Body mass index associates with amyotrophic lateral sclerosis survival and metabolomic profiles

Goutman, Stephen A.; Boss, Jonathan; Iyer, Gayatri; Habra, Hani; Savelieff, Masha G.; Karnovsky, Alla; Mukherjee, Bhramar; Feldman, Eva L.

doi:10.1002/mus.27744

Cited by 15 publications

(11 citation statements)

References 77 publications

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“…194 Moreover, a recent Michigan cohort was reported to show BMI gain 10-15 years pre-onset, followed by BMI loss 5 years pre-onset. 195 This is precisely the pattern predicted here: the initial BMI gain is due to chronic secretion possibly followed by mild IR, while the subsequent BMI loss is due to the collapse of insulin function and the core disease processes.…”

Section: Insulin Trajectories Db1 and Bmi In Alssupporting

confidence: 78%

Insulin in Amyotrophic Lateral Sclerosis: Impairment, Tests and Treatment

Rappoport¹

2023

Preprint

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Background. Amyotrophic Lateral Sclerosis (ALS) is a devastating disease involving motor neuron degeneration. The few drugs approved for treatment have at most a marginal benefit, and death usually occurs 2-5 years after diagnosis. Methods. A thorough manual examination of the relevant literature, covering over 35,000 papers. Results. Two major phenomena that are generally not known to clinicians were found. First, insulin signaling is impaired in ALS even in patients not diagnosed with diabetes (DB). Almost all studies that have explicitly tested insulin function in non-DB ALS patients using glucose tolerance tests (18 out of 20, 1964-2022, different groups) have found it to be impaired. Second, there is strong evidence for excessive insulin-independent glucose uptake (IIGU) in ALS. In addition, (i) early/late diabetes are associated with increased/decreased risk, respectively; (ii) insulin-based diabetes drugs are protective in ALS in large retrospective human studies; and (iii) strong animal and human evidence shows that insulin opposes all of the major pathological processes in ALS. Conclusion. Most ALS patients have insulin impairment, yet this is commonly not diagnosed, likely because excessive IIGU normalizes glucose levels. The impairment promotes disease progression. Late diabetes is associated with decreased risk because high glucose levels indicate non-excessive IIGU, and because diabetes drugs are protective. Insulin-based treatment (e.g., GLP1 agonists, insulin) is beneficial and can be disease-modifying in ALS and in frontotemporal dementia variants comorbid with ALS. ALS patients should be routinely tested for insulin function and treated if test results are positive.

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Section: Insulin Trajectories Db1 and Bmi In Alssupporting

confidence: 78%

Insulin in Amyotrophic Lateral Sclerosis: Impairment, Tests and Treatment

Rappoport¹

2023

Preprint

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“…1). Prior to diagnosis, a significant proportion of ALS patients display a lower body mass index (BMI) [4 ▪▪ ], and two-thirds lost already weight at diagnosis [5–7]. The progressive weight loss is a strong indicator of a faster disease progression and a shorter survival, acting as an independent prognosis factor [4 ▪▪ ,5,6,7].…”

Section: Weight Loss: the Hallmark Of Metabolic Dysfunction In Amyotr...mentioning

confidence: 99%

“…Prior to diagnosis, a significant proportion of ALS patients display a lower body mass index (BMI) [4 ▪▪ ], and two-thirds lost already weight at diagnosis [5–7]. The progressive weight loss is a strong indicator of a faster disease progression and a shorter survival, acting as an independent prognosis factor [4 ▪▪ ,5,6,7]. Besides, lower body fat mass increases the risk of developing ALS [8], while higher body fat content and subcutaneous fat are associated with a decreased risk of ALS and mortality [9–11].…”

Section: Weight Loss: the Hallmark Of Metabolic Dysfunction In Amyotr...mentioning

confidence: 99%

“…In addition, untargeted metabolomics helped to identify differential altered metabolic pathways in ALS patients [43]. Recently, Goutman and collaborators analyzed the correlation between blood metabolic profiles and BMI trajectories [4 ▪▪ ]. The authors first showed that ALS patients were characterized by a significant BMI loss 5 years but not 10 years before study entry and that decreased BMI was associated with shorter survival and distinct metabolomic profile [4 ▪▪ ].…”

Section: The Amyotrophic Lateral Sclerosis Metabolic Profile Correlat...mentioning

confidence: 99%

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Abnormal energy metabolism in ALS: a key player?

Burg

Bosch

2023

Current Opinion in Neurology

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Purpose of the review Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance. Recent findings The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach. Summary Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.

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“…Amyotrophic lateral sclerosis (ALS) is a phenotypically heterogeneous disease, encompassing cases with a predominance of either upper or lower motor neuron degeneration, different degrees of bulbar function involvement, and varied levels of cognitive impairment, ranging from normal cognition to frontotemporal dementia. Goutman and colleagues 1 reported that 10‐y body mass index (BMI) trends differed in ALS versus controls, with BMI loss in the 5 y prior to diagnosis despite BMI gains 10–5 y prior in both groups. This paper highlights the role of BMI in ALS, both in the premorbid phase and during the clinical phase of the disease, supporting the notion of the presence of a “metabolic axis” alongside the classic motor and cognitive/behavioral axes.…”

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confidence: 99%