Feline irradiated diet-induced demyelination; a model of the neuropathology of sub-acute combined degeneration?

Autoři: Abigail B. Radcliff aff001;  Moones Heidari aff001;  Aaron S. Field aff002;  Ian D. Duncan aff001
Působiště autorů: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America aff001;  Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States of America aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0228109


Irradiation of food at 50–55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain. There is no evidence of oligodendrocyte death. The spinal cord dorsal column is initially spared yet eventually becomes severely demyelinated with subsequent loss of axons in the core and then surface of the fasciculus gracilis. However remyelination of the sub-pial axons in the dorsal column results in their protection. While there was a lack of biochemical evidence of Vitamin B12 deficiency, the pathological similarities of FIDID with sub-acute combined degeneration (SCD) led us to explore treatment with Vitamin B12. Treatment led to recovery or improvement in some cats and neurologic relapse on cessation of B12 therapy. While the reason that irradiated food is myelinotoxic in the cat remains unresolved, nonetheless the neuropathological changes match exactly what is seen in SCD and its models and provide an ideal model to study the cellular and molecular basis of remyelination.

Klíčová slova:

Axons – Cats – Central nervous system – Cobalamins – Diet – Macrophages – Vitamin B12 deficiency – Spinal cord


1. Duncan ID, Radcliff AB (2016) Inherited and acquired disorders of myelin: The underlying myelin pathology. Exp Neurol 283: 452–475. doi: 10.1016/j.expneurol.2016.04.002 27068622

2. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354: 942–955. doi: 10.1056/NEJMra052130 16510748

3. Lassmann H (2014) Mechanisms of white matter damage in multiple sclerosis. Glia 62: 1816–1830. doi: 10.1002/glia.22597 24470325

4. Stadelmann C, Wegner C, Bruck W (2011) Inflammation, demyelination, and degeneration—recent insights from MS pathology. Biochim Biophys Acta 1812: 275–282. doi: 10.1016/j.bbadis.2010.07.007 20637864

5. Stys PK, Zamponi GW, van Minnen J, Geurts JJ (2012) Will the real multiple sclerosis please stand up? Nat Rev Neurosci 13: 507–514. doi: 10.1038/nrn3275 22714021

6. Harper C, Butterworth R (1996) Nutritional and metabolic disorders. In: Graham DI, Lantos PL, editors. Greenfield's Neuropathology vol 1. 6th ed. New York: Arnold. pp. 601–655.

7. Stabler SP, Allen RH (2004) Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 24: 299–326. doi: 10.1146/annurev.nutr.24.012003.132440 15189123

8. Allen LH (2009) How common is vitamin B-12 deficiency? Am J Clin Nutr 89: 693S–696S. doi: 10.3945/ajcn.2008.26947A 19116323

9. Hathout L, El-Saden S (2011) Nitrous oxide-induced B(1)(2) deficiency myelopathy: Perspectives on the clinical biochemistry of vitamin B(1)(2). J Neurol Sci 301: 1–8. doi: 10.1016/j.jns.2010.10.033 21112598

10. Russell JSR, Batten FE, Collier J (1900) Subacute combined degeneration of the spinal cord. Brain 23: 39–100.

11. McCaddon A (2013) Vitamin B12 in neurology and ageing; clinical and genetic aspects. Biochimie 95: 1066–1076. doi: 10.1016/j.biochi.2012.11.017 23228515

12. Reynolds E (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol 5: 949–960. doi: 10.1016/S1474-4422(06)70598-1 17052662

13. Rusher DR, Pawlak R (2013) A Review of 89 Published Case Studies of Vitamin B12 Deficiency. Journal of Human Nutrition & Food Science 1: 1–12.

14. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, et al. (1988) Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. Nutrition 11: 181; discussion 180, 182.

15. Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lucking CH (1998) Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. Journal of Neurology, Neurosurgery, and Psychiatry 65: 822–827. doi: 10.1136/jnnp.65.6.822 9854956

16. Pittock SJ, Payne TA, Harper CM (2002) Reversible myelopathy in a 34-year-old man with vitamin B12 deficiency. Mayo Clinic Proceedings 77: 291–294. doi: 10.4065/77.3.291 11888035

17. Vasconcelos OM, Poehm EH, McCarter RJ, Campbell WW, Quezado ZM (2006) Potential outcome factors in subacute combined degeneration: review of observational studies. J Gen Intern Med 21: 1063–1068. doi: 10.1111/j.1525-1497.2006.00525.x 16970556

18. Puri V, Chaudhry N, Goel S, Gulati P, Nehru R, et al. (2005) Vitamin B12 deficiency: a clinical and electrophysiological profile. Electromyogr Clin Neurophysiol 45: 273–284. 16218195

19. Jain KK, Malhotra HS, Garg RK, Gupta PK, Roy B, et al. (2014) Prevalence of MR imaging abnormalities in vitamin B12 deficiency patients presenting with clinical features of subacute combined degeneration of the spinal cord. J Neurol Sci 342: 162–166. doi: 10.1016/j.jns.2014.05.020 24857760

20. Pant SS, Asbury AK, Richardson EP Jr. (1968) The myelopathy of pernicious anemia. A neuropathological reappraisal. Acta Neurol Scand 44: Suppl 5:1–36.

21. Green R, Van Tonder SV, Oettle GJ, Cole G, Metz J (1975) Neurological changes in fruit bats deficient in vitamin B12. Nature 254: 148–150. doi: 10.1038/254148a0 1118003

22. Agamanolis DP, Chester EM, Victor M, Kark JA, Hines JD, et al. (1976) Neuropathology of experimental vitamin B12 deficiency in monkeys. Neurology 26: 905–914. doi: 10.1212/wnl.26.10.905 822371

23. Agamanolis DP, Victor M, Harris JW, Hines JD, Chester EM, et al. (1978) An ultrastructural study of subacute combined degeneration of the spinal cord in vitamin B12-deficient rhesus monkeys. J Neuropathol Exp Neurol 37: 273–299. doi: 10.1097/00005072-197805000-00006 96220

24. Scalabrino G (2009) The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency. Prog Neurobiol 88: 203–220. doi: 10.1016/j.pneurobio.2009.04.004 19394404

25. Scalabrino G, Monzio-Compagnoni B, Ferioli ME, Lorenzini EC, Chiodini E, et al. (1990) Subacute combined degeneration and induction of ornithine decarboxylase in spinal cords of totally gastrectomized rats. Lab Invest 62: 297–304. 2314049

26. Duncan ID, Brower A, Kondo Y, Curlee JF Jr., Schultz RD (2009) Extensive remyelination of the CNS leads to functional recovery. Proc Natl Acad Sci USA 106: 6832–6836. doi: 10.1073/pnas.0812500106 19342494

27. Cassidy JP, Caulfield C, Jones BR, Worrall S, Conlon L, et al. (2007) Leukoencephalomyelopathy in specific pathogen-free cats. Vet Pathol 44: 912–916. doi: 10.1354/vp.44-6-912 18039904

28. Caulfield CD, Kelly JP, Jones BR, Worrall S, Conlon L, et al. (2009) The experimental induction of leukoencephalomyelopathy in cats. Vet Pathol 46: 1258–1269. doi: 10.1354/vp.08-VP-0336-C-FL 19605900

29. Child G, Foster DJ, Fougere BJ, Milan JM, Rozmanec M (2009) Ataxia and paralysis in cats in Australia associated with exposure to an imported gamma-irradiated commercial dry pet food. Aust Vet J 87: 349–351. doi: 10.1111/j.1751-0813.2009.00475.x 19703134

30. van den Ingh T, Grinwis GCM, Corbee RJ (2019) Leukoencephalomyelopathy in cats linked to abnormal fatty acid composition of the white matter of the spinal cord and of irradiated dry cat food. J Anim Physiol Anim Nutr (Berl).

31. Duncan ID, Radcliff AB, Field AS, McLellan G, Ver Hoeve JN. Promotion of remyelination by Vitamin B12 in model with global demyelination, and the cell/s responsible; 2015; Chicago, IL.

32. Allen RH, Stabler SP, Savage DG, Lindenbaum J (1993) Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. Faseb J 7: 1344–1353. doi: 10.1096/fasebj.7.14.7901104 7901104

33. Lindenbaum J, Savage DG, Stabler SP, Allen RH (1990) Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 34: 99–107. doi: 10.1002/ajh.2830340205 2339684

34. NRC (2006) Nutrient Requirements of Dogs and Cats. Washington, DC: The National Academies Press.

35. Goodman BP, Chong BW, Patel AC, Fletcher GP, Smith BE (2006) Copper deficiency myeloneuropathy resembling B12 deficiency: partial resolution of MR imaging findings with copper supplementation. AJNR Am J Neuroradiol 27: 2112–2114. 17110677

36. Winston GP, Jaiser SR (2008) Copper deficiency myelopathy and subacute combined degeneration of the cord—why is the phenotype so similar? Med Hypotheses 71: 229–236. doi: 10.1016/j.mehy.2008.03.027 18472229

37. Caulfield CD, Cassidy JP, Kelly JP (2008) Effects of gamma irradiation and pasteurization on the nutritive composition of commercially available animal diets. J Am Assoc Lab Anim Sci 47: 61–66.

38. Duncan ID, Hoffman RL (1997) Schwann cell invasion of the central nervous system of the myelin mutants. Journal of Anatomy 190: 35–49. doi: 10.1046/j.1469-7580.1997.19010035.x 9034880

39. Weil MT, Mobius W, Winkler A, Ruhwedel T, Wrzos C, et al. (2016) Loss of myelin basic protein function triggers myelin breakdown in models of demyelinating diseases. Cell Reports 16: 314–322. doi: 10.1016/j.celrep.2016.06.008 27346352

40. Heidari M, Radcliff AB, McLellan G, Ver Hoeve JN, Chan K, et al. (2019, In Press) Remyelination of the optic nerve results in improvement of the visual evoked potential that can be used as treatment outcome. Proc Natl Acad Sci.

41. Susuki K (2016) Node of Ranvier disruption in Guillain–Barré syndrome. Clinical and Experimental Neuroimmunology 7: 324–329.

42. Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, et al. (2018) Ultrastructural mechanisms of macrophage-induced demyelination in CIDP. Neurology 91: 1051–1060. doi: 10.1212/WNL.0000000000006625 30429275

43. Pillai AM, Thaxton C, Pribisko AL, Cheng JG, Dupree JL, et al. (2009) Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains. J Neurosci Res 87: 1773–1793. doi: 10.1002/jnr.22015 19185024

44. Dutta DJ, Woo DH, Lee PR, Pajevic S, Bukalo O, et al. (2018) Regulation of myelin structure and conduction velocity by perinodal astrocytes. Proc Natl Acad Sci U S A 115: 11832–11837. doi: 10.1073/pnas.1811013115 30373833

45. Olabarria M, Putilina M, Riemer EC, Goldman JE (2015) Astrocyte pathology in Alexander disease causes a marked inflammatory environment. Acta Neuropathol 130: 469–486. doi: 10.1007/s00401-015-1469-1 26296699

46. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, et al. (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157: 267–276. doi: 10.1016/S0002-9440(10)64537-3 10880396

47. Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131: 1464–1477. doi: 10.1093/brain/awn080 18490361

48. Mei F, Lehmann-Horn K, Shen YA, Rankin KA, Stebbins KJ, et al. (2016) Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife 5:e18246. doi: 10.7554/eLife.18246 27671734

49. Schultz V, van der Meer F, Wrzos C, Scheidt U, Bahn E, et al. (2017) Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination. Glia 65: 1350–1360. doi: 10.1002/glia.23167 28560740

50. Duncan ID, Radcliff AB, Heidari M, Kidd G, August BK, et al. (2018) The adult oligodendrocyte can participate in remyelination. Proc Natl Acad Sci U S A doi: 10.1073/pnas.1808064115 30487224

51. Troncoso J, Mancall EL, Schatz NJ (1979) Visual evoked responses in pernicious anemia. Arch Neurol 36: 168–169. doi: 10.1001/archneur.1979.00500390086010 435137

52. Fine EJ, Hallett M (1980) Neurophysiological study of subacute combined degeneration. J Neurol Sci 45: 331–336. doi: 10.1016/0022-510x(80)90176-8 7365506

53. Tomoda H, Shibasaki H, Hirata I, Oda K (1988) Central vs peripheral nerve conduction. Before and after treatment of subacute combined degeneration. Arch Neurol 45: 526–529. doi: 10.1001/archneur.1988.00520290058014 3358705

54. Palmer AC, Medd RK (1984) Spinal cord degeneration in hound ataxia. JSmall AnimPract 25: 139–148.

55. Sheahan BJ, Caffrey JF, Gunn HM, Keating JN (1991) Structural and biochemical changes in a spinal myelinopathy in twelve English foxhounds and two harriers. Vet Pathol 28: 117–124. doi: 10.1177/030098589102800203 2063513

56. Palmer AC, Cavanagh JB (1995) Encephalomyelopathy in young cats. J Small Anim Pract 36: 57–64. doi: 10.1111/j.1748-5827.1995.tb02822.x 7723290

57. Salvadori C, Cantile C, De Ambrogi G, Arispici M (2003) Degenerative myelopathy associated with cobalamin deficiency in a cat. J Vet Med A Physiol Pathol Clin Med 50: 292–296. doi: 10.1046/j.1439-0442.2003.00545.x 12887621

58. Hagen G, Bjerkas I (1990) Spongy degeneration of white matter in the central nervous system of silver foxes (Vulpes vulpes). Vet Pathol 27: 187–193. doi: 10.1177/030098589002700306 2191490

59. Hagen G, Bjerkas I (1991) Spongy degeneration of white matter in silver foxes: genetic and clinical aspects. Progress in Veterinary Neurology 2: 15–20.

60. Franklin RJM, ffrench-Constant C (2017) Regenerating CNS myelin—from mechanisms to experimental medicines. Nat Rev Neurosci 18: 753–769. doi: 10.1038/nrn.2017.136 29142295

61. Shen S, Sandoval J, Swiss VA, Li J, Dupree J, et al. (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11: 1024–1034. doi: 10.1038/nn.2172 19160500

62. Dayan AD, Ramsey RB (1974) An inborn error of vitamin B12 metabolism associated with cellular deficiency of coenzyme forms of the vitamin. Pathological and neurochemical findings in one case. J Neurol Sci 23: 117–128. doi: 10.1016/0022-510x(74)90147-6 4850549

63. Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, et al. (1986) Subacute combined degeneration of the cord, dementia and parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 49: 920–927. doi: 10.1136/jnnp.49.8.920 3755752

64. Smith SE, Kinney HC, Swoboda KJ, Levy HL (2006) Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab 88: 138–145. doi: 10.1016/j.ymgme.2006.02.007 16574454

65. Simpson KW, Fyfe J, Cornetta A, Sachs A, Strauss-Ayali D, et al. (2001) Subnormal concentrations of serum cobalamin (vitamin B12) in cats with gastrointestinal disease. J Vet Intern Med 15: 26–32. doi: 10.1892/0891-6640(2001)015<0026:scoscv>2.3.co;2 11215907

66. Ruaux CG, Steiner JM, Williams DA (2001) Metabolism of amino acids in cats with severe cobalamin deficiency. Am J Vet Res 62: 1852–1858. doi: 10.2460/ajvr.2001.62.1852 11763170

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