Recent Studies Demonstrate Benefits of Cholinesterase Inhibitors in DLB
Two recent studies on the use of donepezil for dementia with Lewy bodies add to the strong case for cholinesterase inhibitor (ChEI) treatment in LBD. One study indicated that donepezil improves cognitive and neuropsychiatric symptoms in dementia with Lewy bodies (DLB), while also decreasing caregiver burden. The other demonstrates that people with DLB who do not demonstrate coexisting Alzheimer’s disease on certain brain imaging tests, are more likely to improve with ChEI treatment.
Donepezil Improves Cognition, Behavior and Caregiver Burden in DLB
In both dementia with Lewy bodies and Alzheimer’s disease there is a loss of cholinergic neurons, but the loss appears to occur earlier in DLB and is far greater than in Alzheimer’s disease. Three medications in a class of drugs called cholinesterase inhibitors (ChEIs), donepezil (Aricept), rivastigmine (Exelon) and galantamine (Razadyne), are commonly used in Lewy body dementia. These drugs were originally developed, and are now FDA-approved, for treatment of Alzheimer’s disease. There are no FDA-approved treatments for dementia with Lewy bodies, and only one FDA-approved treatment for Parkinson’s disease dementias, which are the two clinical diagnoses that fall under the umbrella of Lewy body dementias.
Dr. Etsuro Mori of the Tohoku University Graduate School of Medicine and colleagues led a randomized, placebo-controlled trial of 140 DLB patients who received placebo or 3, 5 or 10 mg of donepezil hydrochloride daily for 12 weeks. Patients given 5 or 10 mg donepezil showed greater improvement in the majority of cognitive and behavioral measures on the Mini Mental State Exam (MMSE) and the Neuropsychiatric Inventory (NPI). Those receiving donepezil also demonstrated improvement in global functioning and reduced caregiver burden.
Patients receiving donepezil demonstrated improvements in several neuropsychiatric domains affected by DLB, specifically delusions, hallucinations and cognitive fluctuations. Patients receiving 5 or 10 mg donepezil showed greater improvement in the majority of the cognitive and behavioral measures. MMSE score improved by 2.0 to 3.8 points in those receiving donepezil over placebo, which is a larger difference than that reported in other studies of ChEIS in DLB, Alzheimer’s and Parkinson’s disease dementia.
ChEIs More Likely to Improve Cognition in DLB with No Co-existing Alzheimer’s Pathology
More than half of people with Lewy body dementia have some of the hallmark changes of Alzheimer’s in the brain without having the usual clinical features of the disorder. And approximately 50% of those with Alzheimer’s disease also have some Lewy body changes in the brain as well. Research cannot yet tell us why this co-existence of multiple neurodegenerative disease processes is common.
A recent study by Jonathan Graff-Radford and colleagues at Mayo Clinic performed a retrospective analysis on 54 people diagnosed with dementia with Lewy bodies. Study participants underwent neuropsychological assessment with the Mattis Dementia Rating Scale before and after treatment with ChEIs. All patients underwent magnetic resonance imaging (MRI) within 2 years of treatment, to measure whether any brain shrinkage typically associated with Alzheimer’s disease was present. Seven patients also were given a Pittsburgh compound B positron emission tomography scan (PiB PET) within one to eight weeks after the MRI. A positive PiB scan indicates an abnormal degree of amyloid is present, which is another hallmark of Alzheimer’s disease.
The breakdown of what ChEIs were used in this study are as follows: 47 people were treated with donepezil, 3 with galantamine and 4 with rivastigmine. Six were also treated with memantine, another medication designed for Alzheimer’s disease, but which may benefit people with LBD.
After approximately one year of treatment with ChEIs, 12 patients demonstrated reliable decline, 29 patients remained stable and 13 patients showed reliable improvement on the Dementia Rating Scale. Improvements were demonstrated in attention and conceptualization, as well as in memory. Those with reliable cognitive improvement had larger hippocampal volumes than those that declined or remained cognitively stable.
The MRI results in patients with DLB with reliable cognitive decline closely resembled the pattern of grey matter atrophy observed in patients with pathologically confirmed Alzheimer’s disease. And for those who underwent PiB PET scans, those who had positive scans (indicating coexisting Alzheimer’s disease pathology) declined or stayed stable. Only those with DLB who had negative PiB PET scans improved on the Dementia Rating Scale after treatment with ChEIs. Only one patient who was PiB negative stayed stable and did not demonstrate improvement on the Dementia Rating Scale.
This study demonstrates that people diagnosed with DLB and who have larger hippocampal volumes on MRI are likely to improve cognitively when treated with ChEIs. In addition, a person with DLB and a negative PiB PET scan may also indicate a favorable cognitive response to ChEIs. Interestingly, no other DLB symptoms were found to distinguish those who improved on ChEIs from those who remained stable or declined.
This may be the first study demonstrating the effectiveness of treatment with ChEIs is associated with the imaging biomarkers of Alzheimer’s disease-related pathology. Therefore, assessing people with DLB for co-existing Alzheimer’s-related pathology may be critical for treatment decisions as well as planning for clinical trials in DLB.