ALS is the most common acquired motor neuron disease. It typically presents in the 6th decade of life, but can strike its victims anytime in adulthood. The incidence rate is 2 per 100,000. A definite cause for ALS remains unknown, although approximately 10% of cases have a familial basis. The most commonly identifiable mutation responsible for 15% of these cases is in the copper/zinc superoxide dismutase (SOD1) gene on chromosome 21. ALS is characterized by the degeneration and loss of upper motor neurons (UMNs) originating from the cerebral cortex and of lower motor neurons (LMNs) arising from the brainstem and spinal cord. Neuronal atrophy, loss and inclusions are accompanied by subcortical white matter tract degeneration and astrocytic gliosis.1 In the brain, the burden of degeneration is most severe in the precentral gyrus followed by the postcentral gyrus, and is less severe and variably present outside this peri-rolandic zone.
Clinical manifestations consist of muscular wasting, fasciculations and severe weakness from LMN involvement. In addition to weakness, UMN degeneration produces limb spasticity, hyperreflexia and loss of fine motor control. The diagnosis of ALS requires demonstration of clinical signs of combined UMN and LMN dysfunction.2 Due
Sanjay Kalra, Division of Neurology, Department of Medicine, University of Alberta, 2E3.18 WMC, 8440-112 Street, Edmonton, Alberta, T6G 2B7, Canada, (780) 407-8786, fax (780) 407-1325, [email protected]. Douglas L. Arnold, Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada.
to extramotor involvement cognitive impairment with frontotemporal deficits is present in upwards of 50% of patients.3
Depending on the regional pathological burden in the neuraxis, clinical manifestations may present in the limbs and/or bulbar territory with speech or swallowing impairment. The disease is relentlessly progressive and eventually renders its victims quadriplegic, mute, unable to swallow and completely dependent. Half of those affected die secondary to respiratory muscle weakness within 3 years of diagnosis and upwards of 90% die within 5 years of diagnosis.4
Despite the fact that ALS is invariably and often rapidly fatal, treatment for the most part remains symptomatic. The only disease modifying agent is riluzole which modestly slows progression and prolongs life by approximately 3-6 months without providing any functional improvement.5 Therefore, intense effort has been directed towards discovering an effective treatment for the disease. As there is no antemortem test to positively diagnose ALS, this effort is greatly hampered by difficulties in establishing the diagnosis at an early stage and by a lack of sensitive and objective markers of disease progression. An accurate measure would aid in earlier diagnosis and allow quicker access to therapies and inclusion into research trials. A neuroprotective drug would presumably be more effective the sooner it is started. The most reliable end points in clinical trials are death and tracheostomy. Such "hard" endpoints, and others like muscle strength and disability scales (e.g. the revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]), require lengthy and expensive trials with hundreds of patients per treatment arm. A more sensitive and less variable endpoint would make development of new drugs speedier and less costly. Objective, non-invasive techniques to quantitatively evaluate the targeted cell in ALS, namely the motor neuron, are lacking.
Reliable scales for evaluation of UMN involvement in particular are sorely needed. This combined with the fact that UMN signs may be absent on physical exam even in the presence of UMN pathology6-9 has been the impetus for the application of various imaging modalities to evaluate potential biomarkers of UMN degeneration. These have been reviewed elsewhere10 and include magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), diffusion weighted imaging (DWI), functional MRI, single photon computed tomography (SPECT) and positron emission tomography (PET).
The following is an overview of the application of MRS in ALS with a focus on what has been learned by imaging ^-acetylaspartate (NAA).
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