The Importance of Diagnostic and Prognostic Biomarker Identification and Classification Towards Understanding ALS Pathogenesis

Kadena, Katerina; Vlamos, Panayiotis

doi:10.1007/978-3-030-78787-5_16

Cited by 4 publications

(5 citation statements)

References 15 publications

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“…ALS is increasingly perceived as a multisystem neurodegenerative disorder; thus, the development of biomarker panels, and multimodal biomarkers, in which different modalities of investigation are combined to obtain more sensitive measurements, will be needed to fully capture all the different facets of ALS pathology [14].…”

Section: Discussionmentioning

confidence: 99%

“…Biomarkers can be used as tools for early diagnosis, predictors of prognosis, indicators of target engagement or therapeutic response, and to enable the discovery of future therapeutics for ALS [13,14]. Increasing our knowledge about energy-metabolism-related molecules, including Aco2, may help us to find an efficient therapeutic strategy [15].…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients

González-Mingot

Miana-Mena

Iñarrea

et al. 2023

JCM

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Background: Amyotrophic lateral sclerosis (ALS) is a multisystemic, progressive, neurodegenerative disorder. Despite it being generally fatal within a period of 2–4 years, it is highly heterogeneous; as a result, survival periods may vary greatly among individual patients. Biomarkers can serve as tools for diagnosis, prognosis, indicators of therapeutic response, and future therapeutics. Free-radical-dependent mitochondrial damage is believed to play a crucial role in neurodegeneration in ALS. Mitochondrial aconitase, which is also known as aconitase 2 (Aco2), is a key Krebs cycle enzyme and is involved in the regulation of cellular metabolism and iron homeostasis. Aco2 is very sensitive to oxidative inactivation and can aggregate and accumulate in the mitochondrial matrix, causing mitochondrial dysfunction. Loss of Aco2 activity may therefore reflect increased levels of mitochondrial dysfunction due to oxidative damage and could be relevant to ALS pathogenesis. The aim of our study was to confirm changes in mitochondrial aconitase activity in peripheral blood and to determine whether such changes are dependent on, or independent of, the patient’s condition and to propose the feasibility of using them as possible valid biomarkers to quantify the progression of the disease and as a predictor of individual prognosis in ALS. Methods: We measured the Aco2 enzymatic activity in the platelets of blood samples taken from 22 controls and 26 ALS patients at different stages of disease development. We then correlated antioxidant activity with clinical and prognostic variables. Results: Aco2 activity was significantly lower in the 26 ALS patients than in the 22 controls (p < 0.05). Patients with higher levels of Aco2 activity survived longer than those with lower levels (p < 0.05). Aco2 activity was also higher in patients with earlier onset (p < 0.05) and in those with predominantly upper motor neuron signs. Conclusions: Aco2 activity seems to be an independent factor that could be used in the long-term survival prognosis of ALS. Our findings suggest that blood Aco2 could be a leading candidate for use as a biomarker to improve prognosis. More studies are needed to confirm these results.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients

González-Mingot

Miana-Mena

Iñarrea

et al. 2023

JCM

View full text Add to dashboard Cite

show abstract

“…ALS is increasingly perceived as a multisystem neurodegenerative disorder, thus the development of biomarker panels, and of multimodal biomarkers, in which different modalities of investigation are combined to obtain more sensitive measurements, will be needed to fully capture all the different facets of ALS pathology [54].…”

Section: Discussionmentioning

confidence: 99%

“…Until another more reliable diagnostic test for ALS is developed, it is possible to use biomarkers as tools for early diagnosis, predictors of prognoses, and indicators of target engagement and/or therapeutic responses; they may also aid in the discovery and development of future therapeutic treatments for ALS [13,14]. It may be possible to nd an e cient therapeutic strategy by improving our knowledge of energy metabolism-related molecules, including that of Aco2 [15].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Aconitase enzymatic activity: a potential long survival biomarker in the blood of ALS patients

González-Mingot

Miana

Iñarrea

et al. 2023

Preprint

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Background: Amyotrophic Lateral Sclerosis (ALS) is a multisystemic, progressive, neurodegenerative disorder. Despite it being generally fatal within a period of 2–4 years, it is highly heterogeneous; as a result, survival periods may vary greatly among individual patients. In the absence of a single reliable test for ALS, Biomarkers can serve as tools for diagnosis, prognosis, indicators of therapeutic response, and future therapeutics. Free radical-dependent mitochondrial damage is believed to play a crucial role in neurodegeneration in ALS. Mitochondrial Aconitase, which is also known as Aconitase 2 (Aco2), is a key Krebs cycle enzyme and is involved in the regulation of cellular metabolism and iron homeostasis. Aco2 is very sensitive to oxidative inactivation and can aggregate and accumulate in the mitochondrial matrix, causing mitochondrial dysfunction. A loss of Aco2 activity may therefore reflect increased levels of mitochondrial dysfunction due to oxidative damage and could be relevant to ALS pathogenesis. The aim of our study was to confirm changes in Mitochondrial Aconitase activity in peripheral blood and to determine whether such changes are dependent on, or independent of, the patient's condition and to explore the feasibility of using them as valid biomarkers for quantifying disease progression and as an individual prognosispredictor in ALS. Methods: We measured Aco2 enzymatic activity in platelets of blood samples taken from 22 controls and 26 ALS patients at different stages of disease development. We then correlated antioxidant activity with clinical and prognostic variables. Results: Aco2 activity was significantly lower in the 26 ALS patients than in the 22 controls (p<0.05). Patients with higher levels of Aco2 activity survived longer than those with lower levels (p<0.05). Aco2 activity was also higher in patients with earlier onsets (p< 0.05) and in those with predominantly upper motor neuron signs. Conclusions: Aco2 activity is an independent factor that can be used in the long-survival prognosis of ALS. Our findings suggest that blood Aco2 is a leading candidate for use as a biomarker for improving prognosis. It could facilitate participant stratification in future ALS therapeutic trials and offer additional potential for therapeutic targeting.

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“…However, this classification system is often found to be inadequate due to the heterogeneity and non-specific nature of the initial symptoms of ALS, leading to a diagnostic delay of 9-15 months from onset to diagnostic confirmation, with dire consequences in a relentlessly progressive disorder where prompt therapeutic intervention is crucial. Therefore, elucidating complex mechanisms underlying sALS and identifying new reliable biomarkers represents an urgent need to improve diagnostic speed and accuracy and provide the basis for the development of effective therapeutics [8].…”

Section: Introductionmentioning

confidence: 99%

A Diagnostic Gene-Expression Signature in Fibroblasts of Amyotrophic Lateral Sclerosis

Morello

Cognata

Guarnaccia

et al. 2023

Cells

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Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease with limited treatment options. Diagnosis can be difficult due to the heterogeneity and non-specific nature of the initial symptoms, resulting in delays that compromise prompt access to effective therapeutic strategies. Transcriptome profiling of patient-derived peripheral cells represents a valuable benchmark in overcoming such challenges, providing the opportunity to identify molecular diagnostic signatures. In this study, we characterized transcriptome changes in skin fibroblasts of sporadic ALS patients (sALS) and controls and evaluated their utility as a molecular classifier for ALS diagnosis. Our analysis identified 277 differentially expressed transcripts predominantly involved in transcriptional regulation, synaptic transmission, and the inflammatory response. A support vector machine classifier based on this 277-gene signature was developed to discriminate patients with sALS from controls, showing significant predictive power in both the discovery dataset and in six independent publicly available gene expression datasets obtained from different sALS tissue/cell samples. Taken together, our findings support the utility of transcriptional signatures in peripheral cells as valuable biomarkers for the diagnosis of ALS.

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The Importance of Diagnostic and Prognostic Biomarker Identification and Classification Towards Understanding ALS Pathogenesis

Cited by 4 publications

References 15 publications

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients

Mitochondrial Aconitase enzymatic activity: a potential long survival biomarker in the blood of ALS patients

A Diagnostic Gene-Expression Signature in Fibroblasts of Amyotrophic Lateral Sclerosis

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