Hostname: page-component-8448b6f56d-tj2md Total loading time: 0 Render date: 2024-04-23T09:23:03.871Z Has data issue: false hasContentIssue false
  • English
  • Français

Treatment of Moderate to Severe Alzheimer's Disease: Rationale and Trial Design

Published online by Cambridge University Press:  02 December 2014

Nathan Herrmann
Nathan Herrmann*
Affiliation:
The Department of Psychiatry, Division of Geriatric Psychiatry, Faculty of Medicine, University of Toronto, Sunnybrook
*
Department of Psychiatry, Division of Geriatric Psychiatry, Faculty of Medicine, University of Toronto, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, M4N 3M5, Canada.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Moderate to severe Alzheimer's disease (AD) is characterized by increasing cognitive, functional, and behavioural dysfunction that results in increased caregiver burden and, eventually, complete dependence. Despite its significance as a societal health problem, there are few treatment trials of cognitive enhancers or disease modifying agents for this stage of illness. Studies suggest the cholinesterase inhibitors, especially donepezil, may provide benefit. Several studies provide support for the use of the NMDA receptor antagonist memantine as monotherapy or added to a cholinesterase inhibitor for moderate to severe AD. While there are no published guidelines for the treatment of moderate to severe AD, these studies do provide guidance for recommendations for study design and outcome measures. Such studies are urgently needed.

Résumé:

RÉSUMÉ:

La maladie d'Alzheimer de modérée à sévère est caractérisée par une dysfonction cognitive, fonctionnelle et comportementale progressive qui engendre un fardeau croissant pour les soignants et une dépendance complète éventuelle. En dépit de son importance comme problème de santé au niveau sociétal, il existe peu d'essais thérapeutiques portant sur des stimulateurs cognitifs ou des agents modificateurs de la maladie à ce stade de la maladie. Les études suggèrent que les inhibiteurs de la cholinestérase, spécialement le donépézil sont bénéfiques. Selon plusieurs études, l'utilisation de la mémantine, un antagoniste du récepteur NMDA, en monothérapie ou en association à un inhibiteur de la cholinestérase serait bénéfique dans la MA de modérée à sévère. Bien qu'il n'y ait pas de lignes directrices publiées concernant le traitement de la MA de modérée à sévère, ces études peuvent servir de guide pour formuler des recommandations sur le plan d'étude et les critères d'évaluation. Il est urgent de procéder à de telles études.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 34 , Issue S1 , March 2007 , pp. S103 - S108
Copyright
Copyright © The Canadian Journal of Neurological 2007

References

1. Canadian Study of Health and Aging Working Group. Patterns of caring for people with dementia in Canada. Can J Aging. 1994;13:470–87.Google Scholar
2. Tariot, PN. Medical management of advanced dementia. J Am Geriatr Soc. 2003;51: S305–13.Google Scholar
3. Hux, MJ, O’Brien, BJ, Iskedjian, M, Goeree, R, Gagnon, M, Gauthier, S. Relation between severity of Alzheimer’s disease and costs of caring. CMAJ. 1998;159:457–65.Google ScholarPubMed
4. Wimo, A, Karlsson, G, Nordberg, A, Winblad, B. Treatment of Alzheimer’s disease with tacrine: a cost-analysis model. Alzheimer Dis Assoc Disord. 1997;11:191–200.Google Scholar
5. Di Patre, PL, Read, SL, Cummings, JL, Tomiyasu, U, Vartavarian, LM, Secor, DL, et al. Progression of clinical deterioration and pathological changes in patients with Alzheimer’s disease evaluated at biopsy and autopsy. Neurology. 1999;56:1254–61.Google Scholar
6. Lanctôt, KL, Herrmann, N, Mazzotta, P. Role of serotonin in the behavioural and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2001;13:5–21.CrossRefGoogle Scholar
7. Herrmann, N, Lanctôt, KL, Khan, LR. The role of norepinephrine in the behavioural and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2004; 16:261–76.CrossRefGoogle Scholar
8. Lanctôt, KL, Herrmann, N, Mazzotta, P, Khan, LR, Ingber, N. GABA-ergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry. 2004;49:439–53.Google Scholar
9. Cacabelos, R, Takeda, M, Winbald, B. The glutamatergic system and neurodegeneration in dementia: preventative strategies in Alzheimer’s disease. Int J Geriatr Psychiatry. 1999; 14:3–47.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
10. Davis, KL, Mohs, RC, Marin, D. Cholinergic markers in elderly patients with early signs of Alzheimer’s disease. JAMA. 1999;281:1401–6.Google Scholar
11. Feldman, H, Gauthier, S, Hecker, J, Vellas, B, Subbiah, P, Whalen, E. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57:613–20.CrossRefGoogle ScholarPubMed
12. Folstein, MF, Folstein, SE, McHugh, PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.Google Scholar
13. Herrmann, N. Recommendation for the management of behavioural and psychological symptoms of dementia. Can J Neurol Sci. 2001;28(Suppl 1):S96–107.Google Scholar
14. Lanctôt, KL, Herrmann, N, Yau, KK, Khan, LR, LouLou, MM, Einarson, TR. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ. 2003;169:557–64.Google Scholar
15. Blesa, R, Davidson, M, Kurza, A, Reichman, W, van Baelen, B, Schwalen, S. Galantamine provides sustained benefits in patients with advanced moderate Alzheimer’s disease for at least 12 months. Dement Geriatr Cogn Disord. 2003;15:79–87.Google Scholar
16. Doraiswany, PM, Krishnan, KR, Anand, R, Sohn, H, Danyluk, J, Hartman, RD, et al. Long-term effects of rivastigmine in moderately severe Alzheimer’s disease: does early initiation of therapy offer sustained benefits? Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:705–12.CrossRefGoogle Scholar
17. Sclan, SG, Reisberg, B. Functional assessment staging (FAST) in Alzheimer’s disease: reliability, validity, and ordinality. Int Psychogeriatr. 1992;4(Suppl 1):S55–69.CrossRefGoogle ScholarPubMed
18. Schneider, LS, Olin, JT, Doody, RS, Clark, CM, Morris, JC, Reisberg, B, et al. Validity and reliability of the Alzheimer’s disease cooperative study-clinical global impression of change. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S22–32.CrossRefGoogle ScholarPubMed
19. Saxton, J, McGonigle-Gibson, G, Swihart, A, Miller, VJ, Boller, F. Assessment of the severely impaired patient: description and validation of a new neuropsychological test battery. Psychol Assessment: J Consulting Clin Psychology. 1990;2:298–303.Google Scholar
20. Gelinas, I, Gauthier, L, McIntyre, M, Gauthier, S. Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther. 1999;53:471–81.Google Scholar
21. Lawton, MP, Brody, EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:179–86.Google Scholar
22. Cummings, JL. The neuropsychiatric interview: assessing psychopathology in dementia patients. Neurology. 1994;44: 2308–14.CrossRefGoogle Scholar
23. Feldman, H, Schulzer, M, Wang, S, Tuokko, H, Beattie, BL. The functional rating scale in Alzheimer’s disease assessment: a longitudinal study. In: Iqbal, K, Mortimer, JA, Winbald, B, Wisniewski, HM, editors. Research advances in Alzheimer’s disease and related disorders. Chichester, UK: Wiley; 1995. p. 235–41.Google Scholar
24. Pearlin, LI, Mullan, JT, Semple, SJ, Skaff, MM. Caregiving and the stress process: an overview of concepts and their measures. Gerontologist. 1990;30:583–94.Google Scholar
25. McHorney, CA, Ware, JE. Construction and validation of an alternate form general mental health scale for the medical outcomes study short-form 36-item health survey. Med Care. 1995;33:15–28.Google Scholar
26. Østbye, T, Crosse, E. Net economic costs of dementia in Canada. CMAJ. 1994;151:1457–64.Google ScholarPubMed
27. Tariot, PN, Cummings, JL, Katz, IR, Mintzer, J, Perdomo, CA, Schwam, EM, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc. 2001;49:1590–9.Google Scholar
28. Morris, JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology. 1993;43:2412–14.CrossRefGoogle ScholarPubMed
29. Winblad, B, Poritis, N. Memantine in severe dementia: results of the M-Best study (benefits and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999;14:135–46.Google Scholar
30. Reisberg, B, Ferris, SH, de Leon, MJ, Crook, T. The global deterioration scale (GDS): an instrument for the assessment of primary degenerative dementia (PDD). Am J Psychiatry 1982;139:1136–9.Google Scholar
31. National Institute of Mental Health. Clinical Global Impressions. In: Guy, W, editor. ECDEU Assessment Manual for Psychopharmacology. National Institute of Mental Health, Rockville, MD. 1986: p. 217–22.Google Scholar
32. Van der Kam, P, Mol, F, Wimmers, M. Beoordelingschool voon oudere patienten (BOP). Deventer, the Netherlands: Van Loghum Slaterus; 1971.Google Scholar
33. Ferm, L. Behavioural activities in demented geriatric patients. Geront Clin. 1974;16:185–94.Google Scholar
34. Reisberg, B, Doody, R, Stoffler, A, Schmitt, F, Ferris, S, Mobius, HJ. Memantine in moderate-severe Alzheimer’s disease. N Engl J Med. 2003;348:1333–41.Google Scholar
35. Galasko, DR, Schmitt, FA, Jin, S. Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer’s disease. Neurobiol Aging. 2000; 21 (suppl 1):S168.Google Scholar
36. Wimo, A, Wetterholm, AL, Mastey, V, Winblad, B. Evaluation of the healthcare resource utilization and caregiver time in antidementia drug trials - a quantitative battery. In: Wimo, A, Johnsson, D, Karlson G. Winblad, B, editors. Health economics of dementia. Chichester, England: John Wiley; 1998. p. 465–99.Google Scholar
37. Livingston, G, Katona, C. The place of memantine in the treatment of Alzheimer’s disease: a number needed to treat analysis. Int J Geriatr Psychiatry. 2004;19:919–25.Google Scholar
38. Tartiot, PN, Farlow, MR, Grossberg, GT, Graham, SM, McDonald, S, Gergel, I. Memantine treatment in patients with moderate to severe Alzheimer’s disease already receiving donepezil. JAMA. 2004; 291:317–24.Google Scholar
39. Sano, M, Ernesto, C, Thomas, RG, Klauber, MR, Schafer, K, Grundman, M, et al. A controlled trial of selegiline, alpha-tocopherol on both as treatment for Alzheimer’s disease. N Engl J Med. 1997;336:1216–22.Google Scholar
40. Blessed, G, Tomlinson, BE, Roth, M. The association between quantative measures of dementia and of senile changes in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114:797–811.CrossRefGoogle Scholar
41. Rosen, WG, Mohs, RC, Davis, KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141:1356–64.Google Scholar
42. Stern, Y, Albert, SM, Sano, M. Assessing patient dependence in Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 1994;49: M216–22.CrossRefGoogle ScholarPubMed
43. Tariot, PN, Mack, JL, Patterson, MB. The behaviour rating scale for dementia of the consortium to establish a registry for Alzheimer’s disease: the behavioural pathology committee of the consortium to establish a registry for Alzheimer’s disease. Am J Psychiatry. 1995;152:1349–57.Google Scholar
44. Drachman, DA, Leber, P. Treatment of Alzheimer’s disease—searching for a breakthrough, settling for less. N Engl J Med. 1997;336:1245–7.Google Scholar
45. Ferris, SH, Yan, B. Differential diagnosis and clinical assessment of patients with severe Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2003;17(Suppl 3):S92–5.CrossRefGoogle Scholar
46. Doody, RS, Stevens, JC, Beck, C, Dubinsky, RM, Kaye, JA, Gwyther, L, et al. Practice parameter: management of dementia (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2001;56:1154–66.Google Scholar
47. Streiner, DL. Unicorns do exists: a tutorial on “proving” the null hypothesis. Can J Psychiatry. 2003;48:756–61.CrossRefGoogle ScholarPubMed
48. Boller, F, Verny, M, Hugonot-Diener, L, Saxton, J. Clinical features and assessment of severe dementia: a review. Eur J Neurol. 2002;9:125–36.Google Scholar