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August 23, 2005; 65 (4) Articles

Prevalence and patterns of cognitive impairment in sporadic ALS

G. M. Ringholz, S. H. Appel, M. Bradshaw, N. A. Cooke, D. M. Mosnik, P. E. Schulz
First published August 22, 2005, DOI: https://doi.org/10.1212/01.wnl.0000172911.39167.b6
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Abstract

Objective: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study.

Methods: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes.

Results: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance.

Conclusions: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Recent studies on amyotrophic lateral sclerosis (ALS) suggest that there are structural and pathologic changes that extend beyond motor neurons and that some of these changes correlate with cognitive dysfunction.1 The prevalence and types of cognitive impairment reported in association with ALS vary greatly. Early reports suggested that the frequency of cognitive impairment in ALS was about 1 to 4%.2–5 The largest previous study indicated that 36% of patients with ALS had clinically significant cognitive impairment.6 More recent studies have described some degree of impairment in 55 to 75% of patients with ALS.7,8

Descriptions of the types of dementia associated with ALS have included a rapidly progressive aphasic dementia9 and a thalamic dementia syndrome.10 However, the majority of studies have focused on the overlap between ALS and frontotemporal dementia (FTD).11 There are also descriptions of less severe cognitive impairment associated with ALS. These studies suggest that in many non-demented patients with ALS there is impairment of attention, working memory, verbal fluency, and other frontal executive functions.5,6,12

Likewise, a number of clinical, pathologic, and imaging studies have emphasized involvement of the frontal lobes in ALS. ALS-dementia has been associated with frontal gyral atrophy, microvacuolation of layer II cortex in frontal and temporal regions, and gliosis of frontal subcortical white matter.13 Other studies have reported ubiquitin-positive, tau-negative, and synuclein-negative neuronal inclusions in the cingulate gyrus and superficial linear spongiosis of frontal cortex in cognitively impaired patients with ALS.1 Frontal atrophy on CT and MRI has been described,8,14–17 and SPECT and PET studies have demonstrated reduced activation in dorsolateral and medial prefrontal cortices.18–21 However, correlation of pathologic and imaging data with changes in cognitive function has been hindered by the lack of a consensus among researchers on the definition and measurement of cognitive impairment in ALS.

In order to better address the issues of prevalence and patterns of performance, we conducted detailed clinical and neuropsychological examinations on a large sample of patients tested across a wide range of cognitive functions.

Methods.

Subjects consisted of consecutive referrals to the Neurology Service of the Methodist Hospital and the Baylor College of Medicine MDA-ALS Clinic. All patients had probable or definite ALS according to the El Escorial World Federation of Neurology diagnostic criteria for ALS.22 A total of 316 individuals were evaluated. Patients were excluded who had a history of other neurologic conditions affecting cognition (e.g., stroke, traumatic brain injury), had serious mental illness (e.g., schizophrenia, major depression), had a family history of ALS, or whose initial diagnosis of ALS was later changed to another diagnosis (e.g., multifocal motor neuropathy). The remaining individuals (n = 279) were enrolled in this study. Neuropsychological data also were obtained from normal control subjects enrolled in a concurrent study of Alzheimer disease (AD). Using the same exclusionary criteria applied above, 129 subjects were enrolled. Both protocols were approved by the Institutional Review Board of Baylor College of Medicine.

Neuropsychological measures.

Subjects with ALS completed an extensive battery of neuropsychological measures. Tests were chosen that assessed multiple areas of cognition, and included the following: a modified (Satz-Mogel)23 version of the Wechsler Adult Intelligence Scale Revised (WAIS-R); the Mini-Mental State Examination (MMSE)24; the American version of the National Adult Reading Test (AMNART)25; Stroop Color and Word Test26; the Verbal Series Attention Test (VSAT)27; and Verbal Fluency for letters (FAS) and categories (animals)28; Logical Memory and Visual Reproduction subtests from the Wechsler Memory Scale–Revised (WMS-R)29; Symbol Digit Modalities Test (Oral and Written)30; the Benton Facial Recognition Test31; the Boston Naming Test32; and the Repetition, Sequential Commands, and Auditory Comprehension subtests from the Western Aphasia Screening Battery.33

Supplementary measures included speech rating scales (for phrase length, paraphasic errors, word-finding difficulty, and dysarthria), Luria’s motor examination,34 and the Geriatric Depression Scale.35

A subset (n = 146) of patients referred for initial evaluation returned to the MDA-ALS outpatient clinic at the Baylor College of Medicine for follow-up care. These patients received motor scores using the Appel ALS Rating Scale (Total ALS Score).36

Normal controls were testing using the MMSE,24 the VSAT,27 Logical Memory and Visual Reproduction subtests from the WMS-R,29 the Benton Facial Recognition Test31 as a measure of visuoperceptual abilities, and the AMNART,25 as an estimate of verbal IQ.

Classification methods.

Prevalence estimates of dementia vary based upon reliance on neuropsychological testing, consideration of functional impairment as a criterion for dementia, and the inclusion of cognitive impairment without dementia in the diagnostic classification.37 Other studies have indicated the variability of prevalence estimates of mild cognitive impairment due to application of different diagnostic criteria.38 A number of methods have been applied to estimate the frequency8 of dementia and cognitive impairment in ALS. These have included cluster analysis,7,8 use of cutting scores,6 and clinical diagnosis based on cognitive screening and application of criteria for FTD.39 All these methods were used here as follows.

  1. Cluster analysis—combined normalized (adjusted for age and education) data from controls and patients with ALS on untimed (non-motor-speed-dependent) neuropsychological tests were subjected to K-means cluster analysis to identify potential subgroups.

  2. Cutting scores based on MMSE—intact > 27; mild impairment 25–27; and moderate to severe impairment < 25.

  3. Cutting scores based on neuropsychological test data—mild impairment was defined as performance below the fifth percentile as compared to normal controls on two or more non-motor-speed-dependent neuropsychological measures; moderate to severe impairment was defined as ≥ 2 SD below the normal control mean on three or more non-motor-speed-dependent neuropsychological measures.

  4. Clinical diagnosis—patients underwent comprehensive neurologic examination and neuropsychological evaluation including an interview, a family interview, screening for depression, and cognitive testing. Diagnoses of dementia were established applying Diagnostic and Statistical Manual of Mental Disorders-IV criteria,40 National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for AD,41 and the Work Group on Frontotemporal Dementia and Pick’s Disease Criteria for FTD42 as appropriate. Patients who had clinical evidence of cognitive impairment but did not meet criteria for dementia were classified as mildly impaired.

Results.

The population under study was typical of patients with ALS. The mean age was 58.8 (SD = 14.4) years. Sixty-one percent were men. Ninety-five percent were right-handed and 90% were white. The mean education was 13.6 years. The mean MMSE was 27.4 (±2.8), the mean Full Scale IQ was 101.5 (±13.6), and the mean AMNART score, an estimate of premorbid verbal IQ, was 109.7 (±10). The mean score on the Geriatric Depression Scale was 7.8 (±6) indicating that the group did not generally endorse a significant number of depressive symptoms.

Of the 252 patients with complete clinical data, 86 (34%) had primarily bulbar onset and 156 (66%) had limb onset. The mean score on the Appel ALS Rating Scale (Total ALS Score) was 68.8 (±20.7), which is in the mild-to-moderately impaired range. The mean score on the Speech Rating Scale-dysarthria domain was 0.66 (±0.96), which is indicative of mild dysarthria. Normal controls were older (mean age = 74.4; SD = 6.3), and slightly more educated (15.6 years; SD = 2.2) than the patients with ALS as a whole, but were not significantly different in terms of sex, race, or handedness. Due to these differences in age and education, normalized test scores (adjusted for age and education) were used in the remaining statistical analyses.

Levels of cognitive impairment.

Neuropsychological test data from both controls and patients with ALS were combined and subjected to cluster analysis to identify potential subgroups. To avoid potential confounding effects of motor and verbal output response times, only untimed measures were used in the analysis. The final cluster centers are shown in table E-1 (on the Neurology Web site at www.neurology.org). Overall, performance on the eight variables included in the analysis varied along a single dimension of progressively lower scores, and labels were assigned accordingly.

Table E-2 shows the distribution of controls and patients with ALS by cluster. Seven of the controls (5%) fell into the mildly impaired range. All the remaining controls (95%) fell into the intact cluster. Only 49% of patients with ALS, in contrast, fell into the intact cluster. The majority of those remaining fell into the mild cluster and 19% fell into the moderately to severely impaired clusters.

The control patients were slightly older than patients with ALS, and they were slightly more educated (table E-3). The MMSE scores were similar between controls and patients with ALS, except for the severely impaired patients who averaged 20.1. AMNART scores were again similar, except for the severely impaired patients who averaged 92.9. Patients with ALS scored more poorly on tests of memory (LM I and II, VR I and II) and attention/concentration (VSAT). This was true, even for the ALS-intact subgroup (table E-3 and the figure).

Figure

Figure. Comparison of cognitive performance in normal controls vs four amyotrophic lateral sclerosis groups. BFRT = Benton Facial Recognition Test; VSAT = Verbal Series Attention Test; AMNART = American National Reading Test; LMI = Logical Memory subtest from the Wechsler Memory Scale-Revised (immediate recall); LMII = Logical Memory subtest from the Wechsler Memory Scale-Revised (delayed recall); VRI = Visual Reproduction subtest from the Wechsler Memory Scale-Revised (immediate recall); VRII = Visual Reproduction subtest from the Wechsler Memory Scale-Revised (delayed recall).

Table E-4 compares levels of cognitive impairment among patients with ALS derived by the various classification methods described above. The four methods are in statistical agreement (Kappa coefficients range from 0.34 to 0.53; p < 0.0001).

Patterns of performance.

Patient performance on neuropsychologic tests (table E-5) was compared using a multiple regression model. Errors on a measure of attention, concentration, and working memory (VSAT) accounted for nearly 50% of the variance between the groups (R-square change = 0.495; p < 0.0001). Visual recall (WMS Visual Reproduction II) added an additional 16%. Confrontation naming (Boston Naming Test) made a unique contribution of 2% to the model, and Verbal Recall (WMS Logical Memory II) 1.6%. Other measures did not make unique contributions to the differences between the groups (overall R-square = 0.693; p < 0.0001).

With regard to clinical diagnoses, 147 patients were intact; 89 patients had cognitive impairment but did not meet criteria for dementia. As noted above, these individuals were classified as mildly impaired. Of the 43 patients clinically diagnosed with dementia, 41 met criteria for FTD (15 with behavioral onset, 26 with language onset). The remaining 2 patients had severe impairment in memory and multiple other cognitive domains and were given a diagnosis of probable AD.

Comparisons of clinical disease variables were carried out via analysis of variance with planned contrasts between the patient subgroups (ALS-intact, -mild, -moderate, and -severe). Analysis of clinical disease variables indicated that patients with cognitive impairment (ALS-mild, -moderate, and -severe) were more likely to have motor programming difficulties, dysarthria, decreased phrase length, and difficulty with word-finding (table E-6). Patients with bulbar vs limb onset ALS were not different in either level of impairment or pattern of performance.

Discriminant analysis was applied to establish a method for accurate classification of cases with a smaller number of variables. A neuropsychological screening battery (approximately 45 minutes testing time) consisting of the VSAT (error score), the WMS–Logical Memory and Visual Reproduction subtests, the MMSE, and the Boston Naming Test was shown to detect and discriminate levels of cognitive impairment in patients with ALS compared to controls with 88% accuracy.

Discussion.

This study examined cognitive function in a large group of consecutively evaluated patients with sporadic ALS. Very similar estimates of cognitive impairment were obtained through different but converging techniques, including cutoff scores, statistical clustering, and clinical diagnosis. Comparison with a control group confirmed that significant cognitive differences exist between normal subjects and patients with ALS. Overall, 50% of patients had some degree of cognitive impairment. For 30% of the patients, this impairment was mild, but approximately 20% of patients had impairment in multiple domains severe enough to be considered for a diagnosis of dementia.

Prior estimates of the prevalence of cognitive problems associated with ALS have varied over time. Early studies reported a low incidence of dementia or cognitive decline in ALS, i.e., 1 to 4%.2,4,5 Subsequent studies suggested somewhat higher rates. As noted earlier, the largest previous study found that 36% of patients with ALS had “significant cognitive decline.”6 Another study reported that 31% of patients with ALS were globally impaired and that another 24% had deficits in attention and executive function; thus, 55% were cognitively impaired.7 Other researchers found that 70% of 60 patients with ALS had some degree of cognitive impairment.8 The most recent studies suggest that approximately one-half of patients with ALS have measurable cognitive impairment. A recent study of the overlap between ALS and FTD found that 23 (52%) of 44 patients with ALS had executive deficits. Of 100 patients screened with word generation tests, 15 met research criteria for FTD.11 The results of our study support the more recent prevalence estimates.

As noted above, the majority of the impaired patients in this study had deficits in attention, concentration, and working memory. Other functions, including memory and confrontation naming, also were impaired, but to a lesser degree. In the past, this pattern has been described as a frontal/subcortical syndrome.43 However, this simply may reflect an intermediate level of severity or a stage in a progressive neurodegenerative disease. Other patients had moderate to severe declines on measures of attention/concentration, verbal fluency, and naming. This pattern of deficits has been described in patients with ALS and language-onset FTD.39 In fact, of the 43 patients in our sample who had been given a clinical diagnosis of dementia, 41 met criteria for FTD. The remaining 2 patients were diagnosed with probable AD. As noted above, severe memory impairment is not a common feature of the dementia associated with ALS, and may help to distinguish it from other dementias such as AD.

As with other dementias, lower levels of education appear to be correlated with cognitive decline in patients with ALS. This was evident despite controlling for the effect of education on the cognitive scores used in the classification. Patients with cognitive impairment also tended to have greater overall severity of disease as measured by their Total ALS Score, but this trend did not reach significance. In our study, patients with bulbar-onset disease were not significantly different from limb-onset patients in terms of their level or pattern of cognitive impairment. This result is consistent with the findings of at least one study in the literature,8 but differs from the results of other studies in which bulbar onset patients had greater cognitive dysfunction.44–46 The reason for this discrepancy is not completely clear. However, in our sample, patients with bulbar onset disease were older (mean age = 62.1; SD = 13.6) than those with limb onset (mean age = 56.8; SD = 14.8; p = 0.006), and their symptom duration defined as the time between onset of symptoms and the date of evaluation was lower (11 months vs 19 months; p = 0.029). The effect of age was controlled for in our study through the use of normalized (age, sex, and education-corrected) scores. However, if, as one other study46 has suggested, patients with bulbar-onset disease have more rapid decline of cognitive abilities, a method for controlling for stage of disease will need to be employed before direct comparisons of limb-onset and bulbar-onset patients can be made.

This large-scale study confirmed the presence of cognitive impairment in approximately half of patients with ALS. Mild executive dysfunction typified by impairment of attention, concentration, and verbal fluency is the more common pattern. However, moderate to severe cognitive impairment, typically with features of FTD, does occur. Current data do not support the conclusion that these different patterns represent discrete subtypes. In fact, the striking similarity in the patterns of cognitive performance across ALS patient groups is more suggestive of differing levels of severity or stages of a progressive disease. This interpretation is supported by a recent pathologic study of tau-positive neuronal and astrocytic inclusions in the frontal cortex of patients with ALS. These inclusions were found to greater extent in those patients with cognitive impairment than those who were cognitively intact. This suggests that patients with ALS with and without cognitive impairment represent a disease continuum.47

A prospective, longitudinal study is required to determine whether ALS-intact patients or ALS-mildly impaired patients indeed progress to the ALS-moderate/severe stage. Current data suggest that the majority of patients with ALS and moderate/severe cognitive impairment meet criteria for FTD. However, it is unclear whether all patients with ALS eventually will meet these criteria, or if other subgroups exist. The gathering and organization of additional neuropathologic and neuroimaging data will be facilitated by an empirically sound classification of cognitive impairment in ALS.

Acknowledgment

The authors thank the patients with ALS and their caregivers.

Footnotes

  • Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the August 23 issue to find the title link for this article.

    The Vicki Appel/MDA ALS clinic is supported by the Muscular Dystrophy Association.

    Disclosure: The authors report no conflicts of interest.

    Received March 14, 2003. Accepted in final form May 13, 2005.

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