Randomized, Placebo-Controlled Trial of the Effects of Donepezil on Neuronal Markers and Hippocampal Volumes in Alzheimer’s Disease

Krishnan, K. Ranga Rama; Charles, H. Cecil; Doraiswamy, P. Murali; Mintzer, Jacobo; Weisler, Richard H.; Yu, Xin; Perdomo, Carlos; Ieni, John R.; Rogers, Sherise C.

doi:10.1176/appi.ajp.160.11.2003

Cited by 253 publications

(159 citation statements)

References 40 publications

Supporting

Mentioning

147

Contrasting

Unclassified

Order By: Relevance

“…MRI based measurements have been employed as adjunct outcome measures in several therapeutic trials for patients with AD Krishnan et al, 2003;Fox et al, 2005;Hashimoto et al, 2005). To our knowledge this is the first study evaluating the utility of MRI measurements in a therapeutic trial of MCI subjects.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Jack

Petersen

Grundman³

et al. 2008

Neurobiology of Aging

133

View full text Add to dashboard Cite

The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE ∈4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE ∈4 carriers than non-carriers. MRI APCs and changes Disclosure Statement for AuthorsThe authors have no conflicts of interest to disclose. The industry sponsors had no role in the analysis or interpretation of these data nor in the content of the paper. Appropriate approval procedures were used concerning human subjects. NIH Public Access IntroductionThe vitamin E and donepezil clinical trial for the treatment of mild cognitive impairment (MCI) was conducted in 769 subjects at 69 centers in North America . The study was designed to determine whether the antioxidant vitamin E or donepezil, the only cholinesterase inhibitor available at the time the study was designed, would be effective at delaying the clinical progression of subjects with the amnestic form of MCI to the clinical diagnosis of Alzheimer's disease (AD). While vitamin E had no beneficial effect, donepezil reduced the risk of progression from amnestic MCI to clinically possible or probable AD for up to 12 months. This treatment effect was extended to 24 months in carriers of the apolipoprotein E ∈4 (APOE e4) allele. Twenty-four of the recruiting sites voluntarily participated in a Magnetic Resonance Imaging (MRI) sub study which was grafted onto the existing clinical therapeutic study design. The purpose of the MRI sub study was to determine if a therapeutic effect of either vitamin E or donepezil could be detected on rates of brain atrophy from serial MRI studies. Four different brain atrophy brain measures were assessed; the hippocampus, entorhinal cortex (ERC), whole brain, and ventricular volume. Each of these MRI measurements has figured prominently in anatomic MRI based studies of MCI, AD, and normal aging (Jack et al., 1992;Fox et al., 1996;Jack et al., 1997;Fox et al., 1999;Killiany 2000;Dickerson et al., 2001;Killiany et al., 2002;Du et al., 2003). A primary objective of this analysis was to test the hypothesis that vitamin E or donepezil slowed the rate of brain atrophy relative to placebo in subjects with amnestic MCI (Petersen 1995;Pe...

show abstract

Section: Discussionmentioning

confidence: 99%

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Jack

Petersen

Grundman³

et al. 2008

Neurobiology of Aging

133

View full text Add to dashboard Cite

show abstract

“…One included trial 43 allowed the inclusion of patients with vascular dementia; however, the predominant disorder was AD and therefore the trial met the present review inclusion criteria (see Appendix 2). Eight published RCTs were parallel comparisons of donepezil with placebo, 41,[43][44][45][46][47][48][49] three RCTs compared two doses of donepezil with placebo, [50][51][52] one compared three doses of donepezil with placebo 53 and one was a crossover comparison of donepezil with placebo. 54 One unpublished RCT reports data on participants with mild AD.…”

Section: Donepezil Quantity and Quality Of Researchmentioning

confidence: 99%

“…54 One unpublished RCT reports data on participants with mild AD. 55 In four of the eight trials with a two-arm comparison, the dose of donepezil was 5 mg/day for 28 days followed by 10 mg/day for the remainder of the study duration, 41,[45][46][47] and in another the dose of donepezil was 5 mg/day for 42 days followed by 10 mg/day for the remainder of the study duration. 55 In one the dose was 5 mg/day, 44 in another the dose was 5 or 10 mg donepezil per day 43 and in one the dose was 10 mg/day.…”

Section: Donepezil Quantity and Quality Of Researchmentioning

confidence: 99%

The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease

Loveman

Green²,

Kirby³

et al. 2006

Health Technol Assess

163

114

View full text Add to dashboard Cite

Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is £2 per monograph and for the rest of the world £3 per monograph.You can order HTA monographs from our Despatch Agents:-fax (with credit card or official purchase order) -post (with credit card or official purchase order or cheque) -phone during office hours (credit card only).Additionally the HTA website allows you either to pay securely by credit card or to print out your order and then post or fax it. NHS libraries can subscribe free of charge. Public libraries can subscribe at a very reduced cost of £100 for each volume (normally comprising 30-40 titles). The commercial subscription rate is £300 per volume. Please see our website for details. Subscriptions can only be purchased for the current or forthcoming volume. Contact details are as follows: Payment methods Paying by chequeIf you pay by cheque, the cheque must be in pounds sterling, made payable to Direct Mail Works Ltd and drawn on a bank with a UK address. Paying by credit cardThe following cards are accepted by phone, fax, post or via the website ordering pages: Delta, Eurocard, Mastercard, Solo, Switch and Visa. We advise against sending credit card details in a plain email. Paying by official purchase orderYou can post or fax these, but they must be from public bodies (i.e. NHS or universities) within the UK. We cannot at present accept purchase orders from commercial companies or from outside the UK. How do I get a copy of HTA on CD?Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact Direct Mail Works (see contact details above) by email, post, fax or phone. HTA on CD is currently free of charge worldwide.The website also provides information about the HTA Programme and lists the membership of the various committees. HTAThe clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease NHS R&D HTA ProgrammeT he research findings from the NHS R&D Health Technology Assessment (HTA) Programme directly influence key decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the 'National Knowledge Service' that is being developed to improve the evidence of clinical practice throughout the NHS.The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care.The HTA Programme commissions research only on topics where it has identified key ...

show abstract

“…Furthermore, it remains unclear if such drug-derived benefit is mechanistically similar to the protective action of environmental factors such as higher educational attainment known to correlate with reduced risk of Alzheimer-and Parkinson-related dementia (Snowdon et al, 1996;Glatt et al, 1996). It is not unreasonable to assume that both environmental and AChEI disease-modifying action(s) require persisting alteration in molecular mechanisms that underpin cognitive function in the medial temporal lobe, as these structures are particularly sensitive to degeneration in Alzheimer's disease (Terry et al, 1991;Dickson et al, 1995;Gomez-Isla et al, 1996;Krishnan et al, 2003). Associating molecular mechanisms with this drug-derived benefit provides an important step in the development of more effective therapeutic strategies for neurodegenerative conditions such as Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Murphy

Foley

O’Connell

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a diseasemodifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memoryassociated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.

show abstract

Randomized, Placebo-Controlled Trial of the Effects of Donepezil on Neuronal Markers and Hippocampal Volumes in Alzheimer’s Disease

Abstract: These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

Cited by 253 publications

References 40 publications

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Contact Info

Product

Resources

About