Evidence-Based Reviews

Differentiating Alzheimer’s disease from dementia with Lewy bodies

Current Psychiatry. 2012 November;11(11):22-30

References

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18. Weiner MF, Hynan LS, Parikh B, et al. Can Alzheimer’s disease and dementias with Lewy bodies be distinguished clinically? J Geriatr Psychiatry Neurol. 2003;16(4):245-250.

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Evidence is insufficient to support using electroencephalographic and polysomnographic studies when initially evaluating patients with dementia. Brain CT or MRI are recommended as part of the initial evaluation of dementia patients to exclude treatable causes of dementia and help clarify the differential diagnosis. Occipital hypometabolism and hypoperfusion demonstrated on PET and SPECT imaging have high sensitivity and specificity for differentiating AD from DLB.

Clinical Point

Hypoperfusion and occipital hypometabolism seen on imaging studies have high sensitivity for distinguishing AD from DLB

To diagnose DLB more consistently, look for core features of the disease, RBD, antipsychotic hypersensitivity, and decreased striatal binding at presynaptic DaT sites.¹⁵ Abnormal (low binding) DaT activity is the most reliable diagnostic marker for DLB.³⁴ Myocardial scintigraphy with MIBG is sensitive to pathologic changes of DLB before clinical expression and could overcome the difficulties of using clinical criteria alone to identify patients with DLB.³⁵ MIBG scintigraphy may be preferred to DaT scan because it is less expensive and its sensitivity and specificity to DLB are independent of the presence of parkinsonism.³⁵

For an overview of pharmacotherapy options for patients with AD or DLB, see Box 2.

Box 2

Treatments for Alzheimer’s disease and dementia with Lewy bodies

Pharmacotherapy options for patients with Alzheimer’s disease (AD) or dementia with Lewy bodies (DLB) include cholinesterase inhibitors, memantine, antipsychotics, and other agents.

Cholinesterase inhibitors. Donepezil, rivastigmine, and galantamine are FDA-approved for treating AD. Their efficacy appears to be similar, so the choice of agent is based largely on cost, patient tolerability, and physician experience.

No medications are FDA-approved for treating DLB. Neocortical cholinergic activity assessed by choline acetyltransferase levels is more severely depleted in DLB than in AD, and this deficit is correlated with the presence of visual hallucinations and global severity of cognitive impairment.^a Therefore, drugs that enhance central cholinergic function offer a therapeutic approach for DLB; cognitive and hallucinatory symptoms are the anticipated targets. Multiple anecdotal reports, open-label studies,^b,^c and 1 randomized, placebo-controlled trial^d suggest that cholinesterase inhibitors are efficacious in DLB, with reported benefits in cognition, fluctuations, psychotic symptoms, and parkinsonian symptoms. A 20-week randomized, double-blind, placebo-controlled multicenter study^d of patients with DLB found rivastigmine, 6 to 12 mg/d, was superior to placebo. Patients receiving rivastigmine exhibited significantly reduced anxiety, delusions, and hallucinations and significantly better performance on a computerized battery of neuropsychological tests, especially tasks that required sustained attention. Differences between rivastigmine and placebo disappeared after drug discontinuation.

Memantine is a noncompetitive antagonist of N-methyl-d-aspartate receptors that is effective in AD.^e The possible involvement of glutamate in DLB has provided a rationale for treating DLB with memantine. Two randomized controlled trials in DLB found that patients treated with memantine for 24 weeks performed better on Clinical Global Impression of Change, but not on most other secondary outcome measures.^f,^g In both studies, memantine was well tolerated. However, other studies have noted worsening of delusions and hallucinations with memantine in DLB patients.^h

Antipsychotics. Agitation is common in moderate and advanced AD. Atypical antipsychotics have been used with variable efficacy to treat agitation, but their use is associated with excess mortality. DLB patients pose a considerable therapeutic challenge because antipsychotics—the mainstay of treatment of psychosis and behavioral problems in most other disorders—can provoke severe, irreversible, and often fatal sensitivity reactions in this type of dementia.ⁱ A 2- to 3-fold increased mortality risk associated with antipsychotic sensitivity reactions in DLB is partly mediated via acute blockade of postsynaptic dopamine D2 receptors in the striatum. For severe and disabling psychosis, a trial of a cholinesterase inhibitor and/or lowering the dose of antiparkinsonian medication should be considered first. In urgent situations, small doses of an atypical antipsychotic that is least associated with parkinsonism side effects—such as quetiapine or aripiprazole—should be used.

Other treatments. Treatment of parkinsonian symptoms in DLB patients is similar to that for Parkinson’s disease, but the risk of psychotic symptoms in DLB warrants a conservative approach. Levodopa seems to be more effective than dopamine agonists and produces fewer side effects.^j Rapid eye movement sleep behavior disorder often responds to low doses of clonazepam (0.25 to 1.5 mg). Depression and anxiety disorders are common in AD at all stages and their treatment is not fundamentally different than in geriatric patients without dementia. Selective serotonin reuptake inhibitors and electroconvulsive therapy have been used successfully in depressed patients with AD or DLB.^k,^l

Disease-modifying treatments. Researchers are evaluating an array of antiamyloid and neuroprotective therapeutic approaches for AD based on the hypothesis that amyloid-beta protein plays a pivotal role in disease onset and progression. Interventions that reduce amyloid production, limit aggregation, or increase clearance may block the cascade of events comprising AD pathogenesis. Reducing tau hyperphosphorylation, limiting oxidation and excitotoxicity, and controlling inflammation also may be beneficial strategies. Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic factor enhancers, and stem cell-related approaches also are being investigated.

There are no large-scale studies of disease-modifying treatments for DLB. Potential areas of research include the relationship between proteasome function and a-synuclein pathology, the role of beta-synuclein, and the impact of alterations to alpha-synuclein on its propensity to aggregate.

References

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b. Beversdorf DQ, Warner JL, Davis RA, et al. Donepezil in the treatment of dementia with lewy bodies. Am J Geriatr Psychiatry. 2004;12(5):542-544.

c. Edwards K, Royall D, Hershey L, et al. Efficacy and safety of galantamine in patients with dementia with Lewy bodies: a 24-week open-label study. Dement Geriatr Cogn Disord. 2007;23(6):401-405.

d. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet. 2000;356(9247):2031-2036.

e. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317-324.

f. Aarsland D, Ballard C, Walker Z, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8(7):613-618.

g. Emre M, Tsolaki M, Bonuccelli U, et al. Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(10):969-977.

h. Ridha BH, Josephs KA, Rossor MN. Delusions and hallucinations in dementia with Lewy bodies: worsening with memantine. Neurology. 2005;65(3):481-482.

i. McKeith I, Fairbairn A, Perry R, et al. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. BMJ. 1992;305(6855):673-678.

j. Fernandez HH, Wu CK, Ott BR. Pharmacotherapy of dementia with Lewy bodies. Expert Opin Pharmacother. 2003;4(11):2027-2037.

k. Swartz M, Barak Y, Mirecki I, et al. Treating depression in Alzheimer’s disease: integration of differing guidelines. Int Psychogeriatr. 2000;12(3):353-358.

l. Takahashi S, Mizukami K, Yasuno F, et al. Depression associated with dementia with Lewy bodies (DLB) and the effect of somatotherapy. Psychogeriatrics. 2009;9(2):56-61.