Heterogeneity Of Amyotrophic Lateral Sclerosis Research Articles

Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials.

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.

Molecular subtypes of ALS are associated with differences in patient prognosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood clinical heterogeneity, underscored by significant differences in patient age at onset, symptom progression, therapeutic response, disease duration, and comorbidity presentation. We perform a patient stratification analysis to better understand the variability in ALS pathology, utilizing postmortem frontal and motor cortex transcriptomes derived from 208 patients. Building on the emerging role of transposable element (TE) expression in ALS, we consider locus-specific TEs as distinct molecular features during stratification. Here, we identify three unique molecular subtypes in this ALS cohort, with significant differences in patient survival. These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS.

Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A.MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between −6.0 and −2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events.DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup.Trial registrationEudraCT number 2020-000579-19. Registered on 29 March 2021.

Microglial heterogeneity in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease of the central nervous system that is pathologically characterized by motor neuron loss. Although the cause of the disease is still unknown, its pathophysiology is considered heterogeneous. In recent years, there have been a series of reports on the existence of disease-associated microglia (DAM) in the lesions of various neurodegenerative diseases. DAM have also been reported in SOD1-deficient mice, a disease model of ALS. However, the role of DAM in sporadic ALS remains unclear. This study revealed that spinal cord lesions in ALS can be pathologically distinguished into 2 subgroups (TMEM119+ and TMEM119- microglia) according to the type of microglia. Expression of the microglial activation marker CD68 and endothelial activation were also observed in the TMEM119+ microglia group, suggesting the presence of inflammatory processes in ALS lesions. Since DAM suppress the expression of TMEM119, the TMEM119+ microglia group may indicate DAM-independent inflammatory neurodegeneration. These results may explain why, in some clinical trials of anti-inflammatory drugs for ALS, only some cases showed suppression of disease progression.

Blood biomarkers in ALS: challenges, applications and novel frontiers.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease among adults. With diagnosis reached relatively late into the disease process, extensive motor cell loss narrows the window for therapeutic opportunities. Clinical heterogeneity in ALS and the lack of disease-specific biomarkers have so far led to large-sized clinical trials with long follow-up needed to define clinical outcomes. In advanced ALS patients, there is presently limited scope to use imaging or invasive cerebrospinal fluid (CSF) collection as a source of disease biomarkers. The development of more patient-friendly and accessible blood biomarker assays is hampered by analytical hurdles like the matrix effect of blood components. However, blood also provides the opportunity to identify disease-specific adaptive changes of the stoichiometry and conformation of target proteins and the endogenous immunological response to low-abundance brain peptides, such as neurofilaments (Nf). Among those biomarkers under investigation in ALS, the change in concentration before or after diagnosis of Nf has been shown to aid prognostication and to allow the a priori stratification of ALS patients into smaller sized and clinically more homogeneous cohorts, supporting more affordable clinical trials. Here, we discuss the technical hurdles affecting reproducible and sensitive biomarker measurement in blood. We also summarize the state of the art of non-CSF biomarkers in the study of prognosis, disease progression, and treatment response. We will then address the potential as disease-specific biomarkers of the newly discovered cryptic peptides which are formed down-stream of TDP-43 loss of function, the hallmark of ALS pathobiology.

Lipid Metabolic Alterations in the ALS-FTD Spectrum of Disorders.

There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS–FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.

Modeling Amyotrophic Lateral Sclerosis Progression: Logic in the Logit.

BackgroundAmyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) has emerged as a clinical prognostic marker for clinical and research purposes in amyotrophic lateral sclerosis (ALS). However, tools for predicting disease progression are still underdeveloped. The aim of this study was to mathematically model ALS progression to provide a reliable and personalized approach to the prognosis for ALS patients. Also, it aimed to provide a reliable prediction tool for the current and newly diagnosed patients.MethodsTwenty patients from the South-East England Amyotrophic Lateral Sclerosis register (SEALS) database were included in the analysis. A non-linear logistic regression model was used to describe disease progression from baseline health to the theoretical maximum disease. The reliability of predicted variables and correlation between model parameters were assessed separately for each subject.ResultsThe logistic regression model best described the disease progression in patients with a high progression rate. Most notably, the model fitted better when a patient has progressed enough to approximately the midpoint of the functional rating scale. The model failed to characterize the disease course in patients defined as slow progressors. Furthermore, the linear relationship between the rate of progression and time since onset at ALFRS-R score of 24 was evident in 65% of patients.ConclusionThese results indicate that the rate of disease progression and time when ALSFRS-R declines to half the maximum score are correlated with functional outcomes. Nonetheless, the logistic model failed to describe disease course in patients with slow progression rates. Different rates of progression can be attributed to the genetic heterogeneity of ALS. Thus, clinicians and patients can benefit from adding a gene factor to the equation. With the outlined limitations, the model can provide a good prognostic tool.

Cortical and subcortical grey matter atrophy in Amyotrophic Lateral Sclerosis correlates with measures of disease accumulation independent of disease aggressiveness

There is a growing demand for reliable biomarkers to monitor disease progression in Amyotrophic Lateral Sclerosis (ALS) that also take the heterogeneity of ALS into account.In this study, we explored the association between Magnetic Resonance Imaging (MRI)-derived measures of cortical thickness (CT) and subcortical grey matter (GM) volume with D50 model parameters.T1-weighted MRI images of 72 Healthy Controls (HC) and 100 patients with ALS were analyzed using Surface-based Morphometry for cortical structures and Voxel-based Morphometry for subcortical Region-Of-Interest analyses using the Computational Anatomy Toolbox (CAT12). In Inter-group contrasts, these parameters were compared between patients and HC. Further, the D50 model was used to conduct subgroup-analyses, dividing patients by a) Phase of disease covered at the time of MRI-scan and b) individual overall disease aggressiveness. Finally, correlations between GM and D50 model-derived parameters were examined.Inter-group analyses revealed ALS-related cortical thinning compared to HC located mainly in frontotemporal regions and a decrease in GM volume in the left hippocampus and amygdala. A comparison of patients in different phases showed further cortical and subcortical GM atrophy along with disease progression. Correspondingly, regression analyses identified negative correlations between cortical thickness and individual disease covered. However, there were no differences in CT and subcortical GM between patients with low and high disease aggressiveness.By application of the D50 model, we identified correlations between cortical and subcortical GM atrophy and ALS-related functional disability, but not with disease aggressiveness. This qualifies CT and subcortical GM volume as biomarkers representing individual disease covered to monitor therapeutic interventions in ALS.

Between-sex variability of resting\xa0state functional brain networks in amyotrophic lateral sclerosis (ALS)

The organization of brain functional connectivity (FC) has been shown to differ between sexes. Amyotrophic lateral sclerosis (ALS) is characterized by sexual dimorphism, showing sex-specific trends in site of onset, phenotypes, and prognosis. Here, we explored resting state (RS) FC differences within major large-scale functional networks between women and men in a sample of ALS patients, in comparison to healthy controls (HCs). A group-level independent component analysis (ICA) was performed on RS-fMRI time-series enabling spatial and spectral analyses of large-scale RS FC networks in 45 patients with ALS (20 F; 25 M) and 31 HCs (15 F; 16 M) with a focus on sex-related differences. A whole-brain voxel-based morphometry (VBM) was also performed to highlight atrophy differences. Between-sex comparisons showed: decreased FC in the right middle frontal gyrus and in the precuneus within the default mode network (DMN), in affected men compared to affected women; decreased FC in the right post-central gyrus (sensorimotor network), in the right inferior parietal gyrus (right fronto-parietal network) and increased FC in the anterior cingulate cortex and right insula (salience network), in both affected and non-affected men compared to women. When comparing affected men to affected women, VBM analysis revealed atrophy in men in the right lateral occipital cortex. Our results suggest that in ALS sex-related trends of brain functional and structural changes are more heavily represented in DMN and in the occipital cortex, suggesting that sex is an additional dimension of functional and structural heterogeneity in ALS.

Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials

BackgroundInterventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power.MethodsIn 125 patients with ALS from three independent prospective studies—one observational study and two interventional trials—we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS).ResultsAmong the parameters provided, the NfL levels (P < 0.001) and the interaction with site of onset (P < 0.01) contributed significantly to the prediction, forming a robust NfL prediction model (R = 0.67). Model application in the trial cohorts confirmed its applicability and revealed superiority over lead-in and ΔFRS-based approaches. The NfL model improved statistical power by 61% and 22% (95% confidence intervals: 54%–66%, 7%–29%).ConclusionThe use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could significantly increase the trial power.NCT00868166, registered March23, 2009; NCT02306590, registered December 2, 2014.

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

Lipidomic traits of plasma and cerebrospinal fluid in amyotrophic lateral sclerosis correlate with disease progression.

Since amyotrophic lateral sclerosis cases exhibit significant heterogeneity, we aim to investigate the association of lipid composition of plasma and CSF with amyotrophic lateral sclerosis diagnosis, its progression and clinical characteristics. Lipidome analyses would help to stratify patients on a molecular basis. For this reason, we have analysed the lipid composition of paired plasma and CSF samples from amyotrophic lateral sclerosis cases and age-matched non-amyotrophic lateral sclerosis individuals (controls) by comprehensive liquid chromatography coupled to mass spectrometry. The concentrations of neurofilament light chain—an index of neuronal damage—were also quantified in CSF samples and plasma. Amyotrophic lateral sclerosis versus control comparison, in a moderate stringency mode, showed that plasma from cases contains more differential lipids (n = 122 for raw P < 0.05; n = 27 for P < 0.01) than CSF (n = 17 for raw P < 0.05; n = 4 for P < 0.01), with almost no overlapping differential species, mainly characterized by an increased content of triacylglyceride species in plasma and decreased in CSF. Of note, false discovery rate correction indicated that one of the CSF lipids (monoacylglycerol 18:0) had high statistic robustness (false discovery rate-P < 0.01). Plasma lipidomes also varied significantly with the main involvement at onset (bulbar, spinal or respiratory). Notably, faster progression cases showed particular lipidome fingerprints, featured by decreased triacylclycerides and specific phospholipids in plasma, with 11 lipids with false discovery rate-P < 0.1 (n = 56 lipids in plasma for raw P < 0.01). Lipid species associated with progression rate clustered in a relatively low number of metabolic pathways, mainly triacylglyceride metabolism and glycerophospholipid and sphingolipid biosynthesis. A specific triacylglyceride (68:12), correlated with neurofilament content (r = 0.8, P < 0.008). Thus, the present findings suggest that systemic hypermetabolism—potentially sustained by increased triacylglyceride content—and CNS alterations of specific lipid pathways could be associated as modifiers of disease progression. Furthermore, these results confirm biochemical lipid heterogeneity in amyotrophic lateral sclerosis with different presentations and progression, suggesting the use of specific lipid species as potential disease classifiers.

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses.

Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions—excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

Structural MRI outcomes and predictors of disease progression in amyotrophic lateral sclerosis

Background and aimsConsidering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline. Methods50 ALS patients underwent clinical evaluations and 3 T MRI scans at regular intervals for a maximum of 2 years (total MRI scans = 164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features. ResultsThe rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression. ConclusionsIn this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes.

Epidemiological and clinical features of amyotrophic lateral sclerosis in a Tunisian cohort

Objective: To describe the phenotypic heterogeneity of amyotrophic lateral sclerosis (ALS) in Tunisian patients, and to define the sociodemographic features, treatments, and survival rate with ALS. Methodology: The study included 210 patients with ALS diagnosed between 2003 and 2019 in The Neurology department, Razi Hospital Tunisia. ALS patients were phenotyped and followed until their death. Results: median age of ALS onset was 54.93 ± 14.08 years (men = 56.21 ± 12.58, women = 52.36 ± 16.49). The sex-ratio was 2.0 with obvious male predominance. Juvenile ALS form was found in 5.71% of our cohort and 94, 76% of the patients had the classic ALS form. In the latter, 76.3% had spinal onset whereas bulbar onset was seen in 20.1% of patients. Spinal onset was most frequent in Juvenile ALS patients. Approximately half of the ALS patients used Riluzole (58.5%). Median survival rate was 60 months (5 years). According to univariate analysis, the factors related to survival rate of ALS patient were: age at onset, diagnostic delay, site of onset, phenotype and treatment use. The multivariate analysis revealed that age at onset, gender, diagnostic delay, superior muscles atrophy, treatment use, consanguinity, cognitive signs, dysautonomia, and ALSFRS-R score were independent prognostic factors of survival among ALS patients. Conclusion: Our Tunisian cohort was characterized by a slower disease progression and a better prognosis. Juvenile ALS patients were more common. Initial ALSFRS-R scores were higher in our population. Age at onset of Bulbar ALS was younger. Our study highlights the possible presence of genetic and environmental factors that may influence the clinical phenotype of ALS in Tunisia.

Amyotrophic lateral sclerosis mortality rates among ethnic groups in a predominant admixed population in Latin America: a population-based study in Ecuador

Current evidence suggests heterogeneity of amyotrophic lateral sclerosis (ALS) among geographic areas and populations. Lower mortality rates have been reported in admixed populations compared to European origin populations. We aimed to describe and compare ALS mortality rates among ethnic groups using a population-based approach in a multiethnic country. Annual mortality cause registers were searched to determine ALS deaths from the National Institute of Statistics and Censuses in Ecuador (INEC) from 1990 to 2016. Mid-year population was considered for each year. The time trend was assessed using a negative binomial regression. Rate ratio statistics were performed to compare the age and sex standardized rates based on the 2010 US population among ethnic groups. Overall, 570 ALS deaths were identified. ALS mortality showed an age-related profile with a peak between 55 and 70 years. After age–sex standardization on the 2010 US population, mortality rate was 0.33 (CI 0.30–0.36) per 100,000. The time trend showed an increase of ALS mortality (p < 0.001). There was no statistical difference in age–sex standardized mortality rates per 100,000 when admixed was compared to white (p = 0.231) and black (p = 0.125). Differences reached statistical significance between admixed and other ethnics (p = 0.015). Our population-based study supports the hypothesis that ALS occurrence is lower in predominant admixed populations from Latin America compared to European and Northern American populations. Further studies are needed to clarify the role of ancestral origin in ALS susceptibility.

Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials.

ObjectiveTo assess the effect of eligibility criteria on exclusion rates, generalizability, and outcome heterogeneity in amyotrophic lateral sclerosis (ALS) clinical trials and to assess the value of a risk-based inclusion criterion.MethodsA literature search was performed to summarize the eligibility criteria of clinical trials. The extracted criteria were applied to an incidence cohort of 2,904 consecutive patients with ALS to quantify their effects on generalizability and outcome heterogeneity. We evaluated the effect of a risk-based selection approach on trial design using a personalized survival prediction model.ResultsWe identified 38 trials. A large variability exists between trials in all patient characteristics for enrolled patients (p < 0.001), except for the proportion of men (p = 0.21). Exclusion rates varied widely (from 14% to 95%; mean 59.8%; 95% confidence interval 52.6%–66.7%). Stratification of the eligible populations into prognostic subgroups showed that eligibility criteria lead to exclusion of patients in all prognostic groups. Eligibility criteria neither reduce heterogeneity in survival time (from 22.0 to 20.5 months, p = 0.09) nor affect between-patient variability in functional decline (from 0.62 to 0.65, p = 0.25). In none of the 38 trials were the eligibility criteria found to be more efficient than the prediction model in optimizing sample size and eligibility rate.ConclusionsThe majority of patients with ALS are excluded from trial participation, which questions the generalizability of trial results. Eligibility criteria only minimally improve homogeneity in trial endpoints. An individualized risk-based criterion could be used to balance the gains in trial design and loss in generalizability.

Unraveling the Complexity of Amyotrophic Lateral Sclerosis Survival Prediction.

Objective: The heterogeneity of amyotrophic lateral sclerosis (ALS) survival duration, which varies from <1 year to >10 years, challenges clinical decisions and trials. Utilizing data from 801 deceased ALS patients, we: (1) assess the underlying complex relationships among common clinical ALS metrics; (2) identify which clinical ALS metrics are the “best” survival predictors and how their predictive ability changes as a function of disease progression.Methods: Analyses included examination of relationships within the raw data as well as the construction of interactive survival regression and classification models (generalized linear model and random forests model). Dimensionality reduction and feature clustering enabled decomposition of clinical variable contributions. Thirty-eight metrics were utilized, including Medical Research Council (MRC) muscle scores; respiratory function, including forced vital capacity (FVC) and FVC % predicted, oxygen saturation, negative inspiratory force (NIF); the Revised ALS Functional Rating Scale (ALSFRS-R) and its activities of daily living (ADL) and respiratory sub-scores; body weight; onset type, onset age, gender, and height. Prognostic random forest models confirm the dominance of patient age-related parameters decline in classifying survival at thresholds of 30, 60, 90, and 180 days and 1, 2, 3, 4, and 5 years.Results: Collective prognostic insight derived from the overall investigation includes: multi-dimensionality of ALSFRS-R scores suggests cautious usage for survival forecasting; upper and lower extremities independently degenerate and are autonomous from respiratory decline, with the latter associating with nearer-to-death classifications; height and weight-based metrics are auxiliary predictors for farther-from-death classifications; sex and onset site (limb, bulbar) are not independent survival predictors due to age co-correlation.Conclusion: The dimensionality and fluctuating predictors of ALS survival must be considered when developing predictive models for clinical trial development or in-clinic usage. Additional independent metrics and possible revisions to current metrics, like the ALSFRS-R, are needed to capture the underlying complexity needed for population and personalized forecasting of survival.

Progression and effect of cognitive-behavioral changes in patients with amyotrophic lateral sclerosis.

To prospectively evaluate the progression of cognitive-behavioral function in amyotrophic lateral sclerosis (ALS) and examine the association of cognitive-behavioral deficits with disease progression, patient quality of life (QOL), and caregiver burden. We evaluated cognitive-behavioral function using the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen at enrollment and after 7 months in a cohort of patients with ALS. Paired t tests were used to evaluate the change in the 2 assessments. Linear regression and Kruskal-Wallis tests were applied to investigate how initial cognitive or behavioral status related to outcomes. The mean test-retest interval was 6.8 months (SD 1.6). Cognitive status of the study population (n = 49) overall did not change over the study period (p = 0.06) despite progression of motor weakness (p < 0.001), though small subsets of the sample demonstrate cognitive change. Patients initially classified as behaviorally normal showed increased behavioral problems over time (t = -2.8, p = 0.009). Decline in cognitive (β = -1.3, p = 0.03) and behavioral (β = -0.76, p = 0.002) status predicted increasing caregiver burden. Behavioral abnormalities predicted decline in forced vital capacity and ALS Functional Rating Scale-Revised score (p = 0.008, 0.012) in the study population and patient QOL in the most severely affected group (t = 4.3, p = 0.003). Cognitive-behavioral change is a key aspect of disease heterogeneity in ALS. Executive function in ALS overall remains stable over 7 months as detected by an administered screening tool. However, patients may develop caregiver-reported behavioral symptoms in that time period. Screening for caregiver-reported symptoms has a particular utility in predicting future clinical decline, increased caregiver burden, and worsening patient QOL.

P 28 Voxel-based Morphometry (VBM) subcortical white matter changes correlate with disease progression in amyotrophic lateral sclerosis

Introduction Amyotrophic lateral sclerosis (ALS) is a progressive, multisystemic disorder.Signs of lower motor neurone involvement are readily detectable but the involvement of the upper motor neurone is elusive.Hence, we must identify the extent and development of ALS related changes in the brain in different subtypes of ALS to facilitate an early diagnosis and stratification for clinical trials.Previous studies applying Voxel-based morphometry (VBM) provided inconsistent results. Objective The aim of this study is to describe the heterogeneity of ALS with regard to the site of onset (bulbar vs.limb), disease duration (long vs.short), degree of disability (high vs.low) and disease progression rate (rapid vs.slow) in a large cohort of well characterized ALS patients.ALS related MRI changes should correlate with clinical parameters, such as ALSFRS-R score and D50 (50% disease progression in a model of sigmoidal decay of the ALSFRS-R). The long-term aim of this study is to evaluate VBM as a predictive marker for ALS in a representative number of subjects ( n > 100 ). Methods High resolution T1-weighted FLASH 3D scans (fl3d) in 92 ALS patients and 62 healthy controls were analyzed using VBM8 in SPM8 on matlab 2009b.Clinical parameters were collected regularly: disease duration, date and location of the first symptom, rate of disease progression and degree of disability (ALSFRS-R). Based on these clinical parameters, patients were classified into the subgroups and analyzed to determine changes in the gray and white matter. Results The mean age of 62 controls was 53.97y and of the 92 patients 60.24y.The patient group included 24 bulbar and 68 limb onsets.Average disease duration was 25 mo, wherein 26 patients had a long ( ⩾ 24mo) and 35 had a short ( ⩽ 12mo) disease duration.Mean ALSFRS-R was 37.8.46 patients had a “low” degree of disability (ALSFRS-R ⩾ 40), whereas 17 patients were “highly” impaired ( ⩽ 30).Mean progression rate was 0.66.A subgroup with a rapid form of ALS included 16 patients, with a slow form 46.Using VBM, more rapid progression, longer disease duration and more severely affected patients had a more pronounced reduction in GMV in the central, and frontal brain regions, whereas subcortical WM was more severely altered. Conclusion Using VBM in high resolution T1 in a large cohort of ALS patients, we were able to identify the key regions of ALS pathology which correlated well with three clinical progression parameters.It is likely that previous studies were underpowered and ALS related heterogeneity obscured the relevant pathology in computerized voxel-based analyses. Acknowledgement This research is supported by BMBF (Bundesministerium fur Bildung and Forschung) in the framework of the E-RARE programme (PYRAMID) and JPND (OnWebDUALS and SOPHIA) of the European Union in collaboration with the Neuroimaging Society in ALS (NiSALS) MRI repository Jena.