Tom Burke

What does the ALSFRS-R really measure? A longitudinal and survival analysis of functional dimension subscores in amyotrophic lateral sclerosis.

Introduction ALS functional rating scale (revised) (ALSFRS-R) is the most widely used functional rating system in patients with amyotrophic lateral sclerosis (ALS). However, heterogeneity in ALSFRS-R progression renders analysis challenging. We have explored the characteristics of total ALSFRS-R, and ALSFRS-R subscores in longitudinal and survival models, to determine whether subscore analysis enhances the precision of the instrument. Methods All cases with ALSFRS-R scores on the Irish ALS register were included. ALSFRS-R subscores were defined for bulbar, motor and respiratory domains. Longitudinal models were used to visualise fitted total ALSFRS-R and ALSFRS-R subscore progression. In addition, the prognostic value of convenience and computed ALSFRS-R slope and subscore slopes were compared. Results 407 incident cases were identified with a complete ALSFRS-R measure. 233 (57%) patients were male, and 125 (31%) had bulbar-onset disease. ALSFRS-R bulbar and motor subscore slopes provided a better fit in prognostic models when combined over the total ALSFRS-R slope. Longitudinal analysis revealed that the ALSFRS-R motor subscore deteriorated earlier in spinal-onset disease over bulbar-onset disease, while in bulbar-onset disease the ALSFRS-R bulbar subscore deteriorated earlier and faster than in spinal-onset disease. Discussion Our analysis builds on previous knowledge of ALSFRS-R subscores. Decline in ALSFRS-R motor subscores in patients with spinal-onset disease, and decline in ALSFRS-R bulbar subscores in patients with bulbar-onset disease, may predate reported disease onset dates. Respiratory subscores were not prognostically informative after adjustment for bulbar and motor subscores. These results provide robust evidence that the ALSFRS-R should not be reported as a single combined score, but rather as domain specific subscores.

Functional Connectivity Changes in Resting-State EEG as Potential Biomarker for Amyotrophic Lateral Sclerosis.

Background Amyotrophic Lateral Sclerosis (ALS) is heterogeneous and overlaps with frontotemporal dementia. Spectral EEG can predict damage in structural and functional networks in frontotemporal dementia but has never been applied to ALS. Methods 18 incident ALS patients with normal cognition and 17 age matched controls underwent 128 channel EEG and neuropsychology assessment. The EEG data was analyzed using FieldTrip software in MATLAB to calculate simple connectivity measures and scalp network measures. sLORETA was used in nodal analysis for source localization and same methods were applied as above to calculate nodal network measures. Graph theory measures were used to assess network integrity. Results Cross spectral density in alpha band was higher in patients. In ALS patients, increased degree values of the network nodes was noted in the central and frontal regions in the theta band across seven of the different connectivity maps (p<0.0005). Among patients, clustering coefficient in alpha and gamma bands was increased in all regions of the scalp and connectivity were significantly increased (p=0.02). Nodal network showed increased assortativity in alpha band in the patients group. The Clustering Coefficient in Partial Directed Connectivity (PDC) showed significantly higher values for patients in alpha, beta, gamma, theta and delta frequencies (p=0.05). Discussion There is increased connectivity in the fronto-central regions of the scalp and areas corresponding to Salience and Default Mode network in ALS, suggesting a pathologic disruption of neuronal networking in early disease states. Spectral EEG has potential utility as a biomarker in ALS.

A Novel CMKLR1 Small Molecule Antagonist Suppresses CNS Autoimmune Inflammatory Disease.

Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated β-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. α-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof-of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.

Screening for cognitive dysfunction in ALS: validation of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) using age and education adjusted normative data

Abstract Background: Cognitive and behavioural changes are an important aspect in Amyotrophic Lateral Sclerosis (ALS). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) briefly assesses these changes in ALS. Objective: To validate the ECAS against a standardised neuropsychological battery and assess its sensitivity and specificity using age and education adjusted cut-off scores. Method: 30 incident ALS cases were assessed on both, ECAS and neuropsychological battery. Age and education adjusted cut-off scores were created from a sample of 82 healthy controls. Results: ECAS composite scores (Total, ALS Specific and Non-Specific) were highly correlated with battery composite scores. High correlations were also observed between ECAS and full battery cognitive domains and subtests. The ECAS Total, ALS Specific and Non-Specific scores were highly sensitive to cognitive impairment. ECAS ALS-Specific cognitive domains also evidenced high sensitivity. Individual subtest sensitivity was medium to low, suggesting that caution should be used when interpreting these scores. Low positive predictive values indicated the presence of false positives. Conclusions: Psychometric properties of the ECAS using age and education adjusted norms indicate that the ECAS, when used as an overall measure of cognitive decline, is highly sensitive. Further comprehensive assessment is required for patients that present as impaired on the ECAS.

Measurement of Social Cognition in Amyotrophic Lateral Sclerosis: A Population Based Study

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Executive dysfunction is common in patients with ALS, with up to 50% of patients performing within an impaired range. There is evidence that social cognitive deficits associated with ALS are a function of deficits in executive function. The ‘Reading the Mind in the Eyes’ Test is a recognized test of social cognitive function, although the reliability of this instrument remains to be established. Methodology: Patients with ALS (n = 106), and age and IQ matched controls (n = 50) were recruited and asked to perform the Reading the Mind in the Eyes Test as part of an on-going population-based study of cognitive function. ALS patients were sub-stratified based on the presence, and/or extent of executive dysfunction. Results: Cronbach’s Alpha of .73 was observed, indicating good reliability on this measure. Split-half reliability analysis further confirms these findings (p = 0.826). The Reading the Mind in the Eyes test had excellent psychometric properties when discriminating between ALS patients who are cognitively intact, and those who have executive impairment, with an overall medium difficulty. There was a large magnitude significant difference between patients and controls (p< 0.001; η2 = .19). Post-hoc analysis revealed that controls performed significantly higher than patients with executive impairment (p< 0.001), and patients with single executive deficits (p = 0.002). Conclusion: Executive dysfunction impacts on social cognitive performance. This study contributes not only to the psychometric knowledge of this measure, but also to the usability, efficacy, and reliability of social cognitive assessment in ALS. Using population-specific normative data, we confirm the Reading the Mind in the Eyes Test is a reliable measure of social cognitive processes in ALS.

Discordant performance on the ‘Reading the Mind in the Eyes’ Test, based on disease onset in amyotrophic lateral sclerosis

Abstract Executive dysfunction is a core feature of amyotrophic lateral sclerosis (ALS) and is associated with brain atrophy in cortical and subcortical regions. Social cognitive deficits may also be a prominent feature of ALS. This study investigated executive, and social cognitive performance, in a population based cohort of patients with ALS, stratified by disease onset. Participants were recruited as part of a population based study investigating cognitive decline in ALS. Patients carrying pathogenic C9orf72 hexanucleotide repeat were excluded. Participants were stratified based on bulbar (n = 20) or spinal (n = 39) disease onset (n = 59). Matched healthy controls were used to generate culturally specific comparative data for within-patient analyses (n = 59). Results showed that ALS patients performed significantly worse than controls on a number of measures of executive function. When sub-stratified by disease onset, there was a significant difference between bulbar- and spinal-onset patients with respect to the ‘Reading the Mind in the Eyes’ Test scores (p < 0.001). Conversely, standardized scores of executive function did not differ between the patient groups. In conclusion, patients performed significantly worse than matched controls on measures of executive function. Bulbar-onset ALS patients evidenced more social-affective deficits compared to spinal-onset patients, with matched performance on measures of executive function.

Identifying behavioural changes in ALS: Validation of the Beaumont Behavioural Inventory (BBI)

Abstract Objective: Behavioural changes are an important part of amyotrophic lateral sclerosis (ALS). However, most tools do not account for the influence of motor impairment. Furthermore, they do not fully measure the broad range of behavioural changes specific to ALS. This study aimed to develop and validate an ALS specific behavioural inventory, the Beaumont Behavioural Inventory (BBI). Methods: The BBI was validated in a cohort of ALS patients (n = 85) and 78 age-, gender-, and education-matched controls. The scale was validated against the Frontal Systems Behaviour Scale (FrSBe) and The Frontal Assessment Battery (FAB) for convergent validity, and against other non-behavioural measures to assess discriminant validity. Reliability was assessed with Cronbachs alpha. Results: The instrument showed high internal consistency (Cronbach’s alpha value =0.891). BBI scores highly correlated with the FrSBe and moderately with the FAB. However, the measure was independent from non-behavioural measures. Using a cut-off score of 7 for mild behavioural changes, the BBI displayed high sensitivity and specificity (87.9% and 78.85%, respectively). The cut-off score for moderate changes, consistent with a diagnosis of ALS-FTD, is set at 22.5, showing 90% sensitivity and 96% specificity. Discussion: The BBI is a sensitive and specific tool to assess the entire behavioural spectrum of ALS.

Clustering of Neuropsychiatric Disease in First-Degree and Second-Degree Relatives of Patients With Amyotrophic Lateral Sclerosis

Importance Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition primarily involving the motor system. There is increasing epidemiologic evidence of an association between ALS and a wider spectrum of neurodegenerative and neuropsychiatric disorders among family members, including schizophrenia and psychotic illness and suicidal behavior. Objective To examine the frequency and range of neuropsychiatric conditions that occur within individual first-degree and second-degree relatives of patients with ALS. Design, Setting, and Participants In this population-based, case-control family aggregation study, all 202 patients included in the Irish ALS Register between January 1, 2012, and January 31, 2014, with definite, probable, or possible ALS as defined by El Escorial criteria were invited to participate. A total of 75 patients were unable or refused to participate and were excluded; the remaining 127 patients with incident ALS were genotyped for the C9orf72 repeat expansion and 132 age- and sex-matched controls were included in the study. Main Outcome and Measures The prevalence of defined neuropsychiatric disease in first-degree and second-degree relatives of patients with ALS and matched controls was determined. Results Mean (SD) age at diagnosis of the 127 patients in the study (58 women and 69 men) was 64.2 (10.7) years. Data from 2116 relatives of patients with ALS were reported, including 924 first-degree relatives, 1128 second-degree relatives, and 64 third-degree relatives. Data from controls were reported from 829 first-degree and 1310 second-degree relatives. A total of 77 patients with ALS (61.4%) and 51 control participants (38.6%) reported at least 1 first-degree or second-degree relative with a history of schizophrenia, psychosis, suicide, depression, alcoholism, or autism (relative risk [RR], 1.50; 95% CI, 1.08-2.17; P = .02). Cluster analysis suggested the following 2 subgroups based on the number of family members with a neuropsychiatric condition: expected (0-2) and high (≥3). Within the high subgroup, ALS kindreds presented a significantly higher rate of psychiatric illness than did controls (28 of 39 [71.8%]; mean [SD] number of siblings, 4.29 [1.41]; P = .001). A strong family history of schizophrenia (RR, 3.40; 95% CI, 1.27-9.30; P = .02), suicide (RR, 3.30; 95% CI, 1.07-10.05; P = .04), autism (RR, 10.10; 95% CI, 1.30-78.80; P = .03), and alcoholism (RR, 1.48; 95% CI, 1.01-2.17; P = .045) was reported in ALS kindreds. A total of 5 of 29 probands (17.2%) with a strong family history of neuropsychiatric conditions (≥3 first-degree or second-degree relatives) carried the C9orf72 repeat expansion. Conclusions and Relevance Neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS kindreds than in controls. The presence of the C9orf72 repeat expansion does not fully account for this finding, suggesting the presence of additional pleiotropic genes associated with both ALS and neuropsychiatric disease in the Irish population.

A Cross-sectional population-based investigation into behavioral change in amyotrophic lateral sclerosis: subphenotypes, staging, cognitive predictors, and survival

Amyotrophic Lateral Sclerosis (ALS) is a clinically heterogeneous neurodegenerative disorder associated with cognitive and behavioral impairment. The primary aim of this study was to identify behavioral subphenotypes in ALS using a custom designed behavioral assessment tool (Beaumont Behavioural Inventory, BBI). Secondary aims were to (1) investigate the predictive nature of cognitive assessment on behavioral change, (2) report the behavioral profile associated with the C9orf72 expansion, (3) categorize behavioral change through disease staging, and (4) to investigate the relationship between cross‐sectional behavioral classification and survival.

Visual encoding, consolidation, and retrieval in amyotrophic lateral sclerosis: executive function as a mediator, and predictor of performance

Abstract Objective: This study aimed to illustrate the variation of non-executive cognitive processes, i.e. visual memory, considering executive dysfunction in amyotrophic lateral sclerosis (ALS). Methods: Patients with ALS (n = 203), and matched healthy controls (n = 117) completed a battery of neuropsychological tests. Sub-stratification was based on whether cognitive assessment detected no cognitive abnormalities (NCA: n = 117), multiple executive cognitive deficits (ALS-Exec; n = 56), or a comorbid frontotemporal dementia process (ALS-FTD; n = 30). The Rey-Osterrieth Complex Figure Test (ROCFT) was the main dependent variable for visual memory in this study. Results: Patients and controls significantly differed on the Copy trial (p < 0.0001: ω2 = 0.317) immediate recall (p < 0.0001: ω2 = 0.272) and delayed recall (p < 0.0001: ω2 = 0.308) of the ROCFT. Sub-stratification based on executive dysfunction revealed an association with greater executive dysfunction and lower ROCFT performance. Regression analysis predicted that premorbid IQ, executive function, and demographics predict performance on the ROCFT delayed recall trial (R2 = 0.833). Conclusions: These findings illustrate that patients without executive dysfunction do not show visual memory impairments within this cohort; that patients with executive dysfunction have poorer performance on visual memory tasks; and that the severity of executive dysfunction, as per cognitive categorisation, is related to increased visual memory impairment as tested with the ROCFT.