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Abstract

Dementia with Lewy bodies is a progressive neurodegenerative disorder, clinically characterized by gradual cognitive impairment and fluctuating cognition, behavioral changes and recurrent visual hallucinations, and autonomic function and movement symptoms in the type of parkinsonism. It is the second most common type of dementia in the Western world after Alzheimer disease. Over the last 20 years, many neurophysiological, neuroimaging, and cerebrospinal fluid (CSF) biomarkers have been described toward a better discrimination between dementia with Lewy bodies, Alzheimer disease, and other neurodegenerative conditions.In the present review, we aim to describe the neurophysiological, imaging, and CSF biomarkers in dementia with Lewy bodies and to question whether they could be reliable tools for the clinical practice.

Keywords

dementia with Lewy bodies biomarkers CSF physiological neuroimaging

Introduction

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative condition clinically characterized by gradual cognitive impairment and fluctuating cognition, behavioral changes and recurrent visual hallucinations, and autonomic function and movement symptoms in the type of parkinsonism. Dementia with Lewy bodies accounts for the 15% of dementia cases at autopsy and is the second most common type of neurodegenerative dementia after Alzheimer disease (AD).¹ Day-to-day clinical practice is not always easy to differentiate between the different types of dementia based only on clinical features, especially when the characteristic symptoms are not present, and the definite diagnosis can only be confirmed by postmortem findings; however, several neurophysiological, neuroimaging, and cerebrospinal fluid (CSF) markers can increase the accuracy of the diagnosis and to organize the best possible treatment plan for the patients and their carriers. In the present review, we aim to describe the neurophysiological, imaging, and CSF biomarkers in DLB.

Clinical and Pathological Hallmarks

Dementia with Lewy bodies is clinically characterized by cognitive impairment with fluctuations of cognition, extrapyramidal features, visual hallucinations, and/or rapid eye movement sleep behavior disorder.² Fluctuating cognition with pronounced variations in attention and alertness, recurrent well-formed and detailed visual hallucinations, rapid eye movement sleep behavior disorder, and one or more spontaneous cardinal features of parkinsonism are the core clinical features of the disease. The current diagnostic criteria for DLB require the presence of 2 or more core clinical features with or without indicative biomarkers for probable DLB, and only 1 core clinical feature with no indicative biomarkers or one or more indicative biomarkers with no core clinical features for possible DLB.²

The pathological hallmark of the disease includes aggregation of α-synuclein in cellular inclusions and dystrophic neurites throughout the brain³, and furthermore, AD-like pathology can be found in up to 89% of patients with DLB in autopsy studies.^4,5

Cerebrospinal Fluid Biomarkers

α-Synuclein

α-Synuclein is one of the potential CSF biomarkers for DLB; however, the outcomes of different studies are controversial. Spies et al, analyzing the levels of α-synuclein in the CSF of 40 patients with DLB, 131 patients with AD, 28 patients with vascular dementia, and 39 patients with frontotemporal dementia found no significant differences in CSF α-synuclein levels between different groups.⁶ Two additional studies reported significant differences in CSF α-synuclein levels between DLB, Parkinson disease (PD), non-DLB dementias, and control patients.^7,8 Mollenhauer et al, using enzyme-linked immunosorbent assay to measure total α-synuclein level in CSF in 57 patients with DLB, 35 patients with AD, and control cases, found lower mean α-synuclein concentrations in DLB⁷, while Kasuga et al examined the total and α-synuclein levels in 34 patients with DLB, 31 patients with AD, and 21 other dementia cases and found significantly lower α-synuclein levels in DLB compared to AD and other dementias.⁸ A total of 15 studies were found for the role of α-synuclein in the discrimination between DLB, PD, and AD. The outcomes, although controversial, showed that α-synuclein in the CSF is a reliable biomarker for the differential diagnosis between DLB and AD but cannot be used for the discrimination between DLB and PD^{9

–20}(Table 1).

Table 1.

Details of the Findings on the Studies on the Use of α-Synuclein for the Diagnosis of Dementia With Lewy Bodies.

Study	DLB			AD
Study	Mean	SD	Patients	Mean	SD	Patients
Bougea et al⁹	161.2	104.8	28	95	41.7	19
Hansson et al¹⁰	58	15	71	67	18	48
Kanemaru et al¹⁹	199.1	233.2	8	654.3	550.2	13
Kapaki et al¹¹	174.7	103.5	16	99.1	42.4	18
Kasuga et al⁸	8200	4200	31	12 200	5800	34
Mollenhauer et al⁷	1420	1260	55	1850	1470	62
Oeckl et al¹²	200.5	36.4	10	294	19	19
Öhrfelt et al¹³	323.5	53.7	15	296	34.5	66
Shi et al¹⁴	421	179.5	16	487	115	165
Spies et al (2009)⁶	38 000	29 000	40	37 000	36100	131
van Steenoven et al¹⁵	1480	80	42	2140	1400	39
van Steenoven et al¹⁶	1400	400	41	2000	500	35
Slaets et al²⁰	111	61	13	147	74	124
Wennström et al¹⁷	380	80	18	420	135	26
Wennström et al¹⁸	585.01	216.44	29	781.68	222	45

Abbreviations: DLB, Dementia with Lewy Bodies, AD, Alzheimer’s disease, SD, standard deviation.

Tau Protein

Although CSF phosphorylated tau 181 (p-tau 181) is present in several neurodegenerative disorders, it seems to be often implicated in DLB.²¹ Patients with AD have significantly higher CSF levels of p-tau 181 compared to controls and patients with DLB²² and can be used for the differentiation between DLB and AD with a sensitivity of 91% and specificity of 94%.²³ In another study in autopsy-confirmed cases, CSF p-tau 181 exhibited a sensitivity of 75%, specificity of 61%, and a diagnostic accuracy of 73% in discrimination between DLB and AD.²⁴ Hamper et al reported similar results while they found that increased CSF levels of p-tau 181 have a sensitivity of 94% and a specificity of 64% for the differentiation of DLB against AD.²⁵ Studies on whether the total CSF tau protein can be used for the discrimination between DLB and AD are controversial, while both nonsignificant and significant differences have been reported.^26,27 An additional study reported significantly lower levels of total tau in DLB than in AD and substantially higher levels than PD and PD dementia.²⁸

Analysis of 1221 CSF samples from different memory centers in France, of which 57 with pro-DLB, 154 with DLB, 132 with prodromal AD, 783 with AD, and 95 controls, for phospho-Tau181, total-Tau, amyloid β (Aβ) 43, and Aβ40, showed reduced levels of Aβ43 in late stages of DLB, compared to AD cases, where Aβ42 levels were decreased even from early stages. The Aβ42/Aβ40 ratio in pro-DLB was similar to controls, and total Tau protein (t-Tau) and phospho-Tau181 were unchanged in DLB cases, independent of the stage. The study concludes that CSF t-Tau and phospho-Tau181 are potential biomarkers for the differential diagnosis between DLB and AD²⁹ (Table 2).

Table 2.

Summary of the Most Important Findings on Cerebrospinal Fluid Biomarkers for the Diagnosis of Dementia With Lewy Bodies.

Tau protein

Patients with AD have significantly higher CSF levels of p-tau 181 compared to controls and patients with DLB²²

α-Synuclein can be used for the differentiation between patients with DLB and AD with a sensitivity of 91% and specificity of 94%²³

CSF p-tau 181 shows a sensitivity of 75%, specificity of 61%, and a diagnostic accuracy of 73% in discrimination between patients with DLB and AD²⁴

Increased CSF levels of p-tau 181 have a sensitivity of 94% and a specificity of 64% for the differentiation of DLB from AD²⁵

Aβ peptide

Aβ peptide 1-40 is significantly decreased in patients with DLB compared to patients with AD⁶

The ratio between Aβ1-42/Aβ1-40 is a reliable biomarker for the discrimination between AD and other dementias including DLB³⁰

An oxidized α-helical form of Aβ peptide was significantly increased in patients with DLB in comparison to patients with PD dementia, having a sensitivity of 81% and specificity of 71% at DLB and PD dementia differentiation³¹

Abbreviations: Aβ, amyloid β; DLB, dementia with Lewy bodies, AD, Alzheimer disease, SD, standard deviation; PD, Parkinson disease; CSF, cerebrospinal fluid; t-Tau, total tau protein.

Amyloid β Peptide

Amyloid β peptide 1-42 is characteristic for AD and however can also be found in DLB, in combination with lower levels of cystatin C, a peptide known to inhibit fibril formation and oligomerization of the amyloid peptide.³² Furthermore, Aβ peptide 1-40 is significantly decreased in DLB compared to AD.⁶ Although CSF levels of Aβ42 on their own cannot be used to differentiate DLB from AD, they have been reported to be significantly lower than controls in both conditions but with no significant difference between them^33,34; the ratio between Aβ1-42 and Aβ1-40 is considered a reliable biomarker for the discrimination between AD and other dementias including DLB.³⁰ An oxidized α-helical form of Aβ peptide, referred as Aβ1-40*, was found to be significantly increased in patients with DLB in comparison to PD dementia, having a sensitivity of 81% and specificity of 71% at DLB and PD dementia differentiation³¹ (Table 2). Furthermore, reduced glutathione, but not the oxidized form, was significantly lower in patients with DLB than in controls; however, the total glutathione which has been studied in several neurodegenerative diseases including AD did not show any significant difference.³⁵

Other CSF Biomarkers

A study on 26 patients with AD, 18 patients with DLB, and 24 controls reported significantly decreased CSF orexins levels in patients with DLB, being more prominent in female patients, and concluding that CSF orexins are specific to DLB versus AD but can be related to gender that warrants further investigation.¹⁸

Older studies on inflammatory markers in the CSF showed that none of the interleukins 1b and 6, the precursor enkephalins, and substance P peptides could be used to differentiate DLB from other dementias.^36,37 However, Wennstrom et al in a more recent study found significantly lower CSF levels of interleukin 6 (IL-6) in patients with DLB compared to patients with AD.¹⁷

The cocaine- and amphetamine-regulated transcript neuropeptides were found to be significantly reduced in the CSF of patients with DLB in comparison to patients with AD and controls.³⁸

Asparagine, glycine, and nitric oxide are also raised in the CSF of patients with DLB compared to controls and can be used as supportive biomarkers for the diagnosis of DLB^39,40; however, they have not been tested against other dementias.

Calcium and magnesium levels were elevated in DLB compared to AD and controls and using combined measurements of both had a sensitivity of 93% and specificity of 85% to differentiate DLB from AD⁴¹ (Table 2).

Neurophysiological Biomarkers

Electroencephalography

The presence of posterior temporal transient slow or sharp waves is included in the diagnostic criteria as a supportive feature for the diagnosis of DLB.^42
–44 Certain electroencephalography (EEG) topographical differences between DLB and AD have also been described, while in DLB, abnormalities are found in posterior regions and in AD in temporal lobes^45,46; in addition, patients with DLB exhibit increased posterior slow-wave activity compared to controls and patients with AD.^{43,45,47
–49}

Patients who were not taking donepezil showed increased spectral power density in δ and θ bands in comparison to controls, while patients with AD did not exhibit the same changes.⁵⁰ Andersson et al described a greater degree of parietal delta power band variability in DLB against AD and controls⁵⁰; nevertheless, similar findings have been described by different studies in patients with AD, making this feature nonspecific for DLB.⁵¹

Electroencephalography coherence between left anterior, right anterior, left posterior, and right posterior has been found to be increased in the delta band but decreased in the alpha band in patients with DLB versus controls.⁵⁰ Further differences in intrahemispheric and temporo-centro-parieto-occipital beta band coherence values between patients with DLB and AD have been reported by Kai et al.⁵²

Patients with DLB exhibited greater fluctuations in frequencies on a second-by-second basis compared to patients with AD and controls.^45,53

A longitudinal study on 47 individuals with mild cognitive impairment, 50 individuals with DLB, 50 patients with AD, and 50 controls revealed typical abnormalities in patients with mild cognitive impairment who converted to probable DLB, including a reduced dominant frequency and increased dominant frequency variability.⁵⁴ Londos et al analyzing retrospectively resting EEG recordings from 45 AD and 48 DLB cases reported no significant differences between the 2 groups⁵⁵ (Table 3).

Table 3.

Summary of the Most Important Findings on Neurophysiological Biomarkers for the Diagnosis of Dementia With Lewy Bodies.

EEG

Posterior temporal transient slow or sharp waves are present in DLB^41
–43

Patients who were not taking donepezil showed increased spectral power density in delta and theta bands in comparison to controls, while patients with AD did not exhibit the same changes⁴⁹

Electroencephalogram coherence between left anterior, right anterior, left posterior, and right posterior was increased in delta band but decreased in alpha band in patients with DLB patients vs controls⁵⁰

Differences in intrahemispheric and temporo-centro-parieto-occipital beta band coherence values between patients with DLB and AD⁵⁰

Patients with DLB exhibited greater fluctuations in frequencies on a second-by-second basis compared to patients with AD and controls^44,52.

Mild cognitive impairment patients who converted to probable DLB showed reduced dominant frequency and increased dominant frequency variability⁵³.

Retrospective analysis of resting EEG reported no significant differences between AD and DLB⁵⁴

Evoked potentials

Patients with DLB showed lower amplitude and greater latency of auditory P300 and an overall inversion of the pattern of P300 amplitude gradients compared to patients with AD⁵⁵

Patients with DLB showed reduced prepulse inhibition of the N1/N2 component of auditory-evoked potentials compared to patients with AD and controls⁵⁵

Blink reflex studies

Patients with DLB showed a significant delay in blink reflex response with increased latency compared to patients with AD, patients with MSA, and controls⁵⁶

Additional physiological biomarkers

Abnormal startle reaction profile for patients with DLB ⁵⁷.

Sympathetic skin response and heart rate variability significantly different in DLB, with lower sympathetic response and a lower ratio of low-frequency to high-frequency power⁵⁸

Reduced sweat response amplitudes in patients with DLB and PD compared to controls, lower vasomotor reflex amplitudes in patients with DLB but not patients with PD, and significantly lower coefficient variation in R-R intervals value in DLB⁵⁹

Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DLB, dementia with Lewy bodies, EEG, electroencephalogram; MSA, Multiple System Atrophy; SD, standard deviation; PD, Parkinson disease.

Event-Related Potential Studies

Bonanni et al reported a lower amplitude and greater latency of auditory P300 in patients with DLB compared to AD and an overall inversion of the pattern of P300 amplitude gradients.⁵⁷ The presence of inverted amplitude differentiated DLB from AD with a sensitivity of 70% and a specificity of 97%.⁴⁶ Perriol et al examined the prepulse inhibition of the N1/N2 component of auditory-evoked potentials in 10 DLB, 10 AD, and 10 PD dementia cases, and found a reduced prepulse inhibition in DLB compared to AD and control individuals⁵⁶ (Table 3).

Blink Reflex Studies

Blink reflex studies have also shown worth-mentioned findings. Bonanni et al studying patients with DLB, AD, and multiple system atrophy against controls demonstrated a significantly delayed blink reflex response with increased latency in the DLB group⁵⁷ (Table 3).

Additional Physiological Biomarkers

Auditory startle reaction is another neurophysiological index that has been investigated in DLB. Kofler et al examined the auditory startle reaction in DLB cases, patients with other parkinsonian syndromes, and control individuals and found an abnormal startle reaction profile for patients with DLB.⁵⁸

Additional physiological markers that have been investigated include autonomic response markers. Sympathetic skin response and heart rate variability were reported to be significantly different in DLB, with lower sympathetic response and a lower ratio of low-frequency to high-frequency power with the sensitivities being 85% and 90%, respectively, and the specificity of each method being 85% and 85%, respectively.⁵⁹

In another study on autonomic responses in DLB, Akaogi et al found reduced sweat response amplitudes in patients with DLB and PD compared to controls, lower vasomotor reflex amplitudes in patients with DLB but not patients with PD, and significantly lower coefficient variation in R-R intervals value in patients with DLB⁶⁰ (Table 3).

Transcranial Magnetic Stimulation

The short-latency afferent inhibition, a corticomotor parameter, was reduced in comparison with controls^61,62 and in fact was correlated with visual hallucinations severity⁶²; however, whether this could be a reliable biomarker remains controversial, while Nardone et al reported no significant difference between patients with DLB and controls.⁶³

Neuroimaging Biomarkers

Structural MRI

Compared to AD, DLB brains exhibit relatively preserved volumes of hippocampus and medial temporal lobes in structural magnetic resonance imaging (MRI)⁶⁴ and additional studies that described mild hippocampal atrophy in patients with DLB compared to normal controls.⁶⁵ Lebedev et al, using a multivariate classification of cortical thickness, have shown that this has a sensitivity of 82.1% and a specificity of 85.7% in the differentiation between DLB and AD.⁶⁶ Dementia with Lewy bodies showed atrophy predominantly to the superior temporo-occipital and lateral orbitofrontal regions, and the middle and posterior cingulate cortices, while AD brains are characterized by cortical thinning within the temporal pole, subgenual cingulate regions, and the parahippocampal areas.⁶⁶ The rate of cerebral atrophy in DLB is higher than in normal controls but significantly lower than in AD.⁶⁷ Another study revealed elective atrophy of different hippocampal areas in DLB compared to AD. In DLB, the perirhinal cortex and the parahippocampus are mainly affected, whereas in AD, the cornu ammonis and the subiculum undergo significant atrophy.⁶⁸ Reduced amygdala volume and atrophy in other cortical and subcortical areas such as the striatum, substantia innominata, hypothalamus, and dorsal midbrain have been described in DLB cases.^69,70

Cortical thinning in DLB is more significant than in PD as Burton et al described using voxel-based morphometry, with reductions being more significant in the temporal, parietal, and occipital lobes^69,70; however, another study was unable to identify different patterns of cortical atrophy between DLB and PD.⁷¹ Further studies have described an additional occipital and striatal cortical thinning in DLB, compared to PD, and a positive relationship between anterior cingulate, right hippocampus, and amygdala gray matter reduction and cognitive performance as well as loss of cortical thickness in the left precuneus and inferior frontal lobe and visual hallucinations have also been reported.^73,74

Apart from different patterns of cortical loss between patients with DLB, AD, and PD, a greater burden at baseline white matter hyperintensities has been described in patients with AD compared to healthy controls, patients with DLB, and patients with PD, but the importance of this finding remains poorly understood⁷⁵ (Table 4).

Table 4.

Summary of the Most Important Findings on Neuroimaging Biomarkers for the Diagnosis of Dementia With Lewy Bodies.

Structural MRI

DLB vs AD

DLB preserves volumes of hippocampus and medial temporal lobes in comparison to AD.⁶³

Patients with DLB show mild hippocampal atrophy compared to controls.⁶⁴

DLB showed atrophy to the superior temporo-occipital and lateral orbitofrontal regions and the middle and posterior cingulate cortices.⁶⁵

Higher rate of cerebral atrophy compared to controls but lower than patients with AD.⁶⁶

Perirhinal cortex and parahippocampus are mainly affected.⁶⁷

Reduced amygdala volume and atrophy in other cortical and subcortical areas such as the striatum, substantia innominata, hypothalamus, and dorsal midrbain.^68,69

DLB vs PD

More significant cortical thinning in DLB.^68,69

Another study failed to recognize difference in cortical atrophy patterns.⁷¹

Occipital and striatal thinning in DLB, and positive relationship between anterior cingulate, right hippocampus, and amygdala gray matter reduction and cognitive performance.⁷²

Cortical thinning in the left precuneus and inferior frontal lobe related to visual hallucinations.⁷³

Diffusion tensor imaging

Increased diffusion and decreased fractional anisotropy in the coprus callosum and pericallosal areas and in frontal, parietal, and occipital areas compared to controls.⁷⁵

Reduced fractional anisotropy in the precuneus compared to controls and patients with AD.⁷⁶

Reduced fractional anisotropy in parieto-occipital white matter tracts compared to controls.⁷⁷

Greater longitudinal increase in mean diffusivity in parietal and temporal regions.⁷⁷

Susceptibility-weighted imaging.

Hypointensity of the caudal and posterolateral parts of the substantia nigra compared to AD and other dementias.^78,79

Nigrosome 1 hypointensity measurements with SWI have 90% diagnostic accuracy, with 93% sensitivity and 87% specificity.⁷⁸

Functional MRI

Increased functional connectivity between the right posterior cingulate gyrus and the inferior parietal cortex and putamen and decreased connectivity in the frontoparietal operculum, medial prefrontal cortex, and the primary visual cortex compared to patients with AD.⁸⁰

Increased connectivity in the default mode network in comparison to AD.⁸¹

Decreased within-network connectivity in patients with DLB compared to controls, mainly in motor, temporal, and frontal networks.⁸²

Greater activation in the superior temporal sulcus compared to AD, especially during motion tasks.⁸³

No significant differences were found in functional response to objects, motion stimuli, or checkerboard in V1, V2, and V3 occipital areas.⁸⁴

Reduction in V5/MT brain areas activation in response to motion stimuli.⁸⁴

Greater alterations in functional connectivity at the precentral and postcentral gyri, cerebellar, occipital, and temporal regions compared to controls, whereas in PD functional connectivity changes are mainly limited to frontal cortex and the precuneus.⁸⁵

Abbreviations: DLB, Dementia with Lewy bodies, AD, Alzheimer disease, PD, Parkinson disease; SWT, susceptibility-weighted imaging; MRI, magnetic resonance imaging.

Diffusion Tensor Imaging

Dementia with Lewy bodies brains show increased diffusion and decreased fractional anisotropy in corpus callosum and pericallosal areas and in frontal, parietal, and occipital areas in comparison to normal controls.⁷⁶ Furthermore, patients with DLB show reduced fractional anisotropy in the precuneus area compared to both normal controls and patients with AD⁷⁷ and in parieto-occipital white matter tracts compared to normal controls, which seems to be an early phenomenon.⁷⁸ The same study also showed that in AD there is no evidence of longitudinal changes in mean diffusivity or fractional anisotropy, but there is a greater longitudinal increase in mean diffusivity in parietal and temporal regions.⁷⁸ Additional reduced fractional anisotropy in the pons and left thalamus in DLB did not seem to be reproducible⁷⁸ (Table 4).

Susceptibility-Weighted Imaging

Kamagata et al reported that measuring nigrosome 1 hypointensity with susceptibility-weighted imaging achieved 90% diagnostic accuracy with 93% sensitivity and 87% specificity, and Shams et al showed that the caudal and posterolateral part of the substantia nigra is hypointense in patients with DLB compared to patients with AD and other dementias.^79,86

Functional MRI

Functional MRI studies suggest increased functional connectivity between the right posterior cingulate gyrus and the inferior parietal cortex and putamen and decreased connectivity in the frontoparietal operculum, medial prefrontal cortex, and the primary visual cortex when compared to AD, while a reversal of connectivity was observed in the right hippocampus.^80,81 Dementia with Lewy bodies has been shown to display increased connectivity in the default mode network in comparison to AD.⁸⁷ Memory function is relatively preserved in DLB, and the nonsignificant difference in hippocampal connectivity between DLB cases and normal controls is in keeping with this.⁸² Schumacher et al investigating functional connectivity changes in 31 patients with DLB compared to 31 healthy controls and 29 patients with AD using dual regression and FSLNets found decreased within-network connectivity in patients with DLB compared to controls, mainly in motor, temporal, and frontal networks. Moreover, they described intact between-network connectivity and increased frontal and temporal network connectivity in patients with DLB, and subtle differences between patients with DLB and patients with AD. They concluded that patients with DLB and AD may show more similarities than differences in mild disease cases.⁸³ Patients with DLB also demonstrated greater activation in the superior temporal sulcus compared to AD, especially during motion tasks,⁸⁴ but those findings were not reproduced in another study which examined the response of visual and parieto-occipital cortex of 17 DLB cases and 19 controls to visual stimuli, and no significant differences were found in functional response to objects, motion stimuli, or checkerboard in V1, V2, and V3 occipital areas.⁸⁵ The same study also reported a reduction in V5/MT brain areas activation in response to motion stimuli,⁸⁵ concluding that the visual system in DLB is dysfunctional. Patients with DLB also exhibit greater alterations in functional connectivity at the precentral and postcentral gyri, cerebellar, occipital, and temporal regions compared to controls, whereas in PD functional connectivity changes are mainly limited to frontal cortex and the precuneus⁸⁸; however, no significant difference was found on DLB versus PD comparison (Table 4).

Positron Emission Tomography and Single-Photon Emission Computed Tomography

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies have shown decreased glucose metabolism and deficits in perfusion in parietotemporal and occipital areas in DLB, while AD is characterized by more generalized decreased cerebral metabolism.^89

–93 Decreased 18 F-fluorodopa reuptake in the striatum can be used to differentiate DLB from AD having high sensitivity and specificity according to a recent study.⁹⁴ Liu et al using Pittsburgh compound B (C-PIB) PET scans for Aβ deposition and 18F-FDG PET scans for regional cerebral metabolism in 37 patients with DLB reported Aβ deposition in the cortex and hypometabolism in the temporo-parieta-ooccipital regions bilaterally as well as the frontal lobe, the insular lobe, the posterior cingulate, the precuneus, and caudate nuclei.⁹⁵

A combined study of 18F-FDG PET scan and C11 Pittsburgh compound B PET in 39 DLB cases, 39 AD, 78 controls, and 10 autopsies examined for Braak neurofibrillary tangle staging revealed a higher ratio of posterior cingulate to precuneus plus cuneus metabolism, cingulate island sign than AD, and this was independent of Aβ load. The same study also describes an inverse relationship between higher cingulate island sign ratio and Braak staging and cognitive symptoms.^96,97

Reduced dopamine transporter binding in the caudate and posterior putamen have also been described by different studies^98,99 in DLB compared to AD but with no difference from PD. Dopamine transporter imaging with SPECT yields a sensitivity of 88% and a specificity of 100% in the differential diagnosis between patients with DLB and AD¹⁰⁰ but cannot be used to differentiate between patients with DLB and PD, where there is a profound loss of dopamine transporter binding in the striatum.¹⁰¹ A phase III multicenter study on 326 patients with probable (n = 94), possible (n = 57) DLB, or non-DLB dementia (n = 147) reported a mean sensitivity of 77.7% of Dopamine Transporters (DAT) scan for detecting probable DLB, with a specificity of 90.4% for excluding non-DLB dementia, concluding that low DAT uptake in the basal ganglia can be a suggestive feature for diagnosis of DLB over non-DLB dementia.

Thoracic SPECT studies have also shown reduced cardiac reuptake in DLB, significantly different from AD but with no difference from PD.¹⁰² A number of studies have shown diminished cardiac (123) I-metaiodobenzylguanidine uptake in PD and DLB, and in 2005, the Dementia With Lewy Bodies Consortium considered (123) I-metaiodobenzylguanidine cardiac scintigraphy a “supportive” diagnostic feature. A meta-analysis based on 46 studies demonstrated that (123) I-metaiodobenzylguanidine cardiac scintigraphy can accurately distinguish DLB and AD but cannot be used to discriminate DLB from PD.¹⁰³ Pittsburgh compound B, an in vivo indicator of Aβ, has shown an 80% increased amyloid load in DLB with a respective 20% in PD.¹⁰⁴

Amyloid β deposition cannot distinguish DLB from AD where Aβ retention is comparable, but it can be used to differentiate DLB where cortical Aβ burden is significantly high from PD where Aβ is scarce¹⁰⁵, and it seems that Aβ deposits are associated with cognitive impairment in DLB and not PD, dementia in PD, or PD with mild cognitive impairment.¹⁰⁶ Furthermore, amyloid deposition is positively related to cortical thinning and ventricular expansion in DLB.¹⁰⁷

A study using the radioligand fluorine 18-labeled AV-1451, which has been proven suitable to assess tau deposition, has shown variable and higher cortical tau uptake in the inferior temporal gyrus and precuneus compared to controls, and this was associated with cognitive impairment, indicating a role of tau pathology in DLB pathophysiology.¹⁰⁸ Another study using the same ligand demonstrated significantly more extensive tau uptake within the medial temporal lobe in AD than in DLB.¹⁰⁹

Further differences in the spatial distribution of cholinergic deficiencies between DLB and AD have been reported, while in DLB there is a widespread reduction predominantly at the neocortex, the posterior regions, and in the thalamus, whereas in AD the deficits are more prominent in the temporal lobes.¹¹⁰

Nedelska et al in a recent study on 33 patients with DLB, 18 patients with posterior cortical atrophy, and 100 controls, using tau PET with the 18F-AV-1451 tracer, revealed a significant difference in the AV-1451 uptake, with patients with posterior cortical atrophy showing the greatest uptake throughout all the gray matter, and they conclude that this AV-1451 uptake has a sensitivity of 88% and specificity of 100% in the discrimination between DLB and posterior cortical atrophy which usually share similar clinical features¹¹¹ (Table 5).

Table 5.

Summary of the Most Important Findings on PET and SPECT Biomarkers for the Diagnosis of Dementia With Lewy Bodies.

PET and SPECT
Decreased glucose metabolism and deficits in perfusion in parietotemporal and occipital areas.^88 –92
Decreased 18 F-fluorodopa reuptake in the striatum can be used to differentiate DLB from AD.⁹³
Amyloid-β deposition in the cortex and hypometabolism in the temporo-parieta-ooccipital regions bilaterally as well as the frontal lobe, the insular lobe, the posterior cingulate, the precuneus and caudate nuclei.⁹⁴
Higher ratio of posterior cingulate to precuneus plus cuneus metabolism, cingulate island sign than AD.^95,96
Reduced dopamine transporter binding in the caudate and posterior putamen^97,98 in DLB compared to AD but with no difference from Parkinson disease.
Reduced cardiac reuptake in DLB, significantly different from AD, but with no difference from PD.¹⁰¹
Pittsburgh compound B showed a 80% increased amyloid load in DLB, with a respective 20% in PD.¹⁰³
Amyloid β deposition cannot distinguish DLB from AD where amyloid-β retention is comparable, but it can be used to differentiate DLB where cortical amyloid-β burden is significantly high from PD where amyloid-β is scarce.¹⁰⁴

Abbreviations: AD, Alzheimer disease; DLB, dementia with Lewy bodies, PD, Parkinson disease; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

Magnetic Resonance Spectroscopy

Magnetic resonance spectroscopy studies revealed reduced N-acetylaspartate in the temporal lobes and increased myo-inositol, while in DLB N-acetylaspartate–creatine ratio and myo-inositol levels are relatively normal.^112,113

Discussion

Numerous studies have been carried out in order to identify reliable biomarkers for the differential diagnosis of DLB from AD, dementia in PD, and other dementias. Although most of the results are controversial, few CSF, imaging, and physiological biomarkers have been reported to be significant enough and can be used as a supportive to clinical suspicion for increased accuracy in the diagnosis of the probable DLB. α-Synuclein, tau protein, Aβ peptides, and other miscellaneous biomarkers have been extensively studied in DLB and other dementias, and although the data are either controversial or not enough, most of them when combined could be critical for the differential diagnosis of DLB.

Total α-synuclein, combined with Aβ peptide 1-42 and either total of phosphorylated tau, improves the differential diagnosis between different dementia types, including DLB, AD, frontotemporal dementia, and other neurological conditions.

The ratios Aβ 40/42 and tau/ Aβ 42 are also potentially significant biomarkers and when combined with α-synuclein can severely increase both the sensitivity and the specificity of the test. The ratio of Aβ1-42 to Aβ1-38 and Aβ1-42 to Aβ1-37, when combined with t-tau levels, has 100% sensitivity and 92% specificity in differentiating AD from DLB and controls.¹¹⁴ The oxidized α-helical form of Aβ peptide, known as Aβ 1-40*, has also a sensitivity of 81% and specificity of 71% at DLB and PD dementia differentiation.¹¹⁴

Total tau was found to be of no significance in the discrimination between DLB and other dementia types, and mainly AD; however, p-tau 181 is considered as a reliable biomarker.

Orexins, IL-6, cocaine, and amphetamine-regulated transcript neuropeptide, asparagine, glycine, and nitric oxide, and the combination of calcium and magnesium are also potentially significant biomarkers^38,41; however, further studies are needed in order for their significance to be confirmed.

Among physiological biomarkers, the most important ones are the topographical differences between DLB and AD, with DLB exhibiting mainly increased posterior slow-wave activity. Indeed, the presence of posterior transient slow or sharp waves are included in the diagnostic criteria as a supportive feature for the diagnosis of DLB.^42
–44

Auditory-evoked potential also showed significant evidence in differentiation between DLB and AD,^54,55 and another significant physiological parameter seems to be blink reflex which showed substantial differences between patients with DLB and AD, multiple system atrophy, and controls; however, further studies are needed to confirm whether this marker is sufficiently robust to diagnostically separate DLB from other dementias. Abnormal startle reaction and differences in autonomic nervous system response have also been shown to be significant biomarkers and could be used in the differential diagnosis between DLB and other dementias. While overall the findings for autonomic nervous system responses could also be particularly salient to the detection of early DLB,¹¹⁵ further investigation is necessary before they could be used in the clinical practice. Magnetic transcranial stimulation although promising has not shown any noteworthy biomarkers so far.

In addition to CSF and physiological biomarkers, DLB brains exhibit certain neuroimaging differences in comparison to PD, AD, and other neurodegenerative disorders. The main structural differences can be summarized in topographical dissimilarities, whereas DLB shows atrophy mainly in the perirhinal cortex, the parahippocampus, the amygdala, the striatum, the substantia innominata, the hypothalamus, and the dorsal midbrain in cortical thickness and the rate of cerebral atrophy which is higher than in controls but significantly lower than in AD, although the latter remains debated.

Diffusion tensor imaging and susceptibility-weighted imaging can also be potential tools for the discrimination between patients with DLB, controls, patients with AD, and patients with other dementias.

Functional MRI, PET, and SPECT also provide potentially momentous biomarkers. Definite differences in functional connectivity and different cortical activation patterns in response to external stimuli can be used to discriminate between DLB and AD and/or PD. Dissimilarities in brain glucose metabolism and perfusion and differences in tracers’ uptake can also make a significant difference in the differential diagnosis between the aforementioned disorders, and other neurodegenerative diseases, such as frontotemporal dementia, multiple system atrophy, and posterior cortical atrophy which may share a few common clinical similarities especially in the initial stages. The great heterogeneity in many studies on biomarkers in DLB and other dementias could be explained by differences in methodology, in clinical design of the studies, and in relation to technical aspects. The sample sizes, inclusion criteria, clinical assessment methods, the number of dementia types analyzed, and the definition of control groups are comparatively clearly different.

To conclude, many biomarkers are currently available for the discrimination between DLB and other dementia types; however, a detailed history and well-organized, detailed clinical and psychological examinations remain the golden standard for the initial clinical suspicion and probable diagnosis, with biomarkers being clearly supportive for an improved diagnostic accuracy. Although many biomarkers have been proven significant, the combination of more than one, and more specific the combination of different biomarkers including at least CSF and/or neuroimaging, can reduce the limitations of their application and provide reliable support in the diagnosis of DLB.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ioannis Mavroudis

References

McKeith

. Dementia with Lewy bodies. Dialogues Clin Neurosci. 2004;6(3):333–341.

McKeith

Boeve

Dickson

et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88–100.

Kosaka

. Lewy bodies in cerebral cortex, report of three cases. Acta Neuropathol. 1978;42(2):127–134.

Howlett

Whitfield

Johnson

et al. Regional multiple pathology scores are associated with cognitive decline in lewy body dementias. Brain Pathol. 2015;25(4):401–408.

Dugger

Adler

Shill

et al. Concomitant pathologies among a spectrum of parkinsonian disorders. Parkinsonism Relat Disord. 2014;20(5):525–529.

Spies

Melis

RJF

Sjögren

MJC

Rikkert

MGMO

Verbeek

. Cerebrospinal fluid α-synuclein does not discriminate between dementia disorders. J Alzheimers Dis. 2009;16(2):363–369.

Mollenhauer

Cullen

Kahn

et al. Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2008;213(2):315–325.

Kasuga

Tokutake

Ishikawa

et al. Differential levels of α-synuclein, β-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2010;81(6):608–610.

Bougea

Stefanis

Paraskevas

et al. Neuropsychiatric symptoms and α-Synuclein profile of patients with Parkinson’s disease dementia, dementia with Lewy bodies and Alzheimer’s disease. J Neurol. 2018;265(10):2295–2301.

10.

Hansson

Hall

Öhrfelt

et al. Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease. Alzheimers Res Ther. 2014; 6(3):25.

11.

Kapaki

Paraskevas

Emmanouilidou

Vekrellis

The diagnostic value of CSF α-synuclein in the differential diagnosis of dementia with lewy bodies vs. Normal subjects and patients with Alzheimer’s disease. Plos One. 2013;8(11):e81654.

12.

Oeckl

Metzger

Nagl

et al. Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer’s and Creutzfeldt - Jakob disease but No Alteration in Synucleinopathies. Mol Cell Proteomics. 2016;15(10):3126–3138.

13.

Öhrfelt

Grognet

Andreasen

et al.

Cerebrospinal fluid α-synuclein in neurodegenerative disorders-A marker of synapse loss?

Neurosci Lett. 2009;450(3):332–335.

14.

Shi

Tang

Toledo

et al. Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer’s disease. Alzheimers Dement. 2018;14(8):1052–1062.

15.

van Steenoven

Majbour

Vaikath

et al. Alpha-synuclein species as potential CSF biomarkers for dementia with Lewy bodies. Alzheimers Dement. 2017;13(7):P338.

16.

van Steenoven

Majbour

Vaikath

et al. α-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies. Mov Disord. 2018;33(11):1724–1733.

17.

Wennström

Hall

Nägga

Londos

Minthon

Hansson

. Cerebrospinal fluid levels of IL-6 are decreased and correlate with cognitive status in DLB patients. Alzheimers Res Ther. 2015;7(1):63.

18.

Wennström

Londos

Minthon

Nielsen

. Altered CSF orexin and α-synuclein levels in dementia patients. J Alzheimers Dis. 2012;29(1):125–132.

19.

Kanemaru

Murayama

. Assessment of CSF A-synuclein levels distinguishes dementia with Lewy bodies from Alzheimer’s disease. Alzheimers Dement. 2014;10(4):P350

20.

Slaets

Vanmechelen

Le Bastard

et al. Increased CSF alpha-synuclein levels in Alzheimer’s disease: correlation with tau levels. Alzheimers Dement, 2014;10(5):S290–S298.

21.

The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging. Consensus report of the Working Group on: molecular and biochemical markers of Alzheimer’s disease. Neurobiol Aging. 1998;19(2):109–116.

22.

Vanderstichele

De Vreese

Blennow

et al. Analytical performance and clinical utility of the INNOTEST® PHOSPHO-TAU(181P) assay for discrimination between Alzheimer’s disease and dementia with Lewy bodies. Clin Chem Lab Med. 2006;44(12):1472–1480.

23.

Simic

Boban

Sarac

et al. New Trends in Alzheimer and Parkinson Related Disorders, ADPD 2007. Salzburg, Austria: Medimond; 2007. CSF tau proteins in evaluation of patients with suspected dementia.

24.

Koopman

Le Bastard

Martin

Nagels

De Deyn

Engelborghs

. Improved discrimination of autopsy-confirmed Alzheimer’s disease (AD) from non-AD dementias using CSF P-tau181P. Neurochem Int. 2009;55(4):214–218.

25.

Hampel

Buerger

Zinkowski

et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry. 2004;61(1):95–102.

26.

Parnetti

Lanari

Amici

Gallai

Vanmechelen

Hulstaert

. CSF phosphorylated tau is a possible marker for discriminating Alzheimer’s disease from dementia with Lewy bodies. Neurol Sci. 2001;22(1):77–78.

27.

Arai

Morikawa

Y-I

Higuchi

et al. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochem Biophys Res Commun. 1997;236(2):262–264.

28.

Compta

Martí

Ibarretxe-Bilbao

et al. Cerebrospinal tau, phospho-tau, and beta-amyloid and neuropsychological functions in Parkinson’s disease. Mov Disord. 2009;24(15):2203–2210.

29.

Bousiges

Bombois

Schraen

et al.For the ePLM network and collaborators. Cerebrospinal fluid Alzheimer biomarkers can be useful for discriminating dementia with Lewy bodies from Alzheimer’s disease at the prodromal stage. J Neurol Neurosurg Psychiatry. 2018;89(5):467–475.

30.

Spies

Sjögren

Kremer

Verhey

Rikkert

Verbeek

. The cerebrospinal fluid amyloid beta (42/40) ratio in the differentiation of Alzheimer’s disease from non-Alzheimer’s dementia. Curr Alzheimer Res. 2010;7(5):470–476.

31.

Bibl

Mollenhauer

Esselmann

et al. CSF amyloid-β-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain. 2006;129(5):1177–1187.

32.

Tizon

Ribe

Troy

Levy

. Cystatin C protects neuronal cells from amyloid-β-induced toxicity. J Alzheimers Dis. 2010;19(3):885–894.

33.

Parnetti

Tiraboschi

Lanari

et al. Cerebrospinal fluid biomarkers in Parkinson’s disease with dementia and dementia with Lewy bodies. Biol Psychiatry. 2008;64(10):850–855.

34.

Vanderstichele

van Kerschaver

Hesse

et al. Standardization of measurement of β-amyloid(1-42) in cerebrospinal fluid and plasma. Amyloid. 2000;7(4):245–258.

35.

Maetzler

Schmid

Wurster

et al., Reduced but not oxidized cerebrospinal fluid glutathione levels are lowered in Lewy body diseases. Mov Disord. 2011;26(1):176–181.

36.

Schmidt

Curb

Masaki

White

Launer

. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia aging study. Ann Neurol. 2002;52(2):168–174.

37.

Gómez-Tortosa

Gonzalo

Fanjul

et al. Cerebrospinal fluid markers in dementia with Lewy bodies compared with Alzheimer disease. Arch Neurol. 2003;60(9):1218–1222.

38.

Schultz

Wiehager

Nilsson

et al. Reduced CSF CART in dementia with Lewy bodies. Neurosci Lett. 2009;453(2):104–106.

39.

Molina

Leza

Ortiz

et al. Cerebrospinal fluid and plasma concentrations of nitric oxide metabolites are increased in dementia with Lewy bodies. Neurosci Lett. 2002;333(2):151–153.

40.

Molina

Gómez

Vargas

et al. Neurotransmitter amino acid in cerebrospinal fluid of patients with dementia with Lewy bodies. J Neural Transm. 2005;112(4):557–563.

41.

Lippa

Duda

Grossman

et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007;68(11):812–819.

42.

Barber

Varma

Lloyd

Haworth

Snowden

Neary

. The electroencephalogram in dementia with Lewy bodies. Acta Neurol Scand. 2000;101(1):53–56.

43.

Briel

McKeith

Barker

et al. EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 1999;66(3):401–403.

44.

McKeith

Dickson

Lowe

. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology. 2005;65(12):1863–1872.

45.

Bonanni

Thomas

Tiraboschi

Perfetti

Varanese

Onofrj

. EEG comparisons in early Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease with dementia patients with a 2-year follow-up. Brain. 2008;131(pt 3):690–705.

46.

Bonanni

Franciotti

Onofrj

et al. Revisiting P300 cognitive studies for dementia diagnosis: early dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Neurophysiol Clin. 2010;40(5-6);255–265.

47.

Calzetti

Bortone

Negrotti

Zinno

Mancia

. Mancia Frontal intermittent rhythmic delta activity (FIRDA) in patients with dementia with Lewy bodies: a diagnostic tool? Neurol Sci. 2002;23:S65–66.

48.

Fernández-Torre

Figols

Alonso

et al. Detailed electroencephalographic long-term follow-up study in dementia with Lewy bodies with periodic sharp wave complexes. J Neurol. 2007;254(3):384–387.

49.

Roks

Korf

van der Flier

Scheltens

Stam

. Stam The use of EEG in the diagnosis of dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2008;79(4):377–380.

50.

Andersson

Hansson

Minthon

Rosén

Londos

Electroencephalogram variability in dementia with Lewy bodies, Alzheimer’s disease and controls. Dement Geriatr Cogn Disord. 2008;26(3):284–290.

51.

Jackson

Snyder

. Electroencephalography and event-related potentials as biomarkers of mild cognitive impairment and mild Alzheimer’s disease. Alzheimers Dement. 2008;4(1 suppl 1):S137–S143.

52.

Kai

Asai

Sakuma

Koeda

Nakashima

. Quantitative electroencephalogram analysis in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Sci. 2005;237(1-2):89–95.

53.

Walker

Ayre

Perry

et al. Quantification and characterization of fluctuating cognition in dementia with Lewy bodies and Alzheimer’s disease. Dement Geriatr Cogn Disord. 2000;11(6):327–335.

54.

Bonanni

Perfetti

Bifolchetti

et al. Quantitative electroencephalogram utility in predicting conversion of mild cognitive impairment to dementia with Lewy bodies. Neurobiol Aging. 2015;36(1):434–445.

55.

Londos

Passant

Brun

Rosén

Risberg

Gustafson

. Regional cerebral blood flow and EEG in clinically diagnosed dementia with Lewy bodies and Alzheimer’s disease. Arch Gerontol Geriatr. 2003;36(3):231–245.

56.

Perriol

Dujardin

Derambure

et al. Disturbance of sensory filtering in dementia with Lewy bodies: comparison with Parkinson’s disease dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2005;76(1):106–108.

57.

Bonanni

Anzellotti

Varanese

Thomas

Manzoli

Onofrj

. Delayed blink reflex in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2007;78(10):1137–1139.

58.

Kofler

Müller

Wenning

et al. The auditory startle reaction in parkinsonian disorders. Mov Disord. 2001;16(1):62–71.

59.

Negami

Maruta

Takeda

Adachi

Yoshikawa

. Sympathetic skin response and heart rate variability as diagnostic tools for the differential diagnosis of dementia with Lewy bodies and Alzheimer’s disease: a diagnostic test study. BMJ Open. 2013;3(3):e001796.

60.

Akaogi

Asahina

Yamanaka

Koyama

Hattori

. Sudomotor, skin vasomotor, and cardiovascular reflexes in 3 clinical forms of Lewy body disease. Neurology. 2009;73(1):59–65.

61.

Di Lazzaro

Pilato

Dileone

et al. Functional evaluation of cerebral cortex in dementia with Lewy bodies. Neuroimage. 2007;37(2):422–429.

62.

Marra

Quaranta

Profice

et al. Central cholinergic dysfunction measured ‘‘in vivo’’ correlates with different behavioral disorders in Alzheimer’s disease and dementia with Lewy body. Brain Stimul. 2012;5(4):533–538.

63.

Nardone

Bratti

Tezzon

. Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer’s disease. J Neural Transm. 2006;113(11):1679–1684.

64.

Burton

Barber

Mukaetova-Ladinska

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.

65.

Sabattoli

Boccardi

Galluzzi

Treves

Thompson

Frisoni

. Hippocampal shape differences in dementia with Lewy bodies. Neuroimage. 2008;41(3):699–705.

66.

Lebedev

Westman

Beyer

et al. Multivariate classification of patients with Alzheimer’s and dementia with Lewy bodies using high-dimensional cortical thickness measurements: an MRI surface-based morphometric study. J Neurol. 2013;260(4):1104–1115.

67.

O’Brien

Paling

Barber

et al. Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology. 2001;56(10):1386–1388.

68.

Delli Pizzi

Franciotti

Bubbico

Thomas

Onofrj

Bonanni

. Atrophy of hippocampal subfields and adjacent extrahippocampal structures in dementia with Lewy bodies and Alzheimer’s disease. Neurobiol Aging. 2016;40:103–109.

69.

Burton

Mukaetova-Ladinska

Perry

Jaros

Barber

O’Brien

. Neuropathological correlates of volumetric MRI in autopsy-confirmed dementia with Lewy bodies. Neurobiol Aging. 2012;33(7):1228–1236.

70.

Kantarci

Ferman

Boeve

et al. Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies. Neurology. 2012;79(6):553–560.

71.

Beyer

Larsen

Aarsland

. Gray matter atrophy in Parkinson disease with dementia and dementia with Lewy bodies. Neurology. 2007;69(8):747–754.

72.

Burton

McKeith

Burn

Williams

O’Brien

. Cerebral atrophy in Parkinson’s disease with and without dementia: a comparison with Alzheimer’s disease, dementia with Lewy bodies and controls. Brain. 2004;127(Pt 4):791–800.

73.

Sanchez-Castaneda

Rene

Ramirez-Ruiz

et al. Correlations between gray matter reductions and cognitive deficits in dementia with Lewy bodies and Parkinson’s disease with dementia. Mov Disord. 2009;24(12):1740–1746.

74.

Sanchez-Castaneda

Rene

Ramirez-Ruiz

et al. Frontal and associative visual areas related to visual hallucinations in dementia with Lewy bodies and Parkinson’s disease with dementia. Mov Disord. 2010;25(5):615–622.

75.

Baggio

Segura

Sala-Llonch

et al. Cognitive impairment and resting-state network connectivity in Parkinson’s disease. Hum Brain Mapp. 2015;36(1):199–212.

76.

Bozzali

Falini

Cercignani

et al. Brain tissue damage in dementia with Lewy bodies: an in vivo diffusion tensor MRI study. Brain. 2005;128(pt 7):1595–1604.

77.

Firbank

Colloby

Burn

McKeith

O’Brien

. Regional cerebral blood flow in Parkinson’s disease with and without dementia. Neuroimage. 2003;20(2):1309–1319.

78.

Watson

Blamire

Colloby

et al. Characterizing dementia with Lewy bodies by means of diffusion tensor imaging. Neurology. 2012;79(9):906–914.

79.

Kamagata

Nakatsuka

Sakakibara

et al. Diagnostic imaging of dementia with Lewy bodies by susceptibility-weighted imaging of nigrosomes versus striatal dopamine transporter single-photon emission computed tomography: a retrospective observational study. Neuroradiology. 2017;59(1):89–98.

80.

Kenny

Blamire

Firbank

O’Brien

. Functional connectivity in cortical regions in dementia with Lewy bodies and Alzheimer’s disease. Brain. 2012;135(pt 2):569–581.

81.

Galvin

Price

Yan

Morris

Sheline

. Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease. Neurology. 2011;76(21):1797–1803.

82.

Kenny

O’Brien

Firbank

Blamire

. Subcortical connectivity in dementia with Lewy bodies and Alzheimer’s disease. Br J Psychiatry. 2013;203(3):209–214.

83.

Schumacher

Peraza

Firbank

et al. Functional connectivity in dementia with Lewy bodies: A within- and between-network analysis. Hum Brain Mapp. 2018;39(3):1118–1129.

84.

Sauer

ffytche

Ballard

Brown

Howard

. Differences between Alzheimer’s disease and dementia with Lewy bodies: an fMRI study of task-related brain activity. Brain. 2006;129(Pt 7):1780–1788.

85.

Taylor

Firbank

et al. Visual cortex in dementia with Lewy bodies: magnetic resonance imaging study. Br J Psychiatry. 2012;200(6):491–498.

86.

Shams

Fallmar

Schwarz

et al. MRI of the swallow tail sign: a useful marker in the diagnosis of Dementia with Lewy bodies?. AJNR Am J Neuroradiol. 2017;38(9):1737–1741.

87.

Greicius

Srivastava

Reiss

Menon

. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA. 2004;101(13):4637–4642.

88.

Peraza

Colloby

Firbank

et al. Resting state in Parkinson’s disease dementia and dementia with Lewy bodies: commonalities and differences. Int J Geriatr Psychiatry. 2015;30(11):1135–1146.

89.

Lobotesis

Fenwick

Phipps

et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology. 2001;56(5):643–649.

90.

Albin

Minoshima

D’Amato

Frey

Kuhl

Sima

. Fluoro-deoxyglucose positron emission tomography in diffuse Lewy body disease. Neurology. 1996;47(2):462–466.

91.

Edison

Rowe

Rinne

et al. Amyloid load in Parkinson’s disease dementia and Dementia with Lewy bodies measured with [11C]PIB positron emission tomography. J Neurol Neurosurg Psychiatry. 2008;79(12):1331–1338.

92.

Klein

Eggers

Kalbe

et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010;74(11):885–892.

93.

Perneczky

Drzezga

Boecker

Forstl

Kurz

Haussermann

. Cerebral metabolic dysfunction in patients with dementia with Lewy bodies and visual hallucinations. Dement Geriatr Cogn Disord. 2008;25(6):531–538.

94.

Okamura

Arai

et al. 18F-fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia with Lewy bodies. Neurology. 2000;55(10):1575–1577.

95.

Liu

Wang

et al. Clinical and neuroimaging characteristics of Chinese dementia with Lewy bodies. PLoS One. 2017;12(3):e0171802.

96.

Graff-Radford

Murray

Lowe

et al. Dementia with Lewy bodies: basis of cingulate island sign. Neurology. 2014;83(9):801–809.

97.

Iizuka

Kameyama

. Cingulate island sign on FDG-PET is associated with medial temporal lobe atrophy in dementia with Lewy bodies. Ann Nucl Med. 2016;30(6):421–429.

98.

O’Brien

McKeith

Walker

et al. Diagnostic accuracy of 123I-FP-CIT SPECT in possible dementia with Lewy bodies. Br J Psychiatry. 2009;194(1):34–39.

99.

McKeith

O’Brien

Walker

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.

100.

Brigo

Turri

Tinazzi

. 123I-FP-CIT SPECT in the differential diagnosis between dementia with Lewy bodies and other dementias. J Neurol Sci. 2015;359(1–2):161–171.

101.

Chang

Liu

Chang

Chen

Lee

. (99 m)Tc-ethyl cysteinate dimer brain SPECT findings in early stage of dementia with Lewy bodies and Parkinson’s disease patients: a correlation with neuropsychological tests. Eur J Neurol. 2008;15(1):61–65.

102.

Yoshita

Taki

Yamada

. A clinical role for [(123)I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer’s-type and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2001;71(5):583–588.

103.

King

Mintz

Royall

. Meta-analysis of 123I-MIBG cardiac scintigraphy for the diagnosis of Lewy body-related disorders. Mov Disord. 2011;26(7):1218–1224.

104.

Foster

Campbell

Burack

et al. Amyloid imaging of Lewy body-associated disorders. Mov Disord. 2010;25(15):2516–2523.

105.

Petrou

Dwamena

Foerster

et al. Amyloid deposition in Parkinson’s disease and cognitive impairment: a systematic review. Mov Disord. 2015;30(7):928–935.

106.

Gomperts

Locascio

Marquie

et al. Brain amyloid and cognition in Lewy body diseases. Mov Disord. 2012;27(8):965–973.

107.

Jokinen

Scheinin

Aalto

et al. [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson’s disease with and without dementia. Parkinsonism Relat Disord 2010;16(10):666–670.

108.

Gomperts

Locascio

Makaretz

et al. Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases. JAMA Neurol. 2016;73(11):1334–1341.

109.

Kantarci

Lowe

Boeve

et al. AV-1451 tau and beta-amyloid positron emission tomography imaging in dementia with Lewy bodies. Ann Neurol. 2017;81(1):58–67.

110.

Kotagal

Müller

MLTM

Kaufer

Koeppe

Bohnen

. Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders. Neurosci Lett. 2012;514(2):169–172.

111.

Nedelska

Josephs

Graff-Radford

et al. 18F-AV-1451 uptake differs between dementia with lewy bodies and posterior cortical atrophy. Mov Disord. 2019;34(3):344–352.

112.

Firbank

Harrison

O’Brien

. A comprehensive review of proton magnetic resonance spectroscopy studies in dementia and Parkinson’s disease. Dement Geriatr Cogn Disord. 2002;14(2):64–76.

113.

Kantarci

Petersen

Boeve

et al. 1 H MR spectroscopy in common dementias. Neurology. 2004;63(8):1393–1398.

114.

Bibl

Mollenhauer

Esselmann

et al. CSF diagnosis of Alzheimer’s disease and dementia with Lewy bodies. J Neural Transm. 2006;113(11):1771–1778.

115.

Donaghy

O’Brien

Thomas

. Prodromal dementia with Lewy bodies. Psychol Med. 2015;45(2):259–268.

Cerebrospinal Fluid,Imaging,and Physiological Biomarkers in Dementia With Lewy Bodies

Abstract

Keywords

Introduction

Clinical and Pathological Hallmarks

Cerebrospinal Fluid Biomarkers

α-Synuclein

Tau Protein

Amyloid β Peptide

Other CSF Biomarkers

Neurophysiological Biomarkers

Electroencephalography

Event-Related Potential Studies

Blink Reflex Studies

Additional Physiological Biomarkers

Transcranial Magnetic Stimulation

Neuroimaging Biomarkers

Structural MRI

Diffusion Tensor Imaging

Susceptibility-Weighted Imaging

Functional MRI

Positron Emission Tomography and Single-Photon Emission Computed Tomography

Magnetic Resonance Spectroscopy

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References