title: Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.
abstract: OBJECTIVE
  Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients.
  
  
  METHODS
  For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance.
  
  
  RESULTS
  In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant.
  
  
  CONCLUSIONS
  It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.
authors.affiliation: Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.forename: Judith
authors.initials: J
authors.lastname: Guedalia
authors.forename: Glen M
authors.initials: GM
authors.lastname: Doniger
authors.forename: Ely S
authors.initials: ES
authors.lastname: Simon
authors.forename: Vered
authors.initials: V
authors.lastname: Antebi
authors.forename: Yael
authors.initials: Y
authors.lastname: Arnon
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
mesh_terms: D017485:1-Deoxynojirimycin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000188:drug therapy* / Q000523:psychology*; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D015588:Observer Variation; D011594:Psychometrics; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat