Cognitive impairment, frontotemporal dementia, and the motor neuron diseases

Traditionally, amyotrophic lateral sclerosis (ALS) has been considered to be a disorder in which the primary pathology resides in the degeneration of motor neurons, giving rise to progressive, diffuse muscle wasting, weakness, and spasticity. This view is rapidly being challenged to include a more widespread disease process in which motor system degeneration remains the core feature but not the sole system affected. Although its incidence remains to be determined, the evidence of cognitive impairment in ALS is overwhelming. However, it is important to recognize that there is likely to exist a continuum of cognitive dysfunction in ALS, ranging from mild cognitive impairment (ALSci) to a more fulminant progressive dementia of the frontotemporal type (FTD) with a small subset with an aphasic pattern. Most commonly, ALSci is reported as a subtle neurological presentation marked by deficits primarily in frontal and temporal functions. Although in the Japanese population, alterations in cognition have been reported to precede the motor system manifestations, typically the cognitive dysfunction follows the onset of neuromuscular deficits. Individuals with bulbar-onset disease appear to be at greater risk for the development of cognitive impairment, although these deficits are found to a lesser degree in limb-onset patients. Typical impairments include alterations in mental flexibility, verbal and nonverbal fluency, abstract reasoning, and memory, for both verbal and visual material. Less often, there is a rapidly progressive aphasic dementia. ALSci language characteristics include word-finding difficulty, lexical disorganization, and reliance on stereotypical sentences. Anterior-based language functions (eg, fluency, syntax, and grammar) are compromised. The relationship between FTD, FTD with ALS, and FTD with the neuropathological features of ALS in the absence of clinical findings remains to be clarified. There is likely to be significant overlap among these entities, as illustrated in a study of 36 FTD patients with no known diagnosis of ALS, 5 of whom met clinical and electrophysiological criteria for a definite diagnosis of ALS and an additional 13 who met criteria for possible ALS, of whom 1 subsequently developed ALS. The converse is also true. A study of word generation tests in 100 consecutive ALS patients identified a subset of 44 patients with impairments. Of these, diminished word generation was found in one third. Of this latter group, nearly all were shown to meet research criteria for FTD. In addition, one quarter of the patients with normal word generation who agreed to further evaluation met research criteria for FTD; these patients had new-onset personality changes. In addition to the precentral gyrus atrophy that is well recognized in ALS, neuroimaging in ALSci demonstrates a more widespread frontal and temporal cortical atrophy, with variable involvement of the precentral and postcentral gyrus, the anterior cingulate gyrus, corpus callosum, and brainstem tegmentum. Functional neuroimaging techniques, including single-positron emission tomography studies with either I-Nisopropyl-p-iodoamphetamine or Tc-d,l-hexamethylproplene–amine oxime (HM-PAO), and positron emission tomography, are sensitive to reduced frontal and temporal cortical blood flow in ALSci. Reductions in the N-acetylaspartase to creatine ratio of anterior cingulate gyrus neurons with the use of proton magnetic resonance spectroscopy has been shown to be a sensitive marker of ALSci. The typical neuropathological features of ALS include degeneration of the descending supraspinal motor pathways and their neurons of origin, and of brainstem and spinal motor neurons in addition to