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OBJECTIVE: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD. METHODS: Biomarkers of Alzheimer disease neuropathology (amyloid-ß 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. RESULTS: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. INTERPRETATION: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313.
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Doença de Alzheimer , Demência , Doenças Neurodegenerativas , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3 , Proteínas tau/líquido cefalorraquidiano , Estudos Transversais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidianoRESUMO
OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Tomografia por Emissão de Pósitrons , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Feminino , Masculino , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Idoso de 80 Anos ou mais , Estudos Transversais , Fatores de Tempo , Idade de Início , Estudos de Coortes , Progressão da Doença , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologiaRESUMO
BACKGROUND: Diagnosing acute kidney injury (AKI) and chronic kidney disease (CKD) relies on creatinine, which lacks optimal diagnostic sensitivity. The kidney-specific proximal tubular enzyme myo-inositol oxygenase (MIOX) catalyzes the conversion of myo-inositol (MI) to D-glucuronic acid. We hypothesized that proximal tubular damage, which occurs in AKI and CKD, will decrease MIOX activity, causing MI accumulation. To explore this, we developed an LC-MS/MS assay to quantify plasma MI and assessed its potential in identifying AKI and CKD patients. METHODS: MI was quantified in plasma from 3 patient cohorts [normal kidney function (n = 105), CKD (n = 94), and AKI (n = 54)]. The correlations between MI and creatinine were determined using Deming regression and Pearson correlation and the impact of age, sex, and ethnicity on MI concentrations was assessed. Receiver operating characteristic curve analysis was employed to evaluate MI diagnostic performance. RESULTS: In volunteers with normal kidney function, the central 95th percentile range of plasma MI concentrations was 16.6 to 44.2 µM. Age, ethnicity, and sex showed minimal influence on MI. Patients with AKI and CKD exhibited higher median MI concentrations [71.1 (25th percentile: 38.2, 75th percentile: 115.4) and 102.4 (77, 139.5) µM], respectively. MI exhibited excellent sensitivity (98.9%) and specificity (100%) for diagnosing CKD. In patients with AKI, MI increased 32.9 (SD 16.8) h before creatinine. CONCLUSIONS: This study unveils MI as a potential renal biomarker, notably elevated in plasma during AKI and CKD. Plasma MI rises 33 h prior to serum creatinine, enabling early AKI detection. Further validation and exploration of MI quantitation in kidney disease diagnosis is warranted.
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INTRODUCTION: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Mutação/genética , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Neurocalcina/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidianoRESUMO
BACKGROUND: Neurogranin in cerebrospinal fluid (CSF) correlates with cognitive decline and is a potential novel biomarker for Alzheimer disease (AD) dementia. We investigated the analytical and diagnostic performance of 3 commonly used neurogranin assays in the same cohort of patients to improve the interpretability of CSF neurogranin test results. METHODS: The neurogranin Erenna® assay from Washington University, St. Louis, MO (WashU); ELISA from ADx Neurosciences; and ELISA from Gothenburg University, Mölndal, Sweden (UGot), were compared using silver staining and Western blot after gel electrophoresis. Clinical performance of the 3 assays was compared in samples from individuals diagnosed with subjective cognitive decline (n = 22), and in patients with AD (n = 22), frontotemporal dementia (n = 22), dementia with Lewy bodies (n = 22), or vascular dementia (n = 20), adjusted for sex and age. RESULTS: The assays detected different epitopes of neurogranin: the WashU assay detected the N-terminal part of neurogranin (S10-D23) and a C-terminal part (G49-G60), the ADx assay detected C-terminal neurogranin truncated at P75, and the UGot assay detected the C-terminal neurogranin with intact ending (D78). Spearman ρ was 0.95 between ADx and WashU, 0.87 between UGot and WashU, and 0.81 between UGot and ADx. ANCOVA (analysis of covariance) showed group differences for ranked neurogranin concentrations in each assay (all P < 0.05), with specific increases in AD. CONCLUSIONS: Although the 3 assays target different epitopes on neurogranin and have different calibrators, the high correlations and the similar group differences suggest that the different forms of neurogranin in CSF carry similar diagnostic information, at least in the context of neurodegenerative diseases.
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Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Líquido Cefalorraquidiano/metabolismo , Neurogranina/metabolismo , Anticorpos/análise , Estudos de Coortes , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Humanos , Neurogranina/imunologiaRESUMO
INTRODUCTION: Individuals in early stages of Alzheimer's disease are a targeted population for secondary prevention trials aimed at preserving normal cognition. Understanding within-person biomarker(s) change over time is critical for trial enrollment and design. METHODS: Longitudinal cerebrospinal fluid samples from the Alzheimer's Disease Neuroimaging Initiative were assayed for novel markers of neuronal/synaptic injury (visinin-like protein 1, Ng, and SNAP-25) and neuroinflammation (YKL-40) and compared with ß amyloid 42, tau, and phospho-tau181. General linear mixed models were used to compare within-person rates of change in three clinical groups (cognitively normal, mild cognitive impairment, and Alzheimer's disease) further defined by ß amyloid status. RESULTS: Levels of injury markers were highly positively correlated. Despite elevated baseline levels as a function of clinical status and amyloid-positivity, within-person decreases in these measures were observed in the early symptomatic, amyloid-positive Alzheimer's disease group. DISCUSSION: Knowledge of within-person biomarker change will impact interpretation of biomarker outcomes in clinical trials that are dependent on disease stage.
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Idade de Início , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Idoso , Cognição , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Neurocalcina/líquido cefalorraquidiano , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
We hypothesized that one mechanism underlying the association between obstructive sleep apnea (OSA) and Alzheimer's disease is OSA leading to decreased slow wave activity (SWA), increased synaptic activity, decreased glymphatic clearance, and increased amyloid-ß. Polysomnography and lumbar puncture were performed in OSA and control groups. SWA negatively correlated with cerebrospinal fluid (CSF) amyloid-ß-40 among controls and was decreased in the OSA group. Unexpectedly, amyloid-ß-40 was decreased in the OSA group. Other neuronally derived proteins, but not total protein, were also decreased in the OSA group, suggesting that OSA may affect the interaction between interstitial and cerebrospinal fluid. Ann Neurol 2016;80:154-159.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Sistema Nervoso Central/metabolismo , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Apneia Obstrutiva do Sono/líquido cefalorraquidiano , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PolissonografiaRESUMO
Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer's disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aß40lumi and Aß42/Aß40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer's disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aß40lumi and t-tau/Aß40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aß40lumi, p-tau181/Aß40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer's disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer's disease clinical practice and trials.
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BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. METHODS: We compared biomarkers measured in ADNI (Nâ=â689), Knight-ADRC (Nâ=â870), DIAN (Nâ=â115), and Barcelona-1 (Nâ=â92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (râ>â0.9). sTREM2 had a fair correlation (râ>â0.6), whereas SNAP-25 showed weak correlation (râ=â0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.
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Doença de Alzheimer , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Imunoensaio , Neurogranina/líquido cefalorraquidiano , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.
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Apolipoproteína E4/genética , Cognição/fisiologia , Heterozigoto , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurogranina/líquido cefalorraquidiano , Fatores de RiscoRESUMO
OBJECTIVE: To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. METHODS: Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients. RESULTS: Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; p = 0.01), lower VILIP-1 (ρ = -0.60; p < 0.01) and SNAP-25 (ρ = -0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. CONCLUSIONS: CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.
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Encefalite Antirreceptor de N-Metil-D-Aspartato/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Neurocalcina/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/imunologia , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Criança , Pré-Escolar , Encefalite/líquido cefalorraquidiano , Encefalite/imunologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/imunologia , Neurogranina/líquido cefalorraquidiano , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Adulto JovemRESUMO
IMPORTANCE: Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. OBJECTIVE: To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. MAIN OUTCOMES AND MEASURES: Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. RESULTS: A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: ß estimate, 0.29; P = .001; global composite scores: ß estimate, -0.11; P = .001; episodic memory scores: ß estimate, -0.18; P < .001; and semantic memory scores: ß estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181. CONCLUSIONS AND RELEVANCE: The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Neurogranina/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina/metabolismo , Apolipoproteína E4/genética , Atrofia/patologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Vida Independente , Masculino , Pessoa de Meia-Idade , Neurocalcina/líquido cefalorraquidiano , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Curva ROC , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Tiazóis/metabolismo , Proteínas tau/líquido cefalorraquidianoRESUMO
IMPORTANCE: Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse. OBJECTIVE: To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic-based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014. MAIN OUTCOME AND MEASURE: Levels of NGRN in CSF samples. RESULTS: Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aß42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD. CONCLUSIONS AND RELEVANCE: Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Progressão da Doença , Neurogranina/líquido cefalorraquidiano , Sinapses/metabolismo , Idoso , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: We examined the utility of cerebrospinal fluid (CSF) proteins, Chitinase-3-like protein 1 (CHI3L1 or YKL-40), a putative marker of inflammation, and Visinin-like protein-1 (VILIP-1), a marker for neuronal injury, for diagnostic classification and monitoring of disease progression in a memory clinic cohort. METHODS: CSF levels of YKL-40 and VILIP-1 were measured in 37 cognitively normal, 61 Mild Cognitive Impairment (MCI) and 65 Alzheimer's disease (AD) patients from the memory clinic-based Amsterdam Dementia Cohort who underwent two lumbar punctures, with minimum interval of 6 months and a mean (SE) interval of 2.0(0.1) years. Mean(SE) cognitive follow-up was 3.8 (0.2) years. ANOVA was used to compare baseline differences of log-transformed CSF measures. Cox proportional hazard models were used to evaluate disease progression as a function of CSF tertiles. Linear mixed models were used to evaluate longitudinal change over time. All analyses were sex and age adjusted. RESULTS: Baseline levels of YKL-40, but not VILIP-1, were higher in MCI and AD patients compared to cognitively normal individuals (mean (SE) pg/mL, 304 (16) and 288 (12) vs. 231 (16), p = 0.03 and p = 0.006). Baseline levels of both YKL-40 and VILIP-1 in MCI predicted progression to AD (HR 95% CI = 3.0 (1.1-7.9) and 4.4 (1.5-13.0), respectively, for highest vs. lowest tertile). YKL-40 increased longitudinally in patients with MCI and AD (mean (SE) pg/mL per year, 8.9 (3.0) and 7.1 (3.1), respectively), but not in cognitively normal individuals, whereas levels of VILIP-1 increased only in MCI (mean (SE), 10.7 (2.6) pg/mL per year). CONCLUSIONS: CSF levels of YKL-40 may have utility for discriminating between cognitively normal individuals and patients with MCI or AD. Increased levels of both YKL-40 and VILIP-1 may be associated with disease progression. These CSF biomarkers should be considered for future evaluation in the characterization of the natural history of AD.