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Evidence-Based Reviews

Differentiating Alzheimer’s disease from dementia with Lewy bodies

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

Vol. 11, No. 11 / November 2012

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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;

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).

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.

Neuropsychiatric features. DLB patients are more likely than AD patients to exhibit psychiatric symptoms and have more functional impairment.18 In an analysis of autopsy-confirmed cases, hallucinations and delusions were more frequent with Lewy body pathology (75%) than AD (21%) at initial clinical evaluation.18 By the end stages of both illnesses, the degree of psychotic symptoms is comparable.19 Depression is common in DLB; whether base rates of depressed mood and major depression differ between DLB and AD is uncertain.20

Psychosis in AD can be induced by medication or delirium, or triggered by poor sensory perceptions. Psychotic symptoms occur more frequently during the moderate and advanced stages of AD, when patients present with visual hallucinations, delusions, or delusional misidentifications. As many as 10% to 20% of patients with AD experience hallucinations, typically visual. Delusions occur in 30% to 50% of AD patients, usually in the later stages of the disease. The most common delusional themes are infidelity, theft, and paranoia. Female sex is a risk factor for psychosis in AD. Delusions co-occur with aggression, anxiety, and aberrant motor behavior.

Visual hallucinations—mostly vivid, well-formed, false perceptions of insects, animals, or people—are the defining feature of DLB.21 Many patients recognize that they are experiencing visual hallucinations and can ignore them. DLB patients also may experience visual illusions, such as misperceiving household objects as living beings. Delusions—typically paranoid—are common among DLB patients, as are depression and anxiety.1 Agitation or aggressive behavior tends to occur late in the illness, if at all.

The causes of psychotic symptoms in DLB are not fully understood, but dopamine dysfunction likely is involved in hallucinations, delusions, and agitation, and serotonin dysfunction may be associated with depression and anxiety. Rapid eye movement (REM) sleep/wakefulness dysregulation, in which the dream imagery of REM sleep may occur during wakefulness, also has been proposed as a mechanism for visual hallucinations in DLB.22 In DLB, psychotic symptoms occur early and are a hallmark of this illness, whereas in AD they usually occur in the middle to late stages of the disease.

Motor symptoms. In AD, extrapyramidal symptoms (EPS) are common later in the disease, are strongly correlated with disease severity, and are a strong, independent predictor of depression severity.23 EPS are more common in DLB than in AD24 and DLB patients are at higher risk of developing EPS even with low doses of typical antipsychotics, compared with AD patients.25

Other symptoms. REM sleep behavior disorder (RBD) is characterized by enacting dreams—often violent—during REM sleep. RBD is common in DLB and many patients also have excessive daytime somnolence. Other sleep disorders in DLB include insomnia, obstructive sleep apnea, central sleep apnea, restless legs syndrome, and periodic limb movements during sleep.

In AD patients, common sleep behaviors include confusion in the early evening (“sundowning”) and frequent nighttime awakenings, often accompanied by wandering.26 Orthostatic hypotension, impotence, urinary incontinence, and constipation are common in DLB. Lack of insight concerning personal cognitive, mood, and behavioral state is highly prevalent in AD patients and more common than in DLB.

Diagnostic evaluation

Because there are no definitive clinical markers for DLB, diagnosis is based on a detailed clinical and family history from the patient and a reliable informant, as well as a physical, neurologic, and mental status examination that looks for associated noncognitive symptoms, and neuropsychological evaluation. Reasons DLB may be misdiagnosed include:

  • Some “core” clinical features of DLB may not appear or may overlap with AD.
  • Presence and severity of concurrent AD pathology in DLB may modify the clinical presentation, with decreased rates of hallucinations and parkinsonism and increased neurofibrillary tangles.
  • Failure to reliably identify fluctuations—variations in cognition and arousal, such as periods of unresponsiveness while awake (“zoning out”), excessive daytime somnolence, and disorganized speech.27

Detecting and characterizing cognitive deficits in dementia patients using neuropsychological testing is important in establishing a clinical diagnosis, determining baseline levels of impairment, forming a prognosis, and initiating disease-specific treatments. Differences in neuropsychological findings in AD and DLB are outlined in Table 2.16,28-33 Several studies have suggested using these measures to differentiate patients with DLB from those with AD.20

Table 2

Diagnostic testing for Alzheimer’s disease and dementia with Lewy bodies

Alzheimer’s disease

Dementia with Lewy bodies

Neuropsychological testing findings

Relatively more impairment on verbal memory tasks, delayed recall, delayed recognition, and encoding and storing information.28 Dysfunction of episodic memory function

Relatively more impairment on attention or concentration, verbal fluency, visuoperceptual, visuoconstructive, visual memory tests, and frontal executive functions.28 Relatively preserved confrontation naming and verbal memory

MRI findings

Diffuse cortical atrophy, relatively greater volume loss in hippocampus and medial temporal lobe structures (strong correlation with severity)29

Mild generalized cerebral cortical atrophy with minimal hippocampal atrophy and relative preservation of medial temporal lobe structures30


Widespread metabolic deficits in neocortical association areas, with sparing of the basal ganglia, thalamus, cerebellum, primary sensory motor cortex, and visual cortex

Widespread cortical hypometabolism, more marked in primary visual and occipital association areas, and less severe in parietal, frontal, and anterior cingulate cortices.31 Severe cholinergic deafferentation of the neocortex, particularly in posterior cortical regions32

Single photon emission computed tomography

Parietotemporal hypoperfusion

Occipital hypoperfusion

123I-FP-CIT SPECT (DaT scan)

No significant loss of DaT

Low nigrostriatal terminal density of DaT caused by severe nigrostriatal degeneration16

Myocardial scintigraphy with MIBG

No significant change in MIBG uptake

Decreased MIBG uptake33

123I-FP-CIT: 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane; DaT: dopamine transporter; FDG PET: [18F]-fluoro-d-glucose positron emission tomography; MIBG: metaiodobenzylguanidine; SPECT: single photon emission computed tomography

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.

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

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