Recognising facial onset sensory motor neuronopathy syndrome: insight from six new cases.

Facial onset sensory and motor neuronopathy (FOSMN) was first described in 2006 as an apparently sporadic neurodegenerative disease. Thirty cases have been reported to date. We summarise six new cases, highlighting the key clinical aspects of FOSMN and how to differentiate it from motor neurone disease (amyotrophic lateral sclerosis). Typically, patients present with slowly evolving numbness of the face followed by bulbar and proximal (neck and arm) weakness. However, one of our patients presented with a motor syndrome and his abnormal blink reflex studies provided a useful diagnostic clue. This extends the spectrum of the syndrome and emphasises that FOSMN should be considered in the differential diagnosis of motor neurone disease. We discuss the pathophysiology, diagnosis, prognosis and management considerations of FOSMN.

Evaluation of cerebrospinal fluid alpha-synuclein seed amplification assay in PSP and CBS.

Background: Seed amplification assay (SAA) testing has become an important biomarker in the diagnosis of alpha-synuclein related neurodegenerative disorders. Objectives: To assess the rate of alpha-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and analyse the clinical and pathological features of SAA positive and negative cases. Methods: 106 CSF samples from clinically diagnosed PSP (n=59), CBS (n=37) and indeterminate parkinsonism cases (n=10) were analysed using alpha-synuclein SAA. Results: Three cases (1 PSP, 2 CBS) were Multiple System Atrophy (MSA)-type SAA positive. 5/59 (8.5%) PSP cases were Parkinson's disease (PD)-type SAA positive, and these cases were older and had a shorter disease duration compared with SAA negative cases. In contrast, 9/35 (25.7%) CBS cases were PD-type SAA positive. Conclusions: Our results suggest that PD-type seeds can be detected in PSP and CBS using a CSF alpha-synuclein SAA, and in PSP this may impact on clinical course.

Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS.

BACKGROUND: The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis. METHOD: 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using 'upper motor neuron burden,' El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length. RESULTS: Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls. CONCLUSIONS: Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease.

Ciliary neurotrophic factor (CNTF) rescues motor neurons in animal models of injury and neurodegeneration, and disruption of the mouse CNTF gene results in motor neuron degeneration in mature adults. Glial cells increase nerve growth factor (NGF) expression in neuropathological conditions, and the sensory system can be affected in the amyotrophic lateral sclerosis (ALS) type of motor neuronic disease. We therefore studied CNTF and NGF levels in post mortem spinal cord and cerebral cortex from patients with ALS and matched controls. We report a marked decrease of CNTF in the ventral horn of spinal cord in ALS, with no change in cerebral motor cortex. In contrast, NGF levels were decreased in ALS cerebral motor cortex, where the corticospinal tract originates, but increased in the lateral column of spinal cord, which includes the region of corticospinal tract degeneration in ALS. Both CNTF and NGF levels were decreased in ALS dorsal spinal cord.

An estimate of amyotrophic lateral sclerosis heritability using twin data.

BACKGROUND: Causative gene mutations have been identified in about 2% of those with amyotrophic lateral sclerosis (ALS), often, but not always, when there is a strong family history. There is an assumption that there is a genetic component to all ALS, but genome-wide association studies have yet to produce a robustly replicated result. A definitive estimate of ALS heritability is therefore required to determine whether ongoing efforts to find susceptibility genes are worth while. METHODS: The authors performed two twin studies, one population- and one clinic-based. The authors used structural equation modelling to perform a meta-analysis of data from these studies and an existing twin study to estimate ALS heritability, and identified 171 twin pairs in which at least one twin had ALS. RESULTS AND DISCUSSION: Five monozygotic twin pairs were concordant-affected, and 44 discordant-affected. No dizygotic twin pairs were concordant-affected, and 122 discordant-affected. The heritability of sporadic ALS was estimated as 0.61 (0.38 to 0.78) with the unshared environmental component 0.39 (0.22 to 0.62). ALS has a high heritability, and efforts to find causative genes should continue.

Prevalence of depression in amyotrophic lateral sclerosis and other motor disorders.

BACKGROUND: Research suggests the prevalence of severe depression in ALS is <20%. In contrast, studies have reported that severe depression affects 40-50% of patients with other neurodegenerative motor conditions (e.g. multiple sclerosis, Parkinson's disease and Huntington's disease). The comparison with such disorders has generated a clinical impression that patients with ALS have surprisingly low rates of depression. However, comparisons with such disorders do not take into account the markedly different pathological, physical and behavioural profiles associated with these disorders. To assess further the extent to which ALS is associated with a low prevalence of depression, we compared the prevalence of depression in patients with ALS to that in patients with neuromuscular disorders with more comparable disease profiles. METHODS: The Beck Depression Inventory-II (BDI-II), the Major Depression Inventory (MDI), the Hospital Anxiety and Depression Scale (HADS) and the ALS Functional Rating Scale-Revised were sent to 212 patients from a tertiary referral Motor Nerve Clinic in London, UK. RESULTS: Data were obtained from 51 people with ALS and 39 with other neuromuscular disorders. The non-ALS group included patients diagnosed with disorders that are characterized by motor neurone dysfunction and/or a decline in everyday function. Analyses revealed no between-group differences on severity and prevalence rates of depression according to the BDI-II, HADS Depression Subscale and MDI. CONCLUSIONS: Our findings do not support the impression that patients with ALS have lower rates of depression than patients with other varied neuromuscular disorders.

Quantitative magnetic resonance spectroscopic imaging in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy.

BACKGROUND AND PURPOSE: Magnetic resonance spectroscopy (MRS) allows the measurement of a number of brain tissue metabolites in vivo, including N-acetylaspartate (NAA), a putative marker of neuronal integrity. Unlike single voxel MRS, magnetic resonance spectroscopic imaging (MRSI) enables quantification of these metabolites simultaneously from multiple anatomically localized voxels. Both single voxel MRS and MRSI allow the absolute quantification of these metabolites and, when combined with tissue segmentation, can give accurate metabolite concentrations even in the presence of partial volume effects from nearby cerebrospinal fluid. METHODS: Using MRSI with cubic voxels with a nominal volume of 1.0 cm(3), we tested the hypothesis that concentrations of NAA in the basal ganglia in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) would show differences compared to Parkinson's disease (IPD). NAA values (in mM) from MRSI voxels centred to the putamen, pallidum and thalamus were obtained from 11 patients with IPD, 11 with MSA-P, six with MSA-C, 13 with PSP and 18 controls. The mean concentrations of NAA and its bulk grey and white matter values were also estimated over the whole brain slab. RESULTS: N-acetylaspartate concentrations in the pallidum, putamen and lentiform nucleus were significantly lower in patients with MSA-P and PSP compared to IPD and controls. The putaminal values were also significantly reduced in PSP compared to MSA-P. There were no significant differences between groups in the thalamus and over the whole brain slab. CONCLUSION: Our findings support the notion that MRSI can potentially quantify basal ganglia cellular pathology in MSA and PSP.

Glutamate slows axonal transport of neurofilaments in transfected neurons.

Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of neurofilaments are seen in several neurodegenerative diseases, and this suggests that neurofilament transport is defective. Excitotoxic mechanisms involving glutamate are believed to be part of the pathogenic process in some neurodegenerative diseases, but there is currently little evidence to link glutamate with neurofilament transport. We have used a novel technique involving transfection of the green fluorescent protein-tagged neurofilament middle chain to measure neurofilament transport in cultured neurons. Treatment of the cells with glutamate induces a slowing of neurofilament transport. Phosphorylation of the side-arm domains of neurofilaments has been associated with a slowing of neurofilament transport, and we show that glutamate causes increased phosphorylation of these domains in cell bodies. We also show that glutamate activates members of the mitogen-activated protein kinase family, and that these kinases will phosphorylate neurofilament side-arm domains. These results provide a molecular framework to link glutamate excitotoxicity with neurofilament accumulation seen in some neurodegenerative diseases.

WITHDRAWN: Amino acids for amyotrophic lateral sclerosis / motor neuron disease.

BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a progressive neuromuscular disease that causes disability and eventual death. Various amino acid preparations, the three branched-chain amino acids (L-leucine, L-valine and L-isoleucine) or, alternatively, L-threonine have been used as experimental therapy. OBJECTIVES: To examine the efficacy of amino acid therapies in prolonging survival and/or slowing the progression of amyotrophic lateral sclerosis/motor neuron disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2003), MEDLINE (from January 1966 to December 2002) and EMBASE (from January 1980 to December 2002) databases and reports of specialist conferences. Authors of known studies were contacted. SELECTION CRITERIA: We included randomised or quasi-randomised trials of participants with a clinical diagnosis of amyotrophic lateral sclerosis/motor neuron disease treated with all combinations of amino acids. Our primary outcome measure was survival determined by a pooled hazard ratio of all studies. Our secondary outcome measures were (in order of priority): survival at six and 12 months, muscle strength, any validated rating scale of physical function, quality of life, proportion of patients completing therapy and proportion of patients reporting adverse events attributable to treatment. DATA COLLECTION AND ANALYSIS: We identified six eligible trials and rejected a further seven because of incomplete data or inadequate duration. Eligible studies were rated for methodological quality and missing data sought from the authors. After this examination two studies were excluded from analysis. Our pooled survival analysis was performed by the Parmar method, other statistical calculations were done using the Review Manager 4.2 software package. MAIN RESULTS: No benefit could be demonstrated for either branched-chain amino acids or L-threonine in improving survival in amyotrophic lateral sclerosis/motor neuron disease. Neither could we find evidence of an effect of either treatment on muscle strength or disability as measured by functional rating scales. No study assessed quality of life. Both branched-chain amino acids and L-threonine appeared well tolerated and caused a degree of adverse events comparable to that of the control medication. AUTHORS' CONCLUSIONS: There is no evidence to support a beneficial effect of either branched-chain amino acids or L-threonine in amyotrophic lateral sclerosis/motor neuron disease.

Amyotrophic lateral sclerosis in South-East England: a population-based study. The South-East England register for amyotrophic lateral sclerosis (SEALS Registry).

BACKGROUND/AIMS: We aimed to estimate the incidence and prevalence of amyotrophic lateral sclerosis (ALS) in the South East of England. The reported incidence of ALS varies between 0.44 and 3.2 per 100,000 person years. This can partly be explained by differences in design and diagnostic criteria used. There is little population data concerning England, particularly the South East. METHODS: A population study of South-East England (total population: 2,890,482) was carried out and multiple sources including our tertiary centre and district general hospitals were used for complete case ascertainment. RESULTS: Between 1 January 2002 and 30 June 2006 we identified 138 people (76 males; 62 females) with a new diagnosis of ALS, giving a crude incidence of 1.06 per 100,000 person years. The projected age- and gender-adjusted annual incidence rate for England and Wales was 1.10 (95% CI 0.80-1.40). 142 people were alive on 30 June 2006, giving a point prevalence of 4.91 per 100,000 population. CONCLUSION: Our incidence and prevalence rates are similar to those reported in comparable studies from other countries. This argues against the role of a specific exogenous factor in the aetiology of ALS in South-East England.

Altered cortical activation during a motor task in ALS. Evidence for involvement of central pathways.

OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) show increased cortical activation during a motor task compared to both healthy controls and patients with muscle weakness due to peripheral lesions. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure activation during a block design paradigm contrasting right hand movements against rest in sixteen patients with ALS, seventeen healthy controls and nine patients with peripheral lesions. The groups were matched for age and gender and the two patient groups were matched for their degree of upper limb weakness. Analysis used a non-parametric approach to perform a 3 way hypothesis-driven comparison between the groups. RESULTS: During the motor task, patients with ALS showed increased cortical activation bilaterally, extending from the sensorimotor cortex [Brodmann areas (BA) 1, 2, 4] posteriorly into the inferior parietal lobule (BA 40) and inferiorly to the superior temporal gyrus (BA 22) when compared to peripheral lesion patients and controls. In addition, ALS patients showed reduced activation in the dorsolateral prefrontal cortex (DLPFC) extending to anterior and medial frontal cortex (BA 8, 9, 10, 32). CONCLUSIONS: We conclude that alterations in cortical function in ALS differ in sensorimotor and prefrontal regions. Importantly, we have shown that these changes do not reflect confounding by weakness or task difficulty, but are likely to be related to upper motor neuron pathology in ALS.

Prevalence of depression in a 12-month consecutive sample of patients with ALS.

There is an impression both in clinical practice and in research literature that patients with amyotrophic lateral sclerosis (ALS) possess 'heroic stoicism with a low frequency of depression'. Reliance on specific interview methods may have contributed to differing estimates of mood disorder in people with ALS. The objective of the current study was to compare prevalence rates of depression and anxiety in ALS using different assessment tools. The Beck Depression Inventory (BDI), The Hospital Anxiety and Depression Scale (HADS) and the Spielberger State-Trait Anxiety Inventory (STAI) were sent to a 12-month consecutive sample of 190 patients with ALS attending a tertiary referral clinic in the UK. Data were collected from 104 patients with ALS. Using BDI scores, 44% were categorized as not depressed, 37% were mild-moderately depressed, 13% were moderately-severely depressed, and 6% were severely depressed. In contrast, the HADS depression subscale identified 75% as not depressed, 13% were in the borderline range, and 13% were categorized as meeting 'caseness' for depression. Twenty-five percent of the patients were using antidepressant medication. The estimated prevalence of mood disorder amongst patients with ALS may vary significantly depending on the measure used.

[11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS.

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.

Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET.

Five to ten percent of amyotrophic lateral sclerosis (ALS) cases are associated with mutations of the superoxide dismutase-1 (SOD1) gene, and the 'D90A' mutation is associated with a unique phenotype and markedly slower disease progression (mean survival time 14 years). Relative sparing of inhibitory cortical neuronal circuits might be one mechanism contributing to the slower progression in patients homozygous for the D90A mutation (homD90A). The GABA(A) receptor PET ligand [11C]flumazenil has demonstrated motor and extra-motor cortical changes in sporadic ALS. In this study, we used [11C]flumazenil PET to explore differences in the pattern of cortical involvement between sporadic and genetically homogeneous ALS groups. Twenty-four sporadic ALS (sALS) and 10 homD90A patients underwent [11C]flumazenil PET of the brain. In addition, two subjects homozygous for the D90A mutation, but without symptoms or signs ('pre-symptomatic', psD90A), also underwent imaging. Results for each group were compared with those for 24 healthy controls of similar age. Decreases in the binding of [11C]flumazenil in the sALS group were found within premotor regions, motor cortex and posterior motor association areas. In the homD90A group of ALS patients, however, decreases were concentrated in the left fronto-temporal junction and anterior cingulate gyrus. In the two psD90A subjects, a small focus of reduced [11C]flumazenil binding at the left fronto-temporal junction was seen, similar to the pattern seen in the clinically affected patients. Within the sALS group, there was no statistically significant association between decreases in cortical [11C]flumazenil binding and revised ALS functional rating scale (ALSFRS-R score), whereas the upper motor neuron (UMN) score correlated with widespread and marked cortical decreases over the dominant hemisphere. In the homD90A group, there was a stronger statistical association between reduced cortical [11C]flumazenil binding and the ALSFRS-R, rather than the UMN, score, and also with disease duration. This study provides evidence for differences in the distribution of reduced cortical [11C]flumazenil binding in homD90A compared with sALS patients. We hypothesize that this might reflect differences in cortical neuronal vulnerability.

Changes in memory for emotional material in amyotrophic lateral sclerosis (ALS).

The current study sought to examine the performance of non-demented ALS patients on neuropsychological tests involving emotional perception and memory. Nineteen non-demented patients with ALS were compared with 20 healthy controls on assessments of facial expression recognition, social judgement ratings of faces and recognition memory for emotional words. Patients and controls were well matched to exclude a range of potentially confounding variables. The patients and controls demonstrated significant differences on only one test of cognitive functioning. The ALS group demonstrated a failure to show the normative pattern of enhanced recognition memory for emotional words compared to neutral words and produced higher scores than controls on recognition memory for neutral words. These findings suggest that patients with ALS show a different pattern of cognitive performance with respect to memory for emotional material when compared to healthy adults.

Frontotemporal white matter changes in amyotrophic lateral sclerosis.

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.

Accepting or declining non-invasive ventilation or gastrostomy in amyotrophic lateral sclerosis: patients' perspectives.

The objective was to identify factors associated with decisions made by patients with amyotrophic lateral sclerosis (ALS) to accept or decline non-invasive ventilation (NIV) and/or gastrostomy in a prospective population-based study. Twenty-one people with ALS, recruited from the South-East ALS Register who made an intervention decision during the study timeframe underwent a face-to-face in-depth interview, with or without their informal caregiver present. Sixteen had accepted an intervention (11 accepted gastrostomy, four accepted NIV and one accepted both interventions). Five patients had declined gastrostomy. Thematic analysis revealed three main themes: (1) patient-centric factors (including perceptions of control, acceptance and need, and aspects of fear); (2) external factors (including roles played by healthcare professionals, family, and information provision); and (3) the concept of time (including living in the moment and the notion of 'right thing, right time'). Many aspects of these factors were inter-related. Decision-making processes for the patients were found to be complex and multifaceted and reinforce arguments for individualised (rather than 'algorithm-based') approaches to facilitating decision-making by people with ALS who require palliative interventions.

Stereotaxic injection of kainic acid into the striatum of rats induces synthesis of mRNA for heat shock protein 70.

Stereotaxic injection of the excitotoxin kainic acid into the striatum of rats has been shown to induce the production of messenger RNA to the 70 kDa heat shock protein. This was evident 2 h after injection and was maximal 24 h after injection of kainic acid. No change in the level of messenger RNA to beta-actin was detected.

A proton magnetic resonance spectroscopic study in ALS: correlation with clinical findings.

OBJECTIVE: To evaluate neuronal dysfunction in the motor region subcortical white matter in ALS using volumetric localized proton magnetic resonance spectroscopy (1H-MRS). METHODS: Sixteen patients with E1 Escorial definite, probable, or possible ALS and eight healthy age-matched control subjects were studied. The ALS patients were divided into those with limb onset (n = 8) and those with bulbar onset (n = 8). Measurements of the metabolic ratios N-acetylaspartate (NAA)/creatine and phosphocreatine (Cr+PCr), NAA/choline (Cho), and Cho/(Cr+PCr) were correlated with clinical assessments. RESULTS: We found no differences in the metabolic peak area ratios in the motor region when comparing the total ALS group and the control subjects. However, correlations were found between the NAA/(Cr+PCr) ratio and the E1 Escorial category (p = 0.03), the ALS severity scale (p = 0.01), and the Medical Research Council score (p = 0.06). No correlations were found between the NAA/(Cr+PCr) ratio and the Ashworth Spasticity Scale, reflex score, or disease duration (p > 0.16). Bulbar-onset patients had a lower NAA/(Cr+PCr) ratio in the motor region compared with limb-onset patients (p = 0.03). CONCLUSION: In vivo 1H-MRS of the subcortical white matter in the motor region is unlikely to be sensitive enough to detect early disease changes in ALS because there is considerable overlap between the metabolic peak area ratios from patients with ALS and normal control subjects. However, changes in the NAA/(Cr+PCr) metabolic peak area ratios correlate with clinical measures of disease severity, and this measure may be useful in monitoring disease progression.