Evidence-Based Reviews

Differentiating Alzheimer’s disease from dementia with Lewy bodies

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

How to accurately distinguish the 2 most common causes of neurodegenerative dementia

References

1. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47(5):1113-1124.

2. Buracchio T, Arvanitakis Z, Gorbien M. Dementia with Lewy bodies: current concepts. Dement Geriatr Cogn Disord. 2005;20(5):306-320.

3. Fujishiro H, Iseki E, Higashi S, et al. Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia. Neurosci Lett. 2010;486(1):19-23.

4. Kosaka K. Diffuse Lewy body disease. Neuropathology. 2000;20(suppl):S73-S78.

5. McKeith IG, Dickson DW, Lowe J, et al. Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872.

6. Cummings JL, Cole G. Alzheimer disease. JAMA. 2002;287(18):2335-2338.

7. Zaccai J, McCracken C, Brayne C. A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing. 2005;34(6):561-566.

8. Bradshaw J, Saling M, Hopwood M, et al. Fluctuating cognition in dementia with Lewy bodies and Alzheimer’s disease is qualitatively distinct. J Neurol Neurosurg Psychiatry. 2004;75(3):382-387.

9. Singleton AB, Wharton A, O’Brien KK, et al. Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with Lewy bodies. Dement Geriatr Cogn Disord. 2002;14(4):167-175.

10. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263-269.

11. Jack CR, Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):257-262.

12. Mollenhauer B, Cullen V, Kahn I, et al. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2008;213(2):315-325.

13. Parnetti L, Balducci C, Pierguidi L, et al. Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in dementia with Lewy bodies. Neurobiol Dis. 2009;34(3):484-486.

14. Shimada H, Hirano S, Shinotoh H, et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology. 2009;73(4):273-278.

15. McKeith I, O’Brien J, Walker Z, et al. Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol. 2007;6(4):305-313.

16. Walker Z, Jaros E, Walker RW, et al. Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy. J Neurol Neurosurg Psychiatry. 2007;78(11):1176-1181.

17. Bradshaw JM, Saling M, Anderson V, et al. Higher cortical deficits influence attentional processing in dementia with Lewy bodies, relative to patients with dementia of the Alzheimer’s type and controls. J Neurol Neurosurg Psychiatry. 2006;77(10):1129-1135.

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.

19. Stavitsky K, Brickman AM, Scarmeas N, et al. The progression of cognition, psychiatric symptoms, and functional abilities in dementia with Lewy bodies and Alzheimer disease. Arch Neurol. 2006;63(10):1450-1456.

20. Ferman TJ, Smith GE, Boeve BF, et al. Neuropsychological differentiation of dementia with Lewy bodies from normal aging and Alzheimer’s disease. Clin Neuropsychol. 2006;20(4):623-636.

21. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology. 1999;53(5):902-905.

22. Boeve BF, Silber MH, Ferman TJ, et al. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord. 2001;16(4):622-630.

23. Portet F, Scarmeas N, Cosentino S, et al. Extrapyramidal signs before and after diagnosis of incident Alzheimer disease in a prospective population study. Arch Neurol. 2009;66(9):1120-1126.

24. 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.

25. Tarawneh R, Galvin JE. Distinguishing Lewy body dementias from Alzheimer’s disease. Expert Rev Neurother. 2007;7(11):1499-1516.

26. Ancoli-Israel S, Klauber MR, Gillin JC, et al. Sleep in non-institutionalized Alzheimer’s disease patients. Aging (Milano). 1994;6(6):451-458.

27. Ferman TJ, Smith GE, Boeve BF, et al. DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004;62(2):181-187.

28. Salmon DP, Galasko D, Hansen LA, et al. Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn. 1996;31(2):148-165.

29. Jack CR, Jr, Petersen RC, Xu Y, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology. 2000;55(4):484-489.

30. Burton EJ, Barber R, Mukaetova-Ladinska EB, et al. Medial temporal lobe atrophy on MRI differentiates Alzheimer’s disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain. 2009;132(pt 1):195-203.

31. Ishii K, Soma T, Kono AK, et al. Comparison of regional brain volume and glucose metabolism between patients with mild dementia with lewy bodies and those with mild Alzheimer’s disease. J Nucl Med. 2007;48(5):704-711.

32. Klein JC, Eggers C, Kalbe E, et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010;74(11):885-892.

33. Fujishiro H, Nakamura S, Kitazawa M, et al. Early detection of dementia with Lewy bodies in patients with amnestic mild cognitive impairment using 123I-MIBG cardiac scintigraphy. J Neurol Sci. 2012;315(1-2):115-119.

34. O’Brien JT, McKeith IG, Walker Z, et al. Diagnostic accuracy of 123I-FP-CIT SPECT in possible dementia with Lewy bodies. Br J Psychiatry. 2009;194:34-39.

35. Yoshita M, Taki J, Yokoyama K, et al. Value of 123I-MIBG radioactivity in the differential diagnosis of DLB from AD. Neurology. 2006;66(12):1850-1854.

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Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the first and second most common causes of neurodegenerative dementia, respectively.^{“New Alzheimer’s disease guidelines: Implications for clinicians,” Current Psychiatry, March 2012, p. 15-20; http://bit.ly/UNYikk.}

The 2005 report of the DLB Consortium⁵ recognizes central, core, suggestive, and supportive features of DLB (Table 1).^5,10 These features are considered in the context of other confounding clinical conditions and the timing of cognitive and motor symptoms. The revised DLB criteria⁵ require a central feature of progressive cognitive decline. “Probable DLB” is when a patient presents with 2 core features or 1 core feature and ≥1 suggestive features. A diagnosis of “possible DLB” requires 1 core feature or 1 suggestive feature in the presence of progressive cognitive decline.

Table 1

Diagnostic criteria for AD and DLB

NIA-AA criteria for AD (2011)¹⁰
Possible AD: Clinical and cognitive criteria (DSM-IV-TR) for AD are met and there is an absence of biomarkers to support the diagnosis or there is evidence of a secondary disorder that can cause dementia
Probable AD: Clinical and cognitive criteria for AD are met and there is documented progressive cognitive decline or abnormal biomarker(s) suggestive of AD or evidence of proven AD autosomal dominant genetic mutation (presenilin-1, presenilin-2, amyloid-β precursor protein)
Definite AD: Clinical criteria for probable AD are met and there is histopathologic evidence of the disorder
Revised clinical diagnostic criteria for DLB (2005)⁵
Core features: Fluctuating cognition, recurrent visual hallucinations, soft motor features of parkinsonism
Suggestive features: REM sleep behavior disorder, severe antipsychotic sensitivity, decreased tracer uptake in striatum on SPECT dopamine transporter imaging or on myocardial scintigraphy with MIBG
Supportive features (common but lacking diagnostic specificity): repeated falls and syncope; transient, unexplained loss of consciousness; systematized delusions; hallucinations other than visual; relative preservation of medial temporal lobe on CT or MRI scan; decreased tracer uptake on SPECT or PET imaging in occipital regions; prominent slow waves on EEG with temporal lobe transient sharp waves
AD: Alzheimer’s disease; DLB: dementia with Lewy bodies; MIBG: metaiodobenzylguanidine; NIA-AA: National Institute on Aging and the Alzheimer’s Association; PET: positron emission tomography; REM: rapid eye movement; SPECT: single photon emission computed tomography

Biomarkers for AD, but not DLB

The 2011 diagnostic criteria for AD incorporate biomarkers that can be measured in vivo and reflect speci?c features of disease-related pathophysiologic processes. Biomarkers for AD are divided into 2 categories:¹¹

amyloid-beta (Aβ) accumulation: abnormal tracer retention on amyloid positron emission topography (PET) imaging and low cerebrospinal fluid (CSF) Aβ42
neuronal degeneration or injury: elevated CSF tau (total and phosphorylated tau), decreased ?uorodeoxyglucose uptake on PET in temporo-parietal cortices, and atrophy on structural MRI in the hippocampal and temporo-parietal regions.

No clinically applicable genotypic or CSF markers exist to support a DLB diagnosis, but there are many promising candidates, including elevated levels of CSF p-tau 181, CSF levels of alpha- and beta-synuclein,¹² and CSF beta-glucocerebrosidase levels.¹³ PET mapping of brain acetylcholinesterase activity,¹⁴ 123I-2β-carbomethoxy-3β- (4-iodophenyl)-N-(3-fluoropropyl)nortropane single photon emission computed tomography (SPECT) dopamine transporter (DaT) imaging¹⁵ and metaiodobenzylguanidine (MIBG) scintigraphy also are promising methods. DaT scan SPECT is FDA-approved for detecting loss of functional dopaminergic neuron terminals in the striatum and can differentiate between AD and DLB with a sensitivity and specificity of 78% to 88% and 94% to 100%, respectively.¹⁶ This test is covered by Medicare for differentiating AD and DLB.

Differences in presentation

Cognitive impairment. Contrary to the early memory impairment that characterizes AD, memory deficits in DLB usually appear later in the disease course.⁵ Patients with DLB manifest greater attentional, visuospatial, and executive impairments than those with AD, whereas AD causes more profound episodic (declarative) memory impairment than DLB. DLB patients show more preserved consolidation and storage of verbal information than AD patients because of less neuroanatomical and cholinergic compromise in the medial temporal lobe. There is no evidence of significant differences in remote memory, semantic memory, and language (naming and fluency).

Clinical Point

Memory impairment in DLB usually appears later in the disease course than in Alzheimer’s disease

Compromised attention in DLB may be the basis for fluctuating cognition, a characteristic of the disease. The greater attentional impairment and reaction time variability in DLB compared with AD is evident during complex tasks for attention and may be a function of the executive and visuospatial demands of the tasks.¹⁷

Executive functions critical to adaptive, goal-directed behavior are more impaired in DLB than AD. DLB patients are more susceptible to distraction and have difficulty engaging in a task and shifting from 1 task to another. This, together with a tendency for confabulation and perseveration, are signs of executive dysfunction.