None of the cholinesterase inhibitors has been formally approved for patients with any form of dementia other than that associated with AD. It is, however, quite possible that vascular disease and possible LBD contributed to dementia in a high number of patients with probable AD who were involved in pivotal trials of the cholinesterase inhibitors.
Data are now starting to emerge demonstrating that cholinesterase inhibitors have the potential to benefit all patients with dementia, whether they have AD, vascular dementia, LBD, or comorbid pathologies (ie, mixed dementia).
82–86
In fact, placebo-controlled trials have shown that cholinesterase inhibitors can delay the cognitive decline that would otherwise occur within 6 to 12 months in patients who remain untreated. Because cholinesterase inhibitors can be beneficial in patients with probable AD, vascular dementia, LBD, or comorbid pathologies, and exact diagnosis is frequently uncertain before autopsy, patients may benefit from cholinergic replacement therapy regardless of dementia type. As with cholinesterase inhibitor therapy when used in the treatment of patients with AD, if clinical benefits are not evident after a minimum of 4 to 6 months, physicians may yet find the desired benefits for their patients with vascular dementia, LBD, or comorbid pathologies by prescribing another cholinesterase inhibitor.
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Vascular Dementia—When patients present with disease characteristics that are more consistent with vascular dementia than AD, efficacy data from studies of donepezil, 5 mg to 10 mg per day, indicate that these patients can benefit from cholinesterase inhibitor therapy.
82,83 In a 6-month, placebo-controlled trial of 616 patients diagnosed with probable or possible vascular dementia, subjects treated with a daily dose of donepezil, 5 mg or 10 mg, demonstrated a nearly 2-point beneficial effect (decrease) on the ADAS-Cog scale relative to subjects in the placebo group (
P<.01).
82 Greater improvements on the CIBIC-plus were also observed with both donepezil study groups relative to placebo groups (
P<.01).
In addition to having an ameliorating effect on the decline of global cognitive function in subjects with subcortical vascular dementia, rivastigmine (target dose: 6 mg daily) in a controlled study involving 208 subjects was able to stabilize or lessen other symptoms typical of this disorder, including faltering executive function and behavioral problems.
84
During the 12-month study period, deterioration in subjects' MMSE scores was greater in subjects randomized to aspirin (decline of 3.94 points) than in subjects receiving rivastigmine (decline of 2.54 points).
Executive function, as assessed using the Ten-Point Clock Drawing test, deteriorated to a significantly greater extent in subjects receiving aspirin than in those treated with rivastigmine (P<.05). There was a 16.37-point improvement in BEHAVE-AD total scores in the rivastigmine group (P<.01 vs. baseline), as opposed to a 1.44-point deterioration in the aspirin treatment group (P<.01, between-group difference). Apart from the continued presence of one symptom, delusions, all individual BEHAVE-AD items were significantly improved from baseline measures in subjects treated with rivastigmine.
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Dementia with Lewy Bodies—The results of a randomized, double-blind, placebo-controlled trial of rivastigmine (target dose: 6 mg to 12 mg daily) in 120 subjects with a prospective diagnosis of probable LBD have suggested that cholinesterase inhibitors could be a rational treatment choice for amelioration of behavioral manifestations of disease in such patients.
85
The main Lewy body behavior cluster in the patient sample predictably consisted of apathy, delusions, depression, and hallucinations. Over the 20-week study period, rivastigmine had a significant beneficial impact on subjects' behavior (less severe disturbance), as evidenced by a 6.4-point difference between groups on the 10-item NPI score favoring rivastigmine over placebo in an analysis of observed cases (P=.005).
Specifically, patients treated with rivastigmine were less anxious and apathetic, had fewer delusions and hallucinations, and had less aberrant motor behavior than those receiving placebo. Change in subjects' MMSE scores favored rivastigmine, with a 1.5-point improvement in rivastigmine recipients contrasting with a 0.1-point decline in placebo recipients (0.05 <P< .1). There are no published data from equivalent large, randomized, placebo-controlled studies of galantamine or donepezil in patients with LBD.
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Mixed Dementia—Subgroup analyses of results from the 6-month trial by Corey-Bloom and colleagues
67 indicate that high-dose rivastigmine has beneficial effects in patients with AD, regardless of the presence of vascular risk factors.
87 In fact, the effect size was largest in patients with vascular risk factors when subjects in the treatment group were compared with subjects in the placebo group; there was a 6.15-point treatment difference on ADAS-Cog scores for subjects with vascular risk factors and a 4.03-point treatment difference for subjects without vascular risk factors.
Significant beneficial effects of galantamine (target dose: 24 mg daily) on ADL, behavior, cognition, and global function were observed in a 6-month randomized, double-blind, placebo-controlled trial involving 592 patients with a prospective diagnosis of probable vascular dementia or possible AD with concurrent cerebrovascular disease.
88 Compared with subjects in the placebo group, subjects treated with galantamine demonstrated a 2.7-point beneficial treatment effect (decrease) on the ADAS-Cog scale (
P<.001), a 4.6-point benefit on the DAD scale (
P<.005), and a 2.2-point benefit on the NPI (
P<.05). A high proportion of galantamine recipients showed no change or showed improvement on the CIBIC-plus scale (74% vs 59% of placebo recipients;
P=.001).