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dementia with lewy bodies ( dlb ) is a common subtype of dementia and is reported to be the second most common neurodegenerative dementia after alzheimer 's disease ( ad ) in the elderly in several studies [ 13 ] .
dlb is a progressive cognitive disorder characterized by fluctuating cognitive impairment , visual hallucination , and parkinsonism .
diagnosis of dlb in patients with such characteristic clinical features would not be difficult by taking medical history and careful neurological examinations .
however , it could be laborious to make an accurate diagnosis of dlb when patients have a substantial degree of concomitant ad pathology , which affects the clinical symptoms with lower rates of visual hallucinations and parkinsonism [ 5 , 6 ] .
accurate clinical diagnosis of dlb is important because patients may benefit from cholinesterase inhibitors , which improve cognitive function and neuropsychiatric symptoms of dlb .
furthermore , it should be noted that dlb patients are particularly sensitive to neuroleptic drugs [ 4 , 8 ] .
recent intensive research has given hope for disease - modifying therapeutics for dlb to become a reality .
the evaluation of such therapies largely depends on reliable diagnostic and prognostic biomarkers for early detection and monitoring of the stage of dlb .
candidates of such biomarkers are diverse ; clinical biomarkers detected on the basis of olfactory function , myocardial i - metaiodobenzylguanidine ( mibg ) scintigraphy , neuroimaging biomarkers detected by magnetic resonance imaging ( mri ) , single photon emission computed tomography ( spect ) , positron emission tomography ( pet ) , and biochemical biomarkers . in this paper , fluid biomarkers , particularly -synuclein in cerebrospinal fluid ( csf ) and blood in patients with dlb and -synuclein - related disorders
a century ago , in 1912 , lewy originally described neuronal inclusions in the brain of patients with parkinson 's disease ( pd ) .
seven years later , a russian neuropathologist , tretiakoff , named the inclusions as  corps de lewy ( lewy bodies )  . since the discovery , lewy bodies have been considered as intracytoplasmic , spherical , and eosinophilic neuronal inclusions in the substantia nigra of pd patients . in 1976 , kosaka et al . reported the detection of lewy bodies in the cerebral cortex of an elderly patient with dementia .
after his detailed description of cortical lewy bodies , many similar cases were subsequently reported . because the characteristic pathological features of dlb and pd are lewy bodies and lewy neurites , these disorders are considered to belong to a continuum disorder , and the generic term lewy body disease ( lbd ) was proposed [ 4 , 15 ] . in 1997 , spillantini et al . found that -synuclein is the main component of lewy bodies in the brains of pd and dlb patients .
only two months before this report , a mutation was identified in snca , which encodes -synuclein in families with autosomal dominant pd .
in addition , snca multiplication by duplication / triplication has been identified in a large family with phenotypes ranging from dlb to pd .
these neuropathological and genetic findings suggest that -synuclein is essentially implicated in the pathogenesis of lbd including dlb and pd .
recent studies have suggested that the lewy body pathology propagates throughout the brain via neuron - to - neuron transmission of -synuclein aggregates .
it has been demonstrated that glial cytoplasmic inclusions , which are unique pathological inclusions found in brains of patients with multiple system atrophy ( msa ) , are also composed of -synuclein , suggesting an unexpected link between msa and lbd .
-synuclein is a 140-residue ubiquitous protein and is highly expressed in neuronal presynaptic terminals under physiological conditions .
although its physiological functions remain unclear , -synuclein is implicated in synaptic vesicle trafficking particularly in the regulation of synaptic vesicle release   and stabilization of snare complexes .
it has been demonstrated that the c - terminal truncated form of -synuclein promotes the aggregation of -synuclein . because -synuclein has no signal sequence ,
however , it has been shown that -synuclein is secreted into biological fluids [ 27 , 28 ] .
a year after spillantini et al . reported that -synuclein is the main component of lewy bodies , jakowec et al .
they examined the expression of -synuclein in csf from pd patients and control subjects by western blot analysis using an anti--synuclein specific antibody , but failed to detect -synuclein in csf .
detected -synuclein by a method combining immunoprecipitation with immunoblot analysis using two different anti--synuclein antibodies . in their study , however , the intensity of the bands immunoreactive to the anti--synuclein antibodies showed no significant difference between patients with pd and control subjects .
el - agnaf et al . also confirmed that -synuclein is detectable in csf by a similar methodology .
subsequently , tokuda et al . demonstrated using a new system for enzyme - linked immunosorbent assay ( elisa ) that pd patients showed significantly lower -synuclein levels in csf than the control groups .
since then , several studies to determine the total -synuclein level in csf have been carried out by elisa or bead - based flow cytometric assay using various combinations of anti--synuclein antibodies ( tables 1 and 2 ) . a significantly low level of -synuclein in csf from patients with lbd ( pd and/or dlb ) has been shown by independent studies [ 28 , 3138 ] .
our study revealed that total csf -synuclein level shows a significant positive correlation with the csf a42 level in dlb patients .
it has been suggested that a low csf a42 level may be related to amyloid - related pathology in the brains of dlb patients .
in addition , experimental studies have suggested that the a42 species strongly enhances the accumulation of -synuclein . in the csf from lbd patients
, the level of a42 shows a positive correlation with the activity of neprilysin , an enzyme that degrades a .
taken together , the reduction in -synuclein and a42 levels in csf suggests the extent of lewy body pathology and the co - occurrence of amyloid pathology , respectively , in the brain of dlb patients .
interestingly , patients with snca duplication who showed abundant lewy body pathology in the brain   also show low levels of csf -synuclein . because the predominant source of -synuclein in csf is considered to be the central nervous system ,
the decrease in the level of csf -synuclein in dlb may reflect a dysfunction in the metabolism or clearance of -synuclein in the brain , similarly to ad patients with a accumulation in the brain showing a decrease in the level of a42 in csf .
in contrast , comparable levels of total -synuclein in csf between patients with lbd and control subjects have also been reported [ 4550 ] .
this discrepancy is probably not due to the misdiagnosis of lbd , because different studies using csf samples derived from autopsy - confirmed patients showed significantly decreased or comparable -synuclein levels in lbd patients [ 34 , 50 ] .
in addition to methodological differences in the quantification of -synuclein , blood contamination of csf during lumbar puncture should be taken into account when considering the discrepant results .
the level of -synuclein in blood , particularly that stored in red blood cells , is much higher than that in csf [ 33 , 53 ] .
haemolysis in the course of sample collection and processing should be considered as a confounding factor for quantification of -synuclein level in csf and blood .
other factors such as level fluctuations over time and drug treatment may have less effect on the level of -synuclein in csf .
although the level of a in csf fluctuates over time , the level of -synuclein in csf does not significantly change .
it is also reported that drugs such as l - dopa and dopamine agonists do not affect the level of -synuclein in csf [ 34 , 35 ] .  
several groups have recently conducted studies to detect the oligomeric forms of -synuclein in csf , because the oligomer species of -synuclein are considered to be toxic and could enhance pathological accumulation of -synuclein and disease propagation .
demonstrated that the levels of -synuclein oligomers in csf are significantly higher in patients with pd than in patients with progressive supranuclear palsy ( psp ) or ad . in their study , the level of total -synuclein in the csf from pd patients tends to decrease . increased level of -synuclein oligomers in csf from pd patients was also shown by other investigator .
foulds et al . showed that the level of oligomers composed of phosphorylated -synuclein is higher in the postmortem csf from msa patients than in that from with pd , dlb , or psp patients .
sierks et al . also showed a significant increase in the level of -synuclein oligomers in postmortem csf from patients with pd by electrochemical impedance spectroscopy .
these findings suggest a possibility that -synuclein oligomer species are detectable in csf and that their levels may increase in some patients with synucleinopathies .
a potential concern is that the oligomeric forms of -synuclein detected in their studies using different methods may be heterogeneous in size and toxicity ; hence , further validation is still needed .
correlation analysis of clinical parameters , such as minimental state examination ( mmse ) and hoehn yahr scale scores with the total -synuclein level in csf , has shown inconsistent results .
showed an inverse correlation between the total -synuclein level in csf and disease severity determined by the hoehn yahr scale .
a low -synuclein level was reported to correlate with a low mmse score of dlb patients .
these findings suggest that -synuclein level in csf may reflect the severity of pathological changes occurring in patients with lbd .
this notion is supported by the findings of a study that the disease duration in patients with dlb is closely associated with a low -synuclein level in csf .
in contrast to these findings , other studies revealed no significant association of the -synuclein level in csf with mmse score , gender , age at examination , or disease duration in dlb or ad patients .
shi et al . examined whether csf -synuclein level correlates with dopaminergic dysfunction determined by pet in asymptomatic carriers with leucine - rich repeat kinase 2 ( lrrk2 ) gene mutation .
they detected no significant correlations , indicating that csf total -synuclein level may not be a sensitive biomarker of the preclinical phase of pd .
several studies on the quantification of -synuclein in blood have been carried out because drawing blood is much less invasive than lumbar puncture to obtain csf from patients ( table 3 ) .
subsequently , they found higher levels of -synuclein oligomers in plasma from pd patients than in that from control subjects by elisa .
a similar increase in -synuclein level was observed in plasma from patients with pd and msa [ 58 , 59 ] .
found that plasma -synuclein level is higher in patients with pd than in those with msa .
duran et al . demonstrated that drugs such as l - dopa , dopamine agonists , and mao / comt inhibitors do not affect the plasma -synuclein level in patients with pd . the phosphorylated -synuclein level in plasma quantified by elisa as well as western blot analysis is higher in patients with pd than in control subjects . in their study , the level of -synuclein remained stable within the same individuals at least over 3 months .
by contrast , li et al . found a significantly decreased -synuclein level in plasma from patients with pd by western blot analysis , which detected only full - length monomeric -synuclein .
laske et al . also reported a similar decrease in serum -synuclein level in dlb patients compared with ad patients and control subjects .
comparable levels of plasma -synuclein were found among patients with pd , ad , and control subjects in other studies .
results of measurements of -synuclein level in csf and blood have been variable ; hence , it is difficult to unequivocally conclude whether -synuclein is a promising fluid biomarker of dlb and other -synucleinopathies .
more discriminating results for dlb patients could be obtained by examining specific -synuclein species such as truncated , phosphorylated , and oligomeric species on the basis of their analogy to a42 and phosphorylated tau species whose changes in levels are found to be reliable csf biomarkers of ad . in addition , a multicenter study is required to validate the usefulness of -synuclein as a biomarker by standardized methods of quantifying -synuclein .
continuous efforts will be required to establish useful fluid biomarkers for early diagnosis of dlb and evaluation of disease - modifying therapeutics for dlb .
dementia with lewy bodies ( dlb ) is a common subtype of dementia in the elderly . 
 dlb is neuropathologically characterized by the presence of lewy bodies and lewy neurites , both of which are composed of -synuclein . 
 although -synuclein was initially considered to be an exclusively intracellular protein , it has been found to be secreted into biological fluids . 
 -synuclein in biological fluids such as cerebrospinal fluid ( csf ) and blood has been discussed as a potential biomarker of dlb and -synuclein - related disorders , because -synuclein is characteristically accumulated in the brain of patients with these disorders . 
 the -synuclein level in csf has been examined by several investigators , and the majority of studies have shown a reduction in csf -synuclein level in dlb and -synuclein - related disorders . 
 discrepant findings of studies of plasma -synuclein level in patients with dlb have been reported . because the level of -synuclein stored in red blood cells 
 is considerably high , blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of -synuclein . here , the recent progress in the studies of -synuclein as a biomarker of dlb and their potential clinical applications are reviewed .