Behavioural Amyotrophic Lateral Sclerosis Screen Research Articles

An exploratory study on counterfactual thinking in amyotrophic lateral sclerosis.

This study aimed at exploring (1) the motor and non-motor correlates of counterfactual thinking (CFT) abilities in non-demented amyotrophic lateral sclerosis (ALS) patients and (2) the ability of CFT measures to discriminate these patients from healthy controls (HCs) and patients with and without cognitive impairment. N = 110 ALS patients and N = 51 HCs were administered two CFT tasks, whose sum, resulting in a CFT Index (CFTI), was addressed as the outcome. Patients further underwent an in-depth cognitive, behavioral, and motor-functional evaluation. Correlational analyses were run to explore the correlates of the CFTI in patients. Logistic regressions were performed to test whether the CFTI could discriminate patients from HCs. The CFTI was selectively associated (p ≤ 0.005) with fluency and memory subscales of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), but not with other variables. CFTI scores discriminated patients from HCs (p < 0.001) with high accuracy (82%), but not patients with a normal vs. defective performance on the ECAS-Total. CFT measures in non-demented ALS patients were associated with verbal fluency and memory functions, and they were also able to discriminate them from HCs.

Frontotemporal-spectrum disorders and functional independence in non-demented ALS patients

BackgroundThe present study aimed at determining whether, net of motor confounders, neuropsychological features affect functional independence (FI) in activities of daily living (ADLs) in non-demented amyotrophic lateral sclerosis (ALS) patients.MethodsN = 88 ALS patients without frontotemporal dementia were assessed for FI—Katz’s Basic ADL Scale (BADL) and Lawton-Brody’s Instrumental ADL Scale (IADL)—, cognition—Edinburgh Cognitive and Behavioural ALS Screen (ECAS)—and behaviour—Beaumont Behavioural Inventory and Dimensional Apathy Scale. The association between cognitive and behavioural measures and BADL/IADL scores was assessed by covarying for demographics, anxiety and depression levels, disease duration and motor confounders—i.e. ALS Functional Rating Scale-Revised (ALSFRS-R) scores, progression rate and both King’s and Milano-Torino stages.ResultsHigher scores on the ECAS-Language were associated with higher IADL scores (p = 0.005), whilst higher apathetic features—as measured by the Dimensional Apathy Scale (DAS)—were inversely related to the BADL (p = 0.003). Whilst IADL scores were related to all ECAS-Language tasks, the DAS-Initiation was the only subscale associated with BADL scores. Patients with abnormal ECAS-Language (p = 0.023) and DAS (p = 0.008) scores were more functionally dependent than those without.DiscussionAmong non-motor features, language changes and apathetic features detrimentally affect FI in non-demented ALS patients.

Validity and reliability measures of the Swedish Karolinska version of the Edinburgh Cognitive and Behavioral ALS Screen (SK-ECAS)

Objective Cognitive and behavioral impairment is observed in up to 50% of patients with amyotrophic lateral sclerosis (ALS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) is a 5-domain screening tool customized for quick cognitive screening in patients with ALS. Although the ECAS is available in Swedish at the Karolinska University Hospital (SK-ECAS), it has not yet been validated in Sweden stressing the need to assess validity and reliability of the SK-ECAS Version A. Methods The study included 176 patients with ALS or other motor neuron disease diagnosed between September 2017 and October 2021 at the Karolinska ALS Clinical Research Center in Stockholm, Sweden, and 35 age-matched healthy control subjects. SK-ECAS was validated against the Montreal Cognitive Assessment (MoCA) and optimal cutoffs, receiver operating characteristic (ROC) curve and area under the curve (AUC) were calculated. Results We identified an optimal cutoff of 108 for the SK-ECAS total score and 82 for the SK-ECAS ALS-specific score to detect cognitive impairment. The SK-ECAS showed good performance in indicating abnormal cognition with an AUC of 0.73 for SK-ECAS ALS-specific score and 0.77 for SK-ECAS total score. There was good internal consistency with a Cronbach’s alpha of 0.79. Conclusions This study demonstrates good validity and reliability indices for SK-ECAS Version A for the detection of cognitive impairment in newly diagnosed ALS patients.

Examining the validity and reliability of the Persian version of the MiND-B questionnaire in ALS patients.

In addition to affecting the nerves and muscles, amyotrophic lateral sclerosis (ALS) disease also affects the behavior and cognition of patients. In this study, we examine the validity and reliability of the Persian version of Motor Neuron Disease Behavioral instrument (MiND-B) questionnaire to investigate behavioral changes in Persian-speaking ALS patients. Forty-six Persian-speaking patients with ALS filled out the MiND-B questionnaire. Then, the overall scores and each of the domains of this questionnaire were statistically analyzed. Cronbach's alpha coefficient was calculated .70 for the whole questionnaire. To check the validity of the questionnaire, the correlation of its scores with the Edinburgh Cognitive and Behavioral ALS screen (ECAS-A) questionnaire was taken, and this correlation was significant (p=.038). The findings of this study show that the Persian version of the MiND-B questionnaire has the necessary validity and reliability to investigate behavioral changes in Persian-speaking patients with ALS.

Norwegian version of the Edinburgh cognitive and behavioural ALS screen: Construct validity, internal consistency, inter-rater, and test-retest reliability.

Research collaboration highlight a need for validated tests in other languages than English. Translation and culture adjustments may threaten essential features of the original instrument. To assess the internal consistency, inter-rater and test-retest reliability, and construct validity of the Norwegian version of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen (ECAS-N). Performance of 71 subjects with ALS, 85 healthy controls (HC) and 6 controls with Alzheimer's disease (AD) were assessed with the ECAS-N. Test-retest interval was four months. Internal consistency was evaluated using Cronbach's alpha; reliability was assessed using intraclass correlation coefficient (ICC), Cohen's kappa, and Bland Altman plot. Five hypothesis, including the Montreal Cognitive Assessment (MoCA) screen, was evaluated for construct validity. ECAS-N total score produced a Cronbach's alpha of 0.65, had excellent inter-rater reliability (ICC = 0.99) and acceptable test-retest reliability (ICC = 0.73). Construct validity analysis suggested valid use of the ECAS-N to distinguish people with ALS-specific cognitive impairment from HC (p = 0.001) and those with AD (p = 0.002). The MoCA and ECAS-N were moderately correlated (r = 0.53). The ECAS-N has potential to be used by different testers in clinical practice and research to screen patients with ALS who speak Norwegian and for documenting cognitive impairment over time.

Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis.

Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. The aim of our study was to assess if: (i) the burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; (ii) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); and (iii) specific clinical features may help identify ALS subtypes, which remain localized to the site of onset for a prolonged time (regionally entrenching ALS). A single-centre, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype. All patients underwent an extensive evaluation including the following clinical scales: Penn Upper Motor Neuron Score (PUMNS), MRC Scale for Muscle Strength and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The most frequent initial spreading pattern was that towards adjacent horizontal regions (77.3%), which occurred preferentially in patients with lower MRC scores (P = 0.038), while vertical diffusion (21.1%) was associated with higher PUMNS (P < 0.001) and with reduced survival (P < 0.001). Non-contiguous disease spreading was associated with more severe UMN impairment (P = 0.003), while contiguous disease pattern with lower MRC scores. Furthermore, non-contiguous disease spreading was associated with more severe cognitive impairment in both executive and visuospatial ECAS domains. Individuals with regionally entrenching ALS were more frequently female (45.6% versus 36.9%; P = 0.028) and had higher frequencies of symmetric disease onset (40.3% versus 19.7%; P < 0.001) and bulbar phenotype (38.5% versus 16.4%; P < 0.001). Our study suggests that motor phenotypes characterized by a predominant UMN involvement are associated with a vertical pattern of disease progression reflecting ipsilateral spreading within the motor cortex, while those with predominant LMN involvement display more frequently a horizontal spreading from one side of the spinal cord to the other. These observations raise the hypothesis that one of the mechanisms underlying disease spreading in ALS pathology is represented by diffusion of toxic factors in the neuron microenvironment. Finally, it is possible that in our cohort, regionally entrenching ALS forms are mainly observed in patients with atypical bulbar phenotypes, characterized by a slowly progressive course and relatively benign prognosis.

Clinical usability of the Story-Based Empathy Task (SET) in non-demented ALS patients.

This study aimed at assessing the clinical usability of the Story-Based Empathy Task (SET) in non-demented amyotrophic lateral sclerosis (ALS) patients. N = 106 non-demented ALS patients and N = 101 healthy controls (HCs) were administered the SET, which includes three subtests assessing Emotion Attribution (SET-EA), Intention Attribution (SET-IA) and causal inference (SET-CI) - the latter being a control task. Patients also underwent the Reading the Mind in the Eyes Test (RMET), the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and a thorough behavioural and motor-functional evaluation. The diagnostics of the SET-EA and -IA were tested against a defective performance on the RMET. The association between SET subtests and cognitive/behavioural outcomes was examined net of demographic and motor-functional confounders. Case-control discrimination was explored for each SET subtest. Demographically adjusted SET-EA and -IA scoresaccurately detected defective RMET performances at the optimal cutoffs of <3.04 (AUC = .84) and <3.61 (AUC = .88), respectively. By contrast, the SET-CI performed poorly in doing so (AUC = .58). The SET-EA converged with the RMET, as well as with ECAS-Executive and -Memory scores, whilst the SET-IA was unrelated to cognitive measures (including the RMET); the SET-CI was related to the ECAS-Language the ECAS-Executive. SET subscores were unrelated to behavioural outcomes. Only the SET-EA discriminated patients from HCs. The SET as a whole should not be addressed as a social-cognitive measure in this population. At variance, its subtest tapping on emotional processing - i.e., the SET-EA - is recommended for use as an estimate of social-cognitive abilities in non-demented ALS patients.

Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis.

The UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial. Genotype data of the UNC13A rs12608932 SNP (A-major allele; C-minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) - Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models. The rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33-0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (-11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered. Overall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement.

Development and Validation of the Korean Version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS-K).

Cognitive and behavioral changes are common in amyotrophic lateral sclerosis (ALS), with about 15% of patients presenting with overt frontotemporal dementia and 30%-50% with varying degrees of impairments. We aimed to develop and validate the Korean version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS-K), a brief multidomain assessment tool developed for ALS patients with physical disability. We developed the ECAS-K according to the translation guidelines, and administered it to 38 patients with ALS and 26 age- and education-level-matched controls. We also administered the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB) to investigate convergent validity, and the Center for Neurologic Study-Liability Scale to assess the association between pseudobulbar affect and cognitive/behavioral changes. Internal consistency among the ECAS-K test items was found to be high, with a Cronbach's alpha of 0.87. Significant differences were found between patients with ALS and the controls in language, fluency, and memory functions (p<0.05). Abnormal performance based on the ECAS total score was noted in 39.4% of patients, and 66.6% presented behavioral changes in at least one domain. Significant correlations were observed between the scores of the ECAS-K and those of other cognitive screening tools (MoCA and FAB, with correlation coefficients of 0.69 and 0.55, respectively; p<0.01). We developed and validated the ECAS-K which could be used as an effective tool to screen the cognitive and behavioral impairments in Korean patients with ALS.

Gut microbiota links with cognitive impairment in amyotrophic lateral sclerosis: a multi-omics study.

Recently, cognitive impairments (CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis (ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current study, we explored the role of gut microbiota in CI of ALS patients. We collected fecal samples from 35 ALS patients and 35 healthy controls. The cognitive function of the ALS patients was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen. We analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted (bile acids) metabolite mapping between patients with CI and patients with normal cognition (CN). We found altered gut microbial communities and a lower ratio of Firmicutes/ Bacteroidetes in the CI group, compared with the CN group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the CI group, compared with the CN group. These metabolites were mapped to the metabolic pathways associated with bile acids. We further found that cholic acid and chenodeoxycholic acid were significantly lower in the CI group than in the CN group. In conclusion, we found that the gut microbiota and its metabolome profile differed between ALS patients with and without CI and that the altered bile acid profile in fecal samples was significantly associated with CI in ALS patients. These results need to be replicated in larger studies in the future.

The quality of life and depression in primary caregivers of patients with amyotrophic lateral sclerosis is affected by patient-related and culture-specific conditions

Objective: To analyze the quality of life (QoL) and frequency of depression in primary caregivers of patients with amyotrophic lateral sclerosis (ALS) in two neighboring European countries. Methods: a cross-sectional study performed in 164 dyads of ALS patients and caregivers followed at clinical ALS centers in Poland and Germany between 2015 and 2018. The quality of life (Anamnestic Comparative Self-Assessment - ACSA, Quality of Life in Life-Threatening Illness - Family Carer Version - QOLLTI-F) and depression (ALS-Depression-Inventory 12-Items - ADI-12) of the caregivers was assessed and correlated with caregivers- and patient-related factors. Patient’s clinical status was assessed by ALS Functional Rating Scale – revised and the Behavioral Score of the Edinburgh Cognitive and Behavioral ALS Screen. Results: the caregivers reported a positive QoL associated with functional and behavioral status of the patient, disease duration and caregivers’s depression The most impaired domains of the QoL differed depending on the country of provenance, cultural background and/or social support of the caregivers. Depression was present in 1/3 of the caregivers and was significantly more frequent in the Polish group. It positively correlated with female gender, disease duration, sleep disturbances and functional decline. Both QoL and mood were significantly lower in the caregivers more burdened with the functional care of the patients. Conclusions: the wellbeing of caregivers of ALS patients is affected by patient-related and culture-specific conditions. Understanding the needs and background of psychological adaptation of the caregivers from various countries may translate into better QoL and local patient care.

Prevalence and determinants of language impairment in non-demented amyotrophic lateral sclerosis patients.

This study aimed at estimating the prevalence of language impairment (LI) in a large, clinic-based cohort of non-demented amyotrophic lateral sclerosis (ALS) patients and assessing its underpinnings at motor and non-motor levels. Non-demented ALS patients (N=348) underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as well as an assessment of behavioural/psychiatric and motor-functional features. The prevalence of LI was estimated based on the proportion of patients showing a performance below the age- and education-adjusted cut-off on the ECAS-Language. Multiple regression models were run to assess the determinants of language functioning and impairment. The prevalence of LI was 22.7%. 46.6% of the variance of ECAS-Language scores remained unexplained, with only the ECAS-Executive positively predicting them (p < 0.001; η2 =0.07). Similarly, only a lower score on the ECAS-Executive predicted a higher probability of a below cut-off ECAS-Language performance (p < 0.001). Spelling and Naming tasks were the major drivers of ECAS-Language performance. This study suggests that, in non-demented ALS patients, LI occurs in ≈23% of cases, is significantly driven by executive dysfunction but, at the same time, partially independent of it and is not associated with other motor or non-motor features.

Cognitive and behavioral changes in amyotrophic lateral sclerosis

BACKGROUND. Amyotrophic lateral sclerosis (ALS) is not limited only to motor impairment, and can also manifest with cognitive and behavioral disorders. Currently these presentations of ALS are unrecognized. Hence the research of ALS variants with cognitive and behavioral impairments is necessary.&#x0D; AIM. To study the frequency and clinical characteristics of ALS variants with cognitive and behavioral impairments.&#x0D; MATERIAL AND METHODS. The patients were recruited in 20202021. All patients with definite and possible ALS according to El Escorial criteria were included. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) was used to assess cognitive and behavioral changes. 44 patients, 26 males and 18 females, aged 39 to 77 years (median of age 61 years, interquartile range 53.574.5). Statistical analysis was performed using IBM SPSS Statistics 21. Continuous data were analyzed using the MannWhitney test, categorical data was analyzed by exact Fisher criteria. A p-value less than 0.05 was statistically significant.&#x0D; RESULTS. In 43.2% of patients cognitive and/or behavioral changes were observed. The majority of patients (approximately 20%) suffered from a variant of ALS with cognitive impairment, which was mostly presented with executive and social cognitive dysfunction. ALS with behavioral impairment was observed at 9% of patients, which mostly presented with apathy and disinhibition. A combination of cognitive and behavioral impairment was registered in 7% of patients. In another 7% of patients severity of cognitive and behavioral impairment reached a degree of dementia and corresponded to frontotemporal degeneration.&#x0D; CONCLUSION. This cognitive and behavioral impairment is observed in a substantial number of patients with ALS and mostly presented with moderate executive and social cognitive dysfunction, as well as apathy and less often disinhibition.

Validity and diagnostics of the Reading the Mind in the Eyes Test (RMET) in non-demented amyotrophic lateral sclerosis (ALS) patients.

The aim of this study was to explore the construct validity and diagnostic properties of the Reading the Mind in the Eyes Test (RMET) in non-demented patients with amyotrophic lateral sclerosis (ALS). A total of 61 consecutive patients and 50 healthy controls (HCs) were administered the 36-item RMET. Additionally, patients underwent a comprehensive assessment of social cognition via the Story-Based Empathy Task (SET), which encompasses three subtests targeting Causal Inference, Emotion Attribution (SET-EA), and Intention Attribution (SET-IA), as well as global cognitive [the Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and behavioral screening [the Frontal Behavioral Inventory (FBI); the Dimensional Apathy Scale (DAS); the Beck Depression Inventory (BDI); and the State and Trait Anxiety Inventory-Y]. The construct validity of the RMET was tested by regressing it within a stepwise model that encompassed as predictors the abovementioned cognitive and behavioral measures, covarying for demographic and motor confounders. Receiver-operating characteristics (ROC) analyses allowed exploring intrinsic and post-test properties of the RMET both in discriminating patients from HCs and in identifying patients with a defective SET-EA performance. The RMET was solely predicted by the SET-EA (p = 0.003) and SET-IA (p = 0.005). RMET scores showed high accuracy both in discriminating patients from HCs (AUC = 0.81) and in identifying patients with a defective SET-EA score (AUC = 0.82), with adequate-to-optimal both intrinsic and post-test properties. The RMET is a convergently and divergently valid measure of affective social cognition in non-demented ALS patients, also featuring optimal intrinsic and post-test diagnostic properties in both case-control and case-finding scenarios.

CSF p-tau as a potential cognition impairment biomarker in ALS.

Cerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear. The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them. CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software. Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment. The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS.

Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex

Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE +ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition.

Clinical and Metabolic Signature of UNC13A rs12608932 Variant in Amyotrophic Lateral Sclerosis.

Background and ObjectivesTo characterize the clinical and cognitive behavioral phenotype and brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene.MethodsThe study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent 18F-FDG-PET.ResultsThe C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18–2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33–3.92; A/A + C/C: 2.90 years, IQR 1.74–5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain 18F-FDG-PET extending to frontal and precentral areas of the right hemisphere.DiscussionC/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on 18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.

MRI Clustering Reveals Three ALS Subtypes With Unique Neurodegeneration Patterns.

The purpose of this study was to identify subtypes of amyotrophic lateral sclerosis (ALS) by comparing patterns of neurodegeneration using brain magnetic resonance imaging (MRI) and explore their phenotypes. We performed T1-weighted and diffusion tensor imaging in 488 clinically well-characterized patients with ALS and 338 control subjects. Measurements of whole-brain cortical thickness and white matter connectome fractional anisotropy were adjusted for disease-unrelated variation. A probabilistic network-based clustering algorithm was used to divide patients into subgroups of similar neurodegeneration patterns. Clinical characteristics and cognitive profiles were assessed for each subgroup. In total, 512 follow-up scans were used to validate clustering results longitudinally. The clustering algorithm divided patients with ALS into 3 subgroups of 187, 163, and 138 patients. All subgroups displayed involvement of the precentral gyrus and are characterized, respectively, by (1) pure motor involvement (pure motor cluster [PM]), (2) orbitofrontal and temporal involvement (frontotemporal cluster [FT]), and (3) involvement of the posterior cingulate cortex, parietal white matter, temporal operculum, and cerebellum (cingulate-parietal-temporal cluster [CPT]). These subgroups had significantly distinct clinical profiles regarding male-to-female ratio, age at symptom onset, and frequency of bulbar symptom onset. FT and CPT revealed higher rates of cognitive impairment on the Edinburgh cognitive and behavioral ALS screen (ECAS). Longitudinally, clustering remained stable: at 90.4% of their follow-up visits, patients clustered in the same subgroup as their baseline visit. ALS can manifest itself in 3 main patterns of cerebral neurodegeneration, each associated with distinct clinical characteristics and cognitive profiles. Besides the pure motor and frontotemporal dementia (FTD)-like variants of ALS, a new neuroimaging phenotype has emerged, characterized by posterior cingulate, parietal, temporal, and cerebellar involvement. ANN NEUROL 2022;92:1030-1045.

Executive Dysfunction, Social Cognition Impairment, and Gray Matter Pathology in Myotonic Dystrophy Type 2: A Pilot Study.

In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized. To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2. Eleven genetically confirmed individuals with DM2 and 26 age- and education-matched healthy controls were administered the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) to screen for impairment in multiple cognitive domains. MRI data were evaluated by morphometric analyses to identify disease-specific gray and white matter alterations. The following statistical thresholds were used for cognitive comparisons: PFDR < 0.05 and Bayes factor (BF 10 ) >10. The DM2 group exhibited cognitive impairment (ECAS Total score; PFDR = 0.001; BF 10 = 108.887), which was dominated by executive impairment ( PFDR = 0.003; BF 10 = 25.330). A trend toward verbal fluency impairment was also identified. No significant impairments in memory, language, or visuospatial function were captured. The analysis of subscores revealed severe impairments in social cognition and alternation. Voxel-based morphometry identified widespread frontal, occipital, and subcortical gray matter atrophy, including the left superior medial frontal gyrus, right medial orbitofrontal gyrus, right operculum, right precuneus, bilateral fusiform gyri, and bilateral thalami. DM2 may be associated with multifocal cortical and thalamic atrophy, which is likely to underpin the range of cognitive manifestations mostly characterized by executive impairment and specifically by impaired social cognition.

TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis.

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele).