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INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.
Subject(s)
Alzheimer Disease , Atrophy , Biomarkers , Brain , Frontotemporal Lobar Degeneration , Magnetic Resonance Imaging , Neurofilament Proteins , Progranulins , tau Proteins , Humans , Biomarkers/cerebrospinal fluid , Biomarkers/blood , Frontotemporal Lobar Degeneration/pathology , Male , Female , Atrophy/pathology , Aged , Middle Aged , Neurofilament Proteins/cerebrospinal fluid , Neurofilament Proteins/blood , tau Proteins/cerebrospinal fluid , Brain/pathology , Brain/diagnostic imaging , Alzheimer Disease/pathology , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluidABSTRACT
BACKGROUND: Biomarkers of neuronal, glial cells and inflammation in traumatic brain injury (TBI) are available but they do not specifically reflect the damage to synapses, which represent the bulk volume of the brain. Experimental models have demonstrated extensive involvement of synapses in acute TBI, but biomarkers of synaptic damage in human patients have not been explored. METHODS: Single-molecule array assays were used to measure synaptosomal-associated protein-25 (SNAP-25) and visinin-like protein 1 (VILIP-1) (along with neurofilament light chain (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillar acidic protein (GFAP), interleukin-6 (IL-6) and interleukin-8 (IL-8)) in ventricular cerebrospinal fluid (CSF) samples longitudinally acquired during the intensive care unit (ICU) stay of 42 patients with severe TBI or 22 uninjured controls. RESULTS: CSF levels of SNAP-25 and VILIP-1 are strongly elevated early after severe TBI and decline in the first few days. SNAP-25 and VILIP-1 correlate with inflammatory markers at two distinct timepoints (around D1 and then again at D5) in follow-up. SNAP-25 and VILIP-1 on the day-of-injury have better sensitivity and specificity for unfavourable outcome at 6 months than NFL, UCH-L1 or GFAP. Later elevation of SNAP-25 was associated with poorer outcome. CONCLUSION: Synaptic damage markers are acutely elevated in severe TBI and predict long-term outcomes, as well as, or better than, markers of neuroaxonal injury. Synaptic damage correlates with initial injury and with a later phase of secondary inflammatory injury.
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BACKGROUND: VGF and neuroserpin are neurosecretory proteins involved in the pathophysiology of neurodegenerative diseases. We aimed to evaluate their cerebrospinal fluid (CSF) concentrations in patients with Alzheimer's disease (AD) and Lewy body disease (LBD). METHODS: We measured CSF VGF [AQEE] peptide and neuroserpin levels in 108 LBD patients, 76 AD patients and 37 controls, and tested their associations with clinical scores and CSF AD markers. RESULTS: We found decreased CSF levels of VGF [AQEE] in patients with LBD and dementia compared to controls (p = 0.016) and patients with AD-dementia (p = 0.011), but with significant influence of age and sex distribution. Moreover, we observed, on the one hand, a significant associations between lower VGF [AQEE] and neuroserpin levels and poorer cognitive performance (i.e., lower Mini-Mental State Examination scores). On the other hand, higher levels of CSF tau proteins, especially pTau181, were significantly associated with higher concentrations of VGF [AQEE] and neuroserpin. Indeed, LBD patients with AD-like CSF profiles, especially T+ profiles, had higher levels of VGF [AQEE] and neuroserpin compared to controls and LBD/T- cases. DISCUSSION: CSF VGF [AQEE] and neuroserpin may show a complex relationship with cognitive decline when the levels are reduced, and with AD pathology when levels are increased. They may represent novel markers of neurosecretory impairment in neurodegenerative disorders.
Subject(s)
Alzheimer Disease , Biomarkers , Lewy Body Disease , Neuropeptides , Neuroserpin , Serpins , Humans , Female , Male , Aged , Alzheimer Disease/cerebrospinal fluid , Lewy Body Disease/cerebrospinal fluid , Neuropeptides/cerebrospinal fluid , Serpins/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged, 80 and over , Middle Aged , Nerve Growth Factors/cerebrospinal fluidSubject(s)
Heart Failure , tau Proteins , Humans , tau Proteins/blood , Heart Failure/blood , Phosphorylation , Male , Female , Chronic Disease , Aged , Biomarkers/blood , Middle AgedABSTRACT
OBJECTIVES: Increased levels of glial fibrillary acidic protein (GFAP) in blood have been identified as a valuable biomarker for some neurological disorders, such as Alzheimer's disease and multiple sclerosis. However, most blood GFAP quantifications so far were performed using the same bead-based assay, and to date a routine clinical application is lacking. METHODS: In this study, we validated a novel second-generation (2nd gen) Ella assay to quantify serum GFAP. Furthermore, we compared its performance with a bead-based single molecule array (Simoa) and a homemade GFAP assay in a clinical cohort of neurological diseases, including 210 patients. RESULTS: Validation experiments resulted in an intra-assay variation of 10â¯%, an inter-assay of 12â¯%, a limit of detection of 0.9â¯pg/mL, a lower limit of quantification of 2.8â¯pg/mL, and less than 20â¯% variation in serum samples exposed to up to five freeze-thaw cycles, 120â¯h at 4⯰C and room temperature. Measurement of the clinical cohort using all assays revealed the same pattern of GFAP distribution in the different diagnostic groups. Moreover, we observed a strong correlation between the 2nd gen Ella and Simoa (r=0.91 (95â¯% CI: 0.88-0.93), p<0.0001) and the homemade immunoassay (r=0.77 (95â¯% CI: 0.70-0.82), p<0.0001). CONCLUSIONS: Our results demonstrate a high reliability, precision and reproducibility of the 2nd gen Ella assay. Although a higher assay sensitivity for Simoa was observed, the new microfluidic assay might have the potential to be used for GFAP analysis in daily clinical workups due to its robustness and ease of use.
Subject(s)
Glial Fibrillary Acidic Protein , Glial Fibrillary Acidic Protein/blood , Humans , Female , Male , Middle Aged , Aged , Microfluidic Analytical Techniques , Limit of Detection , Biomarkers/blood , Reproducibility of Results , Immunoassay/methodsABSTRACT
INTRODUCTION: Blood-based biomarkers may improve prediction of functional outcome in patients with acute ischemic stroke. The role of neurofilament light chain (NfL) and glial fibrillary acidic (GFAP) as potential biomarkers especially in severe stroke patients is unknown. PATIENTS AND METHODS: Prospective, monocenter, cohort study including consecutive patients with severe ischemic stroke in the anterior circulation on admission (NIHSS score ⩾ 6 points or indication for mechanical thrombectomy). Outcome was assessed 3 months after the index stroke by the modified Rankin Scale (mRS). Serum biomarkers levels of NfL and GFAP were determined by ultrasensitive ELISA. Univariate and multivariate logistic regression models were performed to determine the association of biomarker levels and functional disability. Discrimination, calibration, and overall performance were analyzed in different models via AUROC, calibration plots (with Emax and Eavg), Brier-score and R2 using variables, identified as important covariates for functional outcome in previous studies. RESULTS: Between 06/2020 and 08/2021, 213 patients were included [47% female, mean age 76 (SD ± 12) years, median NIHSS score 13 (interquartile range, IQR 9; 17)]. Biomarker serum levels were measured at a median of 1 [IQR, 1; 2] day after admission. Compared to patients with mRS 0-2 at 3 months, patients with mRS 3-6 had higher serum levels of NfL (median: 136 pg/ml vs 41 pg/ml; p < 0.0001) and GFAP (700 ng/ml vs 9.6 ng/ml; p < 0.0001). Both biomarkers were significantly associated with functional outcome [adjusted logistic regression, odds ratio (95% CI) for NfL: 2.63 (1.62; 4.56), GFAP: 2.16 (1.58; 3.09)]. In all models the addition of serum NfL led to a significant improvement in the AUROC, as did the addition of serum GFAP. Calibration plots showed high agreement between the predicted and observed outcomes and after addition of the two blood-based biomarkers there was an improvement of the overall performance. CONCLUSION: Prediction of functional outcome after severe acute ischemic stroke was improved by the blood-based biomarkers serum NfL and GFAP, measured in the acute phase of stroke. These findings have to be replicated in independent external cohorts.Study registration: DRKS00022064.
Subject(s)
Biomarkers , Glial Fibrillary Acidic Protein , Ischemic Stroke , Neurofilament Proteins , Humans , Glial Fibrillary Acidic Protein/blood , Female , Male , Neurofilament Proteins/blood , Biomarkers/blood , Aged , Ischemic Stroke/blood , Ischemic Stroke/diagnosis , Ischemic Stroke/therapy , Prospective Studies , Aged, 80 and over , Middle Aged , Prognosis , Severity of Illness IndexABSTRACT
We aimed to assess the prognostic value of serum ß-synuclein (ß-syn), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with moderate-to-severe acute ischemic stroke. We measured ß-syn, GFAP and NfL in serum samples collected one day after admission in 30 adult patients with moderate-to-severe ischemic stroke due to middle cerebral artery (MCA) occlusion. We tested the associations between biomarker levels and clinical and radiological scores (National Institute of Health Stroke Scale scores, NIHSS, and Alberta Stroke Program Early CT Score, ASPECTS), as well as measures of functional outcome (modified Rankin Scale, mRS). Serum biomarkers were significantly associated with ASPECTS values (ß-syn p = 0.0011, GFAP p = 0.0002) but not with NIHSS scores at admission. Patients who received mechanical thrombectomy and intravenous thrombolysis showed lower ß-syn (p = 0.029) und NfL concentrations (p = 0.0024) compared to patients who received only mechanical thrombectomy. According to median biomarker levels, patients with high ß-syn, NfL or GFAP levels showed, after therapy, lower clinical improvement (i.e., lower 24-h NIHSS change), higher NIHSS scores during hospitalization and higher mRS scores at 3-month follow-up. Elevated serum concentrations of ß-syn (p = 0.016), NfL (p = 0.020) or GFAP (p = 0.010) were significantly associated with 3-month mRS of 3-6 vs. 0-2 even after accounting for age, sex and renal function. In patients with moderate-to-severe acute ischemic stroke, serum ß-syn, NfL and GFAP levels associated with clinical and radiological scores at different timepoints and were able to predict short- and middle-term clinical outcomes.
Subject(s)
Ischemic Stroke , Stroke , Adult , Humans , beta-Synuclein , Biomarkers , Glial Fibrillary Acidic Protein , Infarction, Middle Cerebral Artery , Intermediate Filaments , Neurofilament Proteins , Prognosis , Stroke/therapyABSTRACT
We analyzed the longitudinal concentrations and prognostic roles of plasma ß-synuclein (ß-syn), glial fibrillary acidic protein (GFAP), and neurofilament proteins (NfL and NfH) in 33 patients with malignant gliomas, who underwent surgical and adjuvant therapy. GFAP and NfL levels were increased in patients with glioblastoma compared to cases with other tumors. ß-syn, NfL and NfH increased after surgery, whereas GFAP decreased at long-term follow-up. ß-syn and neurofilament concentrations were influenced by surgery and/or radiotherapy regimens. GFAP and neurofilament levels were significantly associated with survival. Plasma neuronal and astrocytic biomarkers are differentially altered in malignant glioma types and displayed distinct trajectories after surgical and adjuvant therapy.
Subject(s)
Glioma , Intermediate Filaments , Humans , Glial Fibrillary Acidic Protein , Intermediate Filaments/metabolism , beta-Synuclein , Biomarkers , Glioma/surgeryABSTRACT
Beta-synuclein is a promising cerebrospinal fluid and blood biomarker of synaptic damage. Here we analysed its accuracy in the discrimination between sporadic Creutzfeldt-Jakob disease (n = 150) and non-prion rapidly progressive dementias (n = 106). In cerebrospinal fluid, beta-synuclein performed better than protein 14-3-3 (AUC 0.95 vs. 0.89) and, to a lesser extent, than total tau (AUC 0.92). Further, the diagnostic value of plasma beta-synuclein (AUC 0.91) outperformed that of plasma tau (AUC 0.79) and neurofilament light chain protein (AUC 0.65) and was comparable to that of cerebrospinal fluid biomarkers. Beta-synuclein might represent the first highly accurate blood biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease.
Subject(s)
Creutzfeldt-Jakob Syndrome , Humans , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , beta-Synuclein , 14-3-3 Proteins/cerebrospinal fluid , Biomarkers/cerebrospinal fluidABSTRACT
BACKGROUND AND OBJECTIVES: Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer disease (AD) pathology. CSF biomarkers allow the detection in vivo of AD-related pathologic hallmarks included in the amyloid-tau-neurodegeneration (AT(N)) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuroaxonal damage are correlated with the presence of AD copathology in LBD and can be useful to differentiate patients with LBD with different AT(N) profiles. METHODS: We retrospectively measured CSF levels of AD core biomarkers (Aß42/40 ratio, phosphorylated tau protein, and total tau protein) and of synaptic (ß-synuclein, α-synuclein, synaptosomal-associated protein 25 [SNAP-25], and neurogranin) and neuroaxonal proteins (neurofilament light chain [NfL]) in 28 cognitively unimpaired participants with nondegenerative neurologic conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups. RESULTS: CSF ß-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL levels did not differ between LBD (n = 101, age 67.2 ± 7.8 years, 27.7% females) and controls (age 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI: n = 30, AD-dem: n = 30, age 72.3 ± 6.0 years, 63.3% females) compared with both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuroaxonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and ß-synuclein showed the highest discriminative accuracy between the 2 groups (area under the curve 0.938, 95% CI 0.884-0.991). CSF ß-synuclein (p = 0.0021), α-synuclein (p = 0.0099), and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarker levels within the normal range. CSF α-synuclein was significantly decreased only in patients with LBD with T- profiles compared with controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level. DISCUSSION: LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuroaxonal biomarkers compared with LBD/A-T- and control subjects. Patients with LBD and AT(N)-based AD copathology showed, thus, a distinct signature of synaptic dysfunction from other LBD cases. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CSF levels of ß-synuclein, α-synuclein, SNAP-25, neurogranin, and NfL are higher in patients with AD than in patients with LBD.
Subject(s)
Alzheimer Disease , Lewy Body Disease , Female , Humans , Middle Aged , Aged , Male , tau Proteins , alpha-Synuclein , beta-Synuclein , Retrospective Studies , Neurogranin , Alzheimer Disease/pathology , Biomarkers , Amyloid beta-PeptidesABSTRACT
INTRODUCTION: ß-Synuclein is an emerging synaptic blood biomarker for Alzheimer's disease (AD) but differences in ß-synuclein levels in preclinical AD and its association with amyloid and tau pathology have not yet been studied. METHODS: We measured plasma ß-synuclein levels in cognitively unimpaired individuals with positive Aß-PET (i.e., preclinical AD, N = 48) or negative Aß-PET (N = 61), Aß-positive patients with mild cognitive impairment (MCI, N = 36), and Aß-positive AD dementia (N = 85). Amyloid (A) and tau (T) pathology were assessed by [18 F]flutemetamol and [18 F]RO948 PET. RESULTS: Plasma ß-synuclein levels were higher in preclinical AD and even higher in MCI and AD dementia. Stratification according to amyloid/tau pathology revealed higher ß-synuclein in A+ T- and A+ T+ subjects compared with A- T- . Plasma ß-synuclein levels were related to tau and Aß pathology and associated with temporal cortical thinning and cognitive impairment. DISCUSSION: Our data indicate that plasma ß-synuclein might track synaptic dysfunction, even during the preclinical stages of AD. HIGHLIGHTS: Plasma ß-synuclein is already higher in preclinical AD. Plasma ß-synuclein is higher in MCI and AD dementia than in preclinical AD. Aß- and tau-PET SUVRs are associated with plasma ß-synuclein levels. Plasma ß-synuclein is already higher in tau-PET negative subjects. Plasma ß-synuclein is related to temporal cortical atrophy and cognitive impairment.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/pathology , tau Proteins , Amyloid beta-Peptides , beta-Synuclein , Cognitive Dysfunction/pathology , Biomarkers , Amyloid , Amyloidogenic Proteins , Positron-Emission TomographyABSTRACT
INTRODUCTION: ß-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-ß (Αß) pathology is unclear. METHODS: We investigated the association of plasma ß-synuclein levels with [18F] flutemetamol positron emission tomography (PET) in patients with AD dementia (n = 51), mild cognitive impairment (MCI-Aß+ n = 18, MCI- Aß- n = 30), non-AD dementias (n = 22), and non-demented controls (n = 5). RESULTS: Plasma ß-synuclein levels were higher in Aß+ (AD dementia, MCI-Aß+) than in Aß- subjects (non-AD dementias, MCI-Aß-) with good discrimination of Aß+ from Aß- subjects and prediction of Aß status in MCI individuals. A positive correlation between plasma ß-synuclein and Aß PET was observed in multiple cortical regions across all lobes. DISCUSSION: Plasma ß-synuclein demonstrated discriminative properties for Aß PET positive and negative subjects. Our data underline that ß-synuclein is not a direct marker of Aß pathology and suggest different longitudinal dynamics of synaptic degeneration versus amyloid deposition across the AD continuum. HIGHLIGHTS: Blood and CSF ß-synuclein levels are higher in Aß+ than in Aß- subjects. Blood ß-synuclein level correlates with amyloid PET positivity in multiple regions. Blood ß-synuclein predicts Aß status in MCI individuals.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , beta-Synuclein , Brain/pathology , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Positron-Emission Tomography/methods , Amyloid beta-Peptides/metabolism , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , BiomarkersABSTRACT
INTRODUCTION: ß-synuclein (ß-syn) is a presynaptic protein, whose cerebrospinal fluid (CSF) levels are increased in patients with Alzheimer's diseases (AD) showing mild cognitive impairment (MCI) and dementia (dem). Here, we aimed to investigate CSF ß-syn in subjects at different AD stages, including preclinical AD (pre-AD), and to compare its behaviour with another synaptic biomarker, α-synuclein (α-syn), and two biomarkers of neuro-axonal damage, namely neurofilament light chain protein (NfL) and total tau protein (t-tau). METHODS: We measured ß-syn, α-syn, t-tau and NfL in CSF of 75 patients with AD (pre-AD n=17, MCI-AD n=28, dem-AD n=30) and 35 controls (subjective memory complaints, SMC-Ctrl n=13, non-degenerative neurological disorders, Dis-Ctrl n=22). RESULTS: CSF ß-syn, α-syn, t-tau were significantly elevated in pre-AD patients compared with controls (p<0.0001, p=0.02 and p=0.0001, respectively), while NfL only increased in dem-AD (p=0.001). Pre-AD cases showed lower t-tau concentrations than MCI-AD (p=0.04) and dem-AD (p=0.01). CSF ß-syn had the best diagnostic performance for the discrimination of pre-AD subjects from all controls (area under the curve, AUC=0.97) and from SMC-Ctrl subjects (AUC=0.99). DISCUSSION: CSF ß-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/cerebrospinal fluid , beta-Synuclein , tau Proteins/cerebrospinal fluid , Cognitive Dysfunction/psychology , Biomarkers/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluidABSTRACT
BACKGROUND: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). METHODS: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. RESULTS: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. DISCUSSION: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. HIGHLIGHTS: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).
Subject(s)
Alzheimer Disease , Frontotemporal Dementia , Frontotemporal Lobar Degeneration , Humans , Alzheimer Disease/pathology , beta-Synuclein , tau Proteins , Frontotemporal Lobar Degeneration/pathology , Brain/pathology , Biomarkers , Atrophy/pathology , Amyloid beta-PeptidesABSTRACT
Psychiatric disorders are widely underreported diseases, especially in their early stages. So far, there is no fluid biomarker to confirm the diagnosis of these disorders. Proteomics data suggest the synaptic protein glutamate receptor 4 (GluR4), part of the AMPA receptor, as a potential diagnostic biomarker of major depressive disorder (MDD). A novel sandwich ELISA was established and analytically validated to detect GluR4 in cerebrospinal fluid (CSF) samples. A total of 85 subjects diagnosed with MDD (n = 36), bipolar disorder (BD, n = 12), schizophrenia (SCZ, n = 12) and neurological controls (CON, n = 25) were analysed. The data exhibited a significant correlation (r = 0.74; CI:0.62 to 0.82; p < 0.0001) with the antibody-free multiple reaction monitoring (MRM) mass spectrometry (MS) data. CSF GluR4 levels were lower in MDD (p < 0.002) and BD (p = 0.012) than in CON. Moreover, subjects with SCZ described a trend towards lower levels than CON (p = 0.13). The novel GluR4 ELISA may favour the clinical application of this protein as a potential diagnostic biomarker of psychiatric disorders and may facilitate the understanding of the pathophysiological mechanisms behind these disorders.
Subject(s)
Depressive Disorder, Major , Humans , Depressive Disorder, Major/diagnosis , Proteomics , Receptors, GlutamateABSTRACT
BACKGROUND: Visinin-like protein 1 (VILIP-1) belongs to the group of emerging biomarkers with the potential to support the early diagnosis of Alzheimer's disease (AD). However, studies investigating the differential diagnostic potential in cerebrospinal fluid (CSF) are rare and are not available for blood. METHODS: We set up a novel, sensitive single molecule array (Simoa) assay for the detection of VILIP-1 in CSF and serum. In total, paired CSF and serum samples from 234 patients were investigated: 73 AD, 18 behavioral variant frontotemporal dementia (bvFTD), 26 parkinsonian syndromes, 20 amyotrophic lateral sclerosis (ALS), 22 Creutzfeldt-Jakob disease (CJD), and 75 non-neurodegenerative control (Con) patients. The differential diagnostic potential of CSF and serum VILIP-1 was assessed using the receiver operating characteristic curve analysis and findings were compared to core AD biomarkers. RESULTS: CSF and serum VILIP-1 levels correlated weakly (r=0.32 (CI: 0.20-0.43), p<0.0001). VILIP-1 concentrations in CSF and serum were elevated in AD compared to Con (p<0.0001 and p<0.01) and CJD (p<0.0001 for CSF and serum), and an increase in CSF was observed already in early AD stages (p<0.0001). In the discrimination of AD versus Con, we could demonstrate a strong diagnostic potential for CSF VILIP-1 alone (area under the curve (AUC): 0.87), CSF VILIP-1/CSF Abeta 1-42 (AUC: 0.98), and serum VILIP-1/CSF Abeta 1-42 ratio (AUC: 0.89). CONCLUSIONS: We here report on the successful establishment of a novel Simoa assay for VILIP-1 and illustrate the potential of CSF and serum VILIP-1 in the differential diagnosis of AD with highest levels in CJD.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Humans , Neurocalcin/cerebrospinal fluid , Alzheimer Disease/diagnosis , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluidABSTRACT
BACKGROUND: Chronic heart failure (HF) is known to increase the risk of developing Alzheimer's dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. METHODS: Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). RESULTS: Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = - 0.21; p = 0.013) and pTau (ρ = - 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = - 2.4 for pTau; T = - 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = - 3.1). CONCLUSIONS: pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Heart Failure , Adult , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Biomarkers , Cognitive Dysfunction/diagnosis , Creatine Kinase/metabolism , Female , Ferritins/metabolism , Heart Failure/complications , Heart Failure/diagnostic imaging , Heart Failure/metabolism , Humans , Intermediate Filaments/metabolism , Male , Middle Aged , tau Proteins/metabolismABSTRACT
Traumatic brain injury (TBI) represents a major determining factor of outcome in severely injured patients. However, reliable brain-damage-monitoring markers are still missing. We therefore assessed brain-specific beta-synuclein as a novel blood biomarker of synaptic damage and measured the benchmarks neurofilament light chain (NfL), as a neuroaxonal injury marker, and glial fibrillary acidic protein (GFAP), as an astroglial injury marker, in patients after polytrauma with and without TBI. Compared to healthy volunteers, plasma NfL, beta-synuclein, and GFAP were significantly increased after polytrauma. The markers demonstrated highly distinct time courses, with beta-synuclein and GFAP peaking early and NfL concentrations gradually elevating during the 10-day observation period. Correlation analyses revealed a distinct influence of the extent of extracranial hemorrhage and the severity of head injury on biomarker concentrations. A combined analysis of beta-synuclein and GFAP effectively discriminated between polytrauma patients with and without TBI, despite the comparable severity of injury. Furthermore, we found a good predictive performance for fatal outcome by employing the initial plasma concentrations of NfL, beta-synuclein, and GFAP. Our findings suggest a high diagnostic value of neuronal injury markers reflecting distinct aspects of neuronal injury for the diagnosis of TBI in the complex setting of polytrauma, especially in clinical surroundings with limited imaging opportunities.
Subject(s)
Brain Injuries, Traumatic , Multiple Trauma , Biomarkers , Brain Injuries, Traumatic/diagnosis , Glial Fibrillary Acidic Protein , Humans , Intermediate Filaments , beta-SynucleinABSTRACT
BACKGROUND: Synaptosomal-associated protein 25 (SNAP-25) in cerebrospinal fluid (CSF) is an emerging synaptic biomarker for the early diagnosis of Alzheimer's disease (AD). However, comprehensive studies investigating the marker in Creutzfeldt-Jakob disease (CJD) and in the differential diagnosis of neurodegenerative diseases are still lacking. METHODS: We developed a novel, sensitive ELISA for the measurement of SNAP-25 in CSF. In total, we analysed 316 patients from 6 diagnostic groups comprising patients with AD (n=96), CJD (n=55), Parkinson's disease spectrum (n=41), frontotemporal lobar degeneration (n=25) and amyotrophic lateral sclerosis (n=24) and non-neurodegenerative control patients (n=75). Using receiver operating characteristic curve analysis, we analysed the differential diagnostic potential and compared the results with core AD biomarkers. RESULTS: SNAP-25 CSF concentrations were elevated in AD and CJD (p<0.0001) but not in the other neurodegenerative diseases. Increased levels were observed already at early AD and CJD stages (p<0.0001). In CJD, SNAP-25 levels correlated negatively with survival time (r=-0.33 (95% CI -0.57 to -0.04, p=0.02). For the discrimination of AD from all other diseases except CJD, we observed a good diagnostic performance for CSF SNAP-25 (area under the curve (AUC) 0.85) which was further improved by applying the ratio with CSF amyloid-ß 1-42 (AUC 0.95). For CJD, we could demonstrate a strong differential diagnostic potential against all other groups including AD (AUC 0.97). CONCLUSION: Using the novel established CSF SNAP-25 ELISA, we here demonstrate the applicability of SNAP-25 as an early synaptic biomarker for both AD and CJD with a possible prognostic value in patients with CJD.
ABSTRACT
PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs. RECENT FINDINGS: The diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72 . Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment. SUMMARY: The first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.