Letter to The Editor

Response: We thank Drs. Cairns, Bigio, and MacKenzie for their careful comments regarding the neuropathologic features of motor neuron disease with cognitive impairment. The main focus of our review was on the nature of protein aggregation in amyotrophic lateral sclerosis (ALS) and in this context, our discussion of the frontotemporal degeneration in ALS was necessarily truncated. It did not discuss the nature of the pathology of the broader spectrum of the frontotemporal lobar degenerations (FTLD) in which the pathology of ALS can also be occasionally observed. In this sense, we agree with many of their comments. However, it is important to recognize there exists a fundamental disconnection between the clinical realm of study of frontotemporal dysfunction in ALS and that of the neuropathologist studying FTLD. This is not an issue of omission, but rather reflects the fledgling nature of our understanding of the nonmotor system involvement that may occur in ALS. Clinicians recognize that the spectrum of cognitive dysfunction or dementia that may occur in ALS is heterogeneous, ranging from subtle syndromes of cognitive, behavioral, or executive dysfunction to a florid dementia meeting the Neary criteria for FTD (1) and, in a small proportion, a frontally predominant concomitant Alzheimer disease (2). There are few prospective studies that crisply correlate these clinical phenotypes to their respective neuropathologic substrates, although (with the exception of the latter) the common thread appears to be a FTLD. The problem arises when the neuropathologic substrate of FTLD is found to coexist with features of motor neuron degeneration, the scenario(s) to which the authors allude. We would agree with the authors that a key aspect of the neuropathology of ALS with FTLD is the presence of ubiquitin positive, tau, and α-synuclein-negative intraneuronal inclusions. However, although the overexpression of ubiquitin may be a key aspect of the neuropathology of FTLD with ALS, one cannot rule out the presence of tau and α-synuclein using the methodologies described in references 2 through 5. It would also be erroneous to give the impression that such inclusions are unique to ALS or pathognomonic of ALS coexistent with FTLD. Examples of the caution that needs to be given to interpreting this pathology include the recent description of an akinetic rigid syndrome with supranuclear gaze palsy phenotypically that of progressive supranuclear palsy (PSP) in which the neuropathology was typical of that of ALS with FTLD, including the ubiquitin inclusions (3). Conversely, the failure to find this “typical” pathology has been well described (4). We and others have also suggested that, for a population of patients with ALS with cognitive impairment, it is the “load” of ubiquitin-positive aggregates that also appears to be relevant, as opposed to the absolute presence or absence5. We disagree that the observation of tau aggregation is an incidental finding in that it is now abundantly obvious that alterations in tau metabolism can occur in ALS, including in hyperendemic foci of ALS in Guam and the Kii Peninsula of Japan, familial variants of FTD with ALS (with or without linkage to chromosome 9 or 17) (6), and in at least some cases of sporadic ALS with cognitive impairment(7-9). A careful study of the frontal cortex, in the region most affected in ALS, reveals that such pathologic changes are not observed as a function of normal aging nor that they are nonspecific (10). It is too early in our understanding of the spectrum of ALS with dementia or cognitive impairment to be dogmatic with regard to clinicopathologic classifications. Indeed, until such time as careful molecular and neuropathologic studies are married to equally diligent clinical antemortem studies, this field remains undefined. The likelihood is, however, that the frontotemporal syndromes of ALS will encompass a heterogeneous clinicopathologic syndrome with various neuropathologies superimposed on the more traditional pathology of ALS. Among this grouping will undoubtedly be those disorders in which ALS coexists with alterations in tau metabolism. As highlighted by the authors, the challenge will be to define not only these, but the substrate of the ubiquitin conjugation that also appears to be a marker of a subpopulation of these patients. In this sense, the point of our article remains valid. At the heart of ALS lies a proteinopathy.

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