PMC:4927924 / 29722-33571 JSONTXT

{"project":"TEST0","denotations":[{"id":"26485429-159-166-1671288","span":{"begin":180,"end":183},"obj":"[\"23419373\"]"},{"id":"26485429-195-202-1671289","span":{"begin":537,"end":540},"obj":"[\"22917144\"]"},{"id":"26485429-232-239-1671290","span":{"begin":803,"end":806},"obj":"[\"21930184\"]"},{"id":"26485429-235-242-1671291","span":{"begin":1128,"end":1131},"obj":"[\"23979011\"]"},{"id":"26485429-235-242-1671292","span":{"begin":1405,"end":1408},"obj":"[\"25202803\"]"},{"id":"26485429-235-242-1671293","span":{"begin":1657,"end":1660},"obj":"[\"20540987\"]"},{"id":"26485429-194-201-1671294","span":{"begin":1857,"end":1860},"obj":"[\"23447138\"]"},{"id":"26485429-234-241-1671295","span":{"begin":2160,"end":2163},"obj":"[\"23447138\"]"},{"id":"26485429-115-122-1671296","span":{"begin":2715,"end":2718},"obj":"[\"23884037\"]"},{"id":"26485429-185-192-1671297","span":{"begin":2785,"end":2788},"obj":"[\"25639598\"]"},{"id":"26485429-230-237-1671298","span":{"begin":2927,"end":2930},"obj":"[\"18401018\"]"},{"id":"26485429-206-213-1671299","span":{"begin":3378,"end":3381},"obj":"[\"25596505\"]"},{"id":"26485429-179-186-1671300","span":{"begin":3683,"end":3686},"obj":"[\"21673298\"]"},{"id":"26485429-155-162-1671301","span":{"begin":3844,"end":3847},"obj":"[\"22508282\"]"}],"text":"Molecular biomarkers\nIn addition to the recent genomic discoveries, proteomic markers mostly assessed in the cerebrospinal fluid (CSF) are also subject of great research interest [107]. Alpha-synuclein-related parameters were investigated in CSF of PD patients and control populations, in some studies also in combination with DJ1 (Table 4). Results have been inconsistent, which may be due to various confounders, different methodologies used for specimen collection and analysis and due to a lack of standardized operating procedures [108]. The latter will change with prospective multicentre studies such as PPMI, where 400 newly diagnosed PD patients and 200 healthy controls are undergoing regular CSF and imaging marker assessments in an attempt to identify diagnostic and progression biomarkers [109], as well as premotor and genetic markers in recently added substudies. First results in a cross sectional analysis of a subset of the cohort showed lower levels of Aβ1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aβ 1 - 42 early drug naive PD patients compared with healthy controls with a marked overlap between groups [110]. Also, recent meta-analyses of total a-synuclein in the CSF have found decreased levels compared to healthy controls with, however, substantial overlap resulting in a suboptimal diagnostic accuracy with a good sensitivity of 88% but a poor specificity of 40% for PD [111, 112]. Evaluation of a-synuclein and DJ1 in the plasma has produced conflicting results and may be futile as erythrocytes are the greatest source of these proteins in the blood and the slightest degree of hemolysis considerably influences measurements [113]. Other proteins in the peripheral biofluids have been investigated: Using an unbiased proteomic screening approach, a recent study found 11 plasma proteins to be associated with age at PD onset [114]. Among those, low levels of apolipoprotein A1 (ApoA1), the main component of high density lipoproteins (HDL), correlated with earlier PD onset also in a replication cohort and were furthermore associated with greater putaminal DAT deficit among hyposmic subjects at risk for PD in the PARS cohort [114]. These results have been replicated by the same authors in other cohorts including a subset of the PPMI study, where the same direct association with age at disease onset has been found for HDL levels [115]. ApoA1/HDL would represent a particularly interesting PD risk marker, as it is potentially modifiable by drugs like statins. The latter study did, however, not adjust for cofounders of ApoA1/HDL levels such as statin use [115]. Moreover, studies on the influence of statins on PD risk have been conflicting with some showing a decreased risk [116] and others an increased risk for the disease among statin users [117], the latter being in line with evidence of high total cholesterol and/or low density lipoprotein as a protective factor against PD [118, 119]. Therefore, more experimental and longitudinal clinical and population-basedstudies, thoroughly adjusting for multiple confounders, are warranted before ApoA1/HDL elevating drugs may be tested in prospective clinical neuroprotectiontrials.\nAlthough there are other recent promising advances in molecular biomarker research including the measurement of microRNAs in blood of PD and RBD patients significantly differing from healthy controls [120, 121], there is currently no molecular marker or combination of markers that could reliably show increased risk to develop PD. However, in Alzheimer’s disease, which has a pioneering role in neurodegenerative disease research, such biomarkers have been developed and incorporated in diagnostic guidelines [122]. Given the rapidly advancing biochemical technologies, it is strongly hoped that a premotorbiochemical biomarkers can be discovered in PD-risk populations [123]."}

{"project":"2_test","denotations":[{"id":"26485429-23419373-64047517","span":{"begin":180,"end":183},"obj":"23419373"},{"id":"26485429-22917144-64047518","span":{"begin":537,"end":540},"obj":"22917144"},{"id":"26485429-21930184-64047519","span":{"begin":803,"end":806},"obj":"21930184"},{"id":"26485429-23979011-64047520","span":{"begin":1128,"end":1131},"obj":"23979011"},{"id":"26485429-25202803-64047521","span":{"begin":1405,"end":1408},"obj":"25202803"},{"id":"26485429-20540987-64047522","span":{"begin":1657,"end":1660},"obj":"20540987"},{"id":"26485429-23447138-64047523","span":{"begin":1857,"end":1860},"obj":"23447138"},{"id":"26485429-23447138-64047524","span":{"begin":2160,"end":2163},"obj":"23447138"},{"id":"26485429-23884037-64047525","span":{"begin":2715,"end":2718},"obj":"23884037"},{"id":"26485429-25639598-64047526","span":{"begin":2785,"end":2788},"obj":"25639598"},{"id":"26485429-18401018-64047527","span":{"begin":2927,"end":2930},"obj":"18401018"},{"id":"26485429-25596505-64047528","span":{"begin":3378,"end":3381},"obj":"25596505"},{"id":"26485429-21673298-64047529","span":{"begin":3683,"end":3686},"obj":"21673298"},{"id":"26485429-22508282-64047530","span":{"begin":3844,"end":3847},"obj":"22508282"}],"text":"Molecular biomarkers\nIn addition to the recent genomic discoveries, proteomic markers mostly assessed in the cerebrospinal fluid (CSF) are also subject of great research interest [107]. Alpha-synuclein-related parameters were investigated in CSF of PD patients and control populations, in some studies also in combination with DJ1 (Table 4). Results have been inconsistent, which may be due to various confounders, different methodologies used for specimen collection and analysis and due to a lack of standardized operating procedures [108]. The latter will change with prospective multicentre studies such as PPMI, where 400 newly diagnosed PD patients and 200 healthy controls are undergoing regular CSF and imaging marker assessments in an attempt to identify diagnostic and progression biomarkers [109], as well as premotor and genetic markers in recently added substudies. First results in a cross sectional analysis of a subset of the cohort showed lower levels of Aβ1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aβ 1 - 42 early drug naive PD patients compared with healthy controls with a marked overlap between groups [110]. Also, recent meta-analyses of total a-synuclein in the CSF have found decreased levels compared to healthy controls with, however, substantial overlap resulting in a suboptimal diagnostic accuracy with a good sensitivity of 88% but a poor specificity of 40% for PD [111, 112]. Evaluation of a-synuclein and DJ1 in the plasma has produced conflicting results and may be futile as erythrocytes are the greatest source of these proteins in the blood and the slightest degree of hemolysis considerably influences measurements [113]. Other proteins in the peripheral biofluids have been investigated: Using an unbiased proteomic screening approach, a recent study found 11 plasma proteins to be associated with age at PD onset [114]. Among those, low levels of apolipoprotein A1 (ApoA1), the main component of high density lipoproteins (HDL), correlated with earlier PD onset also in a replication cohort and were furthermore associated with greater putaminal DAT deficit among hyposmic subjects at risk for PD in the PARS cohort [114]. These results have been replicated by the same authors in other cohorts including a subset of the PPMI study, where the same direct association with age at disease onset has been found for HDL levels [115]. ApoA1/HDL would represent a particularly interesting PD risk marker, as it is potentially modifiable by drugs like statins. The latter study did, however, not adjust for cofounders of ApoA1/HDL levels such as statin use [115]. Moreover, studies on the influence of statins on PD risk have been conflicting with some showing a decreased risk [116] and others an increased risk for the disease among statin users [117], the latter being in line with evidence of high total cholesterol and/or low density lipoprotein as a protective factor against PD [118, 119]. Therefore, more experimental and longitudinal clinical and population-basedstudies, thoroughly adjusting for multiple confounders, are warranted before ApoA1/HDL elevating drugs may be tested in prospective clinical neuroprotectiontrials.\nAlthough there are other recent promising advances in molecular biomarker research including the measurement of microRNAs in blood of PD and RBD patients significantly differing from healthy controls [120, 121], there is currently no molecular marker or combination of markers that could reliably show increased risk to develop PD. However, in Alzheimer’s disease, which has a pioneering role in neurodegenerative disease research, such biomarkers have been developed and incorporated in diagnostic guidelines [122]. Given the rapidly advancing biochemical technologies, it is strongly hoped that a premotorbiochemical biomarkers can be discovered in PD-risk populations [123]."}