Highlights
- •ALS patients have altered levels of metabolic proteins and adipokines relative to controls.
- •There is a positive correlation between the expression of plasma nerve growth factor relative to disease duration.
- •There is an inverse correlation between plasma glucagon and ALSFRS-R.
Abstract
Keywords
1. Introduction
- DeJesus-Hernandez M.
- Mackenzie I.R.
- Boeve B.F.
- Boxer A.L.
- Baker M.
- Rutherford N.J.
- Nicholson A.M.
- Finch N.A.
- Flynn H.
- Adamson J.
- Kouri N.
- Wojtas A.
- Sengdy P.
- Hsiung G.Y.
- Karydas A.
- Seeley W.W.
- Josephs K.A.
- Coppola G.
- Geschwind D.H.
- Wszolek Z.K.
- Feldman H.
- Knopman D.S.
- Petersen R.C.
- Miller B.L.
- Dickson D.W.
- Boylan K.B.
- Graff-Radford N.R.
- Rademakers R.
- Kabashi E.
- Valdmanis P.N.
- Dion P.
- Spiegelman D.
- McConkey B.J.
- Vande Velde C.
- Bouchard J.P.
- Lacomblez L.
- Pochigaeva K.
- Salachas F.
- Pradat P.F.
- Camu W.
- Meininger V.
- Dupre N.
- Rouleau G.A.
- Maruyama H.
- Morino H.
- Ito H.
- Izumi Y.
- Kato H.
- Watanabe Y.
- Kinoshita Y.
- Kamada M.
- Nodera H.
- Suzuki H.
- Komure O.
- Matsuura S.
- Kobatake K.
- Morimoto N.
- Abe K.
- Suzuki N.
- Aoki M.
- Kawata A.
- Hirai T.
- Kato T.
- Ogasawara K.
- Hirano A.
- Takumi T.
- Kusaka H.
- Hagiwara K.
- Kaji R.
- Kawakami H.
- Crugnola V.
- Lamperti C.
- Lucchini V.
- Ronchi D.
- Peverelli L.
- Prelle A.
- Sciacco M.
- Bordoni A.
- Fassone E.
- Fortunato F.
- Corti S.
- Silani V.
- Bresolin N.
- Di Mauro S.
- Comi G.P.
- Moggio M.
- Haidet-Phillips A.M.
- Hester M.E.
- Miranda C.J.
- Meyer K.
- Braun L.
- Frakes A.
- Song S.
- Likhite S.
- Murtha M.J.
- Foust K.D.
- Rao M.
- Eagle A.
- Kammesheidt A.
- Christensen A.
- Mendell J.R.
- Burghes A.H.
- Kaspar B.K.
- Shimizu T.
- Nagaoka U.
- Nakayama Y.
- Kawata A.
- Kugimoto C.
- Kuroiwa Y.
- Kawai M.
- Shimohata T.
- Nishizawa M.
- Mihara B.
- Arahata H.
- Fujii N.
- Namba R.
- Ito H.
- Imai T.
- Nobukuni K.
- Kondo K.
- Ogino M.
- Nakajima T.
- Komori T.
- Wills A.M.
- Hubbard J.
- Macklin E.A.
- Glass J.
- Tandan R.
- Simpson E.P.
- Brooks B.
- Gelinas D.
- Mitsumoto H.
- Mozaffar T.
- Hanes G.P.
- Ladha S.S.
- Heiman-Patterson T.
- Katz J.
- Lou J.S.
- Mahoney K.
- Grasso D.
- Lawson R.
- Yu H.
- Cudkowicz M.
- Network M.D.A.C.R.
- Shimizu T.
- Nagaoka U.
- Nakayama Y.
- Kawata A.
- Kugimoto C.
- Kuroiwa Y.
- Kawai M.
- Shimohata T.
- Nishizawa M.
- Mihara B.
- Arahata H.
- Fujii N.
- Namba R.
- Ito H.
- Imai T.
- Nobukuni K.
- Kondo K.
- Ogino M.
- Nakajima T.
- Komori T.
2. Materials and methods
2.1 Study population
Control | ALS | p | |
---|---|---|---|
Number of patients | 34 | 68 | NA |
Age (mean, SD) (years) | 57.3 (10.5) | 60.4 (9.8) | 0.14 |
Median, IQR | 58.0, 50.0–66.3 | 63.0, 53.3–68.0 | |
BMI (mean, SD) (kg/m2) | 28.4 (4.2) | 26.3 (5.1) | 0.10 |
Median, IQR | 27.9, 25.3–31.1 | 26.2, 22.5–30.4 | |
Sex ratio (men/women) | 23/11 | 47/21 | |
ALSFRS-R score (mean, minimum–maximum) | |||
Male | NA | 36.6 (24–48) | |
Female | NA | 36.0 (25–44) | |
Familial/sporadic | |||
Male | NA | 4/43 | |
Female | NA | 3/18 | |
Site of onset (upper/lower limb) | |||
Male | NA | 23/24 | |
Female | NA | 7/14 | |
Riluzole | |||
Male | NA | 18 | |
Female | NA | 8 |
2.2 Plasma collection
2.3 Multiplex assays
2.4 Statistical analysis
3. Results
3.1 Expression of metabolic proteins and adipokines in ALS patients and controls
Control | 95% CI (range) | ALS | 95% CI (range) | p | |
---|---|---|---|---|---|
Metabolic factors | |||||
Amylin (pg/ml) | 26.3 (14.4) | 21.3–31.4 | 31.8 (36.3) | 23.0–40.6 | 0.40 |
c-Peptide (ng/ml) | 3.4 (1.9) | 2.69–4.05 | 3.7 (5.5) | 2.39–5.05 | 0.72 |
Ghrelin (pg/ml) | 25.1 (28.2) | 15.3–35.0 | 13.2 (11.2) | 10.5–15.9 | <0.01 |
GIP (ng/ml) | 0.4 (0.3) | 0.303–0.484 | 0.3 (0.3) | 0.21–0.33 | <0.01 |
GLP-1 (pg/ml) | 30.3 (35.7) | 345–627 | 28.5 (30.7) | 230–379 | 0.80 |
Glucagon (pg/ml) | 44.1 (34.1) | 31.6–56.6 | 37.7 (24.1) | 31.8–43.7 | 0.30 |
Insulin (pg/ml) | 53.4 (46.4) | 37.2–69.6 | 46.6 (51.7) | 34.1–59.1 | 0.52 |
PP (pg/ml) | 485.7 (404.0) | 345–627 | 304.5 (305.5) | 231–378 | <0.01 |
PYY (pg/ml) | 172.8 (123.2) | 130–216 | 158.9 (107.3) | 133–185 | 0.56 |
Adipokines | |||||
Adiponectin (mg/ml) | 26.7 (22.7) | 18.7–34.8 | 40.1 (45.4) | 29.1–51.2 | <0.05 |
HGF (pg/ml) | 352.9 (211.3) | 279–426 | 401.0 (260.2) | 338–464 | 0.35 |
IL-6 (pg/ml) | 3.0 (2.4) | 2.07–3.81 | 9.0 (22.4) | 3.59–145 | <0.05 |
IL-8 (pg/ml) | 3.1 (2.5) | 2.23–3.97 | 4.6 (2.6) | 3.93–5.21 | <0.01 |
Leptin (ng/ml) | 17.2 (27.2) | 7.51–26.8 | 15.0 (27.5) | 8.25–21.7 | 0.71 |
Lipocalin-2 (ng/ml) | 104.3 (40.8) | 90.1–119 | 123.9 (40.9) | 114–134 | <0.05 |
MCP-1 (pg/ml) | 161.6 (76.1) | 135–188 | 164.6 (76.8) | 146–183 | 0.83 |
NGF (pg/ml) | 8.0 (4.1) | 6.59–9.45 | 10.3 (21.9) | 4.98–15.6 | 0.55 |
PAI-1 (ng/ml) | 55.5 (39.8) | 41.6–69.3 | 95.9 (60.6) | 81.2–111 | <0.01 |
Resistin (ng/ml) | 57.6 (37.0) | 44.7–70.5 | 66.2 (39.3) | 56.7–75.7 | 0.30 |
TNFα (pg/ml) | 3.1 (1.4) | 2.59–3.56 | 3.7 (1.4) | 3.40–4.07 | <0.01 |
3.2 Correlation analysis of plasma metabolic proteins and adipokines with clinical features
3.2.1 Correlation of plasma metabolic proteins and adipokines with BMI

3.2.2 Correlation of plasma metabolic proteins and adipokines with ALSFRS-R and disease duration
4. Discussion
Hormone/peptide | Regulation in ALS | Relation to BMI in ALS | Relation to ALSFRS-R | Relation to disease duration | Possible metabolic consequences in ALS |
---|---|---|---|---|---|
Metabolic Factors | |||||
C-peptide | No change | Positive correlation | No correlation | No correlation | Impaired C-peptide release may underlie impaired insulin function and glucose homeostasis in ALS. Unlikely as secretion appears to be normal. |
Ghrelin | Decreased | No correlation | No correlation | No correlation | Reduced hunger leading to reduced food intake and possibly weight loss. |
GIP | Decreased | No correlation | No correlation | No correlation | Reduced insulin secretion resulting in reduced capacity to use glucose as energy; reduced lipogenesis resulting in an inability to accumulate fat mass. |
Glucagon | No change | No correlation | Negative correlation | No correlation | Impaired capacity to increase circulating levels of glucose; impaired glucose tolerance resulting in reduced capacity to use glucose as energy. May not be reflected by circulating levels. |
Insulin | No change | Positive correlation | No correlation | No correlation | Impaired insulin action thought to contribute to impaired glucose tolerance resulting in impaired capacity to use glucose as energy. May not be reflected by circulating levels. |
PP | Decreased | No correlation | No correlation | No correlation | Reduced peripheral insulin action resulting in reduced capacity to use glucose as energy; decreased secretion of gastric juices resulting in gastrointestinal dysfunction. |
Adipokines | |||||
Adiponectin | No change | Negative correlation | No correlation | No correlation | Increased risk of metabolic derangements associated with increased fat mass (eg. insulin resistance). |
IL-6 | Increased | No correlation | No correlation | No correlation | May contribute to the development of insulin resistance resulting in reduced capacity to use glucose as energy. |
IL-8 | Increased | No correlation | No correlation | No correlation | May contribute to the development of insulin resistance resulting in reduced capacity to use glucose as energy. |
Leptin | No change | Positive correlation | No correlation | No correlation | Increased satiety relative to fat mass resulting in reduced food intake as a means to modulate energy balance. |
Lipocalin-2 | Increased | No correlation | No correlation | No correlation | Increased total energy metabolism and increased breakdown of fat leading to depletion of fat mass and subsequent weight loss and reduced BMI. |
NGF | No change | No correlation | No correlation | Positive correlation | Increase relative to disease duration may reflect reduced food intake. |
PAI-1 | Increased | No correlation | No correlation | No correlation | May contribute to the development of insulin resistance resulting in reduced capacity to use glucose as energy. |
TNFα | Increased | No correlation | No correlation | No correlation | Induction of lipolysis resulting in the breakdown and mobilization of fat stores and subsequent weight loss and reduced BMI. |
- Pradat P.F.
- Bruneteau G.
- Gordon P.H.
- Dupuis L.
- Bonnefont-Rousselot D.
- Simon D.
- Salachas F.
- Corcia P.
- Frochot V.
- Lacorte J.M.
- Jardel C.
- Coussieu C.
- Forestier N.L.
- Lacomblez L.
- Loeffler J.P.
- Meininger V.
- Pradat P.F.
- Bruneteau G.
- Gordon P.H.
- Dupuis L.
- Bonnefont-Rousselot D.
- Simon D.
- Salachas F.
- Corcia P.
- Frochot V.
- Lacorte J.M.
- Jardel C.
- Coussieu C.
- Forestier N.L.
- Lacomblez L.
- Loeffler J.P.
- Meininger V.
- Stefan N.
- Vozarova B.
- Funahashi T.
- Matsuzawa Y.
- Weyer C.
- Lindsay R.S.
- Youngren J.F.
- Havel P.J.
- Pratley R.E.
- Bogardus C.
- Tataranni P.A.
- Boekholdt S.M.
- Peters R.J.
- Hack C.E.
- Day N.E.
- Luben R.
- Bingham S.A.
- Wareham N.J.
- Reitsma P.H.
- Khaw K.T.
Acknowledgments
Appendix A. Supplementary data
Supp Table 1. Summary of source and biological role of metabolic factors and adipose specific or enriched proteins (adipokines) assessed.
Supp Table 2, Comparison of the expression of metabolic markers and adipokines between male and female amyotrophic lateral sclerosis (ALS) patients when matched for body mass index (BMI).
Supp Table 3. Spearman correlation analysis relative to body mass index (BMI) and comparison of fit for metabolic factors and adipokines in control subjects and amyotrophic lateral sclerosis (ALS) patients.
Supp Table 4. Spearman correlation analysis of metabolic factors and adipokines relative to amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) scores and disease duration in patients.
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