A Computational Study of Executive Dysfunction in Amyotrophic Lateral Sclerosis

Executive dysfunction is a well-documented, yet nonspecific corollary of various neurological diseases and psychiatric disorders. Here, we applied computational modeling of latent cognition for executive control in amyotrophic lateral sclerosis (ALS) patients. We utilized a parallel reinforcement learning model of trial-by-trial Wisconsin Card Sorting Test (WCST) behavior. Eighteen ALS patients and 21 matched healthy control participants were assessed on a computerized variant of the WCST (cWCST). ALS patients showed latent cognitive symptoms, which can be characterized as bradyphrenia and haphazard responding. A comparison with results from a recent computational Parkinson’s disease (PD) study (Steinke et al., 2020, J Clin Med) suggests that bradyphrenia represents a disease-nonspecific latent cognitive symptom of ALS and PD patients alike. Haphazard responding seems to be a disease-specific latent cognitive symptom of ALS, whereas impaired stimulus-response learning seems to be a disease-specific latent cognitive symptom of PD. These data were obtained from the careful modeling of trial-by-trial behavior on the cWCST, and they suggest that computational cognitive neuropsychology provides nosologically specific indicators of latent facets of executive dysfunction in ALS (and PD) patients, which remain undiscoverable for traditional behavioral cognitive neuropsychology. We discuss implications for neuropsychological assessment, and we discuss opportunities for confirmatory computational brain imaging studies.

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Hippocampal connectivity in Amyotrophic Lateral Sclerosis (ALS): more than Papez circuit impairment

Brain Imaging and Behavior ◽

10.1007/s11682-020-00408-1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Francesca Trojsi ◽

Federica Di Nardo ◽

Giuseppina Caiazzo ◽

Mattia Siciliano ◽

Giulia D’Alvano ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Visual Memory ◽

Diffusion Tensor ◽

Digit Span ◽

Structural Connectivity ◽

Executive Dysfunction ◽

Functional Changes ◽

Papez Circuit ◽

Als Patients ◽

Lateral Sclerosis

Abstract Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p < .05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures.

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Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement

Diagnostics ◽

10.3390/diagnostics11040624 ◽

2021 ◽

Vol 11 (4) ◽

pp. 624

Author(s):

Robert Rusina ◽

Rik Vandenberghe ◽

Rose Bruffaerts

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Impairment ◽

Frontotemporal Dementia ◽

Clinical Manifestations ◽

Executive Dysfunction ◽

Motor Disorder ◽

Behavioral Impairment ◽

Caregiver Support ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) has long been considered to be a purely motor disorder. However, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is now used in these circumstances. This review is intended to be an overview of the cognitive and behavioral manifestations commonly encountered in ALS patients with the goal of improving case-oriented management in clinical practice. We introduce the principal ALS-FTSD subtypes and comment on their principal clinical manifestations, neuroimaging findings, neuropathological and genetic background, and summarize available therapeutic options. Diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestations, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment. Cognitive impairment is found in up to 65%, while frank dementia affects about 15% of ALS patients. ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved. Dementia can precede or develop after the appearance of motor symptoms. ALS-FTSD patients have a worse prognosis and shorter survival rates than patients with ALS or frontotemporal dementia alone. Important negative prognostic factors are behavioral and personality changes. From the clinician’s perspective, there are five major distinguishable ALS-FTSD subtypes: ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, fully developed frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease. Although the most consistent ALS and ALS-FTSD pathology is a disturbance in transactive response DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein metabolism have also been observed in ALS-FTSD. Early detection and careful monitoring of cognitive deficits in ALS are crucial for patient and caregiver support and enable personalized management of individual patient needs.

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Neuropsychological deficits in amyotrophic lateral sclerosis (ALS): a South India experience

Neuropsychological Trends ◽

10.7358/neur-2013-013-raje ◽

2013 ◽

Author(s):

Jamuna Rajeswaran ◽

Atchayaram Nalini

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Deficits ◽

Neuropsychological Test ◽

Executive Dysfunction ◽

Planning Problem ◽

Perceptual Skills ◽

Neuropsychological Profile ◽

Indian Setting ◽

Als Patients ◽

Lateral Sclerosis

ALS is a terminal progressive degenerative neurological disorder studies suggest that approximately 35% to 52% of ALS patients experience cognitive deficits which may be identified early in the course of the disease. Cognitive deficits being the integral part of the disease has not been studied in the Indian setting. This is one of the first studies assessing the pattern of cognitive impairment in ALS in the Indian condition. The objective is to examine the neuropsychological profile of amyotrophic lateral sclerosis. Cognitive function was studied in 20 ALS patients: mean age 45.85 13.9 years (22- 65). Neuropsychological test battery was administered. In all 21 test were administered individually in 4-5 sessions which lasted for 7-8 hours. The results show that the majority of patients were from lower/middle socio-economic background. Scores were compared with gender, age and education specific norms, wherein scores falling below 15th percentile of the normative data were treated as deficits. ALS-associated cognitive impairments include deficiencies in visual attention, working memory, fluency, cognitive flexibility, response inhibition, planning, problem solving, and visual-perceptual skills. These impairments indicate executive dysfunction. In conclusion ALS is a disease that affects higher cognitive frontal functions, especially the EF.

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The Cognitive and Behavioural Profile of Amyotrophic Lateral Sclerosis: Application of the Consensus Criteria

Behavioural Neurology ◽

10.1155/2013/126010 ◽

2013 ◽

Vol 27 (2) ◽

pp. 143-153 ◽

Cited By ~ 35

Author(s):

Monica Consonni ◽

Sandro Iannaccone ◽

Chiara Cerami ◽

Paola Frasson ◽

Marco Lacerenza ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Short Term Memory ◽

Executive Dysfunction ◽

Cognitively Impaired ◽

Action Naming ◽

Cognitive Behavioural ◽

Behavioural Profile ◽

Als Patients ◽

The Impact ◽

Lateral Sclerosis

Objective:The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteria [9]. The study also intends to assess the impact of physical disability on cognitive and behavioural abnormalities.Methods:Detailed neurological, neuropsychological and neurobehavioral evaluations were administered to 23 ALS patients, 11 Lower Motor Neuron Disease (LMND) patients and 39 healthy controls. Strong et al.’s criteria [9] were applied to diagnose the presence of cognitive/behavioural impairment. Clinical and neuropsychological scores were used for group comparisons and correlation analyses.Results:In comparison with LMND and controls, a subgroup of ALS patients (∼30%) manifested executive dysfunction, which was severe enough to classify them as cognitively impaired. Action naming difficulties and short-term memory deficits were also observed. Aspontaneity, disorganization and mental rigidity reached clinical relevance in 20% of ALS patients. A small percentage of ALS patients (13%) also had comorbid dementia. The cognitive or behavioural status was not related to the clinical features of ALS.Conclusion:The use of consensus criteria for cognitive and behavioural impairment and the comparison with the LMND group proved useful in defining the spectrum of non-motor manifestations of ALS.

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Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

Current Neurovascular Research ◽

10.2174/1567202617666200409125227 ◽

2020 ◽

Vol 17 (3) ◽

pp. 275-285 ◽

Cited By ~ 5

Author(s):

Si Chen ◽

Qiao Liao ◽

Ke Lu ◽

Jinxia Zhou ◽

Cao Huang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rat Model ◽

Microglial Activation ◽

Transgenic Rat ◽

Intragastric Administration ◽

Behavioral Deficits ◽

Als Patients ◽

Lateral Sclerosis ◽

Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

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Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200583 ◽

2021 ◽

pp. 1-5

Author(s):

João Morgadinho ◽

Ana Catarina Pronto-Laborinho ◽

Vasco A. Conceição ◽

Marta Gromicho ◽

Susana Pinto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Creatinine Level ◽

Cox Regression ◽

Functional Decline ◽

Plasma Creatinine ◽

Plasma Creatinine Level ◽

Decline Rate ◽

Respiratory Outcome ◽

Als Patients ◽

Lateral Sclerosis

In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, or their decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

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Coping strategies among amyotrophic lateral sclerosis (ALS) patients: an integrative review

Journal of Neurology ◽

10.1007/s00415-021-10472-2 ◽

2021 ◽

Author(s):

Georgiana Soares Leandro ◽

Mário Emílio Teixeira Dourado Júnior ◽

Glauciane Costa Santana ◽

Luan Samy Xavier Dantas

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Coping Strategies ◽

Integrative Review ◽

Als Patients ◽

Lateral Sclerosis

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Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

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Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

Brain Sciences ◽

10.3390/brainsci11070906 ◽

2021 ◽

Vol 11 (7) ◽

pp. 906

Author(s):

Nimeshan Geevasinga ◽

Mehdi Van den Bos ◽

Parvathi Menon ◽

Steve Vucic

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Excitability ◽

Muscular Atrophy ◽

Close Relationship ◽

Bulbar Onset ◽

Als Patients ◽

Transcranial Magnetic Simulation ◽

Cortical Dysfunction ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

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Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽

10.3390/diagnostics11071210 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1210

Author(s):

Júlia Costa ◽

Marta Gromicho ◽

Ana Pronto-Laborinho ◽

Conceição Almeida ◽

Ricardo A. Gomes ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Motor Neurons ◽

Neurological Diseases ◽

Disease Diagnosis ◽

Enzyme Linked Immunosorbent Assay ◽

Progression Rate ◽

Therapeutic Trials ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

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