Table 2:

Biomarkers in the Setting of DLB Co-Pathologies

Pathological change	Biomarker modality	Implications in dementia with Lewy bodies
Disease-Specific Biomarkers
Aβ	CSF and PET biomarkers Plasma assay [109]	Both modalities accurately predict the presence of Aβ plaques in the brain [102, 133] and are in good agreement with each other [103]. Conversion to pathological values of CSF Aβ tends to precede PET abnormalities [134].
Tau	CSF and PET biomarkers Plasma assay [110]	Correlates with tau brain deposition [102, 135]; typically detect neurofibrillary tangle pathology present in AD rather than FTLD-Tau pathology [136, 137]. New tracers are being developed to quantify FTLD-Tau pathology [138].
α-synuclein	CSF real-time quaking-induced conversion (RT-QuIC) [39, 42] and protein misfolding cyclic amplification (PMCA) [43] Skin [34–36, 39, 41] Olfactory Mucosa [37–39] Submandibular gland [39, 40] Colon [39]	Binary detection of the presence/absence of α-synuclein only. Less useful to quantify disease progression. Further studies are needed in DLB.
Disease Nonspecific Biomarkers
Synaptic loss	CSF and blood biomarkers [113]	Structural and functional imaging alterations are strongly correlated with fluid-based biomarkers of synaptic and neurodegenerative tissue change [139].
Brain atrophy	Imaging techniques using either MRI	Correlates with the degree of cognitive impairment and is known to play a significant role in disease presentation and progression [114]. Present in brain aging and can follow a different pattern in cognitively impaired individuals [140, 141].
Neuronal dysfunction and damage	CSF and blood biomarkers [128, 142]	Structural and functional imaging alterations strongly correlate with fluid-based biomarkers of synaptic and neurodegenerative tissue change [139] and can track change in-vivo [113].
Glial activation	CSF and blood biomarkers [130]
Structural and Functional Imaging Biomarkers
Relative preservation of medial temporal lobe structures	MRI CT	Included in the diagnostic criteria for DLB [5].
Reduced basal ganglia dopamine transporter uptake	SPECT
Increased focal and diffuse abnormalities	EEG
Reduced occipital metabolism/cingulate island sign	FDG-PET
Insular thinning and gray matter atrophy	MRI	Reported as requiring further investigation in the research criteria for prodromal DLB.
Medial temporal lobe structures atrophy	Visual rating scales	Greater atrophy in multiple brain regions than in controls and relative preservation of medial temporal lobe structures compared to AD [143–145]. AD co-pathology is associated with greater medial temporal lobe atrophy in DLB, demonstrating that AD co-pathology (and possibly TDP-43) modifies imaging patterns in people with DLB [143, 146, 147].
Abnormalities in the cholinergic system	Volumetry and cortical thickness quantifications	Atrophy of nucleus basalis of Meynert in prodromal MCI stages [148] Associations between nucleus basalis of Meyner atrophy, Aβ, and cognitive changes differ in AD and DLB [149].
Limbic TDP-43 co-pathology	RT-QuIC [42]	Studies are needed in DLB.
Higher WMH burden	MRI	Associated with more neurodegeneration in DLB [57, 67, 150], particularly in brain areas that receive dense cholinergic input [57], which may have implications for the cholinergic treatment of DLB.
Structural connectivity changes	Diffusion tensor imaging (DTI) technique and higher tensor modeling techniques such as fixel-based analysis	Seen in at-risk groups for PDD [118]. Studies are needed in DLB.
	Quantitative susceptibility mapping Quantitative multiparameter maps	Applied in PD [120], revealing a correlation with clinical change. Studies are needed in DLB.
Temporoparietal and occipital hypometabolism	18-Fluorine 18F fluorodeoxyglucose (FDG) and SPECT perfusion imaging	Further studies are needed in DLB with co-pathologies.
“Cingulate island sign”	FDG-PET	May indicate a lower Braak neurofibrillary tangle stage at autopsy [123].
Abnormalities in serotonergic systems	Volumetric measures and PET radiotracers	Further studies are needed in DLB with co-pathologies.
CSF and blood markers of neurodegeneration, synaptic dysfunction, and glial activation
Neuro-axonal damage	Neurofilament Light (NfL)	Elevated already in prodromal DLB stages, higher levels in the presence of AD co-pathology [151].
Glial-related change	Glial fibrillary acidic protein (GFAP), the soluble triggering receptor expressed on myeloid cells 2 (sTREM2, mainly expressed by microglia), and S100 calcium-binding protein B (S100B, mainly expressed by astrocytes).	Elevated in DLB compared to controls [130].
Synaptic dysfunction	Fluid-based biomarkers: synaptosomal-associated protein 25 (SNAP-25), Synaptogamin-1, neurogranin, and β-synuclein.	Further studies are needed in DLB with co-pathologies.