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introduction
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initial pathologic definition of AD constitutes accumulations of amyloid-β (Aβ) and pathologically modified tau proteins to form senile plaque and neurofibrillary tangles, respectively, which are regarded as core pathologic features in AD>>1<<. The measurements of Aβ1-42 (Aβ42), total tau (tTau), and phosphorylated tau at Thr181 (pTau181) in cerebrospinal fluid (CSF), as well as the visualization of fibrillar Aβ protein loads in the brain using a radioactive ligand, have proven
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in cerebrospinal fluid (CSF), as well as the visualization of fibrillar Aβ protein loads in the brain using a radioactive ligand, have proven useful in the early diagnosis of AD, which leads to their inclusion in diagnostic guidelines>>2<<,3 and biological definitions of AD4. Current clinical trials use measurements of Aβ protein and tau proteins in CSF and/or blood to guide participant recruitment and outcome measures5.
n2:mentions
n3:21514250
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in cerebrospinal fluid (CSF), as well as the visualization of fibrillar Aβ protein loads in the brain using a radioactive ligand, have proven useful in the early diagnosis of AD, which leads to their inclusion in diagnostic guidelines2,>>3<< and biological definitions of AD4. Current clinical trials use measurements of Aβ protein and tau proteins in CSF and/or blood to guide participant recruitment and outcome measures5.
n2:mentions
n3:24849862
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well as the visualization of fibrillar Aβ protein loads in the brain using a radioactive ligand, have proven useful in the early diagnosis of AD, which leads to their inclusion in diagnostic guidelines2,3 and biological definitions of AD>>4<<. Current clinical trials use measurements of Aβ protein and tau proteins in CSF and/or blood to guide participant recruitment and outcome measures5.
n2:mentions
n3:29653606
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early saturation of Aβ accumulation in the brain, indicated by plateaus in CSF Aβ42 levels and amyloid PET uptake after clinical symptom onset, limits the usefulness of Aβ biomarkers for monitoring disease progression and drug response>>6<<–8. Tau protein levels are more likely than Aβ to reflect the clinical status; however, their clinical correlations are also lost with the advancement of neurodegeneration, revealing stabilization or a reduction in protein levels8,9.
n2:mentions
n3:23812320 n3:22784036 n3:23034521
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Tau protein levels are more likely than Aβ to reflect the clinical status; however, their clinical correlations are also lost with the advancement of neurodegeneration, revealing stabilization or a reduction in protein levels>>8<<,9. The shortage of Aβ and tau biomarkers is a serious problem during successive failures of Aβ-targeting drug trials. Treatment-responsive improvements in Aβ biomarkers (e.g., reduced Aβ uptake on amyloid PET and increased levels of CSF
n2:mentions
n3:23812320
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Tau protein levels are more likely than Aβ to reflect the clinical status; however, their clinical correlations are also lost with the advancement of neurodegeneration, revealing stabilization or a reduction in protein levels8,>>9<<. The shortage of Aβ and tau biomarkers is a serious problem during successive failures of Aβ-targeting drug trials.
n2:mentions
n3:29580670
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Treatment-responsive improvements in Aβ biomarkers (e.g., reduced Aβ uptake on amyloid PET and increased levels of CSF Aβ)>>10<<–13 and tau biomarkers12 were not accompanied by clinical benefits13–16.
n2:mentions
n3:20189881 n3:22473769 n3:22672770 n3:30970186
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Treatment-responsive improvements in Aβ biomarkers (e.g., reduced Aβ uptake on amyloid PET and increased levels of CSF Aβ)10–13 and tau biomarkers>>12<< were not accompanied by clinical benefits13–16.
n2:mentions
n3:22473769
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Treatment-responsive improvements in Aβ biomarkers (e.g., reduced Aβ uptake on amyloid PET and increased levels of CSF Aβ)10–13 and tau biomarkers12 were not accompanied by clinical benefits>>13<<–16. This finding clearly showed that changes in Aβ and tau biomarkers are not reliable in terms of predicting disease progression and monitoring clinical status. Therefore, new biomarkers are needed to resolve this shortage. Ideally, new
n2:mentions
n3:29365294 n3:30970186 n3:24450890 n3:24450891
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Large neuropathological studies have demonstrated that pure AD pathology is infrequent in elderly patients with cognitive decline>>17<<. The precise pathophysiology, which determines the probability of developing clinical symptoms of dementia, is diverse in terms of the presence of Aβ and tau pathology. The actual contribution of AD pathology to cognitive loss has been
n2:mentions
n3:29244218
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The actual contribution of AD pathology to cognitive loss has been estimated to vary from 22 to 100%>>17<<. This suggests that Aβ and tau pathologies alone cannot sufficiently represent the clinical severity of AD. Considerations of other biomarkers that directly signify pathologic substrates indicative of cognitive dysfunction are necessary.
n2:mentions
n3:29244218
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overview of biological targets for non­-aβ and ­-tau biomarkers
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In addition to senile plaque and neurofibrillary tangles, dystrophic axons and dendrites surrounded by activated glial cells are abundant in the AD brain, which directly represent neurodegeneration and synapse loss>>18<<. Synapse loss is closely correlated with cognitive dysfunction18. Thus, neurodegeneration-related biomarkers may most closely indicate cognitive status. However, these biomarkers have received minimal attention in the field of AD
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n3:22229116
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Synapse loss is closely correlated with cognitive dysfunction>>18<<. Thus, neurodegeneration-related biomarkers may most closely indicate cognitive status.
n2:mentions
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Nonetheless, accumulating evidence supports their clinical usefulness in diagnosis and clinical staging>>19<<–23.Fig. 1Overview of the pathophysiological process in Alzheimer’s disease.
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Although astrogliosis and neuroinflammation are prevalent features in the AD brain>>18<<, the roles of microglia and astrocytes in AD pathophysiology have received less attention than neurons.
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However, many AD-related risk genes identified in genome-wide association studies (e.g., ABCA7, CD33, CR1, EPHA1, MS4A, and TREM2) are reportedly expressed in microglia and involved in neuroinflammation>>24<<. Accumulating experimental data support the active role of neuroinflammation in AD pathogenesis; moreover, it is currently regarded as a target for the development of AD treatments25. Various markers signifying the activation of
n2:mentions
n3:27302364
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Accumulating experimental data support the active role of neuroinflammation in AD pathogenesis; moreover, it is currently regarded as a target for the development of AD treatments>>25<<. Various markers signifying the activation of inflammatory brain cells and the release of neuroinflammation-modulating factors have been suggested as potential biomarkers.
n2:mentions
n3:29260466
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The APOE ε4 allele is the strongest and most prevalent risk gene for AD>>24<<. The primary biological role of the apolipoprotein E (ApoE) protein is to transport lipids and regulate cholesterol metabolism26.
n2:mentions
n3:27302364
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The primary biological role of the apolipoprotein E (ApoE) protein is to transport lipids and regulate cholesterol metabolism>>26<<. Lipid homeostasis is important in the physiological functions of the brain, including cellular membrane function, synaptic integrity, neuronal regeneration, and neuronal plasticity27. The disturbed lipid metabolism in AD is evidenced by
n2:mentions
n3:3283935
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Lipid homeostasis is important in the physiological functions of the brain, including cellular membrane function, synaptic integrity, neuronal regeneration, and neuronal plasticity>>27<<. The disturbed lipid metabolism in AD is evidenced by many lipid droplets within glial cells28, as well as altered lipid content and distribution29, which are expected to contribute to AD pathogenesis. Proteins involved in lipid
n2:mentions
n3:12861382
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The disturbed lipid metabolism in AD is evidenced by many lipid droplets within glial cells>>28<<, as well as altered lipid content and distribution29, which are expected to contribute to AD pathogenesis.
n2:mentions
n3:8713166
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The disturbed lipid metabolism in AD is evidenced by many lipid droplets within glial cells28, as well as altered lipid content and distribution>>29<<, which are expected to contribute to AD pathogenesis.
n2:mentions
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While synthesis of Aβ is the primary problem in AD with genetic mutation, impaired abnormal protein clearance is the main pathogenesis in sporadic AD>>30<<. Inside neurons and other brain cells, abnormal protein burdens are diminished by the autophagy–lysosomal system, ubiquitin–proteasome system and chaperone-mediated autophagy to maintain intracellular homeostasis31. In the extracellular
n2:mentions
n3:15734686
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Inside neurons and other brain cells, abnormal protein burdens are diminished by the autophagy–lysosomal system, ubiquitin–proteasome system and chaperone-mediated autophagy to maintain intracellular homeostasis>>31<<. In the extracellular space, protein clearance is mediated via protease, phagocytosis by astrocytes and microglia and exportation through the glymphatic system and blood–brain barrier (BBB) into CSF and systemic circulation31. Therefore,
n2:mentions
n3:30116051
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In the extracellular space, protein clearance is mediated via protease, phagocytosis by astrocytes and microglia and exportation through the glymphatic system and blood–brain barrier (BBB) into CSF and systemic circulation>>31<<. Therefore, checking protein degradation machinery-related proteins might provide information regarding disease status caused by abnormal protein accumulation.
n2:mentions
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such as TDP-43 (e.g., frontotemporal dementia) and α-synuclein proteinopathy (e.g., Parkinson’s disease, Lewy body dementia, and multiple system atrophy), makes the pathophysiology and clinical manifestations of AD more variable>>17<<. The identification of combined brain pathology is necessary to correctly estimate AD status and predict disease progression because enhanced neurodegeneration can result in augmented cognitive dysfunction when other brain disorders are
n2:mentions
n3:29244218
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pathologic proteins of other neurodegenerative disorders, such as TDP-43 and α-synuclein protein levels, have emerged as potential biomarkers in frontotemporal dementia and Lewy body dementia/Parkinson’s disease dementia, respectively>>32<<,33. This review does not extend to non-AD-specific biomarkers because these have not yet yielded consistent results32,34.
n2:mentions
n3:29460270
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pathologic proteins of other neurodegenerative disorders, such as TDP-43 and α-synuclein protein levels, have emerged as potential biomarkers in frontotemporal dementia and Lewy body dementia/Parkinson’s disease dementia, respectively32,>>33<<. This review does not extend to non-AD-specific biomarkers because these have not yet yielded consistent results32,34.
n2:mentions
n3:29205509
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This review does not extend to non-AD-specific biomarkers because these have not yet yielded consistent results>>32<<,34. Instead, the differential diagnostic values of new biomarkers are discussed in the context of AD vs. non-AD pathologies.
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n3:29460270
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This review does not extend to non-AD-specific biomarkers because these have not yet yielded consistent results32,>>34<<. Instead, the differential diagnostic values of new biomarkers are discussed in the context of AD vs. non-AD pathologies.
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n3:30981640
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neurodegeneration-related biomarkers: synaptic loss and axonal degeneration
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Neurofilament light polypeptide (NFL) is the most abundant component of large myelinated axons, which is released into CSF and systemic circulation when neurodegeneration occurs>>35<<. NFL has been extensively examined in terms of its clinical utility, and many studies have demonstrated its high degree of usefulness in clinical applications (Supplementary Table 1).
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It has also been documented that CSF NFL levels are well correlated with plasma NFL levels, although the levels in plasma are 50-fold lower than those in CSF>>19<<,36,37. Both CSF and plasma NFL levels are increased in relation to AD progression, revealing a high degree of correlation with cognitive functions and a good predictive value for future cognitive decline20–22,36. However, in terms of the
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It has also been documented that CSF NFL levels are well correlated with plasma NFL levels, although the levels in plasma are 50-fold lower than those in CSF19,>>36<<,37. Both CSF and plasma NFL levels are increased in relation to AD progression, revealing a high degree of correlation with cognitive functions and a good predictive value for future cognitive decline20–22,36. However, in terms of the
n2:mentions
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It has also been documented that CSF NFL levels are well correlated with plasma NFL levels, although the levels in plasma are 50-fold lower than those in CSF19,36,>>37<<. Both CSF and plasma NFL levels are increased in relation to AD progression, revealing a high degree of correlation with cognitive functions and a good predictive value for future cognitive decline20–22,36. However, in terms of the
n2:mentions
n3:28692877
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Both CSF and plasma NFL levels are increased in relation to AD progression, revealing a high degree of correlation with cognitive functions and a good predictive value for future cognitive decline>>20<<–22,36. However, in terms of the differentiation of AD from other neurodegenerative disorders, NFL levels are less likely to be beneficial. High plasma NFL levels were frequently observed in progressive supranuclear palsy38, frontotemporal
n2:mentions
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Both CSF and plasma NFL levels are increased in relation to AD progression, revealing a high degree of correlation with cognitive functions and a good predictive value for future cognitive decline20–22,>>36<<. However, in terms of the differentiation of AD from other neurodegenerative disorders, NFL levels are less likely to be beneficial. High plasma NFL levels were frequently observed in progressive supranuclear palsy38, frontotemporal
n2:mentions
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High plasma NFL levels were frequently observed in progressive supranuclear palsy>>38<<, frontotemporal dementia39, multiple system atrophy, and corticobasal degeneration40.
n2:mentions
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High plasma NFL levels were frequently observed in progressive supranuclear palsy38, frontotemporal dementia>>39<<, multiple system atrophy, and corticobasal degeneration40.
n2:mentions
n3:27581216
Subject Item
_:vb110513332
rdf:type
n2:Context
rdf:value
High plasma NFL levels were frequently observed in progressive supranuclear palsy38, frontotemporal dementia39, multiple system atrophy, and corticobasal degeneration>>40<<. The capability of plasma NFL levels to predict cognitive decline and cortical regional atrophy was noticeable in both progressive supranuclear palsy and in AD38. Therefore, NFL levels are currently regarded as representative of
n2:mentions
n3:28179466
Subject Item
_:vb110513333
rdf:type
n2:Context
rdf:value
The capability of plasma NFL levels to predict cognitive decline and cortical regional atrophy was noticeable in both progressive supranuclear palsy and in AD>>38<<. Therefore, NFL levels are currently regarded as representative of neurodegeneration itself, independent of Aβ and tau pathology, which can be useful for proper disease tracking in both AD and non-AD dementia. Increases in NFL levels are
n2:mentions
n3:27042681
Subject Item
_:vb110513334
rdf:type
n2:Context
rdf:value
cognitive impairments: a distinct increase in serum NFL in AD-causative mutation carriers was observed 16.2 years earlier than clinical symptoms began, according to the findings of the Dominant Inherited Alzheimer’s Disease Network study>>19<<. In a study of normal elderly individuals without cognitive impairment, increased CSF NFL levels were observed in those who developed cognitive decline during follow-up9,22.
n2:mentions
n3:30664784
Subject Item
_:vb110513335
rdf:type
n2:Context
rdf:value
In a study of normal elderly individuals without cognitive impairment, increased CSF NFL levels were observed in those who developed cognitive decline during follow-up>>9<<,22. The measurement of NFL in body fluids, especially easily accessible blood, is therefore expected to be applicable for preventative screening of preclinical stages of AD.
n2:mentions
n3:29580670
Subject Item
_:vb110513336
rdf:type
n2:Context
rdf:value
In a study of normal elderly individuals without cognitive impairment, increased CSF NFL levels were observed in those who developed cognitive decline during follow-up9,>>22<<. The measurement of NFL in body fluids, especially easily accessible blood, is therefore expected to be applicable for preventative screening of preclinical stages of AD.
n2:mentions
n3:30853464
Subject Item
_:vb110513337
rdf:type
n2:Context
rdf:value
In cross-sectional comparisons, many reports have demonstrated that neurogranin increases in CSF from patients with AD and patients with mild cognitive impairment (MCI) relative to that from healthy controls>>41<<–44 (Supplementary Table 1).
n2:mentions
n3:26783546 n3:25533203 n3:26826204 n3:26366630
Subject Item
_:vb110513338
rdf:type
n2:Context
rdf:value
Furthermore, increased CSF neurogranin is specific to AD among the various neurodegenerative disorders>>23<<,43,44. The value of CSF neurogranin for the prediction of future cognitive decline was also identified, although the direction differed among studies. Many studies have suggested that increased baseline neurogranin levels are indicative
n2:mentions
n3:29700597
Subject Item
_:vb110513339
rdf:type
n2:Context
rdf:value
Furthermore, increased CSF neurogranin is specific to AD among the various neurodegenerative disorders23,>>43<<,44. The value of CSF neurogranin for the prediction of future cognitive decline was also identified, although the direction differed among studies. Many studies have suggested that increased baseline neurogranin levels are indicative of
n2:mentions
n3:26783546
Subject Item
_:vb110513340
rdf:type
n2:Context
rdf:value
Furthermore, increased CSF neurogranin is specific to AD among the various neurodegenerative disorders23,43,>>44<<. The value of CSF neurogranin for the prediction of future cognitive decline was also identified, although the direction differed among studies. Many studies have suggested that increased baseline neurogranin levels are indicative of
n2:mentions
n3:26826204
Subject Item
_:vb110513341
rdf:type
n2:Context
rdf:value
Many studies have suggested that increased baseline neurogranin levels are indicative of future cognitive deterioration in patients with MCI>>20<<,41,42, while a few studies have suggested that low baseline neurogranin levels are indicative of future cognitive deterioration22.
n2:mentions
n3:27534871
Subject Item
_:vb110513342
rdf:type
n2:Context
rdf:value
Many studies have suggested that increased baseline neurogranin levels are indicative of future cognitive deterioration in patients with MCI20,>>41<<,42, while a few studies have suggested that low baseline neurogranin levels are indicative of future cognitive deterioration22.
n2:mentions
n3:26366630
Subject Item
_:vb110513343
rdf:type
n2:Context
rdf:value
Many studies have suggested that increased baseline neurogranin levels are indicative of future cognitive deterioration in patients with MCI20,41,>>42<<, while a few studies have suggested that low baseline neurogranin levels are indicative of future cognitive deterioration22.
n2:mentions
n3:25533203
Subject Item
_:vb110513344
rdf:type
n2:Context
rdf:value
increased baseline neurogranin levels are indicative of future cognitive deterioration in patients with MCI20,41,42, while a few studies have suggested that low baseline neurogranin levels are indicative of future cognitive deterioration>>22<<. This discrepancy may be caused by dynamic changes in CSF neurogranin levels, depending on disease stage9, which has also been demonstrated for other synapse-related proteins (i.e., an early increase above and subsequent gradual reduction
n2:mentions
n3:30853464
Subject Item
_:vb110513345
rdf:type
n2:Context
rdf:value
This discrepancy may be caused by dynamic changes in CSF neurogranin levels, depending on disease stage>>9<<, which has also been demonstrated for other synapse-related proteins (i.e., an early increase above and subsequent gradual reduction below the levels of controls, corresponding to disease progression)45.
n2:mentions
n3:29580670
Subject Item
_:vb110513346
rdf:type
n2:Context
rdf:value
levels, depending on disease stage9, which has also been demonstrated for other synapse-related proteins (i.e., an early increase above and subsequent gradual reduction below the levels of controls, corresponding to disease progression)>>45<<. The early transient increase in CSF level is presumably due to the active degradation of synapses and compensatory enlargement of the remaining synapses18.
n2:mentions
n3:29370833
Subject Item
_:vb110513347
rdf:type
n2:Context
rdf:value
The early transient increase in CSF level is presumably due to the active degradation of synapses and compensatory enlargement of the remaining synapses>>18<<. Measurements of neurogranin levels in peripheral blood were performed, including neuron-derived exosomes; reduced levels of neurogranin in neuron-derived exosomes were reported in patients with AD compared with controls, but further
n2:mentions
n3:22229116
Subject Item
_:vb110513348
rdf:type
n2:Context
rdf:value
neurogranin levels in peripheral blood were performed, including neuron-derived exosomes; reduced levels of neurogranin in neuron-derived exosomes were reported in patients with AD compared with controls, but further validation is needed>>46<<.
n2:mentions
n3:27601437
Subject Item
_:vb110513349
rdf:type
n2:Context
rdf:value
Visinin-like protein 1 (VILIP-1) is a neuronal calcium sensor protein that is exclusively expressed at high levels in neurons>>47<<. Its release into CSF and systemic circulation is regarded as a marker of neuronal injury.
n2:mentions
n3:22375104
Subject Item
_:vb110513350
rdf:type
n2:Context
rdf:value
However, no differences in VILIP-1 levels between patients with AD and controls>>48<< or between patients with AD and those with vascular dementia or frontotemporal dementia have been reported49.
n2:mentions
n3:26383836
Subject Item
_:vb110513351
rdf:type
n2:Context
rdf:value
However, no differences in VILIP-1 levels between patients with AD and controls48 or between patients with AD and those with vascular dementia or frontotemporal dementia have been reported>>49<<. Considering that longitudinal reduction in VILIP-1 levels occurs with disease progression after the initial increase in AD9, the increased levels of VILIP-1 in CSF could be unclear at certain stages of advanced clinical disease, which
n2:mentions
n3:26836160
Subject Item
_:vb110513352
rdf:type
n2:Context
rdf:value
Considering that longitudinal reduction in VILIP-1 levels occurs with disease progression after the initial increase in AD>>9<<, the increased levels of VILIP-1 in CSF could be unclear at certain stages of advanced clinical disease, which could weaken the validity of VILIP-1 as a biomarker.
n2:mentions
n3:29580670
Subject Item
_:vb110513353
rdf:type
n2:Context
rdf:value
At early stages of AD, such as preclinical and MCI stages, high CSF VILIP-1 levels predict future cognitive decline>>48<<,50 and brain atrophy51.
n2:mentions
n3:26383836
Subject Item
_:vb110513354
rdf:type
n2:Context
rdf:value
At early stages of AD, such as preclinical and MCI stages, high CSF VILIP-1 levels predict future cognitive decline48,>>50<< and brain atrophy51.
n2:mentions
n3:21823155
Subject Item
_:vb110513355
rdf:type
n2:Context
rdf:value
At early stages of AD, such as preclinical and MCI stages, high CSF VILIP-1 levels predict future cognitive decline48,50 and brain atrophy>>51<<.
n2:mentions
n3:25867677
Subject Item
_:vb110513356
rdf:type
n2:Context
rdf:value
Granin proteins are involved in various biological functions, including vasodilation, antiapoptosis, mast cell migration, microglial activation, neurotransmitter release, and synaptic function>>52<<. Altered CSF levels of granins are reportedly correlated with brain regional atrophy in patients with AD45,53,54. Chromogranin-A and secretogranin-1 exhibit characteristically dynamic changes in CSF expression according to disease stage
n2:mentions
n3:20600637
Subject Item
_:vb110513357
rdf:type
n2:Context
rdf:value
Altered CSF levels of granins are reportedly correlated with brain regional atrophy in patients with AD>>45<<,53,54. Chromogranin-A and secretogranin-1 exhibit characteristically dynamic changes in CSF expression according to disease stage in a manner similar to that of neurogranin: increased levels during early stages (i.e., MCI) and reduced
n2:mentions
n3:29370833
Subject Item
_:vb110513358
rdf:type
n2:Context
rdf:value
Altered CSF levels of granins are reportedly correlated with brain regional atrophy in patients with AD45,>>53<<,54. Chromogranin-A and secretogranin-1 exhibit characteristically dynamic changes in CSF expression according to disease stage in a manner similar to that of neurogranin: increased levels during early stages (i.e., MCI) and reduced levels
n2:mentions
n3:26284520
Subject Item
_:vb110513359
rdf:type
n2:Context
rdf:value
Contactin-2 organizes the Ranvier nodes of axons and cell adhesion and was identified as a potential CSF biomarker in AD>>55<<. Myelin basic protein has a role in the formation and maintenance of the myelin sheath and was identified as a candidate CSF biomarker in AD and subcortical vascular disease56. Proteins involved in neurite outgrowth and synaptic
n2:mentions
n3:29859129
Subject Item
_:vb110513360
rdf:type
n2:Context
rdf:value
Myelin basic protein has a role in the formation and maintenance of the myelin sheath and was identified as a candidate CSF biomarker in AD and subcortical vascular disease>>56<<. Proteins involved in neurite outgrowth and synaptic stabilization, such as neurofascin and neuronal pentraxin 1, were suggested as CSF AD biomarkers45,54. Synaptosomal-associated protein 25, which has a role in neurotransmitter release,
n2:mentions
n3:21860087
Subject Item
_:vb110513361
rdf:type
n2:Context
rdf:value
Proteins involved in neurite outgrowth and synaptic stabilization, such as neurofascin and neuronal pentraxin 1, were suggested as CSF AD biomarkers>>45<<,54. Synaptosomal-associated protein 25, which has a role in neurotransmitter release, was also suggested as a candidate CSF biomarker9. These synapse-related proteins have the potential to be valuable disease-tracking biomarkers, as well
n2:mentions
n3:29370833
Subject Item
_:vb110513362
rdf:type
n2:Context
rdf:value
Synaptosomal-associated protein 25, which has a role in neurotransmitter release, was also suggested as a candidate CSF biomarker>>9<<. These synapse-related proteins have the potential to be valuable disease-tracking biomarkers, as well as diagnostic biomarkers, considering that synapse loss is the factor most representative of clinical severity18.
n2:mentions
n3:29580670
Subject Item
_:vb110513363
rdf:type
n2:Context
rdf:value
These synapse-related proteins have the potential to be valuable disease-tracking biomarkers, as well as diagnostic biomarkers, considering that synapse loss is the factor most representative of clinical severity>>18<<.
n2:mentions
n3:22229116
Subject Item
_:vb110513364
rdf:type
n6:Section
dc:title
neuroinflammation-related biomarkers
n6:contains
_:vb110513396 _:vb110513397 _:vb110513398 _:vb110513399 _:vb110513392 _:vb110513393 _:vb110513394 _:vb110513395 _:vb110513400 _:vb110513401 _:vb110513380 _:vb110513381 _:vb110513382 _:vb110513383 _:vb110513376 _:vb110513377 _:vb110513378 _:vb110513379 _:vb110513388 _:vb110513389 _:vb110513390 _:vb110513391 _:vb110513384 _:vb110513385 _:vb110513386 _:vb110513387 _:vb110513365 _:vb110513366 _:vb110513367 _:vb110513372 _:vb110513373 _:vb110513374 _:vb110513375 _:vb110513368 _:vb110513369 _:vb110513370 _:vb110513371
Subject Item
_:vb110513365
rdf:type
n2:Context
rdf:value
β2-Microglobulin is involved in the innate immune system through antigen presentation to the immune system>>57<<. Intercellular adhesion molecule 1 (ICAM1) is a cell-surface glycoprotein in endothelial cells and immune cells, which provides ligands that facilitate adhesion of leukocytes to endothelial cells; this allows leukocyte trafficking into
n2:mentions
n3:2139497
Subject Item
_:vb110513366
rdf:type
n2:Context
rdf:value
adhesion molecule 1 (ICAM1) is a cell-surface glycoprotein in endothelial cells and immune cells, which provides ligands that facilitate adhesion of leukocytes to endothelial cells; this allows leukocyte trafficking into the brain>>58<<. Both β2-microglobulin and ICAM1 in CSF are reportedly increased in patients with AD at the early, preclinical, and MCI stages45,59.
n2:mentions
n3:12098511
Subject Item
_:vb110513367
rdf:type
n2:Context
rdf:value
Both β2-microglobulin and ICAM1 in CSF are reportedly increased in patients with AD at the early, preclinical, and MCI stages>>45<<,59. Moreover, ICAM1 levels in CSF have been correlated with the severity of cognitive decline60.
n2:mentions
n3:29370833
Subject Item
_:vb110513368
rdf:type
n2:Context
rdf:value
Both β2-microglobulin and ICAM1 in CSF are reportedly increased in patients with AD at the early, preclinical, and MCI stages45,>>59<<. Moreover, ICAM1 levels in CSF have been correlated with the severity of cognitive decline60.
n2:mentions
n3:17353378
Subject Item
_:vb110513369
rdf:type
n2:Context
rdf:value
Moreover, ICAM1 levels in CSF have been correlated with the severity of cognitive decline>>60<<.
n2:mentions
n3:30054439
Subject Item
_:vb110513370
rdf:type
n2:Context
rdf:value
Progranulin is involved in neuroinflammatory modulation, specifically toward reducing microgliosis and astrogliosis>>61<<; moreover, it enhances neuronal outgrowth and neuronal survival62.
n2:mentions
n3:20522652
Subject Item
_:vb110513371
rdf:type
n2:Context
rdf:value
Progranulin is involved in neuroinflammatory modulation, specifically toward reducing microgliosis and astrogliosis61; moreover, it enhances neuronal outgrowth and neuronal survival>>62<<. Its expression is highly increased during microglial activation and neuronal maturation. Because GRN gene mutations are pathogenic with respect to the development of frontotemporal dementia spectrum disorders, the relation of progranulin
n2:mentions
n3:18378771
Subject Item
_:vb110513372
rdf:type
n2:Context
rdf:value
However, clinical manifestations of GRN mutations can also extend to AD>>63<<. The possibility of using progranulin as an AD biomarker was recently investigated in a large population of patients with familial and late-onset sporadic AD (Dominant Inherited Alzheimer’s Disease Network and Alzheimer’s Disease
n2:mentions
n3:17826340
Subject Item
_:vb110513373
rdf:type
n2:Context
rdf:value
progranulin as an AD biomarker was recently investigated in a large population of patients with familial and late-onset sporadic AD (Dominant Inherited Alzheimer’s Disease Network and Alzheimer’s Disease Neuroimaging Initiative cohorts)>>64<<. The CSF levels of progranulin were reportedly increased 10 years before the clinical onset of disease in AD mutation carriers.
n2:mentions
n3:30482868
Subject Item
_:vb110513374
rdf:type
n2:Context
rdf:value
In patients with sporadic AD, increased CSF levels of progranulin were evident when neurodegeneration developed>>64<<. Increased levels of progranulin in CSF were also detected in suspected non-AD pathophysiology (SNAP) cases (i.e., normal Aβ biomarkers despite abnormalities in tau or neurodegeneration biomarkers; A−/TN+4)64. However, correlations of CSF
n2:mentions
n3:30482868
Subject Item
_:vb110513375
rdf:type
n2:Context
rdf:value
Increased levels of progranulin in CSF were also detected in suspected non-AD pathophysiology (SNAP) cases (i.e., normal Aβ biomarkers despite abnormalities in tau or neurodegeneration biomarkers; A−/TN+>>4<<)64. However, correlations of CSF progranulin levels with cognitive functions and CSF tau protein levels were present only in patients with AD, not in patients with SNAP64.
n2:mentions
n3:29653606
Subject Item
_:vb110513376
rdf:type
n2:Context
rdf:value
Increased levels of progranulin in CSF were also detected in suspected non-AD pathophysiology (SNAP) cases (i.e., normal Aβ biomarkers despite abnormalities in tau or neurodegeneration biomarkers; A−/TN+4)>>64<<. However, correlations of CSF progranulin levels with cognitive functions and CSF tau protein levels were present only in patients with AD, not in patients with SNAP64.
n2:mentions
n3:30482868
Subject Item
_:vb110513377
rdf:type
n2:Context
rdf:value
However, correlations of CSF progranulin levels with cognitive functions and CSF tau protein levels were present only in patients with AD, not in patients with SNAP>>64<<.
n2:mentions
n3:30482868
Subject Item
_:vb110513378
rdf:type
n2:Context
rdf:value
sTREM2 is an ectodomain of triggering receptor expressed on myeloid cells 2 (TREM2) that is released following proteolytic cleavage by α-secretases, disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and ADAM>>1765<<. TREM2 is expressed on the surface of microglia and is involved in innate immunity through modulation of microglial activity66.
n2:mentions
n3:28855301
Subject Item
_:vb110513379
rdf:type
n2:Context
rdf:value
TREM2 is expressed on the surface of microglia and is involved in innate immunity through modulation of microglial activity>>66<<. Several loss-of-function genetic variants of TREM2 have been shown to increase the risk of AD, including a variant at the His157 site, which affects the rate of release of sTREM2 into the extracellular space65,67. The role of sTREM2 in
n2:mentions
n3:17239445
Subject Item
_:vb110513380
rdf:type
n2:Context
rdf:value
Several loss-of-function genetic variants of TREM2 have been shown to increase the risk of AD, including a variant at the His157 site, which affects the rate of release of sTREM2 into the extracellular space>>65<<,67. The role of sTREM2 in the progression of AD pathogenesis is under active investigation; it is potentially involved in modulating the survival and activity of microglia68,69. The released sTREM2 can be measured in both CSF and blood.
n2:mentions
n3:28855301
Subject Item
_:vb110513381
rdf:type
n2:Context
rdf:value
Several loss-of-function genetic variants of TREM2 have been shown to increase the risk of AD, including a variant at the His157 site, which affects the rate of release of sTREM2 into the extracellular space65,>>67<<. The role of sTREM2 in the progression of AD pathogenesis is under active investigation; it is potentially involved in modulating the survival and activity of microglia68,69. The released sTREM2 can be measured in both CSF and blood. Most
n2:mentions
n3:23150934
Subject Item
_:vb110513382
rdf:type
n2:Context
rdf:value
The role of sTREM2 in the progression of AD pathogenesis is under active investigation; it is potentially involved in modulating the survival and activity of microglia>>68<<,69. The released sTREM2 can be measured in both CSF and blood. Most studies have shown that increased levels of CSF sTREM are indicative of AD; however, a few studies showed no change in these levels in patients with AD (Supplementary
n2:mentions
n3:28209725
Subject Item
_:vb110513383
rdf:type
n2:Context
rdf:value
The role of sTREM2 in the progression of AD pathogenesis is under active investigation; it is potentially involved in modulating the survival and activity of microglia68,>>69<<. The released sTREM2 can be measured in both CSF and blood. Most studies have shown that increased levels of CSF sTREM are indicative of AD; however, a few studies showed no change in these levels in patients with AD (Supplementary Table
n2:mentions
n3:30911003
Subject Item
_:vb110513384
rdf:type
n2:Context
rdf:value
CSF sTREM2 levels were highest at the clinical stage of MCI, compared with other stages of AD>>71<<,72; increases in these levels were most pronounced immediately before the onset of dementia symptoms, when widespread neurodegeneration and synaptic loss were ongoing.
n2:mentions
n3:26941262
Subject Item
_:vb110513385
rdf:type
n2:Context
rdf:value
CSF sTREM2 levels were highest at the clinical stage of MCI, compared with other stages of AD71,>>72<<; increases in these levels were most pronounced immediately before the onset of dementia symptoms, when widespread neurodegeneration and synaptic loss were ongoing.
n2:mentions
n3:30791945
Subject Item
_:vb110513386
rdf:type
n2:Context
rdf:value
Alterations in CSF sTREM2 levels were also identified in patients with other brain disorders, as well as in patients with SNAP>>71<<. Thus, there may not be a specific relationship between sTREM2 and AD. Extensive blood measurements of sTREM2 have rarely been performed; in the few studies involving these measurements, differences based on AD diagnosis were not evident,
n2:mentions
n3:26941262
Subject Item
_:vb110513387
rdf:type
n2:Context
rdf:value
blood measurements of sTREM2 have rarely been performed; in the few studies involving these measurements, differences based on AD diagnosis were not evident, and whether there was a correlation with CSF sTREM2 levels was unclear>>73<<. A recent longitudinal follow-up study in Japan demonstrated that high serum sTREM2 levels were associated with future overall development of dementia, rather than AD or vascular dementia74.
n2:mentions
n3:26754641
Subject Item
_:vb110513388
rdf:type
n2:Context
rdf:value
A recent longitudinal follow-up study in Japan demonstrated that high serum sTREM2 levels were associated with future overall development of dementia, rather than AD or vascular dementia>>74<<. Additional studies with more refined measurement tools are needed to elucidate the precise value of blood sTREM2 levels as a biomarker for AD.
n2:mentions
n3:30485483
Subject Item
_:vb110513389
rdf:type
n2:Context
rdf:value
expression of YKL-40 has mainly been identified in reactive astrocytes in various neurological disorders, including AD, which suggests that YKL-40 is important in the astrocyte response to disease-related environmental conditions>>75<<. Elevated YKL-40 levels in CSF have often been identified and suggested to represent AD-related increased inflammation and astrocytosis in the earlier stages of AD, such as MCI or subclinical disease (Supplementary Table 2).
n2:mentions
n3:20540736
Subject Item
_:vb110513390
rdf:type
n2:Context
rdf:value
The progression of clinical symptoms and brain cortical atrophy are more closely associated with increases in YKL-40 levels>>22<<,76,77. Therefore, increases in YKL-40 are presumably linked to a common pathway that results in neurodegeneration itself, rather than a specific disease process.
n2:mentions
n3:30853464
Subject Item
_:vb110513391
rdf:type
n2:Context
rdf:value
The progression of clinical symptoms and brain cortical atrophy are more closely associated with increases in YKL-40 levels22,>>76<<,77. Therefore, increases in YKL-40 are presumably linked to a common pathway that results in neurodegeneration itself, rather than a specific disease process.
n2:mentions
n3:26827642
Subject Item
_:vb110513392
rdf:type
n2:Context
rdf:value
It is involved in inflammatory processes as a proinflammatory cytokine and modulates the activity of immune cells such as macrophages and microglia>>78<<. Increased CSF osteopontin levels have been reported in patients with AD and MCI compared with healthy controls (Supplementary Table 2). Larger increases in CSF osteopontin may represent disease progression and acute-phase disease79.
n2:mentions
n3:19798593
Subject Item
_:vb110513393
rdf:type
n2:Context
rdf:value
Larger increases in CSF osteopontin may represent disease progression and acute-phase disease>>79<<. However, reports have been contradictory in terms of specificity for AD. Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine72, interleukin-1080, interleukin-1560, lysozyme C45, macrophage
n2:mentions
n3:24347831
Subject Item
_:vb110513394
rdf:type
n2:Context
rdf:value
Levels of various complement proteins>>59<<, including fms-related tyrosine kinase60, fractalkine72, interleukin-1080, interleukin-1560, lysozyme C45, macrophage migration inhibitory factor53 and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:17353378
Subject Item
_:vb110513395
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase>>60<<, fractalkine72, interleukin-1080, interleukin-1560, lysozyme C45, macrophage migration inhibitory factor53 and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:30054439
Subject Item
_:vb110513396
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine>>72<<, interleukin-1080, interleukin-1560, lysozyme C45, macrophage migration inhibitory factor53 and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:30791945
Subject Item
_:vb110513397
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine72, interleukin->>1080<<, interleukin-1560, lysozyme C45, macrophage migration inhibitory factor53 and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:30253800
Subject Item
_:vb110513398
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine72, interleukin-1080, interleukin->>1560<<, lysozyme C45, macrophage migration inhibitory factor53 and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:30054439
Subject Item
_:vb110513399
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine72, interleukin-1080, interleukin-1560, lysozyme C>>45<<, macrophage migration inhibitory factor53 and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:29370833
Subject Item
_:vb110513400
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine72, interleukin-1080, interleukin-1560, lysozyme C45, macrophage migration inhibitory factor>>53<< and monocyte chemoattractant protein 172, are significantly altered in patients with AD.
n2:mentions
n3:26284520
Subject Item
_:vb110513401
rdf:type
n2:Context
rdf:value
Levels of various complement proteins59, including fms-related tyrosine kinase60, fractalkine72, interleukin-1080, interleukin-1560, lysozyme C45, macrophage migration inhibitory factor53 and monocyte chemoattractant protein >>172<<, are significantly altered in patients with AD.
n2:mentions
n3:30791945
Subject Item
_:vb110513402
rdf:type
n6:Section
dc:title
lipid metabolism-related biomarkers
n6:contains
_:vb110513408 _:vb110513409 _:vb110513404 _:vb110513405 _:vb110513406 _:vb110513407 _:vb110513403
Subject Item
_:vb110513403
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Lipid transport is essential for neuronal survival, synaptic activity and immune responses of glial cells in the brain>>81<<. Proteins linked to lipid metabolism have been suggested as candidate AD biomarkers (Table 1 and Supplementary Table 3).
n2:mentions
n3:31367008
Subject Item
_:vb110513404
rdf:type
n2:Context
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in lipid homeostasis through regulation of the production, conversion, and clearance of lipoprotein, as well as in lipid transport via lipidation and subsequent binding to cell-surface receptors (e.g., LDL receptor family members)>>82<<. The presence of ApoE4 isoforms is known to increase AD risk due to the altered physiological function of the ApoE protein in the brain82.
n2:mentions
n3:22393530
Subject Item
_:vb110513405
rdf:type
n2:Context
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The presence of ApoE4 isoforms is known to increase AD risk due to the altered physiological function of the ApoE protein in the brain>>82<<. Measurements of ApoE protein levels in CSF have been performed in relation to the diagnosis of AD; notably, contradictory results have been demonstrated (Supplementary Table 3). ApoE protein levels have been suggested for use in the
n2:mentions
n3:22393530
Subject Item
_:vb110513406
rdf:type
n2:Context
rdf:value
FABP3 is released from myocytes during the early stages of myocardial infarction; thus, blood levels of FABP3 constitute a useful biomarker for early diagnosis of heart attack>>83<<. In patients with AD, FABP3 levels in CSF have been reported to increase as early as the MCI stage (Supplementary Table 3). Higher baseline levels of FABP3 in patients with MCI could predict conversion to AD during follow-up84. FABP3
n2:mentions
n3:21208763
Subject Item
_:vb110513407
rdf:type
n2:Context
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Higher baseline levels of FABP3 in patients with MCI could predict conversion to AD during follow-up>>84<<. FABP3 levels exhibit a weak ability to discriminate AD from other brain disorders involving dementia. However, consideration of pTau181 CSF levels in combination with FABP3 levels has been shown to increase the accuracy of
n2:mentions
n3:23254629
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_:vb110513408
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However, consideration of pTau181 CSF levels in combination with FABP3 levels has been shown to increase the accuracy of differentiating AD from Lewy body dementia>>85<<.
n2:mentions
n3:28750675
Subject Item
_:vb110513409
rdf:type
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pyrophosphatase/phosphodiesterase family member 2 [also known as autotaxin], prosaposin, and vitamin D-binding protein) were reportedly increased in the CSF of patients with AD and have been suggested as possible biomarkers in AD>>86<<.
n2:mentions
n3:26627638
Subject Item
_:vb110513410
rdf:type
n6:Section
dc:title
biomarkers related to the clearance of neurotoxic proteins
n6:contains
_:vb110513416 _:vb110513417 _:vb110513418 _:vb110513419 _:vb110513412 _:vb110513413 _:vb110513414 _:vb110513415 _:vb110513411
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Clusterin is a secretory glycoprotein, is mainly produced by astrocytes in the brain>>87<<, and serves as a molecular chaperone; it binds to partially unfolded proteins, thereby preventing their aggregation88.
n2:mentions
n3:21212797
Subject Item
_:vb110513412
rdf:type
n2:Context
rdf:value
Clusterin is a secretory glycoprotein, is mainly produced by astrocytes in the brain87, and serves as a molecular chaperone; it binds to partially unfolded proteins, thereby preventing their aggregation>>88<<. Clusterin also has a neuronal differentiation-promoting effect and neuroprotective properties87. Missense and small deletion polymorphisms in the clusterin gene increase the risk of AD24; these findings suggest that it plays a role in AD
n2:mentions
n3:17407782
Subject Item
_:vb110513413
rdf:type
n2:Context
rdf:value
Clusterin also has a neuronal differentiation-promoting effect and neuroprotective properties>>87<<. Missense and small deletion polymorphisms in the clusterin gene increase the risk of AD24; these findings suggest that it plays a role in AD pathology. In CSF, levels of clusterin were reported to increase in patients with AD and Lewy
n2:mentions
n3:21212797
Subject Item
_:vb110513414
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n2:Context
rdf:value
Missense and small deletion polymorphisms in the clusterin gene increase the risk of AD>>24<<; these findings suggest that it plays a role in AD pathology.
n2:mentions
n3:27302364
Subject Item
_:vb110513415
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n2:Context
rdf:value
Orexin is a neuropeptide that regulates circadian rhythm and related physiological homeostasis>>89<<. Its reduction in CSF is a well-established biomarker for narcolepsy. In relation to AD, altered levels of orexin in CSF have generally been reported to increase, with a few exceptions (Supplementary Table 4).
n2:mentions
n3:16251950
Subject Item
_:vb110513416
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n2:Context
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Furthermore, infusion of orexin from patients with AD led to increased Aβ production and amyloid deposition in human AβPP transgenic mice carrying the Swedish mutation, which suggested that it has a pathophysiological role in AD>>90<<.
n2:mentions
n3:19779148
Subject Item
_:vb110513417
rdf:type
n2:Context
rdf:value
Transthyretin is an Aβ-binding molecule that has been reported to inhibit Aβ aggregation, thereby reducing Aβ-induced cellular toxicity>>91<<. It has been reported to increase or remain stable in CSF, whereas it has been reported to decrease in blood and in patients with AD who exhibited rapid and severe cognitive decline (Supplementary Table 4).
n2:mentions
n3:18295603
Subject Item
_:vb110513418
rdf:type
n2:Context
rdf:value
LAMP-1, ubiquitin, ubiquitin carboxyl-terminal esterase L1, carboxypeptidase E, carnosine dipeptidase 1, and ectonucleotide pyrophosphatase/phosphodiesterase were found to be higher in the CSF of patients with AD than in that of controls>>86<<. Matrix metalloproteinase proteins are potentially altered in the CSF of patients with AD56.
n2:mentions
n3:26627638
Subject Item
_:vb110513419
rdf:type
n2:Context
rdf:value
Matrix metalloproteinase proteins are potentially altered in the CSF of patients with AD>>56<<.
n2:mentions
n3:21860087
Subject Item
_:vb110513420
rdf:type
n6:Section
dc:title
the combinations of new biomarkers
n6:contains
_:vb110513428 _:vb110513429 _:vb110513430 _:vb110513431 _:vb110513424 _:vb110513425 _:vb110513426 _:vb110513427 _:vb110513436 _:vb110513437 _:vb110513438 _:vb110513432 _:vb110513433 _:vb110513434 _:vb110513435 _:vb110513421 _:vb110513422 _:vb110513423
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The simultaneous consideration of new biomarkers is beneficial in concurrent assessment of various aspects of AD pathophysiology, thereby correctly estimating disease status>>92<<. There have been multiple recent investigations to establish reliable and useful combinations of CSF biomarkers (Table 2).
n2:mentions
n3:30770953
Subject Item
_:vb110513422
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n2:Context
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of neurodegeneration and inflammation markers, neurogranin and YKL-40, improved the accuracy of differential diagnosis of AD from non-AD dementia, achieving an area under the receiver operating characteristic curve of 85%>>93<<. The co-consideration of neurogranin and NFL levels (neurogranin represents synaptic damage while NFL reflects axonal damage) demonstrated improved diagnostic accuracy of AD relative to that of each marker alone20; both proteins showed
n2:mentions
n3:26698298
Subject Item
_:vb110513423
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n2:Context
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The co-consideration of neurogranin and NFL levels (neurogranin represents synaptic damage while NFL reflects axonal damage) demonstrated improved diagnostic accuracy of AD relative to that of each marker alone>>20<<; both proteins showed significant predictive associations with cognitive decline and brain atrophy.
n2:mentions
n3:27534871
Subject Item
_:vb110513424
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associated with cognitive decline and brain atrophy in all patients, regardless of amyloid pathology, while neurogranin levels were significantly associated with cognitive decline and brain atrophy only in patients with amyloid pathology>>20<<. When both biomarkers were compared directly, NFL levels were superior to neurogranin as a prognostic biomarker in MCI patients with positive Aβ biomarker results94 and in normal elderly individuals (mean age, 59.3 ± 6.3 years)95.
n2:mentions
n3:27534871
Subject Item
_:vb110513425
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When both biomarkers were compared directly, NFL levels were superior to neurogranin as a prognostic biomarker in MCI patients with positive Aβ biomarker results>>94<< and in normal elderly individuals (mean age, 59.3 ± 6.3 years)95.
n2:mentions
n3:30419087
Subject Item
_:vb110513426
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CombinationFindingsCSF neurogranin, YKL->>4093<<
n2:mentions
n3:26698298
Subject Item
_:vb110513427
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n2:Context
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+ CSF Aβ42, pTau181, tTau levels>>53<<
n2:mentions
n3:26284520
Subject Item
_:vb110513428
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n2:Context
rdf:value
+ CSF tTau levels>>20<<
n2:mentions
n3:27534871
Subject Item
_:vb110513429
rdf:type
n2:Context
rdf:value
CSF FABP-3, IL-10, NFL>>80<<
n2:mentions
n3:30253800
Subject Item
_:vb110513430
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n2:Context
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CSF neurogranin, NFL>>94<<▪ NFL: highest accuracy in prediction of MCI conversion to AD compared to neurogranin, Aβ42, pTau181, and tTau levels, on >1 yr FUCSF neurogranin, SNAP-25, VILIP-1,
n2:mentions
n3:30419087
Subject Item
_:vb110513431
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n2:Context
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CSF neurogranin, NFL94▪ NFL: highest accuracy in prediction of MCI conversion to AD compared to neurogranin, Aβ42, pTau181, and tTau levels, on >1 yr FUCSF neurogranin, SNAP-25, VILIP-1, YKL->>409<<
n2:mentions
n3:29580670
Subject Item
_:vb110513432
rdf:type
n2:Context
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CSF neurogranin, NFL94▪ NFL: highest accuracy in prediction of MCI conversion to AD compared to neurogranin, Aβ42, pTau181, and tTau levels, on >1 yr FUCSF neurogranin, SNAP-25, VILIP-1, YKL-409,>>98<<
n2:mentions
n3:30846386
Subject Item
_:vb110513433
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▪ NFL: stronger correlation with cognitive decline at FU than neurogranin and tTau levelsCSF clusterin, fractalkine, MCP-1, sTREM2, YKL->>4071<<
n2:mentions
n3:26941262
Subject Item
_:vb110513434
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+ CSF tTau>>22<<
n2:mentions
n3:30853464
Subject Item
_:vb110513435
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n2:Context
rdf:value
synaptic degeneration markers (e.g., neurogranin, synaptosomal-associated protein 25, and VILIP-1) with the inflammation marker YKL-40 revealed a remarkable and differential longitudinal change across the clinical spectrum of AD patients>>9<<. This finding suggests that specific biomarkers become more useful at particular disease stages9,72,80.
n2:mentions
n3:29580670
Subject Item
_:vb110513436
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This finding suggests that specific biomarkers become more useful at particular disease stages>>9<<,72,80. Therefore, synaptic, axonal, and inflammation-related biomarkers are complementary to each other in terms of staging AD and predicting clinical progression, in addition to representing different aspects of AD-related brain
n2:mentions
n3:29580670
Subject Item
_:vb110513437
rdf:type
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This finding suggests that specific biomarkers become more useful at particular disease stages9,>>72<<,80. Therefore, synaptic, axonal, and inflammation-related biomarkers are complementary to each other in terms of staging AD and predicting clinical progression, in addition to representing different aspects of AD-related brain pathology.
n2:mentions
n3:30791945
Subject Item
_:vb110513438
rdf:type
n2:Context
rdf:value
This finding suggests that specific biomarkers become more useful at particular disease stages9,72,>>80<<. Therefore, synaptic, axonal, and inflammation-related biomarkers are complementary to each other in terms of staging AD and predicting clinical progression, in addition to representing different aspects of AD-related brain pathology.
n2:mentions
n3:30253800
Subject Item
_:vb110513439
rdf:type
n6:Section
dc:title
perspective on the utility of new biomarkers
n6:contains
_:vb110513448 _:vb110513449 _:vb110513440 _:vb110513441 _:vb110513442 _:vb110513443 _:vb110513444 _:vb110513445 _:vb110513446 _:vb110513447
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_:vb110513440
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The staging of AD has mainly relied on clinical data, cognitive impairment, and activities of daily living, which can divide AD into the following stages: preclinical AD, MCI due to AD (or prodromal AD), and AD dementia>>2<<,3. Recently, the A/T/N system has provided more precise AD staging based on AD-related pathological processes, i.e., the deposition of Aβ (A) and abnormal tau (T) proteins and neurodegeneration (N)4.
n2:mentions
n3:21514250
Subject Item
_:vb110513441
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The staging of AD has mainly relied on clinical data, cognitive impairment, and activities of daily living, which can divide AD into the following stages: preclinical AD, MCI due to AD (or prodromal AD), and AD dementia2,>>3<<. Recently, the A/T/N system has provided more precise AD staging based on AD-related pathological processes, i.e., the deposition of Aβ (A) and abnormal tau (T) proteins and neurodegeneration (N)4.
n2:mentions
n3:24849862
Subject Item
_:vb110513442
rdf:type
n2:Context
rdf:value
Recently, the A/T/N system has provided more precise AD staging based on AD-related pathological processes, i.e., the deposition of Aβ (A) and abnormal tau (T) proteins and neurodegeneration (N)>>4<<. For clinical application of the A/T/N system, sufficient evidence supporting the utility of CSF and neuroimaging biomarkers is needed, including CSF Aβ42, the CSF Aβ42/Aβ40 ratio and amyloid PET for A; CSF pTau and Tau PET for T; and
n2:mentions
n3:29653606
Subject Item
_:vb110513443
rdf:type
n2:Context
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supporting the utility of CSF and neuroimaging biomarkers is needed, including CSF Aβ42, the CSF Aβ42/Aβ40 ratio and amyloid PET for A; CSF pTau and Tau PET for T; and structural MRI, fluorodeoxyglucose PET and CSF tTau levels for N>>4<<. Since its introduction, new biomarkers to support the A/T/N system have been required4.
n2:mentions
n3:29653606
Subject Item
_:vb110513444
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Since its introduction, new biomarkers to support the A/T/N system have been required>>4<<. For N, which relies on CSF tTau levels (which can be affected by tau pathology), the identification of new biomarkers of neurodegeneration, such as CSF NFL and neurogranin levels, may now be imminent. In many studies, CSF NFL better
n2:mentions
n3:29653606
Subject Item
_:vb110513445
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n2:Context
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In many studies, CSF NFL better reflected clinical severity and predicted future cognitive decline more accurately than Aβ and tau proteins>>22<<,94,95. Therefore, CSF NFL could improve our ability to track disease progression.
n2:mentions
n3:30853464
Subject Item
_:vb110513446
rdf:type
n2:Context
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In many studies, CSF NFL better reflected clinical severity and predicted future cognitive decline more accurately than Aβ and tau proteins22,>>94<<,95. Therefore, CSF NFL could improve our ability to track disease progression.
n2:mentions
n3:30419087
Subject Item
_:vb110513447
rdf:type
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neuroinflammation, lipid dysmetabolism and disturbed protein clearance) would be helpful for predicting the progression of individual facets of the pathology and for understanding their relative contributions to clinical deterioration>>96<<. A comprehensive understanding of disease status will aid in the selection of patients who are most likely to have a favorable response to specific disease-modifying therapies.
n2:mentions
n3:30488277
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_:vb110513448
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Since other brain disorders commonly cooccur with AD>>7<<, considering both disease-specific and more general biomarkers of pathology may increase the likelihood of realizing efficient disease-modifying therapeutics.
n2:mentions
n3:23034521
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_:vb110513449
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Lumbar puncture, which is necessary to obtain CSF, is generally safe and well tolerated; however, it is time consuming and sometimes results in postpuncture headache and other side effects>>97<<. There are increasing efforts to develop easily assessable fluid biomarkers (e.g., from peripheral sources). Specifically, blood levels of NFL have shown strong evidence of usefulness, as described above, which are well correlated with
n2:mentions
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