Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by progressive degeneration of upper and lower motor neurons, culminating in paralysis and death usually due to respiratory failure. Executive function and problem-solving are compromised in 50% of patients with ALS, and 15-20% of ALS patients develop significant frontotemporal dementia (FTD) with behavioral, language, and executive dysfunction. ALS and FTD exist on a neurodegenerative continuum with substantial clinical overlap that is influenced by genetic factors. Over the last two decades, with the advances in gene discovery technologies, more than 40 disease-causing mutations have been identified representing about 10% of cases of ALS. In most cases of ALS, however, a single genetic cause has not been discovered and the disease progresses through a complex cascade involving dysfunction of a multitude of intracellular processes that result in motor neuron degeneration. Accumulation of these intracellular insults causes the initiation of symptomatic disease. Immune and inflammatory factors then contribute to the burden of disease, rates of disease progression, and survival. These immune/inflammatory factors are increased in the blood and characterize ALS as a systemic disorder, and one not just confined to the central nervous system. Despite intensive efforts, no known pharmacotherapy substantially influences either disease progression or survival. Current therapeutic efforts are aimed at a variety of targets including modifying the expression of mutant genes, ameliorating defective intracellular pathways, and modulating neuroinflammation in attempts to slow disease progression, prolong survival, and improve quality of life. The major objectives of this chapter are to recognize the diverse clinical presentations of ALS/FTD and the many mechanisms of disease pathogenesis. ALS is a heterogeneous disorder with no single cause, but a complex cascade that compromises motor and non-motor neurons. The discovery of successful therapeutics will rely on a better understanding of these mechanisms and our ability to stratify ALS populations based on their predicted responses to specific interventions.