Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

Table 3

CSF biomarkers for DLB.

Study	Biomarker(s)	Technique	No. of subjects	No. of controls	Results
Mollenhauer et al. [51]	𝛼-synuclein	Sandwich ELISA	38 DLB; 13 AD; 8 PD; 8 CJD	13 neurological controls	In PD and DLB, 𝛼-synuclein levels significantly reduced (𝑃=.0305) compared to AD and control subjects.
Mukaetova-Ladinska et al. [45]	𝛼-synuclein 𝛾-synucleinIgG	Dot blot	5 LBD; 9 AD; 3 VaD	8	Postmortem ventricular CSF analysis. Elevation of both 𝛼- and 𝛾-synucleins in AD, LBD, and VaD compared to controls. An increase in 𝛼- and 𝛾-synucleins seen from Braak stage III onwards. Results not influenced by age at death or postmortem delay.
Noguchi-Shinohara et al. [46]	𝛼-synuclein	ELISA Assay	16 DLB; 21 AD	(A subgroup of 13 DLB patients matched for duration of disease and MMSE score to those of the AD subjects)	𝛼-synuclein levels do not differ between DLB and AD patients. Lower levels of 𝛼-synuclein in CSF correspond to DLB duration (P < .05).
Ohrfelt et al. [49]	𝛼-synuclein	ELISA	15 DLB; 66 AD; 15 PD	55	Similar levels of 𝛼-synuclein in PD, DLB, and control subjects, whereas, in AD, α-synuclein levels significantly lower compared to controls (P <  .001). AD subjects with MMSE <20 had significantly lower level of 𝛼-synuclein than AD subjects with MMSE ≥20.
Spies et al. [48]	𝛼-synuclein	ELISA	40 DLB; 131 AD; 39 FTD; VaD 28	Two groups: Group A 57 (aged > 50); Group B 55 healthy volunteers	No significant difference in 𝛼-synuclein levels between DLB, AD, FTD, VaD, or control subjects.
Ballard et al. [44]	𝛼-synuclein	Western blot	12 DLB	9	Significant lower levels of 𝛼-synuclein in DLB compared to controls (P  < .05). Mildly cognitively impaired DLB subjects (MMSE > 24) also had lower levels than controls (P < .007).
Kasuga et al. [52]	𝛼-synuclein/ t-tau/p-tau181/A𝛽42	ELISA	34 DLB (including 2 with SNCA duplication); 31 AD; 21 other dementias (12 FTD; 2 PSP, 2 normal pressure hydrocephalus; 2 VaD; 3 unclassified)	No control group	𝛼-synuclein significantly lower in DLB than in AD (𝑃<.05) or other dementias (𝑃<.01). CSF 𝛼-synuclein levels correlated with A𝛽42 level in DLB only (𝑟=0.43; 𝑃=.01). CSF t-tau and p-tau181 levels as well as A𝛽40/A𝛽42 ratio levels significantly lower in DLB in relation to AD (P  < .01), but similar to other dementias.
Arai et al. [54]	t-tau	Sandwich ELISA	6 DLB; 8 FTD; 6 PSP; 3 CBD	19 (data taken from previous study)	Similar levels of tau in AD and DLB (P = .78), but higher than in controls.
Parnett et al. [55]	t-tau/p-tau181/A𝛽42	HT7-AT270 Assay and ROC analysis	43 DLB; 80 AD	40	Strong correlation between t-tau and p-tau independent of diagnostic group (𝑟=0.904). No differences between DLB and AD for A𝛽42. The significant increase in p-tau181 in AD (P = .039) has 80% sensitivity at differentiating between AD and DLB.
Clark et al. [56]	t-tau/A𝛽40/A𝛽42 (includes also postmortem correlation)	ELISA	3 DLB; 74 AD (including 4 genetic AD and 10 LBVAD); 10 FTD; 5 CJD; 3 GSS syndrome; 11 miscellaneous neurologic conditions	73	DLB subjects had 2-fold higher level of t-tau in relation to controls, but two-fold lower levels in relation to AD. No differences in t-tau between LBVAD and AD (𝑃=.30). Aβ42 highly depleted in DLB in comparison to both control (8-fold) and AD (4.4-fold) subjects.
Hampel et al. [57]	p-tau181/p-tau231/p-tau199	ELISA	22 DLB; 108 AD; 24 FTD; 7 VaD; 22 OND	23	Decrease in p-tau199, p-tau231, and p-tau181 (P < .001) in DLB compared to AD, with similar levels to other studied dementia groups.
Parnetti et al. [58]	t-tau/p-tau181/ Ab𝛽42	ELISA	19 DLB; 23 AD; 20 PD; 8 PDD	20	DLB mean CSF t-tau levels significantly lower than in AD patients (𝑃=.039), but significantly higher in PD, PDD, or control subjects. p-tau181 elevated in AD, but similar between DLB, PD, and PDD groups.
Vanderstichel et al. [59]	t-tau/ p-tau181/ A𝛽42	ELISA assay	60 DLB; 94 AD	60^∗∗	Higher levels of p-tau181 in AD than in DLB and controls. p-tau181 was the most statistically significant single variable of the 3 biomarkers to discriminate between AD and DLB.
Simic et al. [60]	t-tau/ p-tau181/ p-tau199	ELISA assay	2 DLB; 11 AD; 5 FTD; 8 VaD	13	p-tau181 differentiates AD and DLB with a sensitivity of 91% and a specificity of 95%.
Koopman et al. [61] (autopsy confirmed dementias)	t-tau/p-tau181/A𝛽42	ELISA	18 DLB; 95 AD; 10 FTD; 6 CJD; 16 VaD	No control group	DLB group had similar level of t-tau, p-tau181, and A𝛽42 as the other dementia groups (FTD, CJD, and VaD); these dementia subjects had significantly lower t-tau (𝑃=.025) and p-tau (P  <.0001) and higher A𝛽42 (𝑃=.001) in comparison to AD.
Mattson et et al. [62] (autopsy confirmed dementias)	t-tau/p-tau181/A𝛽42	ELISA	750 MCI (420 stable MCI; 14 incipient DLB; 271 incipient AD; 28 incipient VaD; 7 incipient FTD; 10 other dementias); 529 AD	304	MCI subjects who developed DLB had significantly lower levels of t-tau and p-tau181 at baseline compared to AD and incipient AD (𝑃<.01), significantly lower A𝛽42 CSF levels in relation to control (𝑃<.001), stable MCI, and AD subjects (𝑃<.01).
Spies et al. [63]	A𝛽1-42/A𝛽1-40/t-tau/p-tau181	ELISA	16 DLB; 69 AD; 26 VaD; 27 FTD	47	Significantly lower levels of A𝛽40 in DLB and VaD in relation to AD (𝑃<.01). AD had similar A𝛽40 level to controls (𝑃=.384). The A𝛽42/A𝛽40 ratio significantly lower in AD in comparison to other dementia groups (P < .001). A𝛽42/A𝛽40 ratio improves differentiating AD from VaD, DLB, and FTD than A𝛽42 measures alone (P < .01). A𝛽42/A𝛽40 ratio performed equally well as the combination of A𝛽42, p-tau181, and t-tau in differentiating AD from FTD and non-AD dementias.
Bibl et al. [64]	Aβ peptides	A𝛽-SDS-PAGE/ immunoblot	21 DLB; 23 AD; 21 PDD	23	The significant increase of a novel peptide with an A𝛽-like immunoreactivity (A𝛽1-40^∗) in DLB patients relative to PDD has a sensitivity of 81% and a specificity of 71% using a cut of point of 0.954% but failed to be classified as a sole biomarker.
Bibl et al. [65]	A𝛽 peptides/tau	A𝛽-SDS-PAGE/ immunoblot and ELISAs for Aβ1-42 and tau	25 probable DLB; 18 probable AD	14	The ratio of A𝛽1-42/A𝛽1-38 and A𝛽1-42/A𝛽1-37 when combined with absolute tau levels produced a diagnostic test with 100% sensitivity and 92% specificity. This ratio discriminated between AD and DLB with a high specificity (P = 6.6 × 10−6).
Wada-Isoe et al. [66, 67]	Aβ42/p-tau 181	ELISA assay	22 DLB; 34 AD	37	No significant difference in p-tau levels in AD and DLB, but a significant increase in the p-tau/Aβ42 ratio in AD in comparison to DLB.
Vanderstichele et al. [59]	Aβ42	ELISA	6 LBD; 39 AD; 10 other dementias, neurological and psychiatric disorder patients∗	12	Significant decrease in CSF A𝛽42 levels in both AD (P <.000l) and LBD (P = 0.002), relative to the control group.
Maetzler et al. [18]	A𝛽42	ELISA	9 DLB; 12 PDD; 14 PD no dementia	No control group	Lower levels of A𝛽42 in DLB and PDD compared to the nondemented PD subjects (P = .024). DLB-PIB-positive subjects had lower levels than the PIB-negative subjects (P = .044), but similar A𝛽42 levels to the PIB-negative subjects who had dementia (P = .42).
Boström et al. [68]	Mg/Ca/Cu	Mass spectrometry	29 DLB	51	Levels of Mg/Ca/Cu increased in CSF in DLB relative to controls, although increases in Cu not significant. The CSF-Mg concentration had a sensitivity of 93% and a specificity of 81% to detect DLB.
Molina et al. [69]	Nitric-oxide metabolites (L-arginine to L-citrulline)	Ionic -exchange chromatography	22 DLB	13	Not statistically significant difference in NO metabolite concentration between DLB and controls.
Molina et al. [70]	Neurotransmitter (NT) amino-acid (AA) concentrations	Ion-exchange chromatography	21 DLB	26^∗∗	No significant differences between control and DLB groups in relation to glutamate, aspartate, and GABA levels; however, higher concentrations of asparagine (+25%) and glycine (+21%) in DLB.
Schultz et al. [71]	Cocaine- and Amphetamine-Regulated Transcript (CART)	Radio-immunoassay	12 DLB; 14 AD	12	Significant decrease (30%) in CART in DLB versus controls (𝑃<.0001), DLB, and AD (𝑃<.05), but concentrations of CART did not indicate DLB progression. CART levels correlated with p-tau protein concentration.
Schultz et al. [72]	Transthyretin (TTR)	Radio-immunoassay	13 DLB; 59 AD	13	No significant differences of TTR concentrations between AD and DLB.

Please note that ELISA assays for t-tau, p-tau, and A𝜷42, unless otherwise specified, refer to commercially available sandwich ELISA assays.
Abbreviations: DLB: Dementia with Lewy bodies; LBD: Lewy Body disease; AD: Alzheimer’s Disease; LBVAD: Lewy Body variant of Alzheimer’s disease; PD: Parkinson’s Disease; PDD: Parkinson disease dementia; CJD: Creutzfeldt-Jakob disease; GSS: Gerstmann-Straussler-Scheinker syndrome; FTD: Frontotemporal dementia; VaD: Vascular Dementia; PSP: Progressive supranuclear palsy; OND: other neurologic disorders (e.g., mild psychiatric or neurologic symptoms); CSF: Cerebrospinal fluid; A𝛽: Amyloid-beta peptide; t-tau: total tau; p-tau: phosphorylated tau; ELISA: Enzyme-Linked Immunosorbent assay; A𝛽-SDS-PAGE: A𝛽-sodium dodecylsulphate-polyacrylamide gel electrophoresis; ROC: Receiver Operating Characteristic; MMSE: Mini Mental State Examination; PIB: 11C-labelled amyloid ligand Pittsburgh Compound B.
∗Specifically vascular dementia (𝑛=3); hypoxia during cardiac arrest (𝑛=1); cerebrovascular lesion (𝑛=1); unspecified dementia (𝑛=2); depression (𝑛=3).
∗∗Age-matched control.