Resilience and distress among amyotrophic lateral sclerosis patients and caregivers

OBJECTIVES: The objectives of this study were to assess the prevalence of depressive disorders and symptoms and their correlates in patients with amyotrophic lateral sclerosis (ALS) and caregiver spouses and to identify dimensions of resilience as well as distress. METHODS: Fifty-six patients with ALS and 31 caregivers were interviewed on one occasion, and 20 patients were subsequently reinterviewed during a scheduled medical visit at an ALS center. Major measures included the Structured Clinical Interview for DSM-IV, the Beck Depression Inventory, the Schedule of Attitudes Toward Hastened Death, quality of life, spirituality, and degree of hopelessness. The ALS Functional Rating Scale, spirometry measures of forced vital capacity, and the Karnofsky Performance Index were used to assess physical status. RESULTS: Neither patients nor caregivers displayed significant psychopathology with respect to either current depressive disorders or scores on symptom scales. Depressive symptoms and psychological distress were not related to time since diagnosis, degree of disability, or illness progression during the period of observation. More interest in hastened death was associated with greater distress, but willingness to consider assisted suicide was not. Among caregivers, perceived caregiver burden was significantly associated with finding positive meaning in caregiving. Concordance between patient and caregiver distress was high, suggesting that attention to the mental health needs of caregivers may alleviate the patient's distress as well. CONCLUSIONS: Clinical depression or significant depressive symptomatology is not an inevitable or common outcome of life-threatening illness, even in the presence of major disability.     

Perceived control and psychological distress in women with breast cancer: a longitudinal study

The relationship between perceived control and psychological distress in cancer patients has been widely studied, but longitudinal designs are scarce. The aim of this study was to examine whether perceived control could predict changes in the evolution of psychological distress in breast cancer patients at stages I or II. One hundred and one women were assessed on five occasions: one week after surgery, and again 1, 3, 6 and 12 months later, using the Mental Adjustment to Cancer (MAC) Scale, a Self-Efficacy Scale, the Personal Competence Scale, the Hospital Anxiety and Depression Scale (HADS), the Profile of Mood Sates (POMS), and the EORTC questionnaire of quality of life. Latent growth curve (LGC) model analysis was used to test the relationship between perceived control and psychological distress in a longitudinal, 1-year study. The results showed that perceived control increases linearly and that distress also decreases linearly. Moreover, the evolution of distress can be predicted from the initial value and the rate of change of perceived control. This close relationship between perceived control and psychological distress was found to be independent of the evolution of the physical state. These findings suggest that perceived control could be used as an early predictor of psychological adjustment to illness.     

A longitudinal study of psychological distress in women with breast symptoms

The aim of the study was to measure psychological distress in women with breast symptoms over a period of three months following an outpatient appointment at a rapid access symptomatic breast clinic. Women were recruited (N = 150) at the weekly clinic and psychological distress was measured using the Hospital Anxiety and Depression Scale, the General Health Questionnaire-12 and the Spielberger State-Trait Anxiety Inventory. Information on age and diagnosis was collected from medical notes. Measures were repeated at two weeks and at three months. Participants were divided into three diagnostic categories: B 1 (benign diagnosis at clinic); B2 (benign after further investigations); and M (breast cancer). Overall, scores of anxiety and GHQ-12 decreased significantly during the follow- up period. However, participants in the B2 group remained significantly more distressed than the rest of the sample throughout the experimental period. Depression remained within the normal range throughout the follow-up period for all categories. The study suggests a relationship between symptomatic breast disease and psychological distress.     

Immunology of amyotrophic lateral sclerosis

Conclusion The antibody detected in the ALS sera with suppressive activity for terminal sprouting is likely directed against an antigen that is normally sequestered. Tolerance to the 56 kd antigen described here is not exhibited in rats, as syngenic immunizations induce an immune response (M. E. Gurney, unpublished observation). Freshly denervated muscle secretes very low amounts of the 56 kd antigen, and the level of secretion rises 2–3 days after denervation in vivo. Of the few antecedent events associated with ALS by case studies, mechanical injuries, participation in physical activities, or bone fractures might all produce nerve damage or periods of limb immobilization [48]. Similar physical insults are stimuli for sprouting in animal models [13, 39], and might result in elevated secretion of sprouting factor, resulting in induction of an immune response in susceptible individuals.The antibodies detected in this study could arise as a secondary response to neuromuscular destruction, as occurs following tissue injury in many organs. The absence of inhibitory activity in sera of patients with neuropathy suggests that denervation per se need not give rise to development of such antibodies, although the extent of denervation and muscle atrophy in the ALS patients was, in general, markedly greater than in patients with neuropathy. Whether sprouting inhibitory antibodies prove to be of primary pathogenic significance, or are only a secondary phenomenon, they provide potentially significant reagents with which to elucidate the existence and nature of human motor neuron growth factors.     

Hippocampal degeneration in patients with amyotrophic lateral sclerosis

There is increasing appreciation of non-motor system involvement in amyotrophic lateral sclerosis (ALS), although its full extent and clinical significance remains to be established. This study tested the hypothesis that memory impairment in patients with ALS is related to hippocampal degeneration. Consecutive patients with ALS (58) and 29 matched controls participated in standardized neuropsychological assessment and magnetic resonance imaging. Patients with ALS performed worse in global cognitive functioning and executive and verbal memory tests (p < 0.05). The hippocampus was manually segmented in each hemisphere, and volumes were calculated with correction for intracranial volume. Analysis of covariance, controlled for the effect of age and education years, showed significantly smaller hippocampal volume on the right (p = 0.004) in patients with ALS. Verbal memory test performance correlated with the left hippocampal volume in patients with ALS (p < 0.05), although there was no significant correlation with tests of executive function and clinical variables underscoring the specificity of the present findings. Hippocampal volume loss and its correlation with the severity of verbal memory impairment highlight significant hippocampal involvement which can occur as a non-motor deficit in patients with ALS.     

Trigemino-cervical response in patients with amyotrophic lateral sclerosis

PURPOSE: The trigemino-cervical response (TCR) was investigated in the patients with amyotrophic lateral sclerosis (ALS) to evaluate its effect for disclosing the bulbar involvement in this disorder. METHODS: We studied 100 normal subjects and 45 patients with ALS. In all normal subjects, stimulation of the infraorbital nerve on one side produced bilateral short latency waves, which consisted of a positive/negative wave described with the mean peak latency (P20/N30). The mean square root of the ratio between the amplitude of P20/N30 and the mean rectified surface EMG activity preceding the stimulus was described by A value. RESULTS: The latency of P20 in controls was 18.5 +/- 1.4 ms, N30 was 28.8 +/- 2.8 ms, and the A value was 1.6 +/- 0.5, respectively. In ALS patients, twelve showed absent, seventeen were delayed in the latencies, six were above normal asymmetry on two sides, and ten showed normal. The latency of P20 in ALS patients was 22.9 +/- 9.4 ms, N30 was 33.7 +/- 11.2 ms, and the A value was 1.5 +/- 0.8, respectively. The parameters of the latencies of TCR between ALS patients and the normal controls were statistically different (P < 0.05). CONCLUSIONS: TCR can be reliably measured in all normal subjects and help in disclosing lower brainstem lesions in ALS patients, even without bulbar symptoms.     

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.     

Autophagy dysregulation in amyotrophic lateral sclerosis

Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.     

Subcortical reorganization in amyotrophic lateral sclerosis

The cerebral cortex reorganizes in response to central or peripheral lesions. Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a—albeit finally ineffective—mechanism to compensate for the ongoing loss of motor neurons in ALS.Konrad C. and Jansen A. contributed equally to their work     

Immunological findings in amyotrophic lateral sclerosis

Conclusions The sporadic form of ALS is the most common form of MND and remains a syndrome of unproven etiology or etiologies. The application of increasingly sensitive immunocyto-chemical techniques to pathological specimens indicates the presence of a humoral and cellular immune response at the site of MN destruction. The magnitude of the response would seem to be quantitatively much less than that found in traditional inflammatory disorders such as multiple sclerosis. The similarity of the response in the autosomal dominant form of the disease, which can be reproduced in mice expressing the mutant SOD transgene, suggests that this response is at most a secondary event in the disease pathogenesis. This pattern of immune response seems rather parallel to that seen in other neurodegenerative disorders. Whether the disease-specific calcium channel antibody which correlates with disease progression also arises in response to tissue injury is not defined, although it is not reported in patients with MN destruction as a result of polio. The failure of even intense forms of immunotherapy to alter the disease course in ALS does further question the primary or secondary role of immune effector mechanisms to the disease process. One cannot exclude that individual cases, such as those arising on the background of lymphoma, may have a more significant immunopathogenesis and be akin to other paraneoplastic syndromes which affect different neuronal populations.The LMN syndromes associated with IgM paraproteins and anti-GM1 antibodies would seem to be examples of motor neuropathies rather than primary neuronopathies, although the neuronotoxic effects of some of these antibodies are of note. Whether the markedly high titers of antibody found represent an intrinsic B cell derangement, as those cases associated with lymphoma or myeloma suggest, or a defect in T cell regulation of the B cell response together with persistent antigen stimulation remains to be resolved. GM1 is not usually considered as a potent antigen, although high-titer responses can be induced with appropriate immunization protocols [15]. The clinical response of some of these cases to immunotherapy strengthens the hypothesis regarding the primary immune basis of the disorder. The inconsistency of the response remains, however, to be defined.     

Homozygosity analysis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering ‘common'' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10⁻⁵), a greater proportion of cases harboured homozygosity (P=2 × 10⁻⁵), a longer average length of segment (P=1 × 10⁻⁵), a longer total genome coverage (P=1 × 10⁻⁵), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10⁻⁵), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9–4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.     

Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study

Depending on individual lesion location and extent, reorganization of the human motor system has been observed with a high interindividual variability. In addition, variability of forces exerted, of motor effort, and of movement strategies complicates the interpretation of functional imaging studies. We hypothesize that a general pattern of reorganization can be identified if a homogeneous patient population is chosen and experimental conditions are controlled. Patients with amyotrophic lateral sclerosis (ALS) and healthy volunteers were trained to perform a simple finger flexion task with 10% of each individual's maximum grip force with constant movement amplitude and frequency. The activation pattern in ALS patients was distinctly different to that in healthy controls: In ALS patients, motor cortex activation was located more anteriorly, encompassing the premotor gyrus. The cluster volume within the supplementary motor area (SMA) was higher and shifted toward the pre-SMA. Contralateral inferior area 6 and bilateral parietal area 40 revealed higher cluster volumes. Our results demonstrate a general pattern of functional changes after motor neuron degeneration. They support the concept of a structurally parallel and functionally specialized organization of voluntary motor control. Degeneration of the first and second motor neurons leads to enhanced recruitment of motor areas usually involved in initiation and planning of movement. Partial compensation between functionally related motor areas seems to be a strategy to optimize performance if the most efficient pathway is unavailable.     

Gene therapy of amyotrophic lateral sclerosis

Two-year experiments were performed to evaluate the neurotrophic effect of hypoxia-inducible factors (vascular endothelial growth factor and angiogenin) expressed in recombinant human adenoviruses in amyotrophic lateral sclerosis. Randomized placebo-controlled trial demonstrated safety and good tolerability of the recombinant antiviral drugs. The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates differential approach to the selection of patients and continuous monitoring of gene therapy. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 467–470, April, 2008