Biochemical alterations associated with ALS

Lawton, Kay A.; Cudkowicz, Merit; Brown, Meredith V.; Alexander, Danny; Caffrey, Rebecca; Wulff, Jacob; Bowser, Robert; Lawson, Robert; Jaffa, Matt; Milburn, Michael V.; Ryals, John; Berry, James

doi:10.3109/17482968.2011.619197

Cited by 86 publications

(83 citation statements)

References 35 publications

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“…Biochemical pathways associated with hypermetabolism have been associated with ALS 20 and our data suggest that a higher BMI at baseline is an independent predictor of longer survival in ALS, though it does not appear to directly predict the rate of decline of ALSFRS-R or VC. This result confirms and extends previously published studies on the association between BMI and survival in people with ALS.…”

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confidence: 62%

The PRO-ACT database

et al. 2014

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Objective: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS.Methods: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p 5 0.003. Results:The ALSFRS-R rate of decline was 1.02 (62.3) points per month and the VC rate of decline was 2.24% of predicted (66.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p 5 0.01) and VC (p , 0.0001), and longer survival (p 5 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p 5 0.01) and VC (p , 0.0001), and longer survival (p 5 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p , 0.0001). Conclusion:The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival. Neurology ® 2014;83:1719-1725 GLOSSARY ALS 5 amyotrophic lateral sclerosis; ALSFRS 5 ALS Functional Rating Scale; ALSFRS-R 5 revised ALS Functional Rating Scale; BMI 5 body mass index; CDS 5 common data structure; CI 5 confidence interval; HR 5 hazard ratio; PRO-ACT 5 Pooled Resource Open-Access ALS Clinical Trials; VC 5 vital capacity.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord. People with ALS have progressive voluntary muscle weakness involving the arms, legs, speech, swallowing, and breathing. Because ALS is a rare disease with an annual incidence of 2/100,000, 2 clinical trials have typically been relatively small, with the largest studies including fewer than 1,000 participants. Therefore, aggregation of studies is needed to allow enough statistical power to answer important questions about ALS natural history and clinical symptoms in order to overcome some of the barriers associated with drug development for orphan diseases.The Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database was designed to provide just such an opportunity. This database represents the largest aggregation of ALS clinical trial data available. Sixteen phase II and III ALS trials and one large observational s...

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confidence: 62%

The PRO-ACT database

et al. 2014

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“…Some studies were limited by the number of samples in the analysis (Turner et al., 2013), and some chose a different control population into the study (Tateishi et al., 2010). In addition, a panel of biomarkers has been detected in either the CSF or serum in some recent studies, but they were either more concerned with a diagnosis rather than a clinically relevant prognosis (Gray et al., 2015; Kuhle et al., 2009; Lawton et al., 2012) or only measuring factors either the CSF or serum (Ehrhart et al., 2015; Mitchell et al., 2009). …”

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confidence: 99%

Evaluating the levels of CSF and serum factors in ALS

et al. 2017

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ObjectivesThe aim of this study was to identify CSF and serum factors as biomarkers that may aid in distinguishing ALS patients from control subjects and predicting ALS progression as well as prognosis.MethodsSerum and CSF samples from 105 patients with ALS and 56 control subjects were analyzed for 13 factors using ELISA. The revised ALS functional rating scale (ALSFRS‐r) was used to evaluate the overall functional status of ALS patients, and we also followed up with ALS patients either by phone or with clinic visits for five years after enrollment in this study. Finally, we examined the correlations between factor levels and various clinical parameters and evaluated the predictive value for prognosis through a multivariate statistic model.ResultsA total of eight factors were obviously elevated in CSF, and twelve markers were increased in serum. In the correlation analyses, there were trends toward higher bFGF, VEGF, MIP‐1α levels in ALS with a longer disease duration and slower disease progression in both CSF and serum. Higher MCP‐1 levels were associated with worse disease severity and faster progression, and the IFN‐γ levels were positively associated with disease progression in either CSF or serum. Finally, a better prognosis was observed with higher levels bFGF in CSF and VEGF in CSF and serum; conversely, patients with higher levels of IFN‐γ in the CSF had shorter overall survival.ConclusionsWe demonstrated that a factor profile of ALS patients is distinct from control subjects and may be useful in clinical practice and therapeutic trials.

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“…Many untargeted metabolite studies have been previously performed in CSF [171,172], plasma [149,173], and serum [174], but metabolite identification is usually confined to searches using in-house databases, which biases the results. Further untargeted studies could yield deeper insights into metabolic dysregulation associated with ALS.…”

Section: Current Status and Future Directionsmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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Biochemical alterations associated with ALS

Cited by 86 publications

References 35 publications

The PRO-ACT database

The PRO-ACT database

Evaluating the levels of CSF and serum factors in ALS

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

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