Impairment In ALS Research Articles

Digital speech markers of cognitive impairment in ALS‐FTD spectrum disorders

AbstractBackgroundComorbid cognitive impairment in amyotrophic lateral sclerosis (i.e., ALS‐FTD), is associated with adverse clinical outcomes and survival. It often exhibits clinical features of behavioral variant frontotemporal dementia (bvFTD) and/or non‐fluent agrammatic primary progressive aphasia (naPPA). Traditional cognitive assessments, such as the Edinburgh Cognitive Assessment Scale (ECAS), require trained personnel for administration. An additional repeatable, objective approach involves automatic analysis of picture descriptions. Prior research identified acoustic and lexical‐semantic impairments in bvFTD, PPAs, and ALS‐FTD (acoustics). This study extends the analysis to the complete speech feature set (n=30) in ALS‐FTD spectrum disorders.MethodANCOVAs (FDR adjusted) compared picture descriptions in n=51 ALS, n=22 ALS‐FTD (n=10 bvFTD‐dominant, n=4 naPPA‐dominant), and n=12 ALS with ECAS‐defined mild cognitive/behavioural impairment (ALS‐MCI). Backward selection identified the best feature subset. Post‐hoc assessments examined associations with ECAS behavioral, language, and executive scores. Longitudinal analysis compared within‐individual change over time in n=11 ALS vs. n=9 ALS+cog (combining ALS‐MCI with ALS‐FTD) with available longitudinal data. All models adjusted for bulbar motor scores.ResultALS‐FTD significantly differed from ALS and ALS‐MCI on twelve features at first visit: slow speaking and articulatory rates, reduced word count, less percent speech time, shorter speech segments, and longer and more frequent pausing. ALS‐FTD also exhibited fewer adjectives and prepositions, more repetitions, lower lexical diversity, and words with a lower mean age of acquisition (AoA). The best model comprising three features (percent speech, prepositions, and lexical diversity) strongly distinguished ALS‐FTD from ALS (AUC=0.90). ALS‐MCI did not differ from ALS on any speech measure. Acoustic measures were all significantly associated with behavioral, language, and executive scores. Fewer prepositions related to worse behavioral and language scores, and more repetitions and lower lexical diversity related to worse language scores. Mean AoA and articulatory rate were not linked to any ECAS sub‐domains. Longitudinally, ALS+cog exhibited increased partial words and reduced word AoA, while ALS showed no significant change.ConclusionAutomated speech analysis strongly distinguishes ALS‐FTD from ALS, declines with cognitive severity, and captures distinctive longitudinal changes in ALS‐FTD. These results highlight the potential of automated speech analysis as an objective tool for assessing cognitive impairment in ALS.

Repeated cognitive assessments show stable function over time in patients with ALS

BackgroundAmyotrophic lateral sclerosis (ALS) is a multisystem disorder with not only motor symptoms but also extra-motor features including cognitive impairment. The most common cognitive profile observed in patients with ALS includes deficits in executive function, language, and social cognition. However, longitudinal studies on cognitive changes over time in ALS are sparse. We aimed to investigate the presence and nature of cognitive impairment at the time of ALS diagnosis and its association with survival as well as explore longitudinal cognitive change.MethodPatients (n = 216) were recruited at the Karolinska University Hospital in Stockholm, Sweden. Follow-up visits (n = 307 in total) were performed every 6 months. Cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and/or Montreal Cognitive Assessment (MoCA).ResultsCognitive impairment was observed in 38% of the patients at the time of ALS diagnosis, and the majority of these patients had deficits in executive function and/or language. Patients with cognitive impairment at the time of diagnosis had a more rapid decline in ALSFRS-R at 12- and 18-months follow-up, and a shorter survival. Cognitive function was stable during the first 2 years after diagnosis, and did not follow the trajectories of decline in motor functions.ConclusionCognitive impairment in ALS was associated with a faster decline of motor functions, and shorter survival. However, cognitive function did not deteriorate over time. Cognitive assessment is essential for the patients and caregivers to understand the phenotypic expression of ALS.

Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

The relationship between ventilatory function and cognitive and behavioral impairment in ALS

Objective: To study the association between ventilatory function and cognitive and behavioral impairment in ALS patients accounting for the effects of pertinent covariates. Methods: Four hundred and eighty-one patients were identified from the Mayo Clinic Florida ALS registry who had concurrent forced vital capacity (FVC) and cognitive and behavioral testing using the ALS Cognitive Behavioral Screen (ALS-CBS). Multiple linear regression analysis was used to study the effects of FVC and relevant covariates on the ALS-CBS cognition score, subscores, and caregiver behavioral inventory. Results: FVC was positively correlated to the cognitive and behavioral subscores on the ALS-CBS (p < 0.001), and the correlation was independent of the effects of site of ALS onset, age, and years of education. Conclusion: Cognitive and behavioral function may be adversely affected by ventilatory impairment in ALS. The presence of cognitive and behavioral impairment warrants a detailed assessment of ventilatory function.

Lateralization of Motor Damage Influences the Features of Cognitive Impairment in ALS. (2519)

Lateralization of Motor Damage Influences the Features of Cognitive Impairment in ALS. (2519)

Strategy for screening cognitive impairment in Chinese patients with amyotrophic lateral sclerosis

BackgroundIt is an economical strategy to design a screening method to decide which patients with amyotrophic lateral sclerosis/ motor neuron disease (ALS/MND) should enter into the stage for further comprehensive neuropsychological investigation. Methods59 patients (including 8 with frank dementia) were recruited. They underwent the extensive neuropsychological evaluation and short screening batteries, namely the Mini-Mental State Examination (MMSE), the Peking Union Medical College Hospital version of Montreal Cognitive Assessment (MoCA-P) and the Frontal Assessment Battery (FAB). Results of the extensive neuropsychological evaluation were set as the gold standard to diagnose cognitive impairment, and the effectiveness of screening tests were measured against them. ResultsBy comparing the sensitivity and specificity, we found that the combination of FAB plus both or either of the other 2 short batteries provided a satisfactorily high sensitivity, but none of these screening batteries was significantly associated with quantitative behavioral measurements among non-demented subjects, the Frontal Behavioral Inventory-ALS version (FBI-ALS). ConclusionsThe combination of the FBI-ALS, the FAB, and the MMSE or the MoCA-P or both could effectively screen comorbid dementia, cognitive and behavioral impairment in ALS but this implicates a limited specificity. And the FAB needed to be validated in large Chinese sample.

Cognitive Syndromes and C9orf72 Mutation Are Not Related to Cerebellar Degeneration in Amyotrophic Lateral Sclerosis.

ObjectiveThe notion that cerebellar pathology may contribute to cognitive impairment in ALS, especially in patients with C9orf72 repeated expansion, has been inconsistently reported. This study aimed exploring the relationship between cerebellar involvement, cognitive impairment and C9orf72 repeated expansion of patients with ALS.MethodsQuantitative in vivo assessment of cerebellar lobules has been investigated in 66 non-demented patients with ALS and 28 healthy controls (HCs). Pathologic C9orf72 repeated expansion was found in 13 patients. Mild cognitive and/or behavioral impairment was diagnosed in 22 C9orf72 negative ALS patients. Measures of cortical volume (CV) and cortical thickness (CT) of cerebellar lobules of all participants were used for Principal Component Analysis (PCA) to identify clusters of lobular measures highly correlated with each other. PCA outcomes were used for between group comparisons and correlation analyses with neuropsychological and clinical features.ResultsDisease severity measured with ALS functional rating scale and index of disease progression rate significantly correlated with CV reduction of the second PCA cluster loading CV measures of anterior lobules. In all patients, cognitive impairment, measured with verbal fluency, was related to CV reduction of the third cluster comprising posterior lobules. No specific cortical thinning or volume reduction of cerebellar clustering patterns could be detected in ALS subgroups.ConclusionOur data show that specific patterns of subregional cerebellar involvement are associated with physical disability or cognitive impairment in ALS, in line with the topographic organization of the cerebellum. However, there was no specific correlation between cerebellar degeneration and cognitive syndromes or C9orf72 mutations.

Validation of the revised classification of cognitive and behavioral impairment in ALS (P1.4-008)

Validation of the revised classification of cognitive and behavioral impairment in ALS (P1.4-008)

The anatomical substrate of bulbar impairment in ALS: insights from multiparametric brainstem imaging, corticobulbar connectivity and somatotopic motor cortex measures (P1.4-004)

The anatomical substrate of bulbar impairment in ALS: insights from multiparametric brainstem imaging, corticobulbar connectivity and somatotopic motor cortex measures (P1.4-004)

The Study of Language in the Amyotrophic Lateral Sclerosis - Frontotemporal Spectrum Disorder: a Systematic Review of Findings and New Perspectives.

Amyotrophic Lateral Sclerosis is a neurodegenerative disorder characterized primarily by motor network disruption. Extra-motor manifestations including executive functions, social cognition, and behavioral changes are now well recognized as important features of ALS, and are associated with frontotemporal and frontostriatal network disruption. However, the presence and characterization of language changes has received less attention. This systematic review characterizes the profile of reported language dysfunction in ALS. PRISMA guidelines were implemented to carry out and report the review. Current evidence suggests that areas of neuroanatomical disruption in ALS spread to language centers such as posterior, inferior frontal and superior temporal areas leading to deficits in word retrieval, syntactic and grammatical processing, and spelling. However, the majority of studies of language in ALS have been limited by the recruitment of small clinic-based prevalent samples and important questions remain regarding the incidence and progression of language impairment in ALS. Further studies from population-based incident cohorts will help to determine the range of language deficits in ALS, and how these relate to previously defined executive and behavioral sub-phenotypes.

Characteristics of semantic impairment in ALS associated with jukujikun

Characteristics of semantic impairment in ALS associated with jukujikun

Primitive reflexes in amyotrophic lateral sclerosis: prevalence and correlates

Identifying frontal impairment in ALS is an important goal albeit disease-dedicated tools are still scarce. For this reason, we decided to consider primitive reflexes (PRs), variably regarded as correlates of frontal release and/or of upper motor neuron (UMN) impairment, often in the setting of dementias. Specifically, the aims of this work consisted in assessing the exact prevalence of the combination of seven PRs in ALS, trying to clarify their role as putative proxies of cognitive impairment or of UMN dysfunction. In this cross-sectional study, 50 consecutive ALS outpatients were evaluated for the presence of: palmomental (PM), corneomandibular (CM), glabella tap (MY), rooting, sucking, snout, and grasping reflexes. Cognitive screening was performed by the Frontal Assessment Battery (FAB) and the Weigl's Sorting test (WST); UMN dysfunction was concomitantly evaluated. PM, CM and MY were more frequently detected (62, 52, and 44 % of the ALS sample, respectively), while the other reflexes were under-represented. Patients displaying three or more PRs had significantly lower FAB and WST scores. On the other hand, UMN dysfunction was only moderately associated to PRs. In conclusion, PRs' assessment is a promising complementary tool for screening cognitive impairment in ALS; however, further work will be necessary to establish its added value with respect to already existing ALS-dedicated screening tools for cognition.

COGNITIVE IMPAIRMENTS IN ALS RELATE TO WHITE MATTER INTEGRITY IN SPECIFIC REGIONS OF INTEREST

ObjectiveCognitive impairment in amyotrophic lateral sclerosis is characterized primarily by deficits in executive functioning, and structural and functional imaging studies have revealed changes in extra-motor areas which are consistent with...

Quality of life and motor impairment in ALS: Italian validation of ALSAQ

Objectives: To evaluate the validity and reliability of the amyotrophic lateral sclerosis assessment questionnaire (ALSAQ) in an Italian cohort of ALS patients and to further characterize the relationship between motor impairment and quality of life (QoL) in ALS.Methods: Seventy-six patients completed the Italian version of ALSAQ-40 and ALSAQ-5. To verify test–retest reliability, 30 patients were revaluated after 3 months. The medical outcome study short form 36 (MOS SF-36) questionnaire and revised ALS functional rating scale (ALSFR-R) scale were used to assess Italian ALSAQ-40 construct validity. The limb muscles' Medical Research Council (MRC) score and forced vital capacity (FVC) were used to measure the degree of motor impairment.Results: The Italian ALSAQ-40 showed a very good internal consistency (all subscales Cronbach's alpha>0.86) and a good construct validity as shown by the patterns of correlation between the subscales and SF-36 (resp. ALSFRS-R) scores. ALSAQ-5 showed a positive correlation with the corresponding ALS patient total score and subscale scores of the ALSAQ-40 (Spearman's correlation coefficient>0.73). The emotional functioning subscale did not correlate with any motor impairment measures.Discussion: Italian ALSAQ-40 and ALSAQ-5 psychometric properties are reliable and similar to those showed by the original English version. We observed emotional aspects to be distinct from physical involvement.

The cognitive profile of amyotrophic lateral sclerosis: A meta-analysis

We aimed to clarify the profile of cognitive impairment in ALS, by meta-analysis of published studies. Criteria for inclusion were: ALS diagnosed according to El Escorial criteria; control group matched for age and education; correction for bias due to motor impairment or dysarthria; no dementia in patients and controls. Effect sizes reflecting a difference in neuropsychological performance between ALS patients and controls were calculated for 12 cognitive domains. The effect of demographic and clinical variables (age, disease duration, site of onset) on cognition was assessed in a moderator analysis. Of 48 eligible articles, 16 studies encompassing 554 ALS patients were included. Significant effect sizes were found for the Mini Mental State Examination (d=0.8), immediate verbal memory (d=0.5), visual memory (d=0.4), fluency (d=0.5), psychomotor speed (d=0.7), language (d=0.5) and executive functioning (d=0.3). The results of the latter three domains are less reliable due to the possibility of publication bias. Psychomotor speed, and to a lesser extent fluency, may have been influenced by motor impairment, despite attempts to correct for motor slowness. In conclusion, the diversity of cognitive problems in ALS seems greater than was previously thought. ALS patients may suffer from cognitive impairment in multiple domains, including memory dysfunction.

A prospective cohort study of neuropsychological test performance in ALS

Our objective was to determine the prevalence and predictors of cognitive impairment in ALS, measure differences in survival among impaired and unimpaired patients, and assess changes in neuropsychological test performance over time. Fifty patients were enrolled in a prospective cohort study of neuropsychological performance. ANOVA and chi(2) tests assessed differences in clinical characteristics and neuropsychologic test results; general estimating equations assessed change in test performance; multiple regression determined which variables contributed to cognitive status; and Cox models compared survival. Thirty-six patients were categorized as cognitively normal, and 14 were impaired. Impaired patients were older at testing (p = 0.024), but no more likely to have bulbar signs. Predicators of impairment were symptom duration (p < 0.001), motor function (p < 0.001), and rate of ALS progression (p < 0.001). The Benton recognition (p < 0.001), Boston naming (p = 0.001), Wisconsin Card Sort (p = 0.001) and word generation (p = 0.001) tests contributed most strongly to cognitive status. Survival was worse in impaired patients (p = 0.027). Over time, only animal word generation declined (p = 0.016). In conclusion, 28% percent of patients were cognitively impaired. Older age and more severe ALS were associated with impairment. The strongest neuropsychological predictors of cognitive status were measures of executive, episodic memory and language function. Cognitively impaired patients had shorter survival time.

Neuropsychological measures in amyotrophic lateral sclerosis and their relationship with CT scan-assessed cerebral atrophy

Twenty-one male patients affected by ALS have been given a short neuropsychological battery and the results have been compared with those obtained by 21 male subjects affected by other non-dementing neurological diseases. Only two ALS patients had definitely low scores on WAIS (performance scale) and on learning tasks, both verbal and spatial, but the ALS group did not differ, on the whole, from the controls. No relationship was observed between cognitive impairment and cerebral atrophy assessed by computerized tomography. The conclusion is suggested that the cognitive impairment in ALS be a discrete, seldom occurring event.

Association between dysarthria and cognitive impairment in ALS: A prospective study

Association between dysarthria and cognitive impairment in ALS: A prospective study

Analysis of extrinsic factors affecting pallestesic threshold (VT) of amyotrophic lateral sclerosis patients.

With the aim of evaluating the occurrence and degree of somatosensory impairment in ALS[l-5] we have assessed a quantitative test of the Vibration Threshold (VT) in healthy subjects and in a group of ALS patients.