Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

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Sympathetic Hyperactivity and Sympathovagal Imbalance in Amyotrophic Lateral Sclerosis

European Neurological Review ◽

10.17925/enr.2013.08.01.46 ◽

2012 ◽

Vol 8 (1) ◽

pp. 46 ◽

Cited By ~ 12

Author(s):

Toshio Shimizu ◽

Keyword(s):

Heart Rate ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Hypertensive Crisis ◽

Individual Treatment ◽

Sympathetic Hyperactivity ◽

Sympathovagal Imbalance ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with progressive loss of upper and lower motor neurons. Autonomic nervous abnormalities, including sympathetic hyperactivity and sympathovagal imbalance, have been found in both early and advanced stages of ALS. In early stage, the dysfunction may be subclinical. Occasionally, elevated blood pressure or heart rate and increased sweating may be observed. In advanced stage when ventilators are required, the sympathetic hyperactivity may lead to hypertensive crisis without counter-regulation of heart rate, followed by the consecutive circulatory collapse, known as the ‘autonomic storm’. The symptoms of ‘autonomic storm’ are similar to that of ‘baroreflex failure’, and ‘autonomic storm’ indicates poor prognosis and may result in sudden death. Careful evaluation and individual treatment are strongly suggested, although appropriate therapeutic approaches have not been established. Causative central nervous lesions remain to be elucidated, although the limbic system may be involved. The autonomic dysfunction further supports the concept that ALS is a multisystem-degenerative disease.

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Practical Measures for Dealing With the Struggles of Nurses Caring for People With Amyotrophic Lateral Sclerosis Comorbid With Cognitive Impairment in Japan

Frontiers in Psychology ◽

10.3389/fpsyg.2021.752461 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mitsuko Ushikubo ◽

Emiko Nashiki ◽

Tadahiro Ohtani ◽

Hiromi Kawabata

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cognitive Impairment ◽

Early Stage ◽

Care Delivery ◽

Care Quality ◽

Daily Lives ◽

Free Writing ◽

Group Interviews ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. This study aimed to explore the situations with which nurses struggled, their implemented practical measures, and the challenges they experienced when caring for patients with ALS comorbid with cognitive impairment (hereinafter, targeted patients). In this qualitative study, we conducted a survey with nurses (n = 121) experienced in caring for ALS patients; the survey contained a free-writing section in which participants described their struggles regarding care delivery for these patients. To collect data on practical measures that nurses had already implemented or wanted to propose regarding care delivery for the targeted patients, we conducted four focus group interviews (n = 22). We used a qualitative inductive approach to extract the categories. Fifty-eight nurses (49.6%) completed the free-writing survey section. The situations in which nurses struggled in care for the targeted patients were organized into three categories: “Patients’ strong persistency on specific requirements for nursing assistance in their daily lives,” “Patients’ problematic behaviors toward nurses,” and “Struggles in communicating with and understanding patients’ wishes.” Nurses reported these situations as stressful, and they affected care quality. The practical measures implemented when caring for the targeted patients were organized into five categories: “Cognitive impairment assessment,” “Care delivery to deal with patients’ strong persistency on specific requirements for assistance in their daily lives,” “Communication,” “Supporting the decision-making process,” and “Collaboration between the hospital and the community.” Multidisciplinary collaboration in the hospital, and collaboration between the hospital and the community from an early stage is necessary to share the results of the assessment and diagnosis of cognitive impairment. Our evidence underlines that guideline and care manual establishment may lead to improved care delivery and to the unification of care deliveries to respond to patients’ strong persistency.

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Utility of phrenic nerve ultrasound in amyotrophic lateral sclerosis

Acta Neurologica Belgica ◽

10.1007/s13760-020-01531-y ◽

2020 ◽

Author(s):

Cezar Thomas Suratos ◽

Naoko Takamatsu ◽

Hiroki Yamazaki ◽

Yusuke Osaki ◽

Tatsuya Fukumoto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Phrenic Nerve ◽

Rating Scale ◽

Neurodegenerative Disorder ◽

Pulmonary Function Tests ◽

Cross Sectional ◽

The Right ◽

Als Patients ◽

Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the upper and lower motor neurons causing progressive weakness. It eventually involves the diaphragm which leads to respiratory paralysis and subsequently death. Phrenic nerve (PN) conduction studies and diaphragm ultrasound has been studied and correlated with pulmonary function tests in ALS patients. However, PN ultrasonography has not been employed in ALS. This study aims to sonographically evaluate the morphologic appearance of the PN of ALS patients. Thirty-eight ALS patients and 28 normal controls referred to the neurophysiology laboratory of two institutions were retrospectively included in the study. Baseline demographic and clinical variables such as disease duration, ALS Functional Rating Scale-Revised score, and ALS region of onset were collected. Ultrasound was used to evaluate the PN cross-sectional area (CSA) of ALS and control subjects. The mean PN CSA of ALS patients were 1.08 ± 0.39 mm on the right and 1.02 ± 0.34 mm on the left. The PN CSA of ALS patients were significantly decreased compared to controls (p value < 0.00001). The PN CSA of ALS patients was not correlated to any of the demographic and clinical parameters tested. This study demonstrates that ALS patients have a smaller PN size compared to controls using ultrasonography.

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Pain in Amyotrophic Lateral Sclerosis: A Neglected Aspect of Disease

Neurology Research International ◽

10.1155/2011/403808 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 28

Author(s):

Chalonda R. Handy ◽

Christina Krudy ◽

Nicholas Boulis ◽

Thais Federici

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Viral Vectors ◽

Neurodegenerative Disorder ◽

Respiratory Dysfunction ◽

Clostridial Neurotoxins ◽

Reduction Of Pain ◽

Als Patients ◽

Number Of Individuals ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons, muscle wasting, and respiratory dysfunction. With disease progression, secondary symptoms arise creating new problematic conditions for ALS patients. Amongst these is pain. Although not a primary consequence of disease, pain occurs in a substantial number of individuals. Yet, studies investigating its pathomechanistic properties in the ALS patient are lacking. Therefore, more exploratory efforts into its scope, severity, impact, and treatment should be initiated. Several studies investigating the use of Clostridial neurotoxins for the reduction of pain in ALS patients suggest the potential for a neural specific approach involving focal drug delivery. Gene therapy represents a way to accomplish this. Therefore, the use of viral vectors to express transgenes that modulate the nociceptive cascade could prove to be an effective way to achieve meaningful benefit in conditions of pain in ALS.

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Fab fragments from amyotrophic lateral sclerosis IgG affect calcium channels of skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1993.264.3.c537 ◽

1993 ◽

Vol 264 (3) ◽

pp. C537-C543 ◽

Cited By ~ 14

Author(s):

O. Delbono ◽

V. Magnelli ◽

T. Sawada ◽

R. G. Smith ◽

S. H. Appel ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Time Course ◽

Specific Antigen ◽

Charge Movement ◽

Mammalian Skeletal Muscle ◽

Fab Fragments ◽

Als Patients ◽

Ca2 Channels ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a human disease involving upper and lower motoneurons. In this paper we studied the action of specific antigen-binding site (Fab) fragments of immunoglobulins from ALS patients on dihydropyridine (DHP)-sensitive Ca2+ channel function in situ. Ca2+ channels in single mammalian skeletal muscle fibers tested by the double Vaseline gap technique and single Ca2+ channels reconstituted into bilayer were tested in these experiments. Although the observed current-voltage relationship was not modified by the addition of Fab fragments (1.5 mg/ml), peak Ca2+ current (ICa) was significantly reduced. The effect of these Fab fragments on the peak ICa reached a stable value after 60 min of incubation. ALS Fab fragments also slowed the ICa rising phase and increased the rate of tail current deactivation. Studies with double pulses demonstrated that ICa inactivation time course, voltage dependence, and recovery were not modified by ALS Fab fragments. Fab fragments from normal subjects and heat-inactivated Fab fragments from ALS patients did not induce any modification on the charge movement and ICa. In single channel studies, ALS Fab fragments reduced channels amplitude. These data support the concept of an immunological interaction between the circulating antibodies from ALS patients and DHP-sensitive Ca2+ channels.

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Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2011.006 ◽

2011 ◽

Vol 6 (1) ◽

Author(s):

Gisella Gargiulo Monachelli ◽

Maria Meyer ◽

Gabriel Rodríguez ◽

Laura Garay ◽

Roberto E. Sica ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Prognostic Factors ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Sporadic Als ◽

Bulbar Onset ◽

Als Patients ◽

Short Time ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

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Amygdala Abnormalities Are Related to Anxiety in Patients With Sporadic Amyotrophic Lateral Sclerosis

10.21203/rs.3.rs-773227/v1 ◽

2021 ◽

Author(s):

Shuangwu Liu ◽

yuying zhao ◽

qingguo ren ◽

gaolang gong ◽

dong zhang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Resting State ◽

Rating Scale ◽

Clinical Staging ◽

Bonferroni Correction ◽

Basal Nucleus ◽

Amygdala Volume ◽

Als Patients ◽

Disease Stages ◽

Lateral Sclerosis

Abstract To explore selective atrophy patterns and resting-state functional connection (FC) alterations in the amygdala at different stages of amyotrophic lateral sclerosis (ALS), and to determine any correlations between amygdala abnormalities and neuropsychiatric symptoms. We used the King’s clinical staging system for ALS to divide 83 consecutive patients with ALS into comparable subgroups at different disease stages. We investigated the pattern of selective amygdala subnucleus atrophy and analysed amygdala-based whole-brain FC analysis in the patients and 94 healthy controls (HCs). Cognitive and emotional functions were also evaluated using a neuropsychological test battery. There were no significant differences between King’s stage 1 ALS patients and HCs for any amygdala subnucleus volumes. Compared with HCs, King’s stage 2 patients had significantly lower left accessory basal nucleus and cortico-amygdaloid transition volumes after Bonferroni correction. Furthermore, after Bonferroni correction, King’s stage 3 patients demonstrated significant reductions in most subnucleus volumes as well as global amygdala volume compared with HCs. Notably, amygdala-based resting-state FC was unaltered in ALS patients until King’s stage 3. Specific subnucleus volumes were significantly associated with Mini-Mental State Examination scores and Hamilton Anxiety Rating Scale scores in ALS patients. In conclusions, our study provides a comprehensive profile of amygdala abnormalities in ALS patients. The pattern of amygdala abnormalities in ALS patients differed across King’s clinical disease stages, and our findings suggest that amygdala abnormalities are an important feature of patients with ALS. Moreover, amygdala volume may play an important role in anxiety and cognitive dysfunction in ALS patients.

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Ice Bucket At First…and then? – Psychopathology in Amyotrophic Lateral Sclerosis Patients and their Caregivers, a Review

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.1957 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S529-S529

Author(s):

A.R. Figueiredo ◽

V. Espírito Santo ◽

R. Almendra ◽

A. Costa

Keyword(s):

Social Support ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Psychological Adaptation ◽

Well Being ◽

Negative Effect ◽

Competing Interest ◽

Als Patients ◽

Lateral Sclerosis

IntroductionAmyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that affects motor neurons in the cerebral cortex, brainstem and spinal cord. The progressive loss of motor function creates profound changes on patient's lives and their caregivers.ObjectiveAssessment of eventual existence of psychopathology in ALS patients and their caregivers.MethodsLiterature review using the terms: ALS, Amyotrophic Lateral Sclerosis, psychopathology, psychiatric disorder; depression; anxiety, caregivers.ResultsModerate depressive or anxious symptoms are often observed. The results are not consistent, some studies showing that major depression is less common that in general population, others that is mildly increased. Some studies show that depressive symptoms are related to poorer QoL and with faster disease progression, others suggests no correlations. Coping strategies, cognitive appraisal and social support are important factors to psychological adaptation to ALS. After the diagnosis, high levels of anxiety can be observed. Psychopathological features are observed at this time, and generally depression does not increase as death approaches. Beyond loss of physical functions, it seems that patients’ neurobehavioral symptoms, such as aggressiveness, disinhibition and impulsivity, cognitive impairment, and also lack of social support have a negative effect on caregivers’ mental health. Concordance between patient and caregiver distress was found.ConclusionsIt is important to assess potential psychological distress in ALS patients and their caregivers, given that cope with disease can affect its course. Caregivers’ needs should be addressed, to benefit their well-being and consequently patients’ QoL. There are few studies about psychopharmacotherapy and/or psychotherapy in these patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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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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Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

10.1101/090977 ◽

2016 ◽

Author(s):

Paul E Young ◽

Stephen Kum Jew ◽

Michael E Buckland ◽

Roger Pamphlett ◽

Catherine M Suter

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Large Scale ◽

Cytosine Methylation ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Monozygotic Twin ◽

Sporadic Als ◽

High Heritability ◽

Als Patients ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in which only a small proportion of patients carry an identifiable causative genetic lesion. Despite high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom previous genome sequencing excluded a genetic basis for their disease discordance. By studying cytosine methylation patterns in peripheral blood DNA we identified thousands of large between-twin differences at individual CpGs. While the specific sites of difference were largely idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all affected individuals. In both instances the differences occurred within genes and pathways related to neurobiological function and dysfunction. Our findings reveal widespread changes in epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These findings may be exploited to develop blood-based biomarkers of ALS and develop further insight into disease pathogenesis. We expect that our findings will provide a useful point of reference for further large scale studies of sporadic ALS.

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