Emma Beeldman

The cognitive profile of ALS: a systematic review and meta-analysis update

Cognitive impairment is present in approximately 30% of patients with amyotrophic lateral sclerosis (ALS) and, especially when severe, has a negative impact on survival and caregiver burden. Our 2010 meta-analysis of the cognitive profile of ALS showed impairment of fluency, executive function, language and memory. However, the limited number of studies resulted in large confidence intervals. To obtain a more valid assessment, we updated the meta-analysis and included methodological improvements (controlled data extraction, risk of bias analysis and effect size calculation of individual neuropsychological tests). Embase, Medline and PsycInfo were searched for neuropsychological studies of non-demented patients with ALS and age-matched and education-matched healthy controls. Neuropsychological tests were categorised in 13 cognitive domains and effect sizes (Hedges’ g) were calculated for each domain and for individual tests administered in ≥5 studies. Subgroup analyses were performed to assess the influence of clinical and demographic variables. Forty-four studies were included comprising 1287 patients and 1130 healthy controls. All cognitive domains, except visuoperceptive functions, showed significant effect sizes compared to controls. Cognitive domains without bias due to motor impairment showed medium effect sizes (95% CI): fluency (0.56 (0.43 to 0.70)), language (0.56 (0.40 to 0.72)), social cognition (0.55 (0.34 to 0.76)), or small effect sizes: delayed verbal memory 0.47 (0.27 to 0.68)) and executive functions (0.41 (0.27 to 0.55)). Individual neuropsychological tests showed diverging effect sizes, which could be explained by bias due to motor impairment. Subgroup analyses showed no influence of bulbar disease onset and depression and anxiety on the cognitive outcomes. The cognitive profile of ALS consists of deficits in fluency, language, social cognition, executive functions and verbal memory. Social cognition is a new cognitive domain with a relatively large effect size, highlighting the overlap between ALS and frontotemporal dementia. The diverging effect sizes for individual neuropsychological tests show the importance of correction for motor impairment in patients with ALS. These findings have implications for bedside testing, the design of cognitive screening measures and full neuropsychological examinations.

The ALS-FTD-Q A new screening tool for behavioral disturbances in ALS

Objective: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We examined the clinimetric properties of a new behavioral questionnaire for patients with ALS (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire [ALS-FTD-Q]). Methods: In addition to other clinimetric properties, we examined reliability, clinical validity, and construct validity of the ALS-FTD-Q, using data from patients with ALS (n = 103), ALS-bvFTD (n = 10), bvFTD (n = 25), muscle disease control subjects (n = 39), and control subjects (n = 31). Construct validity of the ALS-FTD-Q was assessed using the Frontal Systems Behavior scale (FrSBe), Frontal Behavioral Inventory (FBI), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale−Revised, Frontal Assessment Battery, Mini-Mental State Examination, and a fluency index. In addition, the point prevalence of behavioral disturbances according to the ALS-FTD-Q was compared with those obtained with the FrSBe and FBI. Results: The internal consistency of the ALS-FTD-Q was good (Cronbach α = 0.92). The ALS-FTD-Q showed construct validity because it correlated highly with other behavioral measures (r = 0.80 and 0.79), moderately with measures of frontal functions and global cognitive functioning (r = 0.37; r = 0.32), and poorly with anxiety/depression and motor impairment (r = 0.18 for both). The ALS-FTD-Q discriminated between patients with ALS-bvFTD, patients with ALS, and control subjects. The point prevalence of behavioral disturbances in patients with ALS measured with the ALS-FTD-Q was lower than that for the FrSBe and FBI. Conclusion: The ALS-FTD-Q is a feasible and clinimetrically validated instrument for the screening of behavioral disturbances in ALS.

A systematic review of behavioural changes in motor neuron disease

Motor neuron disease (MND) and the behavioural variant of frontotemporal dementia (bvFTD) are thought to be part of a disease spectrum. There is uncertainty about the frequency and characteristics of behavioural changes in MND, and similarly, about a relation between bvFTD and the site of onset of MND. Our aim was to perform a systematic review of the publications on behavioural changes in MND. An extensive search for articles on behavioural changes in MND patients was performed. First, cohort studies of MND patients were reviewed to summarize the prevalence of bvFTD and mild behavioural changes. Secondly, data on bvFTD symptoms (mostly from case reports) of individual MND-bvFTD patients were used to analyse characteristics and pooled prevalences of bvFTD symptoms. In addition, site of onset, survival and demographic variables of MND-bvFTD patients were analysed. Results showed that in cohorts, 8.1% (95% CI 5.6 − 11.5%) of MND patients had bvFTD. In 170 individual patients with MND-bvFTD, perseveration (40%), apathy (29%) and disinhibition (26%) were the most frequently reported behavioural changes; 43% had memory disturbances and bulbar onset was found in 48%. In conclusion, 8% of MND patients have bvFTD, with perseveration being reported most frequently. MND-bvFTD is often accompanied by memory disturbances and is related to bulbar onset.

A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations.

Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin (OPTN) gene were found in 1% of Japanese patients with sporadic amyotrophic lateral sclerosis (ALS). Autosomal dominantly inherited OPTN mutations have been described as a cause of primary open-angle glaucoma in the Netherlands and were also found in two Dutch sporadic MND patients. We report the first Dutch family with autosomal recessively inherited MND caused by mutations in the OPTN gene.

Is the Frontal Assessment Battery reliable in ALS patients

The assessment of frontal functions in ALS patients is important because of the overlap with the behavioural variant of frontotemporal dementia (bvFTD). We investigated the applicability and reliability of the Frontal Assessment Battery (FAB) within a cohort of predominantly prevalent ALS patients. The FAB was administered to 85 ALS patients and eight ALS-bvFTD patients. Original scores and the percentage of items that could be performed were recorded. Item-adjusted scores of the FAB were calculated. The ALS Functional Rating Scale-Revised version (ALSFRS-R) was used to assess disease severity. Eighty-seven patients (94%) had ALS symptoms of more than one year. Twenty patients (21.5%) were not able to perform one or more FAB items. The original FAB score correlated with the ALSFRS-R score (r = 0.30; p < 0.01), while the item-adjusted FAB score did not. In contrast to the original FAB scores, the item-adjusted FAB score was lower in ALS-bvFTD patients (66.7, range 33.3–100) compared to ALS patients without bvFTD (94.4, range 38.9–100; p < 0.01). In summary, 20% of prevalent ALS patients could not complete the FAB, which limits its use in ALS and emphasizes the importance of disease specific instruments and adjusting for motor impairment in cognitive and behavioural examinations of ALS patients.

The verbal fluency index: Dutch normative data for cognitive testing in ALS

Abstract Objective: Executive dysfunction occurs in 30–50% of amyotrophic lateral sclerosis (ALS) patients and is most frequently assessed with the verbal fluency test. The verbal fluency index (VFI) has been developed to correct for slowness of speech in ALS, and reflects the average thinking time per word. However, its use as a marker of cognitive impairment is hindered by the absence of valid norm scores. Therefore, we provide normative data for the VFI. Methods: Dutch volunteers were demographically matched to the Dutch ALS population and completed the verbal fluency index (one-minute and three-minute spoken letter fluency). Multiple stepwise linear regression was performed to assess the influence of demographic variables, past medical history and medication use. Results: 273 volunteers participated in this study. Educational level was negatively correlated to one-minute and three-minute VFI performance (r = –0.3 and r = –0.4, p < 0.001, respectively). No correlations for age, gender, medication and past medical history were found. A formula for standardized z-scores, corrected for educational level, for the one-minute and three-minute VFI was calculated. Conclusions: We provide Dutch normative data for the spoken verbal fluency index, which can be used internationally, but validation in other languages is recommended. The findings illustrate the importance of valid disease-specific norm scores for time-dependent cognitive tests in ALS.

Response to 'Exploring limits of neuropsychological screening in ALS : The FAB problem'

behavioural changes in ALS is estimated to be around 20% and they have investigated 24 ALS patients (2 5). In addition, the low level of motor impair-ment with a small range (ALSFRS-R 40.2 ( 2.1)) did not facilitate the detection of a correlation. Sec-ondly, we did fi nd a correlation between the FrSBe and the ALSFRS-R in 100 ALS patients (

The cognitive profile of behavioural variant FTD and its similarities with ALS: a systematic review and meta-analysis

Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%–14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson’s r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77–1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson’s r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD.

Japanese version of the ALS-FTD-Questionnaire (ALS-FTD-Q-J)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neuropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms. We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or behavioral variant FTD (bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for frontal/executive function, cognition, anxiety/depression, and motor functions. Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach α=0.92). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r=0.79). However, correlations were moderate with anxiety/depression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients.