Cortical and subcortical changes in resting-state neuronal activity and connectivity in early symptomatic ALS and advanced frontotemporal dementia.

The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state magnetoencephalography (MEG) data of 34 ALS patients, 18 bvFTD patients and 18 age- and gender-matched healthy controls (HCs) were projected to source-space using an atlas-based beamformer. Group differences in peak frequency, band-specific oscillatory activity and functional connectivity (corrected amplitude envelope correlation) in 78 cortical regions and 12 subcortical regions were determined. False discovery rate was used to correct for multiple comparisons. BvFTD patients, as compared to ALS and HCs, showed lower relative beta power in parietal, occipital, temporal and nearly all subcortical regions. Compared to HCs, patients with ALS and patients with bvFTD had a higher delta (0.5-4 Hz) and gamma (30-48 Hz) band resting-state functional connectivity in a high number of overlapping regions in the frontal lobe and in limbic and subcortical regions. Higher delta band connectivity was widespread in the bvFTD patients compared to HCs. ALS showed a more widespread higher gamma band functional connectivity compared to bvFTD. In conclusion, MEG in early symptomatic ALS patients shows resting-state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. The findings show the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends.

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.

Cognitive and behavioral status in Japanese ALS patients: a multicenter study.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) patients may present with cognitive and behavioral abnormalities similar to frontotemporal dementia (FTD). In this multicenter study we examined Japanese ALS patients with and without FTD in order to characterize the full extent of cognitive and behavioral abnormalities, including associations with functional motor status, anxiety and depression. METHODS: Patients were evaluated using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale-Revised, spirometry, and verbal fluency tests. Caregivers were asked to complete the ALS-FTD-Questionnaire (ALS-FTD-Q), a behavioral screen. We defined severe cognitive impairment (MoCA < 21 or FAB < 11), mild impairment (11 ≤ MoCA ≤ 25 or 11 ≤ FAB ≤ 15), and normal cognition (MoCA > 25 or FAB > 15). Severe and mild behavioral impairments and normal behavior were defined by the ALS-FTD-Q scores. RESULTS: In 145 ALS patients, better cognitive scores were correlated with earlier age at onset, whereas a worse behavioral score was associated with a longer disease duration and higher level of anxiety and depression. Around seventy percent of all ALS patients showed mild (40-45%) or severe cognitive impairment with cognitive impairment outnumbering behavioral impairment fivefold. Cognitive functions were more impaired in patients with age of onset over 65 years, while behavioral scores were not related to age. CONCLUSIONS: Considering the high prevalence of in particular cognitive impairment, and the diversity of impairments, the cognitive and behavioral aspects of Japanese ALS patients should be given more attention clinically.

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.

The frontotemporal syndrome of ALS is associated with poor survival.

Thirty percent of ALS patients have a frontotemporal syndrome (FS), defined as behavioral changes or cognitive impairment. Despite previous studies, there are no firm conclusions on the effect of the FS on survival and the use of non-invasive ventilation (NIV) in ALS. We examined the effect of the FS on survival and the start and duration of NIV in ALS. Behavioral changes were defined as >22 points on the ALS-Frontotemporal-Dementia-Questionnaire or ≥3 points on ≥2 items of the Neuropsychiatric Inventory. Cognitive impairment was defined as below the fifth percentile on ≥2 tests of executive function, memory or language. Classic ALS was defined as ALS without the frontotemporal syndrome. We performed survival analyses from symptom onset and time from NIV initiation, respectively, to death. The impact of the explanatory variables on survival and NIV initiation were examined using Cox proportional hazards models. We included 110 ALS patients (76 men) with a mean age of 62 years. Median survival time was 4.3 years (95 % CI 3.53-5.13). Forty-seven patients (43 %) had an FS. Factors associated with shorter survival were FS, bulbar onset, older age at onset, short time to diagnosis and a C9orf72 repeat expansion. The adjusted hazard ratio (HR) for the FS was 2.29 (95 % CI 1.44-3.65, p < 0.001) in a multivariate model. Patients with an FS had a shorter survival after NIV initiation (adjusted HR 2.70, 95 % CI 1.04-4.67, p = 0.04). In conclusion, there is an association between the frontotemporal syndrome and poor survival in ALS, which remains present after initiation of NIV.

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.

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.

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.

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

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.

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 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.