Cognitive Impairment In Amyotrophic Lateral Sclerosis Research Articles

The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.

Cognitive dysfunction is an important non-motor symptom in amyotrophic lateral sclerosis (ALS) that has a negative impact on survival and caregiver burden. It shows a wide spectrum ranging from subjective cognitive decline to frontotemporal dementia (FTD) and covers various cognitive domains, mainly executive/attention, language and verbal memory deficits. The frequency of cognitive impairment across the different ALS phenotypes ranges from 30% to 75%, with up to 45% fulfilling the criteria of FTD. Significant genetic, clinical, and pathological heterogeneity reflects deficits in various cognitive domains. Modern neuroimaging studies revealed frontotemporal degeneration and widespread involvement of limbic and white matter systems, with hypometabolism of the relevant areas. Morphological substrates are frontotemporal and hippocampal atrophy with synaptic loss, associated with TDP-43 and other co-pathologies, including tau deposition. Widespread functional disruptions of motor and extramotor networks, as well as of frontoparietal, frontostriatal and other connectivities, are markers for cognitive deficits in ALS. Cognitive reserve may moderate the effect of brain damage but is not protective against cognitive decline. The natural history of cognitive dysfunction in ALS and its relationship to FTD are not fully understood, although there is an overlap between the ALS variants and ALS-related frontotemporal syndromes, suggesting a differential vulnerability of motor and non-motor networks. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of cognitive impairment in ALS, which might even serve as novel targets for effective disease-modifying therapies.

Convenient Auditory-Based Language and Executive Function Test for Patients With Amyotrophic Lateral Sclerosis: A Pilot Study.

About 30%-50% of patients with amyotrophic lateral sclerosis (ALS) show cognitive impairment ranging from mild dysexecutive syndrome to frontotemporal dementia. We aimed to develop a brief cognitive test, convenient auditory-based language and executive function test (CABLET), for rapid detection of cognitive impairment in ALS, with reduced load on motor function. The CABLET comprises two tests using auditory verbal stimuli: Test 1, assessing word repetition and lexical judgment, and Test 2, evaluating verbal short-term memory and semantics knowledge. The administration time of Test 1 and Test 2 was 1 and 3-5min, respectively. Overall, 61 patients with ALS and 46 age-, sex-, and education-matched healthy controls participated in this study. All participants underwent existing neuropsychological tests and the CABLET. We investigated the applicability of the CABLET to detect ALS with cognitive impairment (ALSci) from normal cognition. Receiver operating characteristic analyses showed that both the CABLET total and Test 2 had good diagnostic accuracy (area under the curve [AUC]: total = 0.894, Test 2 = 0.893). Test 2 had the highest sensitivity (100% sensitivity and 71.4% specificity). No significant difference existed in the AUC between the analyses with and without age, education, and disease severity as covariates. Correlations were observed between the CABLET and established neuropsychological tests, supporting its good convergent validity. Our findings indicated that the CABLET could be useful in identifying ALSci quickly without adjusting for confounding factors. Further validation is required to evaluate it in larger groups and compare with ALS-specific cognitive screen.

Defining cognitive impairment in amyotrophic lateral sclerosis: an evaluation of empirical approaches

Objective: Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. We evaluate quantile regression (QR), that accounts for age and education, relative to a traditional two standard deviation (SD) cutoff for defining CI. Methods: QR of cross-sectional data from a multi-center North American Control (NAC) cohort of 269 healthy adults was used to model the 5th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to traditional two SD cutoff approach using the same NAC cohort (2SD-NAC) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI in 182 ALS patients. Results: QR-NAC models revealed that age and education impact cognitive performance on the ECAS. Based on QR-NAC normative cutoffs, the frequency of CI in the 182 PENN ALS patients was 15.9% for ALS specific, 12.6% for ALS nonspecific, and 15.4% for ECAS total. This frequency of CI is substantially more conservative in comparison to the 2SD-UK (20.3%–34.6%) and modestly more conservative to the 2SD-NAC (14.3%–16.5%) approaches for estimating CI. Conclusions: The choice of normative cohort has a substantial impact and choice of statistical method a modest impact on defining CI in ALS. This report establishes normative ECAS thresholds to identify whether ALS patients in the North American population have CI.

Translation, cultural adaptation, and validation of a screening test for cognitive and behavioural changes in amyotrophic lateral sclerosis

Purpose To describe challenges of translating and culturally adapting the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen into Norwegian (ECAS-N), evaluate its content validity; provide age- and education-balanced norms for verbal fluency and cut-off values for abnormal performance. Materials and methods Translation to Norwegian and back-translation to English complied with standard methods. Patients and ALS experts evaluated the relevance, comprehensiveness and comprehensibility of the translated ECAS (ECAS-N). Content validity indexes at the item level (I-CVI), scale level (S-CVI) and inter-rater agreement were calculated. Performance of controls determined norms for written and spoken verbal fluency (n = 559) and cut-off scores for abnormal performance (n = 85). Results High levels of content validity was achieved for all items of the ECAS-N, I-CVI, S-CVI and inter-rater agreement was 87.5%. Age- and education-balanced norms for written and spoken verbal fluency were produced. Cut-off scores of abnormal performance were slightly lower than the original ECAS. Conclusions The ECAS-N holds promise for detecting cognitive and behavioural impairment in Norwegian patients with ALS. Cut-off scores are situational and could slightly vary between different cultures. The ECAS-N can be used in international research, but researchers should be aware of the differences between the tests applied in the studies. Implications for rehabilitation The ECAS-N, a Norwegian version of the English-language ECAS was produced for clinical use in Norway. Rigorous translation methods were used, and expert-judged modifications were made for Norwegian-specific culture and language nuances. Determination of ECAS-N cut-off scores for abnormal cognition was guided by a biostatistician, are slightly lower than the original ECAS, and are based on results from an objectively calculated number of healthy Norwegians. A nuanced picture of cognitive impairment in ALS drawn from a well-developed scale as the ECAS-N can contribute to a management process better tailored to patients’- and carers’ individual needs.

Association of Clinically Evident Eye Movement Abnormalities With Motor and Cognitive Features in Patients With Motor Neuron Disorders.

Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in patients with ALS and to correlate such findings with cognitive-behavioral data. Three consecutive inpatient cohorts of Italian patients with ALS and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided into a discovery cohort and a replication cohort. Controls included a cohort of cognitively impaired individuals and patients with Alzheimer disease (AD). Participants underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed with a standard neuropsychological battery (discovery ALS cohort and AD cohort) and the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS) (replication ALS cohort). We recruited 864 individuals with ALS (635 discovery, 229 replication), 798 who were cognitively unimpaired and 171 with AD. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls (p = 1.2 × 10-14) and 11.4% of patients with AD (p = NS). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMA frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both ALS cohorts (p = 1.1 × 10-25). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathologic scores at the ECAS ALS-specific domains. Last, OMAs could be observed in 35.0% of cognitively impaired patients with ALS vs 11.4% of patients with AD (p = 6.4 × 10-7), suggesting a possible involvement of frontal oculomotor areas in ALS. Patients with ALS showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration, and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.

Risk factors for cognitive impairment in amyotrophic lateral sclerosis: a systematic review and meta-analysis

ObjectiveCognitive impairment is a common, far-reaching but imperceptible manifestation in patients with amyotrophic lateral sclerosis (ALS). We aimed to identify the risk factors for cognitive impairment in ALS.MethodsWe searched PubMed...

Cognitive reserve in amyotrophic lateral sclerosis (ALS): a population-based longitudinal study

BackgroundAmyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between...

Screening for cognition in amyotrophic lateral sclerosis: test characteristics of a new screen

Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) negatively influences the quality of life and survival, and, therefore, screening for these impairments is recommended. We developed a cognitive screening tool, the amyotrophic lateral sclerosis–frontotemporal dementia–cognitive screen (ALS–FTD–Cog) and aimed to validate it in patients with ALS. During the current study, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was published and we, therefore, decided to compare these two cognitive screening methods. The ALS–FTD–Cog was administered to 72 patients with ALS, 21 patients with behavioural variant FTD (bvFTD) and 34 healthy controls. Twenty-nine patients with ALS underwent the ECAS. ROC curve analyses were performed and sensitivity and specificity of the ALS–FTD–Cog and ECAS were calculated, with a neuropsychological examination (NPE) as the gold standard. Cognitive impairment was present in 28% of patients with ALS. ROC curve analyses of the ALS–FTD–Cog and ECAS showed an area under the curve (AUC) of 0.72 (95% CI 0.58–0.86) and 0.95 (95% CI 0.86–1.03), respectively. Compared to a full NPE, sensitivity and specificity of the ALS–FTD–Cog were 65.0% and 63.5% and of the ECAS 83.3% and 91.3%, respectively. The sensitivity and specificity of the ALS–FTD–Cog in patients with bvFTD were 94.4% and 100%, respectively. Test characteristics of the ALS–FTD–Cog were moderate, suggesting restricted practical value, as compared to a comprehensive NPE. The ECAS had an excellent AUC and high sensitivity and specificity, indicating that it is a valid screening instrument for cognitive impairment in ALS.

Metabolic brain changes across different levels of cognitive impairment in ALS: a 18F-FDG-PET study

ObjectiveTo identify the metabolic changes related to the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) imaging.Methods274 ALS patients underwent neuropsychological assessment...

Clinical usefulness of scales for evaluating cognitive impairment in patients with amyotrophic lateral sclerosis

Cognitive impairment is a common non-motor symptom of amyotrophic lateral sclerosis (ALS); however, scales suitable for detecting cognitive impairment in ALS patients in clinical practice are unclear. In this study, the Mini-Mental State Examination, Frontal Assessment Battery, and Montreal Cognitive Assessment (MoCA) were evaluated in 68 patients with ALS. The patients were classified into 3 groups based on the results of these clinical scales: group N, patients with scores higher than the cut-offs in all clinical scales; group M, patients with a score lower than the cut-off in one clinical scale; and group D, patients with scores lower than the cut-offs in two or three clinical scales. Clinical data were compared among the groups. Age at onset was significantly lower, and educational period was longer in group N than in group D. MoCA test reported the highest number of patients with a score lower than the cut-off value. The evaluation item of language in MoCA showed the lowest correct answer rate in group N, and evaluation items of executive function and memory in MoCA showed the lowest correct answer rates in group D. MoCA is the most sensitive clinical scale for evaluating cognitive impairment in ALS among the three scales.

C9orf72 and intracerebral hemorrhage

The chromosome 9 open reading frame 72 (C9orf72) GGGGCC repeat expansion has been associated with several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. It has also been associated with increased white matter changes in frontotemporal dementia and risk of cognitive impairment in ALS. Dementia is common both before and after intracerebral hemorrhage (ICH). Because the mechanisms of cognitive impairment in patients with ICH are uncertain, we investigated whether C9orf72 could influence dementia risk in this patient group. Therefore, we genotyped 1010 clinically characterized ICH cases and 2147 population controls in comparison with prior data of dementia and ALS cases. We did not find any association between C9orf72 repeat expansion and repeat size with ICH compared with controls or with dementia when assessing ICH patients only. The frequency of C9orf72 expansions in our series of individuals born in 1946 (2/2147) and other U.K. controls was age dependent, decreasing with increasing age, highlighting the high age-dependent penetrance of this expansion.

Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS) in Norway: Protocol for validation and a prospective cohort study.

In amyotrophic lateral sclerosis (ALS) cognitive impairment may occur. This could detrimentally influence communication between patient and health-care professionals and make clinical assessment difficult. Given the short life expectancy after diagnosis, it is crucial to accurately identify ALS patients early. Although suitable cognitive screening tools for patients with ALS are available, they have not been evaluated in a Norwegian population. Interpretation of scores for available tests and practical application of scoring is also not well established. The protocol described here involves two related studies that aim to improve the quality of ALS clinical testing instruments used in the Norwegian population. The first is a validation study that evaluates the psychometric properties of the ECAS-Norwegian. The second is a prospective cohort study that evaluates the ECAS-Norwegian as a tool to predict early changes in ability to work, drive a car and the need for advanced therapy. Study 1 is a multicenter study using international quality criteria. Patients with ALS, healthy control subjects, and control subjects with dementia will be included. Primary outcome is ECAS-Norwegian scores. In study 2, patients with ALS will be included. ECAS-Norwegian compared to Clinical Dementia Rating score and Montreal Cognitive Assessment scores will be used as a prognostic tool for working, driving, and initiating advanced life-prolonging therapy. Before clinical implementation, the ECAS-Norwegian needs to be evaluated and validated. Successful validation and implementation of the ECAS-Norwegian may provide early identification of cognitive impairment in ALS, leading to more proactive, individualized treatment.

Correlation between Apolipoprotein E genotype and brain metabolism in amyotrophic lateral sclerosis.

The aim of the study was to evaluate the metabolic correlates of Apolipoprotein E (APOE) genotype in amyotrophic lateral sclerosis (ALS) and to investigate the role of ε2 as a risk factor for cognitive impairment. A total of 159 ALS cases underwent APOE and ALS-related genes analysis, neuropsychological assessment and cerebral 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography. The APOE genotype was regressed against whole brain metabolism as assessed by 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography, with age, sex, education, type of onset and C9orf72 status as covariates. Brain metabolism was significantly positively correlated with APOE genotype from ε2/ε2 to ε3/ε4 in the left prefrontal [Brodmann area (BA) 10], orbitofrontal (BAs 11, 45, 47) and anterior cingulate (BA 32) cortices. There was a tendency to a relative hypometabolism going towards the ε2/ε2 extreme. We found a highly significant, relatively lower metabolism in association with the ε2 allele in extra-motor areas typically affected in frontotemporal dementia (left prefrontal, orbitofrontal and anterior cingulate cortices), strengthening the finding of a role of ε2 as a risk factor for cognitive impairment in ALS. Our data suggested a link between cholesterol homeostasis and neurodegeneration.

Amyotrophic lateral sclerosis in Nordland county, Norway, 2000–2015: prevalence, incidence, and clinical features

Objective: There are some indications of increasing incidence of amyotrophic lateral sclerosis (ALS). Awareness of cognitive impairment in ALS has increased in recent years. We describe the epidemiology and clinical features of ALS in a county in northern Norway over a period of 15 years. Methods: All patients with motor neuron disease (MND) living in Nordland County in the period 2000–2015 were identified and the medical records were scrutinized. The average annual incidence was calculated for the whole period and for five-year periods. Prevalence point was 1 January 2015. Results: We identified 74 cases with MND. The crude point prevalence was 4.1 per 100,000. The average annual incidence was 2.1 per 100,000 for the whole period, 2.0 in the period 2000–2004, 2.3 in 2005–2009, and 2.0 in 2010–2014. All except one of the 22 patients with other forms of MND developed ALS during the course of the disease. The mean survival time was 38 months, patients with bulbar symptoms at diagnosis had a mean survival time of 29 months and those with solely spinal symptoms had a mean survival time of 50 months. Seven patients were diagnosed with frontotemporal dementia (FTD). Conclusion: The incidence was stable during the study period. Other forms of MND converts to clinical ALS given time. Survival time is almost two years shorter in patients with bulbar symptoms at the first examination, compared to those with solely symptoms from spinal muscles. FTD was found in 9% of the patients.

Initial exploration on clinical application of resting-state functional magnetic resonance imaging amplitude of low-frequency fluctuation method on cognitive impairment in amyotrophic lateral sclerosis

Objective To explore diagnostic value of amplitude of low-frequency fluctuation (ALFF) on cognitive impairment in amyotrophic lateral sclerosis (ALS) using resting-state functional magnetic resonance imaging (MRI). Methods Sixteen ALS patients from neurological clinic in Peking Union Medical College Hospital were enrolled between November 2013 and April 2015. The patients were divided into two groups by the presence (ALSi, n=7) or absence (ALSu, n=9) of cognitive impairment. Routine MRI structural images and resting-state functional MRI were collected for comparison between groups through voxel-based morphometry (VBM) and ALFF. Results (1) Neuropsychological analysis showed significant differences in Montreal Cognitive Assessment score (22.9±2.0 vs 25.8±2.3, t=2.622, P=0.020), Frontal Assessment Battery score (12.4±1.6 vs 15.1±1.4, t=3.600, P=0.003), animal listing test (13.6±1.8 vs 16.7±2.9, t=2.482, P=0.026), naming test (2(1) vs 0(1), Z=-2.746, P=0.006), similarity test (7.9±3.7 vs 17.3±2.8, t=5.846, P=0.000)and clock drawing test (2(2) vs 3(0), Z=2.516, P=0.012). (2) VBM analysis showed no significant differences in both gray matter and white matter density between the two groups. (3) ALFF analysis showed significantly increased signals in widespread areas of bilateral cerebrum and cerebellum in ALSi group compared to ALSu group. Conclusion ALFF value has the potential to provide more valuable imaging basis for early diagnosis on cognitive impairment in ALS. Key words: Amyotrophic lateral sclerosis; Cognition disorders; Magnetic resonance imaging; Diagnosis

Executive dysfunction predicts social cognition impairment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor system with recognised extra-motor and cognitive involvement. This cross-sectional study examined ALS patients' performance on measures requiring social inference, and determined the relationship between such changes and variations in mood, behaviour, personality, empathy and executive function. Fifty-five ALS patients and 49 healthy controls were compared on tasks measuring social cognition and executive function. ALS patients also completed measures examining mood, behaviour and personality. Regression analyses explored the contribution of executive function, mood, behaviour and personality to social cognition scores within the ALS sample. A between-group MANOVA revealed that, the ALS group was impaired relative to controls on two composite scores for social cognition and executive function. Patients also performed worse on individual tests of executive function measuring cognitive flexibility, response inhibition and concept formation, and on individual aspects of social cognition assessing the attribution of emotional and mental states. Regression analyses indicated that ALS-related executive dysfunction was the main predictor of social cognition performance, above and beyond demographic variables, behaviour, mood and personality. On at least some aspects of social cognition, impaired performance in ALS appears to be secondary to executive dysfunction. The profile of cognitive impairment in ALS supports a cognitive continuum between ALS and frontotemporal dementia.

Neuropsychological deficits in amyotrophic lateral sclerosis (ALS): a South India experience

ALS is a terminal progressive degenerative neurological disorder studies suggest that approximately 35% to 52% of ALS patients experience cognitive deficits which may be identified early in the course of the disease. Cognitive deficits being the integral part of the disease has not been studied in the Indian setting. This is one of the first studies assessing the pattern of cognitive impairment in ALS in the Indian condition. The objective is to examine the neuropsychological profile of amyotrophic lateral sclerosis. Cognitive function was studied in 20 ALS patients: mean age 45.85 13.9 years (22- 65). Neuropsychological test battery was administered. In all 21 test were administered individually in 4-5 sessions which lasted for 7-8 hours. The results show that the majority of patients were from lower/middle socio-economic background. Scores were compared with gender, age and education specific norms, wherein scores falling below 15th percentile of the normative data were treated as deficits. ALS-associated cognitive impairments include deficiencies in visual attention, working memory, fluency, cognitive flexibility, response inhibition, planning, problem solving, and visual-perceptual skills. These impairments indicate executive dysfunction. In conclusion ALS is a disease that affects higher cognitive frontal functions, especially the EF.

Prospective memory tasks: a more sensitive method for screening cognitive impairment in ALS?

BackgroundCognitive change is prevalent in patients with amyotrophic lateral sclerosis (ALS), but still lack a widely accepted and sensitive screening method. In this study, we try to find a sensitive screening battery for detecting subtle cognitive deficits in patients with ALS.MethodsEighty consecutive ALS patients and 57 matched normal controls underwent the Mini-Mental Status Examination (MMSE), the verbal fluency test (VFT), the Stroop Color Word Interference Test (CWT), and the prospective memory (PM) tests, including event-based (EBPM) and time-based (TBPM).ResultsThe patients did not differ from the controls in the MMSE, the VFT and the CWT. By contrast, statistically significant differences were found in the PM tests (EBPM: P=0.043; TBPM: P<0.001). More interestingly, TBPM was more sensitive than EBPM in the early-phase patients.ConclusionsPrefrontal lobar dysfunction does exist among ALS patients and may spread from the medial to the lateral region. The PM tests seem more sensitive in ALS patients with frontotemporal dysfunction than are the classical cognitive measures.

Specific numerical processing impairment in ALS patients

The present study investigated for the first time numerical processing in sporadic amyotrophic lateral sclerosis (ALS) patients. Twenty-four non-demented patients affected by probable or definite ALS and 27 healthy controls underwent cognitive assessment. Numerical abilities (Number Comprehension, Number Transcoding, Arithmetic Fact retrieval, Calculation Skills and Arithmetic Principles) and neuropsychological functions were evaluated in accordance with Strong's consensus criteria. Clear group differences between the patients and controls were found in Multiplication Facts (Tables), Multiplication Approximation, and Multiplication Principles. These deficits were not statistically related to impairments of more general cognitive functioning. In conclusion, specific, previously unreported arithmetical deficits have been found in ALS patients. This particular impairment pattern could be indicative of damage to the cortico-subcortical circuits involved in some specific aspects of multiplication. Our findings could contribute to further delineate the profile of cognitive impairment in ALS.

The Relationship between Depressive Symptoms, Disease State, and Cognition in Amyotrophic Lateral Sclerosis.

Cognitive impairment (CI) in amyotrophic lateral sclerosis (ALS) may present a serious barrier to a patient’s wellbeing and significantly decrease quality of life. Although reports of CI in ALS without frank dementia are becoming quite common, questions remain regarding the specific cognitive domains affected, as well as how other psychological and medical factors may impact cognitive functioning in these patients. Additionally, the influence of depressive symptoms on disease processes is not known. We aimed to address these questions by completing extensive neuropsychological tests with 22 patients with ALS and 17 healthy volunteers. A subgroup of these patients also completed questionnaires to measure depressive and vegetative symptoms. We tested for overall cognitive differences between groups, the influence of physical (e.g., bulbar and limb), vegetative (e.g., fatigue), and depressive symptoms on cognitive performance, and the relationship between depressive symptoms and disease severity in ALS. Overall, patients performed more poorly than healthy controls (HCs), most notably on tests of executive functioning and learning and memory. Results suggest that true cognitive performance differences exist between patients with ALS and HCs, as these differences were not changed by the presence of vegetative or depressive symptoms. There was no effect of limb or bulbar symptoms on cognitive functioning. Also, patients were not any more depressed than HCs, however increased depressive scores correlated with faster disease progression and decreased limb function. Collectively, it is suggested that translational advances in psychological intervention for those with CI and depression become emphasized in future research.