Cognition and amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is classically described as a pure motor disease; however, there is growing evidence of a range of cognitive impairment. Cognitive abnormalities include deficiencies in frontal executive skills, varying from mild deficits to meeting criteria for diagnosis of frontotemporal dementia (FTD). Cognitive impairment occurs in sporadic and familial forms of ALS. Patients may present with cognitive deficits before, after, or at the onset of motor neuron disease. Structural and functional imaging studies have shown extramotor cortical degeneration corresponding to levels of frontal executive impairment on neuropsychologic testing. In addition, ALS and a subset of FTD patients display common pathological findings on immunohistochemistry staining. It is believed that these disorders represent a continuum between motor and nonmotor cortical degeneration. The purpose of this article is to review the literature on cognitive deficits in ALS. Identifying changes in cognition is critical for physicians and caregivers of ALS patients, as cognitive decline may interfere with patient compliance. Diagnosis and treatment of cognitive symptoms in ALS patients may improve quality of life.     

Emotional adjustment in amyotrophic lateral sclerosis (ALS)

Despite the devastating motor impairment, a significant number of patients with amyotrophic lateral sclerosis (ALS) maintain a good psychosocial adjustment. Here we investigated whether this is specific for ALS or a more general characteristic of terminal disease. Psychosocial adjustment was investigated in 30 ALS patients, 29 cancer patients in palliative treatment and 29 age-, gender- and level of education-matched healthy controls. Subjective quality of life (sQoL), degree of depressive symptoms and coping were evaluated as measures of psychosocial adjustment. Personality factors were described. ALS and cancer patients showed a good psychosocial adjustment. Subjective QoL and depression did not differ significantly. Both patient groups presented a good sQoL. The level of mild depressive symptoms in both patient groups was similar and none showed clinically relevant depression. ALS patients expressed fewer active coping strategies than cancer patients which were explained by gender differences. Both patient groups showed comparable psychosocial adjustment to their disease. Overall, in terminally ill patients the psychological response to the prognosis is not associated with neurobiological changes (e.g., associated with subclinical deficits in ALS) or with physical decline.     

Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients

Iron misregulation promotes oxidative stress, a proposed pathological mechanism in neurodegenerative disease. The aim of this study was to evaluate serum iron metabolism indicators in 60 amyotrophic lateral sclerosis (ALS) patients and 44 age matched controls. Serum ferritin levels were significantly increased in ALS patients compared to controls (p < 0.001), while no differences in the levels of serum iron, transferrin, iron saturation or total iron binding capacity were found. Likewise no differences in C reactive protein (CRP) or caeruloplasmin were detected, suggesting that the elevated ferritin levels in ALS did not merely indicate an acute phase response. The increased ferritin level may reflect a general increase in stored iron or be a consequence of ongoing muscle degeneration.     

A predictive model for amyotrophic lateral sclerosis (ALS) diagnosis

ObjectiveThe clinical diagnosis of amyotrophic lateral sclerosis (ALS) usually takes several months. The delay in diagnosis compromises the effective therapeutic interventions. Therefore, the present study was aimed to develop a statistical model for predicting the risk of ALS at earlier stages for better management of ALS patients.MethodsThe study recruited 44 sporadic ALS patients and 29 normal controls. Thirteen different independent variables (predictors) which were believed to be associated with ALS were included in the study. Forward stepwise (likelihood ratio) binary logistic regression was used to find significant variables and probability of disease prediction.ResultsThe Hosmer–Lemeshow goodness of fit statistic (χ²= 4.379, df=8, p=0.821) indicate the appropriateness of forward stepwise (likelihood ratio) binary logistic regression model. Serum chemokine ligand-2, chemokine ligand-2 mRNA, vascular endothelial growth factor-A mRNA, smoking and alcohol consumption are the independent variables found significant to predict risk of ALS (p<0.05). The current model yielded 93.2% sensitivity and 86.2% specificity with 90.4% overall validity of correct ALS prediction.ConclusionForward stepwise (likelihood ratio) binary logistic regression model is an accurate method to predict ALS in the presence of serum CCL2, CCL2 mRNA, VEGFA mRNA, smoking and alcohol consumption with high sensitivity and specificity. However, bed side diagnostic utility of these variables needs to be validated further in larger ALS cohorts.     

Changes in memory for emotional material in amyotrophic lateral sclerosis (ALS)

The current study sought to examine the performance of non-demented ALS patients on neuropsychological tests involving emotional perception and memory. Nineteen non-demented patients with ALS were compared with 20 healthy controls on assessments of facial expression recognition, social judgement ratings of faces and recognition memory for emotional words. Patients and controls were well matched to exclude a range of potentially confounding variables. The patients and controls demonstrated significant differences on only one test of cognitive functioning. The ALS group demonstrated a failure to show the normative pattern of enhanced recognition memory for emotional words compared to neutral words and produced higher scores than controls on recognition memory for neutral words. These findings suggest that patients with ALS show a different pattern of cognitive performance with respect to memory for emotional material when compared to healthy adults.     

Brain responses to emotional stimuli in patients with amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease, affects movement and communication abilities and emotional processing. Subjective ratings of emotional stimuli depicting social interactions and facial expressions differed significantly between ALS patients and healthy controls in a previous study with a reduction of negative emotional valence (pleasantness) and lower subjective arousal (excitement) in ALS patients. In the present study, sixty similar emotional slides were presented to 13 ALS patients, 15 matched healthy controls and six tetraplegic patients. Subjective reports of valence and arousal as well as brain responses to the affective pictures using functional magnetic resonance imaging (fMRI) were measured. The picture series was presented twice with a 6-months interval to investigate effects of disease progression. ALS patients presented an increased brain response in the right supramarginal area and a reduced brain response in extrastriate visual areas at both measurements compared with healthy controls. Within the ALS patients' group a reduction of brain responses in the anterior insula at the follow-up was correlated with the subjective arousal. The reduced response in the anterior insula is tentatively interpreted as indicating reduced arousal during the course of the disease at the neural and behavioural level. The reduction of activity in extrastriate visual areas might be similarly interpreted. The increased brain response in the right supramarginal area of ALS patients might represent an altered sensitivity to social-emotional cues.     

Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients

OBJECTIVES: An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and anti-sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients. MATERIAL AND METHODS: Serum of 103 and CSF of 79 patients with ALS was examined. The "disease controls" consisted of 22 cases of other motor neuron diseases and 50 healthy, age-matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the "disease controls" and 50 normals. To study the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and sulfatides the ELISA technique has been applied. RESULTS: An increased titer against GM1-gangliosides, AGM1-gangliosides and sulfatides in ALS appeared in serum in 18%, 32%, and 11%, resp., in the "disease controls" the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the "disease controls" a high antibodies titer was a rare finding. CONCLUSIONS: It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury.     

Amino acids acting as transmitters in amyotrophic lateral sclerosis (ALS)

Objectives - In amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin, excitotoxic mechanisms are supposed to be involved. Divergent results are, however, presented either because of the heterogeneity of this disease, and/or different methodologies used to evaluate the excitotoxic amino acids content. The results of the most sensitive high performance liquid chromatography (HPLC) techniques with precolumn derivatization of fasting serum and CSF glutamate, aspartate, glycine and γ-aminobutyric acid (GABA) in mild and severely progressing ALS cases are presented here. Material and methods - We studied 25 ALS patients with different course of the disease and controls, which consisted of 10 cases with other motor neuron diseases and 20 healthy, age-matched subjects. Results - In the ALS patients with a mild course of the disease serum glutamate and aspartate content was either normal or slightly decreased, in all of these cases a rise in GABA and glycine was present. In the severely progressing ALS cases serum glutamate and aspartate was increased. The GABA content was either normal or increased, the glycine level appeared to be either normal or decreased. In CSF the amino acids changes in ALS were less pronounced as compared to serum. The most frequent finding was the increase in GABA concentration both in the mild and the severely progressing group. CSF glutamate in ALS patients with mild course of the disease was decreased, in the severely progressing cases the glutamate level appeared in a broad range from decreased to increased values. CSF aspartate was either normal or elevated, glycine values were present in a broad range from decreased to increased values. In the other tested motor neuron diseases no consistent changes in serum and CSF amino acids concentration was observed. Conclusions - The data from serum and CSF indicate that in ALS an imbalance between excitatory and inhibitory amino acids might be present in the brain, which may be induced in different ways in particular ALS patients. It may be an important factor for the mediation of neurons death.     

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

Journal of Neurology - To identify coping strategies used by amyotrophic lateral sclerosis (ALS) patients. Integrative literature review using the Virtual Health Library, MEDLINE, and ScienceDirect...     

Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS)

Neuropsychological investigations of amyotrophic lateral sclerosis (ALS) patients have revealed variable results on specific tests, despite a similar overall cognitive profile of predominantly executive dysfunction with some evidence of memory impairment. The most striking and consistent deficit is found using tests of verbal fluency. The current investigation explored why verbal fluency is particularly sensitive to the impairment in ALS, by investigating some of the underlying cognitive processes: (i) intrinsic response generation; (ii) phonological loop functions; and (iii) simple word retrieval. Twenty-two ALS patients and 25 healthy controls were investigated. The battery included: (i) written and spoken letter-based fluency, category fluency, design fluency; (ii) the Phonological Similarities effect and Word Length Effect; and (iii) computerised sentence completion and confrontational naming. The tests were designed to control for motor speed and to accommodate for the range of disabilities that are present in ALS patients. Significant impairments were found on some tests of intrinsic response generation, namely the Written Verbal Fluency Test, Category Fluency Test (generation of animal names) and Design Fluency Test. Phonological loop functions appeared to be intact with evidence of both the Phonological Similarities and Word Length Effects, but the ALS patients displayed significantly reduced working memory capacity. No deficits were found on tests of simple word retrieval. The findings indicate that verbal fluency impairments in ALS patients result from a higher order dysfunction, implicating deficits in the supervisory attentional system or central executive component of working memory, and are not caused or exaggerated by an impairment in phonological loop functions or in primary linguistic abilities. The study also demonstrates the importance of controlling for differences in motor speed, which may have served to exaggerate the presence of cognitive deficits in ALS patients reported by some other studies.     

Pathogenesis and therapeutic perspectives for amyotrophic lateral sclerosis (ALS)]

After gene mutations of SOD1 were found in familial amyotrophic lateral sclerosis (ALS) in 1993, many studies have elucidated pathogenesis of this progressive motor neuron disease. Among them, oxidative stress, impaired axonal transport, imbalance of survival & death signals, organellic stress (for mitochondria, endoplasmic reticulum and proteasome) are the most important with linking each other through energy failure within the motor neuron. New therapeutic approaches have also been tried, such as free radical scavenger edaravone, a continuous intra-thecal injection of neurotrophic factor IGF-1, and methylcobalamine as well as gene therapy with GDNF and regenerative therapy with stem cell activation and stem cell transplantation.     

Phenotypic differences of amyotrophic lateral sclerosis (ALS) in China and Germany

Objective

The aim of this study is to explore phenotypical differences of amyotrophic lateral sclerosis (ALS) between two cohorts from Germany and China.

Methods

Registry-based studies of ALS were conducted in South-West Germany from 2010 to 2014 and an ALS clinic in Beijing from 2013 to 2016, respectively. Demographic and clinical features of 663 German and 276 Chinese ALS patients were collected and compared.

Results

Mean age-at-onset was higher in German than in Chinese ALS patients [66.6 years (95% CI 65.7, 67.5) vs. 53.2 years (95% CI 52.0, 54.5)]. Age distribution of ALS patients peaked around 70–74 years in Germany and 50–54 years in China. Bulbar onset was more prevalent among German than among Chinese patients (35.9 vs. 22.8%). Diagnostic delay was higher in the Chinese than in the German study sample (12 vs. 5 months). Cognitive deficits were more pronounced in the Chinese cohort. Both cohorts differed in smoking habits, prevalence of diabetes and in body mass index (BMI).

Conclusions

The apparent discrepancies between German and Chinese ALS patients (age at onset, gender distribution, bulbar forms, cognitive dysfunction, risk factors) reveal a quite different clinical phenotype in China, maybe due to socioeconomic status, environmental factors or genetic background. The observed differences in phenotype need to be pursued by further epidemiological studies on environmental and genetic risk factors.

     

Bereitschaftspotential in amyotrophic lateral sclerosis (ALS): lower amplitudes in patients with hyperreflexia (spasticity)

In a pilot study the Bereitschaftspotential (BP) was investigated in 16 patients suffering from amyotrophic lateral sclerosis (mean age 58.6, mean severity of the illness according to Norris ALS score 76.4 points). Comparing the total ALS group ( n = 16) with matched controls no significant differences in the BP amplitude parameters were found. However, a subgroup of 7 ALS patients with signs of pronounced spasticity (hyperreflexia) differed significantly at the central midline from matched controls and significantly in addition from patients with a lower degree of spasticity. Controls as well as patients with a lower degree of spasticity had significantly higher BP amplitudes at the midline (electrode positions C_z and P_z, P <0.05, H -test). The correlation coefficient between the hyperreflexia Norris score and the various BP parameters for the total ALS sample ( n = 16) revealed a significant correlation especially over the midline. Stronger signs of spasticity (hyperreflexia) are associated with lower amplitudes of the BP.     

Immunoglobulin-mediated activity against red blood cells in the saliva of amyotrophic lateral sclerosis (ALS) patients

Immunoglobulin (Ig)-mediated activity in plasma directed towards normal blood type matched red blood cells (RBC) inducing haemolysis in vitro has earlier been demonstrated to be a characteristic feature in ALS-patients. In this study, saliva of ALS-patients, normal and diseased controls was tested with the same in vitro test. An increased degree of haemolysis was induced by the ALS-patient as compared with control samples. The activity thus found in saliva had the same basic characteristics as that earlier described for plasma; it reacted similarly to serial dilution and was retained in salivary Ig. The effect on red blood cells of saliva from patients with bulbar paralysis was larger than that of saliva from ALS-patients lacking bulbar symptoms. It is discussed whether cytotoxic Ig in saliva could be pathophysiologically active in bulbar paralysis by means of passage through the oral mucosa and local action on motor end plates in perioral muscles.     

Six important themes in amyotrophic lateral sclerosis (ALS) research, 1999

My assignment was to identify the 6 most important ALS papers published in 1999 but, great to relate, there were too many excellent candidates. Rather than confining the search to individual papers, six major themes seemed appropriate for discussion: 1) The study of transgenic mice that carry a mutated human gene for superoxide dismutase-1 (SOD1) has led to many far-reaching advances in ALS research. The mice are regarded as the best test system to evaluate potential therapies, including creatine. Inconsistencies between efficacy in mice and people are noted, however. 2) Transgenic mice have also been used to evaluate the role of glutamate toxicity in the pathogenesis of ALS, a dominant theory. 3) The role of mitochondria in the pathogenesis of ALS is gathering increasing attention. 4) The role of neurofilaments in the pathogenesis of ALS has provided new twists in mice and people. 5) Motor neuropathy is the most important differential diagnosis of ALS. 6) Gene therapy, as exemplified by the use of stem cells, has been applied successfully to animal models of other inherited diseases of the central nervous system.