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MEDI-NEWS - Based on the following article: Mixed Dementia: The most common cause of dementia? Canadian Journal of Diagnosis April 2010; 35-44.

April 2010

Medical reviewer:

Yannick Nadeau, MD, FRCPC

Centre for Stroke Recovery, Sunnybrook Health Sciences Centre, Division of Neurology, University of Toronto

The two most important causes of dementia in the elderly are Alzheimer's disease (AD) and vascular cognitive impairment (VCI), but the presence of these conditions is not mutually exclusive. Autopsy studies suggest that pure AD represents no more than 57% and as few as 21% of dementia cases. In fact, mixed dementia (MD)—which refers to any dementia with more than one etiology but most commonly involves the co-existence of AD and vascular dementia (VaD)—is now regarded as the single most common dementia type. Despite the relatively limited studies conducted specifically in MD, the efficacy of AD drugs in AD and VCI support an important role of cholinesterase inhibitors (ChEIs) in the mixed type, according to a newly published summary. The data do not support large differences between currently available agents.

“There is more evidence for donepezil and galantamine in VCI and in AD with CVD [cerebrovascular disease], but benefits with rivastigmine have also been suggested,” concluded Drs. Yannick Nadeau and Sandra E. Black from their summary overview. The two investigators, both from the Neurology Research Unit, Centre for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, went on to assert that “as in AD, these benefits may be more a class effect of ChEIs than the effect of a particular molecule. In the absence of comparative data, there is no evidence to support the preferential use of one ChEI over another.”

Although the authors were unable to differentiate the efficacy of currently used AD therapies for treatment of MD, they did assemble a substantial body of data to support their efficacy individually. In a summary of results of major studies with these agents in MD or AD with VCI, all four studies with donepezil, three studies with galantamine, two studies with rivastigmine and two studies with memantine generated statistically significant benefits in VaD, MD or both. Even though none of these agents has an indication outside of AD, the efficacy appears to be at least as good in patients with vascular disease as in those without. The data generated by studies of donepezil, several of which were randomized and controlled, were representative. In one study, 16% of the 565 AD patients who were evaluated had VaD. In this subgroup, cognitive response was even greater in those with a history of CVD (P=0.002) than in those without. In a second study of 913 patients, of whom 29.6% had a history of CVD, the difference in response was not significantly greater in the CVD subgroup, but the proportion of responders was greater among those with CVD after only three months of follow-up. In a third study of 603 VaD patients that excluded patients with AD or MD, there were significant improvements in cognition and global function. A fourth study of 616 VaD patients showed the same result.

Of the three galantamine studies, one was limited to patients with probable VaD based on magnetic resonance imaging showing CVD and also demonstrated significant improvement in cognition. Even though this study, which did not provide any information about the potential co-existence of AD, did not show any significant improvement in daily function, it did support activity when vascular disease is considered to be the dominant pathologic feature. The other two studies were related: one was a post-hoc subgroup analysis of a study in which almost all of the 592 patients had probable VaD (43%) or AD with CVD (48%) and still achieved improvement in cognition and global functioning; the other was an open-label extension of this study that included 459 of the initial 592 patients who were enrolled and showed sustained benefits at 12 months regardless of the diagnosis. One of the rivastigmine studies was a post-hoc analysis of 697 patients with AD of which 54% had at least one vascular risk factor. The agent’s treatment effect appeared to be more substantial in general in those with vascular risk factors than in those without. The other investigation was a relatively small pilot study conducted in 50 patients with VaD in which the end point was change in executive function. The study associated the ChEI with significant improvement in category word generation test.

Of the two memantine studies, both enrolled patients with probable VaD. In one, with 321 patients, the study was designed to exclude AD patients. The other was described as a study for patients with probable VaD, but there was no mention of AD or MD in the description of the patients. Both studies associated therapy with a statistically significant improvement in cognition.

Dementia and Hypertension

One of the complexities of differentiating causes of dementia is that there appears to be an interrelationship. For example, impaired vascular function may play a role in slowing elimination of amyloid beta which forms the characteristic AD amyloid plaques. If vascular pathology exacerbates AD, treatment of vascular disease may play a critical role in prevention of MD as well as vascular-related dementia. Some but not all studies have associated blood pressure lowering with protection from dementia. One theory is that reductions in the risk of dementia are not due to the drop in blood pressure but the neuroprotective properties of some of the antihypertensive agents that have been associated with benefit, particularly those that employed a calcium channel blocker (CCB).

The value of treating vascular disease to prevent dementia has also been raised by absence of benefit from other strategies that would be expected to improve vascular function, such as ASA or lipid-lowering drugs. Antihypertensive agents do appear to be useful for preventing cognitive loss but have an uncertain benefit in treating cognitive loss once symptoms are already present. According to the authors of this review, large studies with antiplatelet agents or statins have not yet generated a clear signal of protection from dementia even with a long follow-up in older patients facing a substantial risk of dementia.

Summary

While it may be useful to diagnose co-existing vascular disease in patients with AD, the data accumulated by Drs. Nadeau and Black in MD suggest that the first-line AD agents, such as donepezil and galantamine, are appropriate in patients with AD whether or not they also have vascular disease. Cognitive improvements on these agents have been significant in large studies. These agents have not been compared in MD, preventing conclusions about relative benefits, but the treatment effects have been on a similar scale in independent studies, supporting their clinical utility.

Questions and Answers

This question-and-answer session was conducted with Dr. Yannick Nadeau, Centre for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Ontario.

Q: How important or useful is it to distinguish AD from VaD and MD before initiating therapy? How accurate are current methods of distinguishing these types of dementia?

Dr. Nadeau: It is useful to try to distinguish these forms of dementia. The problem is that we do not have very sensitive tools. Mainly, these disorders are differentiated on the basis of the symptom profile. The types of cognitive loss are different for AD and VaD. Patients with MD, of course, will have both. In patients with a vascular component, the likelihood of vascular disease elsewhere is the basis for treating hypertension, elevated cholesterol, or diabetes. We do not have data that this will affect cognitive function, but this may be an additional health benefit.

Q: Are there any restrictions for using ChEIs in patients with MD?

Dr. Nadeau: In Canada, ChEIs are only indicated for AD, so the indication for treatment is AD symptoms even in the MD patients, but we also believe that these agents are active against symptoms due to VaD. There is evidence to support benefit in these patients but again, this is not a current indication for ChEIs.

Q: Occasionally, it is implied that one mechanism of action among anti-dementia drugs is better than another; your data suggest that these drugs offer comparable efficacy. Is this a fair summary?

Dr. Nadeau: The data for activity against MD are mainly drawn from studies with donepezil and galantamine. There are fewer studies with rivastigmine, but we expect that there is a class effect. As there are no comparative studies with these agents or between memantamine and the ChEIs, we extrapolate that all these agents are equally active in MD. This seems to be the prudent conclusion.

Note: At time of printing, in Canada, cholinesterase inhibitors are not indicated for mixed dementia.