The overlap of amyotrophic lateral sclerosis and frontotemporal dementia

Methods.

Thirty-six consecutive patients with a clinical diagnosis of FTD were referred to clinicians with expertise in ALS (C.L.-H., T.A.) from the University of California, San Francisco (UCSF) and University of California, Los Angeles (UCLA) memory disorders centers. The patients were originally referred from community neurologists from a wide geographic area, including much of California and neighboring states. These patients had no known diagnosis of ALS or family history of ALS or FTD, and there was no preselection of patients with ALS symptoms. Patients with FTD were diagnosed based on clinical and neuropsychological testing and neuroimaging features and all would meet current Neary research criteria for FTD.6 All patients underwent a detailed neuromuscular examination and EMG studies after giving written informed consent for these studies. This study was approved by UCSF and Harbor/UCLA Research Education Institute Institutional Review Boards. The long-term goal of this study was to identify the frequency of ALS in FTD in two tertiary-care dementia centers with a special interest in FTD.

Results.

The results are summarized in the table. Five patients met criteria for the diagnosis of definite ALS based on the World Federation of Neurology criteria.7 All of these patients had severe FTD prior to developing symptoms of ALS. Five patients had fasciculations, but no abnormalities by EMG studies. Benign fasciculations are common, and studies suggest that the presence of fasciculations in the setting of a normal EMG carries a benign prognosis. However, most of these patients did not develop fasciculations until the development of FTD, so they may be more at risk than the general population. Finally, two patients had evidence of neurogenic change in one limb, but did not have other changes to document a diagnosis of ALS. It is difficult to determine whether these changes were related to the start of a motor neuron disease or due to focal injury in the past.

Six additional patients also had trouble with swallowing. It is difficult to determine whether the swallowing difficulty is from upper or lower motor neuron causes without laryngeal EMG studies. The patients with swallowing difficulty were not at any greater risk to have fasciculations or denervation in peripheral muscles than the other patients with FTD studied, but longitudinal follow-up will be important.

Thus, among 36 patients with FTD, we found 14% with definite ALS and an additional 36% with possible ALS. Re-evaluation of one of the five patients with fasciculations after 1 year identified development of definite ALS over the interval, bringing the total number of patients with ALS and FTD to six. This patient had FTD symptoms for 2 years prior to the development of fasciculations, and when first evaluated by EMG, the fasciculations had been present for only 6 weeks. Longitudinal studies will be necessary to determine whether others develop definite ALS, including the 13 other patients with possible ALS as well as the 18 patients with no earlier indication of motor neuron disease.

Discussion.

This study confirms that neuromuscular specialists will find ALS in many patients with FTD. In a previous study based on a chart review of our patient population with FTD, we reported that 15% of all cases either developed ALS or had a first-degree relative with ALS.8 In this prospective study we found that 14% of patients with FTD carried a diagnosis of definite ALS, whereas another 36% had features of this condition. Longitudinal follow-up is in progress that will include neuropathologic confirmation of diagnosis.

The incidence of ALS in familial and sporadic FTD or FTD in ALS has not been extensively studied. A recent review of 151 patients with ALS showed increased risk of PD and dementia in relatives based on clinical history.9 The risk of dementia was significantly higher in relatives of patients with ALS than controls (RR 1.9) and was similar for relatives of patients with sporadic and familial ALS. Similarly, the risk of PD was higher in relatives of patients with familial ALS (RR 5.6) than relatives of patients with sporadic ALS (RR 1.8). However, these patients with ALS did not have neuropsychological testing to determine whether they had any evidence of dementia. ALS is rarely seen in association with AD and we suspect that this association probably reflects the high incidence of FTD with ALS. Similarly, there is often temporal lobe degeneration and cortical ubiquitinated inclusions in ALS with or without dementia.10

For a variety of reasons, all of these earlier studies including our own probably underestimate the association between FTD and ALS. Patients with FTD and ALS tend to present first to an ALS center rather than to a memory disorders center. This is supported by our own work showing a 31% incidence of FTD symptoms in 100 patients with ALS presenting to the ALS Center at UCSF. Multidisciplinary studies that include cognitive and motor evaluations in these populations are rare. We used a cohort of convenience and not a population-based study, which may not reflect the prevalence of a disease in the general community. However, because the study speaks only to the incidence of ALS in FTD and not other dementias, it is appropriate to generalize the data to the FTD population as a whole.

Dementia is difficult to study in patients with ALS because the motor problems interfere with cognitive testing and ALS is difficult to evaluate in FTD because patients are often uncooperative for motor studies. Because patients need to pass a certain threshold before ALS can be diagnosed clinically, a single evaluation is likely to miss many patients who are in the process of losing motor neurons. Neuropathologic evaluations are needed that carefully assess both frontotemporal and motor neurons, yet such studies have not been performed. Ultimately, a better understanding of both conditions can be achieved by multidisciplinary evaluations of patients with both conditions.