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Review
. 2014 Jul 21;6(4):46.
doi: 10.1186/alzrt274. eCollection 2014.

The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis

Affiliations
Review

The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis

Paul C Donaghy et al. Alzheimers Res Ther. .

Abstract

Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia following Alzheimer's disease (AD). DLB is clinically and pathologically related to Parkinson's disease (PD) and PD dementia, and the three disorders can be viewed as existing on a spectrum of Lewy body disease. In recent years there has been a concerted effort to establish the phenotypes of AD and PD in the prodromal phase (before the respective syndromes of cognitive and motor impairment are expressed). Evidence for the prodromal presentation of DLB is also emerging. This paper briefly reviews what is known about the clinical presentation of prodromal DLB before discussing the pathology of Lewy body disease and how this relates to potential biomarkers of prodromal DLB. The presenting features of DLB can be broadly placed in three categories: cognitive impairment (particularly nonamnestic cognitive impairments), behavioural/psychiatric phenomena (for example, hallucinations, rapid eye movement sleep behaviour disorder (RBD)) and physical symptoms (for example, parkinsonism, decreased sense of smell, autonomic dysfunction). Some noncognitive symptoms such as constipation, RBD, hyposmia and postural dizziness can predate the onset of memory impairment by several years in DLB. Pathological studies of Lewy body disease have found that the earliest sites of involvement are the olfactory bulb, the dorsal motor nucleus of the vagal nerve, the peripheral autonomic nervous system, including the enteric nervous system, and the brainstem. Some of the most promising early markers for DLB include the presence of RBD, autonomic dysfunction or hyposmia, (123)I-metaiodobenzylguanidine cardiac scintigraphy, measures of substantia nigra pathology and skin biopsy for α-synuclein in peripheral autonomic nerves. In the absence of disease-modifying therapies, the diagnosis of prodromal DLB is of limited use in the clinic. That said, knowledge of the prodromal development of DLB could help clinicians identify cases of DLB where the diagnosis is uncertain. Prodromal diagnosis is of great importance in research, where identifying Lewy body disease at an earlier stage may allow researchers to investigate the initial phases of dementia pathophysiology, develop treatments designed to interrupt the development of the dementia syndrome and accurately identify the patients most likely to benefit from these treatments.

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Figures

Figure 1
Figure 1
Diagnostic criteria for dementia with Lewy bodies. CT, computed tomography; DLB, dementia with Lewy bodies; EEG, electroencephalogram; MRI, magnetic resonance imaging; MIBG, metaiodobenzylguanidine; PET, positron emission tomography; REM, rapid eye movement; SPECT, single photon emission computed tomography. Adapted from [2].
Figure 2
Figure 2
Nomenclature of Lewy body diseases. Parkinson’s disease dementia is diagnosed when cognitive impairment develops a year or more after the onset of parkinsonism. Dementia with Lewy bodies is diagnosed when cognitive symptoms appear without parkinsonism or less than 1 year after the onset of parkinsonism.
Figure 3
Figure 3
Examples of presenting symptoms of dementia with Lewy bodies. REM, rapid eye movement.
Figure 4
Figure 4
Progression of Lewy body pathology. Schematic diagram of the pattern of alpha-synuclein deposition as hypothesised by Braak and colleagues [32]. Deposition is first seen in the peripheral autonomic nervous system, including the enteric nervous system. This is then followed by deposition in the brainstem, ascending to the limbic system and, finally, the neocortex. Illustration from [88], available under creative commons license.
Figure 5
Figure 5
Hypothetical timelines of biomarker development. (A) Biomarker development in dementia with Lewy bodies (DLB). This hypothesis mirrors that proposed by Jack and colleagues in Alzheimer’s disease [56]. The first biomarkers of DLB will be markers of alpha-synuclein (αSyn) deposition (for example, from skin biopsy). αSyn deposition probably decreases later in the disease process following cell death [40]. This would then be followed by markers of cell damage or death (for example, loss of dopamine transporters in the striatum on single photon emission computed tomography or positron emission tomography) and then clinical symptoms/signs (for example, parkinsonism). (B) Biomarkers in two different sites. In this hypothetical representation, αSyn deposition, cell damage and loss and the development of symptoms (hyposmia) all occur in the olfactory bulb prior to the development of αSyn deposition in the neocortex.
Figure 6
Figure 6
Examples of imaging abnormalities in dementia with Lewy bodies. (A) Dopamine transporter imaging. Both the control and Alzheimer’s disease (AD) subjects display normal dopamine transporter levels in the striatum. The dementia with Lewy bodies (DLB) subject displays reduced uptake in the putamen bilaterally, reflecting nigrostriatal degeneration. (B) Cerebral blood flow imaging. The AD subject shows decreased perfusion compared with control, particularly in the left temporal lobe. The DLB subject also exhibits perfusion deficits, but these are largely confined to posterior regions including the occipital lobes. FP-CIT, N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane; HMPAO, exametazime; SPECT, single photon emission computed tomography.
Figure 7
Figure 7
Hypothetical algorithm for the identification of prodromal Lewy body disease. The first stage consists of assessment for simple markers of functional decline – symptom questionnaires, cognitive tests and simple clinical biomarkers (for example, biomarkers for hyposmia). In the second stage, those with a profile suggestive of Lewy body (LB) disease would undergo tests with greater specificity, identifying death or dysfunction of cell groups affected by LB pathology, or the presence of alpha-synuclein (αSyn) pathology. This may include cardiac metaiodobenzylguanidine (MIBG) scintigraphy, measures of substantia nigra pathology, such as ultrasound or striatal dopamine transporter imaging, or biopsy for the presence of αSyn. FP-CIT, N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane; MCI, mild cognitive impairment.

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