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Stroke. 2003;34:2331-2332
Published online before print September 18, 2003, doi: 10.1161/01.STR.0000094580.14898.7C
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(Stroke. 2003;34:2331.)
© 2003 American Heart Association, Inc.

Original Contributions

Editorial Comment—How to Treat Vascular Dementia?

Raphael M. Bonelli, MD, Guest Editor

University Clinic of Psychiatry, Karl-Franzens University Graz, Graz, Austria

In clinical practice, we deal with a great proportion of elderly people. Many times, we are able to identify cognitive deficits (although not too scarce, we overlook dementia in our patients). However, the further division into the several subtypes of dementing disorders may be complicated and laborious for patients, caregivers, and physicians due to noncompliance, incomplete clinical history, or missing medical equipment. Moreover, considerable clinical overlap makes treatment decisions difficult. So the good news, presented by Black et al in this issue,1 is that the 3 most common forms of dementia—Alzheimer’s disease (AD), vascular dementia (VaD), and dementia with Lewy bodies—do have a common effective treatment schedule: acetylcholinesterase inhibitors (ACEI). Although their efficacy is, indeed, not overwhelming and a considerable proportion of patients will not profit by this medication, they still represent a ray of hope in the sad story of dementia treatment.

In the 1960s, it was widely recognized that AD was responsible for most cases of dementia in the elderly and that cerebral arteriosclerosis was a rare cause of dementia.2 A decade later, research found out that some people develop dementia not due to arteriosclerosis of brain vasculature but rather as a consequence of a series of strokes, affecting different brain regions, and the term multi-infarct dementia was introduced.3 In the 1990s, it also became clear that several other mechanisms (ischemic white matter lesions, lacunes) may underlie vascular damage to the brain, which culminates in cognitive decline; therefore, the broader term vascular dementia was accepted4 and recognized as the second most common cause of dementia. However, as things are going on, separate paths merge sometimes later on. The association between AD and VaD has recently turned out to be more complex. Both AD and VaD increase in prevalence with age; they frequently occur concomitantly; and considerable overlaps are seen in their symptomatology, pathophysiology, and comorbidity.5 Many patients show a combination of degenerative brain changes of the AD type along with evidence of strokes. One or two lacunes in elderly subjects with AD changes in the brain increase 20 times the risk of clinical expression of dementia.6 Moreover, MRI scans show the high frequency of vascular changes in older people with all forms of dementia. These similarities can on the one hand give reason to some (rather courageous) authors to propose that AD should be classified as a vascular disorder,7 and on the other hand explain somehow that AD and VaD both respond to ACEI.

Interestingly, there is growing evidence for the involvement of the cholinergic system in VaD, as is the case in AD. Spontaneously hypertensive stroke-prone rats display a number of symptoms characteristic of patients with VaD, such as cognitive impairment and marked behavioral changes.8 Studies in this animal model for VaD demonstrated significant reductions in the levels of acetylcholine and choline in the cortex, hippocampus, and CSF.9 In humans, postmortem studies have shown that compared with controls, patients with VaD have decreased brain choline acetyltransferase activity (a marker of acetylcholine synthesis) in the cortex, hippocampus, and striatum.10 This suggests that there is a general degeneration of cholinergic neurotransmission in VaD and would explain the therapeutic effect of ACEI. Compared with controls, patients with VaD have significantly lower postmortem CSF acetylcholine concentrations.11

Black and colleagues present a well-designed study of 603 patients with VaD (70% probable, 30% possible VaD) treated with 5 or 10 mg donepezil or placebo for 6 months,1 most of them (>80%) in combination with antithrombotics for stroke prevention. A total of 478 patients completed the study, thus representing the largest clinical trial on VaD so far. Five cognitive tests were performed on 5 different study points, analyzed in 2 different modes. The results are no reason to get euphoric. The authors found improvement in some items of cognition and global function after half a year of treatment, whereas other items did not improve (interestingly, some items improved with 5 mg but failed to do so with the double dose). Anyway, no item deteriorated under donepezil, but this may be explained by the antithrombotic medication, as deterioration is lacking in the placebo group as well. It has to be counted as shortcoming of the study that the study was not powered for a subgroup analysis. It would be essential to know which subtype of VaD responds to inhibition of the acetylesterase (not solely, but also from an economic point of view), and this question should be clarified by the next trials to reduce the immense number needed to treat.

Donepezil, rivastigmine, and galantamine are the first-line choices in the treatment of mild to moderate AD and dementia with Lewy bodies, although the treatment is only effective in about half of the patients for whom it is prescribed. This might be due to their lack of hepatotoxicity, ease of administration, few significant drug-drug interactions, and mild to moderate side effects. Moreover, there are few contraindications to the use of ACEI. For this reason, they have the potential to evolve to the first-line treatment in VaD as well (in combination with antithrombotics), as comparable results to Black’s data were published for galantamine in a similarly designed trial,12,13 and there are positive open-label data available on rivastigmine.14 After analyzing the available randomized, double-blind, placebo-controlled trials, most other treatment options available today show a clearly lower level of evidence: a potential therapeutic role for pentoxifylline,15 posatirelin,16 vincamine,17 naftidrofuryl,18 and propentofylline19 in VaD cannot be ruled out; the evidence for a beneficial effect of vinpocetine,20 denbufylline,21 sulodexide,22 nicergoline,23 and nimodipine24 is inconclusive and does not support clinical use; and there seems to be no therapeutic effect of Gingko biloba on VaD.25

So how to treat our patients with VaD? There definitely seems to be benefit with the N-methyl-D-aspartate receptor antagonist memantine26,27—a drug that acts on the glutamatergic system rather than the cholinergic system. Its benefit seems to be at least comparable to the effect of ACEI. No study ever has combined those 2 substances in VaD, although the mechanism of action is very different, but—wouldn’t some of us treat our relatives with this combination, if they turned out to suffer from VaD?


*    References
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 *References
 

  1. Black S, Roman G, Geldmacher DS, Salloway S, Hecker J, Burns A, Perdomo CA, Kumar D, Pratt RD. Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke. 2003; 34: 2323–2332.[Abstract/Free Full Text]
  2. Korczyn AD, Roman GC, Bornstein NM. Vascular dementia. J Neurol Sci. 2002; 1: 203–204.
  3. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet. 1974; 2: 207–210.[CrossRef][Medline] [Order article via Infotrieve]
  4. Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al. Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology. 1993; 43: 250–260.[Abstract/Free Full Text]
  5. Kalaria R. Similarities between Alzheimer’s disease and vascular dementia. J Neurol Sci. 2002; 203–204:29–34.
  6. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA. 1997; 277: 813–817.[Abstract]
  7. de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002; 33: 1152–1162.[Abstract/Free Full Text]
  8. Grantham C, Geerts H. The rationale behind cholinergic drug treatment for dementia related to cerebrovascular disease. J Neurol Sci. 2002; 203–204:131–136.
  9. Kimura S, Saito H, Minami M, Togashi H, Nakamura N, Nemoto M, Parvez HS. Pathogenesis of vascular dementia in stroke-prone spontaneously hypertensive rats. Toxicology. 2000; 153: 167–178.[Medline] [Order article via Infotrieve]
  10. Gottfries CG, Blennow K, Karlsson I, Wallin A. The neurochemistry of vascular dementia. Dementia. 1994; 5: 163–167.[CrossRef][Medline] [Order article via Infotrieve]
  11. Tohgi H, Abe T, Kimura M, Saheki M, Takahashi S. Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. J Neural Transm. 1996; 103: 1211–1220.[CrossRef]
  12. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002; 359: 1283–1290.[CrossRef][Medline] [Order article via Infotrieve]
  13. Erkinjuntti T, Kurz A, Small GW, Bullock R, Lilienfeld S, Damaraju CV. An open-label extension trial of galantamine in patients with probable vascular dementia and mixed dementia. Clin Ther. 2003; 25: 1765–1782.[CrossRef][Medline] [Order article via Infotrieve]
  14. Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Rivastigmine in subcortical vascular dementia: an open 22-month study. J Neurol Sci. 2002; 203–204:141–146.
  15. Sha MC, Callahan CM. The efficacy of pentoxifylline in the treatment of vascular dementia: a systematic review. Alzheimer Dis Assoc Disord. 2003; 17: 46–54.[CrossRef][Medline] [Order article via Infotrieve]
  16. Parnetti L, Ambrosoli L, Agliati G, Caratozzolo P, Fossati L, Frattola L, Martucci N, Murri L, Nappi G, Puca FM, et al. Posatirelin in the treatment of vascular dementia: a double-blind multicentre study vs placebo. Acta Neurol Scand. 1996; 93: 456–463.[Medline] [Order article via Infotrieve]
  17. Fischhof PK, Moslinger-Gehmayr R, Herrmann WM, Friedmann A, Russmann DL. Therapeutic efficacy of vincamine in dementia. Neuropsychobiology. 1996; 34: 29–35.[Medline] [Order article via Infotrieve]
  18. Moller HJ, Hartmann A, Kessler C, Rainer M, Brown T, Gamand S, Lehert P. Naftidrofuryl in the treatment of vascular dementia. Eur Arch Psychiatry Clin Neurosci. 2001; 251: 247–254.[Medline] [Order article via Infotrieve]
  19. Frampton M, Harvey RJ, Kirchner V. Propentofylline for dementia. Cochrane Database Syst Rev. 2003: CD002853.
  20. Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev. 2003: CD003119.
  21. Treves TA, Korczyn AD. Denbufylline in dementia: a double-blind controlled study. Dement Geriatr Cogn Disord. 1999; 10: 505–510.[Medline] [Order article via Infotrieve]
  22. Parnetti L, Mari D, Abate G, Balestreri R, Cucinotta D, Coppola R, Cherubini A, Ferrari P, Senin U. Vascular Dementia Italian Sulodexide Study (V.A.D.I.S.S.): clinical and biological results. Thromb Res. 1997; 87: 225–233.[CrossRef][Medline] [Order article via Infotrieve]
  23. Saletu B, Paulus E, Linzmayer L, Anderer P, Semlitsch HV, Grunberger J, Wicke L, Neuhold A, Podreka I. Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study. Psychopharmacology (Berl). 1995; 117: 385–395.[CrossRef][Medline] [Order article via Infotrieve]
  24. Lopez A, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev. 2001; 1.
  25. van Dongen M, van Rossum E, Kessels A, Sielhorst H, Knipschild P. Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial. J Clin Epidemiol. 2003; 56: 367–376.[CrossRef][Medline] [Order article via Infotrieve]
  26. Wilcock G, Mobius HJ, Stoffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002; 17: 297–305.[CrossRef][Medline] [Order article via Infotrieve]
  27. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002; 33: 1834–1839.[Abstract/Free Full Text]



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Cardiovascular monitoring with acetylcholinesterase inhibitors: a clinical protocol
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[Abstract] [Full Text] [PDF]

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