New therapeutic approaches for familial amyloidotic polyneuropathy (FAP)

Amyloid

Volumn 10, Issue SUPPL. 1, 2003, Pages 55-66

  Ando, Yukio ^a  

^a KUMAMOTO UNIVERSITY   (Japan)

Author keywords

Familial amyloidotic polyneuropathy; Free radical scavenger therapy; Gene therapy; Metal ions; Oxidative stress; Single stranded oligonucleotide; Transthyretin

Indexed keywords

BENZENE DERIVATIVE; BROMO 2,5 BIS(3 HYDROXYCARBONYL 4 HYDROXY)STYRYLBENZENE; CONGO RED; FREE RADICAL; IMMUNOSUPPRESSIVE AGENT; METAL ION; OLIGONUCLEOTIDE; PREALBUMIN; STYRENE DERIVATIVE; SUPEROXIDE DISMUTASE; UNCLASSIFIED DRUG;

CHIMERA; CONCENTRATION RESPONSE; CONFERENCE PAPER; FAMILIAL AMYLOID POLYNEUROPATHY; GENE THERAPY; HUMAN; LIVER TRANSPLANTATION; OXIDATIVE STRESS; PATIENT CARE; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; RECEPTOR DOWN REGULATION; SENILE PLAQUE;

EID: 0242643739     PISSN: 13506129     EISSN: None     Source Type: Journal    
DOI: 10.1080/13506129.2003.12088569     Document Type: Conference Paper

References (98)

1. Andrade C (1952). A peculiar form of peripheral neuropathy: Familial generalized amyloidosis with special involvement of the peripheral nerves. Brain 75, 408-427
2. Araki S (1984). Type I familial amyloidotic polyneuropathy (Japanese type). Brain Dev 6, 128-133
3. Benson MD (1989). Familial amyloidotic polyneuropathy. Trends Neurosci 12, 88-92
4. Benson MD and Uemichi T (1996). Transthyretin amyloidosis. Amyloid: Int J Exp Clin Invest 3, 44-56
5. Ando Y, Araki S and Ando M (1993). Transthyretin related amyloidosis. Intern Med 32, 920-922
6. Ando Y and Suhr O (1998). Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid: Int J Exp Clin Invest 5, 288-300
7. Holmgren G, Ericzon BG, Groth CG, Steen L, Suhr O, Andersen O, Wallin BG, Seymour A, Richardson S, Hawkins PN and Pepys MB (1993). Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341, 113-116
8. Ericzon BG, Holmgren G, Lundgren E and Suhr OB (1999). New structural information and update on liver transplantation in transthyretin-associated amyloidosis. Report from the 4th International Symposium on Familial Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders & the 3rd International Workshop on Liver Transplantation in Familial Amyloid Polyneuropathy, Umea Sweden, June 1999. Amyloid: Int J Exp Clin Invest 7, 145-147
9. Skinner M, Lewis WD, Jones LA, Kasirsky J, Kane K, Ju ST, Jenkins R, Falk RH, Simms RW and Cohen AS (1994). Liver transplantation as a treatment for familial amyloidotic polyneuropathy. Ann Intern Med 120, 133-134
10. Takei Y, Ikeda S, Hashikura Y, Ikegami T and Kawasaki S (1999). Partial-liver transplantation to treat familial amyloid polyneuropathy: Follow-up of 11 patients. Ann Intern Med 131, 592-595
11. Ando Y, Tanaka Y, Ando E, Yamashita T, Nishida Y, Tashima K, Suga M, Uchino M and Ando M (1995). Effect of liver transplantation on autonomic dysfunction in familial amyloidotic polyneuropathy type I. Lancet 345, 195-196
12. Suhr O, Danielsson A, Rydh A, Nyhlin N, Hietala SO and Steen L (1996). Impact of gastrointestinal dysfunction on survival after liver transplantation for familial amyloidotic polyneuropathy. Dig Dis Sci 41, 1909-1914
13. Lendoire J, Trigo P, Aziz H, Cueto G, Ando Y, Tashima K, Ohlsson PI, Cederquist K, Holmgren G and Suhr OB (1999). Liver transplantation in transthyretin familial amyloid polyneuropathy: First report from Argentina. Amyloid: Int J Exp Clin Invest 6, 297-300
14. Ando Y, Terazaki H, Haraoka K, Tajiri T, Nakamura M, Obayashi K, Misumi S, Shoji S, Hata K, Nakagawa K, Ishizaki T, Uemoto S, Inomata Y, Tanaka K and Okabe H (2002). Presence of autoantibody against ATTRVal30Met after sequential liver transplantation. Transplantation 73, 674-675
15. Ando E, Ando Y and Haraoka K (2001). Ocular amyloid imvolvement after liver transplantation for polyneuropathy. Ann Intern Med 135, 931-932
16. Sales-Luis ML, Galvao M, Carvalho M, Sousa G, Alves MM and Serrao R (1991). Treatment of familial amyloidotic polyneuropathy (Portuguese type) by plasma exchange. Muscle Nerve 14, 377-378
17. Continho P, Macedo E, Estacio A, Saraiva A, Costa PP and Saraiva MJM (1988). Periodic plasma exchanges in treatment of familial amyloid polyneuropathy: Preliminary results. In Isobe T, Araki S, Uchino F, Kito S and Tsubura E (eds). Amyloid and Amyloidosis, pp 845-849. (New York: Plenum Press)
18. Ikegawa S, Tanase S, Morino Y, Yi S, Ando Y, Miyazaki A and Araki S (1988). Evaluation of serum variant prealbumin levels, and its behavior after plasma exchange for familial amyloidotic polyneuropathy (type 1). In Isobe T, Araki S, Uchino F, Kito S and Tsubura E (eds). Amyloid and Amyloidosis, pp 839-844. (New York: Plenum Press)
19. Regnault V, Costa PM, Teixeira A, Rivat C, Stoltz JF, Saraiva MJ and Costa PP (1992). Specific removal of transthyretin from plasma of patients with familial amyloidotic polyneuropathy: Optimization of an immunoadsorption procedure. Int J Artif Organs 15, 249-255
20. Costa PMP and Costa PP (1998). The future of selective apheresis in FAP. Amyloid: Int J Exp Clin Invest 5, 143-144
21. Tokuda T, Kondo T, Hanaoka N, Takei Y, Kametani F, Yamada Y, Tamura Y, Yoshida M, Yamawaki N and Ikeda S (1998). A selective transthyretin-adsorption column for the treatment of patients with familial amyloid polyneuropathy. Amyloid: Int J Exp Clin Invest 5, 111-116
22. Jouquan J, Pennec Y, Mottier D, Boles JM, Morin JF, Youinou P and Garre M (1983). Retinol carrier protein, prealbumin and transferrin. Influence of age and sex on the serum concentration of proteins with a short half-life. Presse Med 12, 1877
23. Dickson PW, Howlett GJ and Schreiber G (1982). Metabolism of prealbumin in rats and changes induced by acute inflammation. Eur J Biochem 129, 289-293
24. Ando Y, Tanaka Y, Nakazato M, Ericzon BG, Yamashita T, Tashima K, Sakashita N, Suga M, Uchino M and Ando M (1995). Change in variant transthyretin levels in patients with familial amyloidotic polyneuropathy type I following liver transplantation. Biochem Biophys Res Commun 211, 354-358
25. Ando Y, Yamashita T, Nakamura M, Tanaka Y, Hashimoto M, Tashima K, Suhr O, Uemura Y, Obayashi K, Terazaki H, Suga M, Uchino M and Ando M (1997). Down regulation of a harmful variant protein by replacement of its normal protein. Biochem Biophys Acta 1362, 39-46
26. Kelly JW and Lansbury PT, Jr (1994). A chemical approach to elucidate the mechanism of transthyretin and β-protein amyloid formation. Amyloid: Int J Exp Clin Invest 1, 186-205
27. Colon W and Kelley JW (1992). Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654-8660
28. McCutchen SL, Colon W and Kelley JW (1993). Transthyretin mutation Leu-55-Pro alters tetrameric stability and increases amyloidogenicity. Biochemistry 32, 12119-12127
29. Alves IL, Divino CM, Schussler GC, Altland K, Almeida MR, Palha JA, Coelho T, Costa PP and Saraiva MJ (1993). Thyroxine binding in a TTR Met 119 kindred. J Clin Endocrinol Metab 77, 484-488
30. Longo Alves I, Hays MT and Saraiva MJ (1997). Comparative stability and clearance of [Met30]transthyretin and [Met119]transthyretin. Eur J Biochem 249, 662-668
31. Almeida MR, Damas AM, Lans MC, Brouwer A and Saraiva MJ (1997). Thyroxine binding to transthyretin Met 119. Comparative studies of different heterozygotic carriers and structural analysis. Endocrine 6, 309-315
32. Almeida MR, Alves IL, Terazaki H, Ando Y and Saraiva MJ (2000). Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy. TTR R104H and TTR T119M. Biochem Biophys Res Commun 270, 1024-1028
33. Terazaki H, Ando Y, Misumi S, Nakamura M, Ando E, Matsunaga N, Shoji S, Okuyama M, Ideta H, Nakagawa K, Ishizaki T, Ando M and Saraiva MJ (1999). A novel compound heterozygote (FAP ATTR Arg104His/ATTR Val30Met) with high serum transthyretin (TTR) and retinol binding protein (RBP) levels. Biochem Biophys Res Commun 264, 365-370
34. Baures PW, Oza VB, Peterson SA and Kelly JW (1999). Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid. Bioorg Med Chem 7, 1339-1347
35. Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC and Kelly JW (1998). Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci USA 95, 12956-12960
36. 3+. Presented at the 5th International Symposium on Familial Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders (Abstract). 2003
37. Guy CD and Jones CK (2001). Abdominal fat pad aspiration biopsy for tissue confirmation of systemic amyloidosis: Specificity, positive predictive value, and diagnostic pitfalls. Diagn Cytopathol 24, 181-185
38. Kaplan B, Vidal R, Kumar A, Ghiso J and Gallo G (1999). Immunochemical microanalysis of amyloid proteins in fine-needle aspirates of abdominal fat. Am J Clin Pathol 112, 403-407
39. Masouye I (1997). Diagnostic screening of systemic amyloidosis by abdominal fat aspiration: An analysis of 100 cases. Am J Dermatopathol 19, 41-45
40. Westermark GT and Westermark P (2000). Endocrine amyloid a subject of increasing interest for the next century. Amyloid: Int J Exp Clin Invest 7, 19-22
41. 123I-labeled serum amyloid P component. N Engl J Med 323, 508-513
42. 99mTc-DPD scintigraphy in transthyretin-related familial amyloidotic polyneuropathy. Eur J Nucl Med 29, 376-379
43. Giger M, Baumgartner HR and Zbinden G (1974). Toxicological effects of Evans blue and Congo red on blood platelets. Agents Actions 4, 173-180
44. Klunk WE, Debnath ML and Pettegrew JW (1995). Chrysamine-G binding to Alzheimer and control brain: Autopsy study of a new amyloid probe. Neurobiol Aging 16, 541-548
45. Klunk WE, Debnath ML, Koros AM and Pettegrew JW (1998). Chrysamine-G, a lipophilic analogue of Congo red, inhibits A beta-induced toxicity in PC12 cells. Life Sci 63, 1807-1814
46. 99Tcm-labelled N2S2 conjugates of chrysamine G for amyloid deposits of systemic amyloidosis. Nucl Med Commun 22, 553-558
47. 99mTc- MAMA-chrysamine G as an in vivo probe for amyloidosis. Amyloid: Int J Exp Clin Invest 8, 202-214
48. 99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease. Eur J Nucl Med 26, 1392-1399
49. Skovronsky DM, Zhang B, Kung MP, Kung HF, Trojanowski JQ and Lee VM (2000). In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 97, 7609-7614
50. Schmidt ML, Schuck T, Sheridan S, Kung MP, Kung H, Zhuang ZP, Bergeron C, Lamarche JS, Skovronsky D, Giasson BI, Lee VM and Trojanowski JQ (2001). The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3- hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse beta-pleated sheet structures in postmortem human neurodegenerative disease brains. Am J Pathol 159, 937-943
51. Klunk WE, Debnath ML and Pettegrew JW (1994). Development of small molecule probes for the beta-amyloid protein of Alzheimer's disease. Neurobiol Aging 15, 691-698
52. Zhuang ZP, Kung MP, Hou C, Plossl K, Skovronsky D, Gur TL, Trojanowski JQ, Lee VM and Kung HF (2001). IBOX(2-(4′-dimethylaminophenyl)-6- iodobenzoxazole): A ligand for imaging amyloid plaques in the brain. Nucl Med Biol 28, 887-894
53. Okahata Y, Niikura K, Sugiura Y, Sawada M and Morii T (1998). Kinetic studies of sequence-specific binding of GCN4-bZIP peptides to DNA strands immobilized on a 27-MHz quartz-crystal microbalance. Biochemistry 37, 5666-5672
54. Matsuno H, Niikura K and Okahata Y (2001). Direct monitoring kinetic studies of DNA polymerase reactions on a DNA-immobilized quartz-crystal microbalance. Chemistry 7, 3305-3312
55. Merlini G, Ascari E, Amboldi N, Bellotti V, Arbustini E, Perfetti V, Ferrari M, Zorzoli I, Marinone MG, Garini P, Diegori M, Trizio D and Ballinari D (1995). Interaction of the anthracycline 4′-iodo-4′- deoxydoxorubicin with amyloid fibrils: Inhibition of amyloidogenesis. Proc Natl Acad Sci USA 92, 2959-2963
56. Gertz MA, Lacy MQ, Dispenzieri A, Cheson BD, Barlogie B, Kyle RA, Palladini G, Geyer SM and Merlini G (2002). A multicenter phase II trial of 4′-iodo-4′-deoxydoxorubicin (IDOX) in primary amyloidosis (AL). Amyloid: J Protein Folding Disord 9, 24-30
57. Sebastiao MP, Merlini G, Saraiva MJ and Damas AM (2000). The molecular interaction of 4′-iodo-4′-deoxydoxorubicin with Leu-55Pro transthyretin 'amyloid-like' oligomer leading to disaggregation. Biochem J 351, 273-279
58. McCord JM (1980). Oxygen free radicals: Release and activities. Agents Actions 10, 522-527
59. Hirota M, Inoue M, Ando Y, Hirayama K, Mirono Y, Sakamoto K, Mori K and Akagi M (1989). Inhibition of stress induced gastric injury in the rat by glutathione. Gastroenterology 97, 853-859
60. Ando E, Ando Y, Kamata R, Inoue M, Morino Y and Okamura R (1990). Inhibition of corneal inflammation by an acylated superoxide dismutase derivation. Invest Ophthalmol Vis Sci 31, 1963-1967
61. Ando Y, Ikegawa S, Miyazaki A, Inoue M, Morino Y and Araki S (1989). Role of variant prealbumin in the pathogenesis of familial amyloidotic polyneuropathy: Rate of normal and variant prealbumin in circulation. Arch Biochem Biophys 274, 87-92
62. Granger D (1988). Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 255, H1269-H1275
63. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group (1994). The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330, 1029-1035
64. Banwell BL and Engel AG (2000). AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 54, 1033-1041
65. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I and Rydel RE (1992). β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12, 376-389
66. Capeillere-Blandin C, Delaveau T and Descamps-Latscha B (1991). Structural modifications of human beta 2 microglobulin treated with oxygen-derived radicals. Biochem J 277, 175-182
67. Toyokuni S, Uchida K, Okamoto K, Hattori-Nakakuki Y, Hiai H and Stadtman ER (1994). Formation of 4-hydroxy-2-nonenal-modified proteins in the renal proximal tubules of rats treated with a renal carcinogen, ferric nitrilotriacetate. P roc Natl Acad Sci USA 91, 2616-2620
68. Mark RJ, Lovell MA, Markesbery WR, Uchida K and Mattson MP (1997). A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β-peptide. J Neurochem 68, 255-264
69. Sagara Y, Dargusch R, Klier FG, Schubert D and Behl C (1996). Increased antioxidant enzyme activity in amyloid β protein-resistant cells. J Neurosci 16, 497-505
70. Skinner M, Stone P, Shirahama T, Connors L, Calore J and Cohen A (1986). The association of an elastase with amyloid fibrils. Proc Soc Exp Biol Med 181, 211-214
71. Stone P, Camistol J, Abraham CR, Rodgers O, Shirahama T and Skinner M (1993). Neutrophil proteases associated with amyloid fibrils. Biochem Biophys Res Commun 30, 130-136
72. Benedetti A, Comporti M and Esterbauer H (1980). Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids. Biochim Biophys Acta 620, 281-296
73. Siems W, Kowalewski J, Werner A, Schimke I and Gerber G (1989). Radical formation in the rat small intestine during and following ischemia. Free Radic Res Commun 7, 347-353
74. Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S and Stadtman ER (1995). Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies. Arch Biochem Biophys 324, 241-248
75. Ando Y, Brnnstrm T, Uchida K, Nyhlin N, Nsman B, Suhr O, Yamashita T, Olsson T, Uchino M and Ando M (1998). Histochemical detection of 4-hydroxynonenal protein in Alzheimer disease amyloid. J Neurol Sci 156, 172-176
76. Hoff HF and O Neil JA (1991). Oxidation of LDL: Role in atherogenesis. Klin Wochenschr 69, 1032-1038
77. Sakashita N, Ando Y, Jinnouchi K, Yoshimatsu M, Terazaki H, Obayashi K and Takeya M (2001). Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhage. Pathol Int 51, 476-480
78. Ando Y, Nyhlin N, Suhr O, Holmgren G, Uchida K, El-Salhy M, Yamashita T, Terasaki H, Nakamura M, Uchino M and Ando M (1997). Oxidative stress is found in amyloid deposits in systemic amyloidosis. Biochem Biophys Res Commun 232, 497-502
79. Ando Y, Suhr O and El-Salhy M (1998). Oxidative stress and amyloidosis. Histol Histopathol 13, 845-850
80. Nyhlin N, Ando Y, Nagai R, Suhr O, El-Salhy M, Terazaki H, Yamashita, Ando M and Horiuchi S (2000). Advanced glycation end product in familial amyloidotic polyneuropathy (FAP). J Intern Med 247, 485-492
81. Sakashita N, Ando Y, Marklund SL, Tashima K, Nilsson P, Yamashita T, Takeya M and Takahashi K (1998). Familial amyloidotic polyneuropathy type I with extracellular superoxide dismutase mutation: A case report. Hum Pathol 13, 845-850
82. Suhr OB, Lang K, Wikstrom L, Anan I, Ando Y, El-Salhy M, Holmgren G and Tashima K (2001). Scavenger treatment of free radical injury in familial amyloidotic polyneuropathy: A study on Swedish transplanted and non-transplanted patients. Scand J Clin Lab Invest 61, 11-18
83. Propsting MJ, Blaschke M, Haas RE, Genschel J, Hedrich HJ, Manns MP and Schmidt HH (1999). Inosine(15.1)-hammerhead ribozymes for targeting the transthyretin-30 mutation. Biochem Biophys Res Commun 260, 313-317
84. Tanaka K, Yamada T, Ohyagi Y, Asahara H, Horiuchi I and Kira J (2001). Suppression of transthyretin expression by ribozymes: A possible therapy for familial amyloidotic polyneuropathy. J Neurol Sci 183, 79-84
85. Yoon K, Cole-Strauss A and Kmiec EB (1996). Targeted gene correction of episomal DNA in mammalian cells mediated by a chimeric RNA.DNA oligonucleotide. Proc Natl Acad Sci USA 93, 2071-2076
86. Cole-Strauss A, Yoon K, Xiang Y, Byrne BC, Rice MC, Gryn J, Holloman WK and Kmiec EB (1996). Correction of the mutation responsible for sickle cell anemia by an RNA-DNA oligonucleotide. Science 273, 1386-1389
87. Kren BT, Cole-Strauss A, Kmiec EB and Steer CJ (1997). Targeted nucleotide exchange in the alkaline phosphatase gene of HuH-7 cells mediated by a chimeric RNA/DNA oligonucleotide. Hepatology 25, 1462-1468
88. Xiang Y, Cole-Strauss A, Yoon K, Gryn J and Kmiec EB (1997). Targeted gene conversion in a mammalian CD34+-enriched cell population using a chimeric RNA/DNA oligonucleotide. J Mol Med 75, 829-835
89. Kren BT, Bandyopadhyay P and Steer CJ (1998). In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotide. Nat Med 4, 285-290
90. Alexeev V and Yoon K (1998). Stable and inheritable changes in genotype and phenotype of albino melanocytes induced by an RNA/DNA oligonucleotide. Nat Biotechnol 16, 1343-1346
91. Kren BT, Parashar B, Bandyopadhyay P, Chowdhury N, Chowdhury JR and Steer CJ (1999). Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide. Proc Natl Acad Sci USA 96, 10349-10354
92. Gamper HB Jr, Cole-Strauss A, Metz R, Parekh H, Kumar R and Kmiec EB (2000). A plausible mechanism for gene correction by chimeric oligonucleotides. Biochemistry 39, 5808-5816
93. Gamper HB, Parekh H, Rice MC, Bruner M, Youkey H and Kmiec EB (2000). The DNA strand of chimeric RNA/DNA oligonucleotides can direct gene repair/conversion activity in mammalian and plant cell-free extracts. Nucleic Acids Res 28, 4332-4339
94. Kishikawa M, Nakanishi T, Miyazaki A and Shimizu A. (1999). Enhanced amyloidogenicity of sulfonated transthyretin in vitro, a hypothetical etiology of senile amyloidosis. Amyloid: Int J Exp Clin Invest 6, 183-186
95. Altland K and Winter P (1999). Potential treatment of transthyretin-type amyloidoses by sulfite. Neurogenetics 2, 183-188
96. Cardoso I, Pereira PJ, Damas AM and Saraiva MJ (2000). Aprotinin binding to amyloid fibrils. Eur J Biochem 267, 2307-2311
97. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M and Arendash GW (2000). A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982-985
98. Imbimbo BP (2002). Toxicity of beta-amyloid vaccination in patients with Alzheimer's disease. Ann Neurol 51, 794