The diagnosis of mitochondrial encephalomyopathies is complex and a system for classification of the diagnosis as definite, probable, and possible has been proposed. The objective of this study was to explore the spectrum of epileptic disorders associated with probable and definite mitochondrial disease in children using this classification system. The patient population with mitochondrial disease and epilepsy was selected from a tertiary care children's hospital. Interictal electroencephalograms and video-EEG recordings were used to characterize seizure types. Ten children fulfilled the criteria for probable or definite mitochondrial disease and had epilepsy. Four had siblings with a similar clinical phenotype. Spasms were the most common seizure type and were the initial seizure type in seven patients and two siblings. Four patients had only partial seizures, with or without generalization, and one patient had seizures that were difficult to classify. Blood lactate concentrations were elevated consistently in patients with partial seizures alone but were occasionally normal in children with spasms. Spasms were the most common presenting seizure type in children with probable and definite mitochondrial disease.     

Early diagnosis of ALS: the search for signs of denervation in clinically normal muscles

AIM AND METHODS: We prospectively investigated whether early diagnosis of amyotrophic lateral sclerosis (ALS) could be facilitated by demonstrating signs of denervation in a muscle of a clinical and electromyographical unaffected region. Muscle fibre conduction velocity (MFCV) was determined in 18 patients in whom the diagnosis ALS was considered but not established beyond a level of clinically possible ALS according to the revised El Escorial criteria. A muscle biopsy was obtained from the same muscle, to demonstrate neurogenic changes. The study followed the guidelines from the STARD initiative. RESULTS AND CONCLUSION: Results were analysed with respect to the final diagnosis. After a mean follow-up of 16 months, 9 patients developed probable or definite ALS. Sensitivity of abnormal MFCV for developing ALS was 89%. Muscle biopsy confirmed that denervation was the cause of abnormal MFCV. We concluded that MFCV can be used to detect denervation in muscles that show no clinical or electromyographical signs of lower motor neuron disease, and thus may contribute to early diagnosis of probable laboratory-supported ALS.     

Epidemiology of amyotrophic lateral sclerosis in Isfahan,Iran

Background: Few studies are carried out on the epidemiology of amyotrophic lateral sclerosis (ALS) in Middle East with no reports from Iran. Objective: To determine the epidemiological and clinical features of ALS amongst the Iranian population living in Isfahan, Iran. Methods: Medical records of all hospitals with a neurology department and outpatient neurology clinics in Isfahan province from 2002 to 2006 were reviewed, and all patients with the diagnosis of ALS according to El Escorial diagnostic criteria were extracted and related demographic and clinical data were gathered and analyzed. Results: We found 98 new patients (66 men and 32 women) with definite, probable, or possible ALS. The average annual incidence was 0.42/100 000, with the highest incidence rate amongst those aged 70–74. On 21 March 2006, the crude prevalence was 1.57/100 000. Median survival from onset was 48 months (95% confidence interval 34–61) and survival rates for 1, 3,and 5 years after the onset were 94%, 66%, and 32%, respectively. Conclusions: The incidence and prevalence of ALS in the Iranian population seems to be lower compared to other populations and the survival of patients was longer than previously reported.     

Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients

Transcranial magnetic stimulation (TMS) was compared to proton magnetic resonance spectroscopy (¹H-MRS) for the detection of upper motor neuron loss or dysfunction in 49 ALS patients classified according to the El Escorial criteria. Abnormal NAA/Cho ratios were detected in 53% of ALS patients. Abnormal TMS results (i.e. cortical inexcitability or prolonged CMCT's) were obtained in 63% of ALS patients. If one or both methods were considered for diagnosis of upper motor neuron degeneration/dysfunction, the percentage of abnormal findings was 77%, whilst in 39% of all patients both methods produced abnormal results. Compared to TMS, ¹H-MRS detected more patients with upper motor neuron involvement in the suspected El Escorial subgroup (42% versus 25%), whereas TMS detected more patients with upper motor neuron involvement in the possible (81% versus 50%), probable (71% versus 57%) and definite El Escorial subgroup (71% versus 64%). We conclude that the combined use of ¹H-MRS and TMS increases diagnostic accuracy for the detection of upper motor neuron involvement in ALS patients.     

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post‐mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease.     

Triple stimulation technique (TST) in amyotrophic lateral sclerosis.

OBJECTIVE: The authors studied amyotrophic lateral sclerosis (ALS) patients using triple stimulation technique (TST) to detect upper motor neuron (UMN) involvement. METHODS: Nineteen ALS patients (aged 45-72 years) were enrolled in the study. According to the El Escorial criteria, 6 diagnoses were suspected or possible, 6 probable, and 7 definite. Patients were examined clinically, with conventional (single-pulse) transcranial magnetic stimulation (TMS), and with TST (on one side only). RESULTS: Among the whole group of patients, TST appeared to be more sensitive than conventional TMS techniques. In particular among suspected/possible ALS patients, TST area ratio was pathologic in 100%, while single-pulse TMS was abnormal only in 50% of cases. Overall, the use of TST area ratio was more sensitive than the analysis of TST amplitude ratio. CONCLUSIONS: The results suggest that TST might be more sensitive and useful in the diagnosis of subclinical UMN involvement than conventional TMS techniques, even if TST is performed on one side only.     

Transcranial magnetic stimulation compared with upper motor neuron signs in patients with amyotrophic lateral sclerosis.

If patients with amyotrophic lateral sclerosis (ALS) present without upper motor neuron signs (UMNS) they do not meet current ALS research criteria. To compare how sensitively degeneration of upper motor neurons is detected clinically and by transcranial magnetic stimulation, 35 patients with ALS were studied. Nineteen patients had definite UMNS, nine patients had probable UMNS, and seven patients had no UMNS. Cortex, cervical nerve roots, and lumbar plexus were stimulated with a magnetic stimulator. Compound muscle action potentials from abductor digiti minimi and from anterior tibial muscles were recorded with surface electrodes. Responses to transcranial magnetic stimulation were considered abnormal if central motor conduction time was above the 99% upper limits or if there was no response to cortical but to peripheral stimulation. In all patients with definite UMNS central motor conduction was abnormal. In patients with probable UMNS it was abnormal in 67%, and in patients without UMNS it was abnormal in 71%. Abnormality of central motor conduction was neither correlated with the duration nor with the severity of the disease. The high rate of abnormalities of central motor conduction found in patients with ALS but without definite UMNS suggests that, in these patients, the diagnosis of ALS can be made more reliably if transcranial magnetic stimulation studies are performed.     

Awaji ALS criteria increase the diagnostic sensitivity in patients with bulbar onset

ObjectiveTo assess whether Awaji criteria improve the sensitivity of diagnosis for amyotrophic lateral sclerosis (ALS). In Awaji ALS criteria, fasciculation potentials are regarded as evidence of acute denervation in the presence of chronic neurogenic changes on needle electromyography.MethodsWe reviewed clinical and neurophysiological data of 113 consecutive patients who were suspected as suffering ALS. The six muscles (trapezius, biceps, first dorsal interosseous, T10-paraspinalis, vastus lateralis, and tibialis anterior muscles) were examined by EMG, focusing on the presence of fasciculation potentials. The sensitivity of revised El Escorial (R-EEC) and Awaji criteria was compared.ResultsProbable or definite ALS was diagnosed in 61% of the patients by R-EEC and 71% by Awaji criteria. By applying Awaji criteria; (1) 17 of the 44 patients categorized as possible ALS by R-EEC reached to probable/definite ALS, 11 of whom had bulbar onset, (2) in 48 patients with bulbar onset, the proportion of probable/definite ALS increased from 59% to 82%, (3) in 62 patients with limb onset, the proportion of probable/definite ALS was 61% (63% by R-EEC).ConclusionsAwaji criteria improve the sensitivity of ALS diagnosis in patients with bulbar onset, but not in those with limb onset.SignificanceAccepting fasciculation potentials as evidence of acute denervation increases the diagnostic sensitivity of ALS, particularly in patients with bulbar onset, and contributes to early diagnosis.     

Lactate stress testing in 155 patients with mitochondriopathy

OBJECTIVE: Few data are available about the diagnostic yield of the lactate stress test (LST) in a large group of patients with mitochondriopathy (MCP). METHODS: Serum lactate was determined once before, three times during, and once after a 15-minute, constant 30W workload on a bicycle in 62 controls, aged 17 to 84 years, 155 patients with MCP, aged 17 to 87 years, and 31 patients with neurological disorders other than MCP. RESULTS: Lactate's upper reference limits at rest, 5, 10, 15 minutes after starting, and 15 minutes after finishing the exercise were 2.0, 2.1, 2.1, 2.1 and 1.8 mmol/l respectively. The test was regarded abnormal if more than two of the five lactate values exceeded the cut-off levels. Among the 103 patients with abnormal LST, 64 (62 %) had normal resting lactate. The sensitivity of the test was 67% and the specificity 94%. CONCLUSION: The LST proved to have a high sensitivity and specificity in the detection of patients with MCP, being thus a simple but powerful tool to assess the impaired oxidative metabolism in MCP patients.     

Amyotrophic lateral sclerosis mimic syndromes: a population-based study

BACKGROUND: The Irish ALS Register is a population-based register of the epidemiological characteristics of amyotrophic lateral sclerosis (ALS) in the republic of Ireland. OBJECTIVE: To describe the clinical and demographic details of those patients included in the Irish ALS Register who were incorrectly diagnosed as having ALS (patients who were ultimately rediagnosed as having an "ALS mimic syndrome"). METHODS: The medical records of each patient referred to the register are routinely reviewed and, where possible, patients are examined by our group during their illness. RESULTS: Between January 1, 1993, and December 31, 1997, 32 patients (representing 7.3% of 437 referrals) were rediagnosed as having a condition other than ALS. The median age at onset for these 32 patients was 56.0 years (range, 19.5-85.8 years) for men and 53.5 years (range, 39.5-70.4 years) for women. Twenty-nine patients (91%) presented with symptoms referable to the limbs, and the remainder presented with symptoms involving the bulbar musculature. Multifocal motor neuropathy was the most common condition mistaken for ALS, accounting for 7 cases (22%), followed closely by Kennedy disease (4 cases [13%]). Factors leading to diagnostic revision included evolution of atypical symptoms, results of specific investigations, and failure of symptoms to progress. Twenty-seven (84%) of the patients with an ALS mimic syndrome fulfilled the El Escorial criteria for either "suspected" or "possible" ALS, 4 (13%) met the criteria for probable ALS, and 1 (3%) had definite ALS. CONCLUSIONS: The application of the El Escorial diagnostic criteria may facilitate early recognition of non-ALS cases. Misdiagnosis of ALS remains a common clinical problem despite the increased availability of investigations and a greater awareness among neurologists of potential diagnostic pitfalls.     

Incidence and prevalence of ALS in Ireland, 1995-1997: a population-based study

BACKGROUND: We conducted a prospective, population-based study of ALS in the Republic of Ireland for the 3-year period 1995 to 1997. METHODS: To ensure complete case ascertainment, multiple sources of information were used, including consultant neurologists, neurophysiologists, primary care physicians, and the Irish Motor Neuron Disease Association. The El Escorial diagnostic criteria for ALS were applied to all cases enrolled on the register and each patient was regularly followed up during his or her illness. RESULTS: Between January 1, 1995, and December 31, 1997, 231 patients were diagnosed with possible, probable, or definite ALS, including 133 men (57.6%) and 98 women (42.4%). The average annual incidence rate was 2.1 per 100,000 person-years (95% CI, 1.8 to 2.4), and 2.8 per 100,000 person-years for the population older than 15 years (95% CI, 2.4 to 3.1). The incidence rate was higher for men, being 2.5 per 100,000 person-years (95% CI, 2.0 to 2.9), than for women, at 1.8 per 100,000 person-years (95% CI, 1.5 to 2.2), and increased with age for both sexes. The median age at onset was 64.2 years for men and 67.8 years for women. On December 31, 1996, the crude prevalence was 4.7 per 100,000 of the total population (95% CI, 4.0 to 5.5), and 6.2 per 100,000 for the population older than 15 years (95% CI, 5.3 to 7.1). Adjusting to the 1996 Irish population as standard, the incidence of ALS in Ireland during the 3-year study period is the third highest reported to date. CONCLUSIONS: There was a trend toward a higher incidence of ALS in the northwestern region of Ireland, although the numbers of cases involved were small and further study is required.     

Early symptom progression rate is related to ALS outcome: a prospective population-based study

OBJECTIVE: To define the factors related to ALS outcome in a population-based, prospective survey. METHODS: The 221 patients (120 men and 101 women) listed in the Piemonte and Valle d'Aosta ALS Register between 1995 and 1996 were enrolled in the study. The patients were prospectively monitored with a standard evaluation form after diagnosis. RESULTS: Mean age at onset was 62.8 (SD = 11.2) years. According to El Escorial diagnostic criteria (EEDC), 112 patients had definite ALS, 85 probable ALS, 18 possible ALS, and six suspected ALS. The median survival time from symptom onset was 915 days (95% CI = 790 to 1065). The median survival time from diagnosis was 580 days (95% CI = 490 to 670). In univariate analysis, outcome was significantly related to age, onset site, EEDC classification, and symptom progression rate (i.e., the rate of decline of muscle strength and bulbar and respiratory function in the 6 months after diagnosis). In the Cox multivariate model, age, progression rate of respiratory, bulbar, and lower limb symptoms, EEDC classification, percutaneous endoscopic gastrostomy, and treatment with riluzole were significantly related to outcome. CONCLUSIONS: The rate of progression of symptoms in early ALS is predictive of disease outcome.     

中央前回质子磁共振波谱在肌萎缩侧索硬化患者临床病情评估中的价值

目的 以质子磁共振波谱(1H-MRS)研究肌萎缩侧索硬化(ALS)的上运动神经元病损情况,以期探寻一种评估病情和疾病进程的指标.方法 对110例ALS和24例下运动神经元综合征(LMNS)患者以及89名健康志愿者进行双侧中央前回单体素1H-MRS检查.以上运动神经元受损体征和反射评分、ALS功能评估量表(ALS-FRS)和APPEL ALS量表(AARS)定量评定患者临床症状和体征.结果 与对照组(1.62±0.18)相比,LMNS患者(1.60±0.17)的NAA/Cr无改变,但ALS患者(1.40±0.25)与两组相比均明显降低(与对照组比较,t=-5.007,P=0.000;与LMNS组比较,t=-2.660,P=0.009);在不同分级的ALS患者中,确诊ALS患者较拟诊ALS者和可能ALS者降低更为明显(与拟诊组比较,t=-2.626,P=0.010;与可能组比较,t=-2.537,P=0.013).结合ALS患者临床表现进一步分析发现,上运动神经元体征明显的患者其NAA/Cr较不明显的患者降低更为明显,差异有统计学意义(t=-2.827,P=0.006),相关分析显示,NAA/Cr与患者的反射评分、ALS-FRS、AARS及其各分项均存在显著相关性(P＜0.05).结论 ALS中央前回1H-MRS检测在一定程度上反映患者上运动神经元受损情况,可作为评估患者病情程度的一项临床指标,但其对该病早期诊断和鉴别诊断的价值有限.     

Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study.

OBJECTIVES: After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty. METHODS: Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain. RESULTS: In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time. CONCLUSIONS: NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.     

Persistent and transient “conduction block” in motor neuron diseases

Although conduction block indicates dysfunction of peripheral nerve, itmay occur in patients with clinically typical motor neuron disease. There are no universally accepted criteria to identify conduction block, so diagnosis may be difficult. In some peripheral neuropathies, conduction block persists over long periods of time. If conduction block persists in motor neuron disease, then a more reproducible means for identification would be available. We repeatedly studied 9 patients with different forms of motor neuron diseases; conduction block was suspected because of excessive loss of the amplitude of motor evoked responses between distal and proximal stimulation sites. Five showed persistent amplitude loss at intervals between 12 and 36 months. All had focal loss of amplitude and area across a specific segment; all were men; none had definite upper motor neuron signs, 2 had probable and 3 had no upper motor neuron signs; 1 had IgM paraproteinemia, one elevated anti-GM₁ titers; the duration of symptoms spanned 4–13 years. Four patients had transient loss of amplitude that was not reproduced in intervals between 3 and 13 months. None had focal loss of both amplitude and area; 2 were men; all had definite upper motor neuron signs and none had symptoms for more than 3–13 months; and none had immunological abnormalities. Thus, patients with persistent amplitude loss fulfill other criteria for conduction block, have prolonged survival but otherwise have clinical syndromes indistinguishable from ALS, except that definite upper motor neuron signs seem to be exceptional. © 1993 John Wiley & Sons, Inc.     

CONSEQUENCES OF MISDIAGNOSING MITOCHONDRIAL DISORDER

Diagnosing mitochondrial disorder remains a challenge. In a 75-year-old women, with short stature, muscle cramps, ptosis, fasciculations and progressive, proximal limb weakness and wasting, hyponatriemia, abnormal lactate-stress-test, and slightly abnormal electromyography, muscle biopsy suggested granulomatous myositis. Corticosteroids and azathioprin were ineffective. After a second work-up amyotrophic-lateral-sclerosis was diagnosed. Riluzole was started, without effect. She developed respiratory insufficiency, requiring mechanical ventilation. Apical ballooning was found. After switching to non-invasive positive pressure ventilation and physiotherapy, she markedly improved. After a third diagnostic work-up, mitochondrial disorder was suspected. Unfortunately, she died suddenly from a cardiac arrhythmia at home. Mitochondrial disorder may mimic motor neuron disease, muscle biopsy may mimic myositis, and may show only little evidence for respiratory chain disorder.     

Evaluation of dysarthria with the assistance of acoustic speech analysis in patients with amyotrophic lateral sclerosis

The aim of the study was to assess dysarthria in ALS subjects using acoustic speech analysis. The study was performed in 47 definite or probable ALS patients aged 29-76 years (mean age 53.7 yr.) and in 30 age and sex matched healthy control subjects. Neurological examination showed 15 dysarthric ALS subjects. Acoustic speech analysis is a quantitative, computer-acoustic method estimating dysarthria and based on assessing of sound distance from speech sound tests. In both group the mean sound distance between chosen sounds was compared to a basic pattern and was measured on time-frequency computer acoustic analyses (delta f = 125 Hz, delta T = 9 ms, delta s = 0.5 dB). Our results demonstrated that all sounds were incorrect in all ALS subjects. These abnormalities were significantly increased in the dysarthric ALS subjects. The mean sound distances which separated ALS from control subjects is 0.2 (by Euclidian principle) in 4 out of 5 measured sounds. We suggest that it is possible to detect and measure dysarthria in ALS patients based on the acoustic speech analysis, also in the limb onset ALS subjects.     

Early detection and longitudinal changes in amyotrophic lateral sclerosis by (1)H MRSI

OBJECTIVE: To determine 1) the reproducibility of metabolite measurements by (1)H MRS in the motor cortex; 2) the extent to which (1)H MRS imaging (MRSI) detects abnormal concentrations of N-acetylaspartate (NAA)-, choline (Cho)-, and creatine (Cre)-containing compounds in early stages of ALS; and 3) the metabolite changes over time in ALS. METHODS: Sixteen patients with definite or probable ALS, 12 with possible or suspected ALS, and 12 healthy controls underwent structural MRI and multislice (1)H MRSI. (1)H MRSI data were coregistered with tissue-segmented MRI data to obtain concentrations of NAA, Cre, and Cho in the left and right motor cortex and in gray matter and white matter of nonmotor regions in the brain. RESULTS: The interclass correlation coefficient of NAA was 0.53 in the motor cortex tissue and 0.83 in nonmotor cortex tissue. When cross-sectional data for patients were compared with those for controls, the NAA/(Cre + Cho) ratio in the motor cortex region was significantly reduced, primarily due to increases in Cre and Cho and a decrease in NAA concentrations. A similar, although not significant, trend of increased Cho and Cre and reduced NAA levels was also observed for patients with possible or suspected ALS. Furthermore, in longitudinal studies, decreases in NAA, Cre, and Cho concentrations were detected in motor cortex but not in nonmotor regions in ALS. CONCLUSION: Metabolite changes measured by (1)H MRSI may provide a surrogate marker of ALS that can aid detection of early disease and monitor progression and treatment response.