Cognition and Amyotrophic Lateral Sclerosis (ALS)

300 origins, and within these familial cases, 20% are linked to mutations in the superoxide-dismutase-1 gene (SOD-1). 3 Although the mechanism of disease is unknown, several proposed theories include: glutamate excitotoxicity; microtubule and cytoskeletal abnormalities; mitochondrial dysfunction; reactive oxygen toxicity; abnormal intracellular calcium regula- tion; and growth factor abnormalities. 4 Mitochondrial dysfunction has also been implicated in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). 5 Originally, few reports of cognitive involvement were described in ALS, most likely because of the profound, dramatic, and swift course of neuromuscu- lar degeneration seen in this disease. Rapid physical debilitation may often overshadow any changes in cognitive functions these patients may have. It is esti- mated that 3% 6 to 10%, 7 or even as high as 52% 8 of ALS patients meet criteria for accompanying dementia. Outside of this subset of patients, more subtle cognitive deficits are present in frontal-executive skills in many ALS patients. In one large-scale study, cognitive deficits were seen in 50% of 146 ALS patients. 9 Although a substantial proportion of the ALS patient population displays cognitive deficits, this A myotrophic lateral sclerosis (ALS) is a progres- sive neurodegenerative disease involving the anterior horn and cortical motor neurons. Clinically, patients are found to have signs of upper and lower motor neuron disease, with signs of spas- ticity and hyperreflexia corresponding to the former, and fasciculations and muscle wasting with the latter condition. Patients may present initially with either weakness distally in one limb (spinal onset) or severe dysarthria and dysphagia (bulbar onset). 1 Cramping, muscle weakness, and fasciculations spread to other areas and most often occur at night or in the early morning. 2 Death from respiratory compromise typi- cally occurs within 3 to 5 years, 3 with bulbar-onset patients displaying a more rapid progression of the disease. 4 The majority of cases are sporadic with unknown cause; however, 10% of cases have familial Cognition and Amyotrophic Lateral Sclerosis (ALS) D. Irwin, MD, Carol F. Lippa, MD, and J. M. Swearer, PhD Amyotrophic lateral sclerosis (ALS) is classically described as a pure motor disease; however, there is growing evidence of a range of cognitive impairment. Cognitive abnormalities include deficiencies in frontal executive skills, varying from mild deficits to meeting criteria for diagnosis of frontotemporal dementia (FTD). Cognitive impairment occurs in sporadic and familial forms of ALS. Patients may present with cognitive deficits before, after, or at the onset of motor neuron disease. Structural and functional imaging studies have shown extramotor cortical degeneration corresponding to levels of frontal executive impairment on neuropsy- chologic testing. In addition, ALS and a subset of FTD patients display common pathological findings on immunohistochemistry staining. It is believed that these disorders represent a continuum between motor and nonmotor cortical degeneration. The purpose of this article is to review the literature on cognitive deficits in ALS. Identifying changes in cognition is critical for physicians and caregivers of ALS patients, as cognitive decline may interfere with patient compliance. Diagnosis and treatment of cognitive symptoms in ALS patients may improve quality of life. Keywords: ALS; dementia; tau; progranulin; frontotemporal dementia; cognition American Journal of Alzheimer’s Disease & Other Dementias ® Volume 22 Number 4 August/September 2007 300-312 © 2007 Sage Publications 10.1177/1533317507301613 http://ajadd.sagepub.com hosted at http://online.sagepub.com From Drexel University College of Medicine, Philadelphia, Pennsylvania (DI, CFL); and the University of Massachusetts Medical School, Worcester, Massachusetts (JMS). Address correspondence to Carol F. Lippa, MD, Department of Neurology, Drexel University College of Medicine, New College Building, 245 N. 15th St., Philadelphia, PA 19102; e-mail: clippa@ drexelmed.edu.

Cognition and Amyotrophic Lateral Sclerosis (ALS)

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