Pathologic hallmark is death of lower motor neurons (consisting of anterior horn cells in the spinal cord and their brainstem homologues innervating bulbar muscles) and upper, or corticospinal, motor neurons (originating in layer five of the motor cortex and descending via the pyramidal tract to synapse with lower motor neurons). Although at onset ALS may involve selective loss of only upper or lower motor neurons, it ultimately causes progressive loss of both; the absence of clear involvement of both motor neuron types should call into question the diagnosis of ALS.