RESUMEN
BACKGROUND: In Alzheimer's disease (AD) diagnosis, a cerebrospinal fluid (CSF) biomarker panel is commonly interpreted with binary cutoff values. However, these values are not generic and do not reflect the disease continuum. We explored the use of interval-specific likelihood ratios (LRs) and probability-based models for AD using a CSF biomarker panel. METHODS: CSF biomarker (Aß1-42, tTau and pTau181) data for both a clinical discovery cohort of 241 patients (measured with INNOTEST) and a clinical validation cohort of 129 patients (measured with EUROIMMUN), both including AD and non-AD dementia/cognitive complaints were retrospectively retrieved in a single-center study. Interval-specific LRs for AD were calculated and validated for univariate and combined (Aß1-42/tTau and pTau181) biomarkers, and a continuous bivariate probability-based model for AD, plotting Aß1-42/tTau versus pTau181 was constructed and validated. RESULTS: LR for AD increased as individual CSF biomarker values deviated from normal. Interval-specific LRs of a combined biomarker model showed that once one biomarker became abnormal, LRs increased even further when another biomarker largely deviated from normal, as replicated in the validation cohort. A bivariate probability-based model predicted AD with a validated accuracy of 88% on a continuous scale. CONCLUSIONS: Interval-specific LRs in a combined biomarker model and prediction of AD using a continuous bivariate biomarker probability-based model, offer a more meaningful interpretation of CSF AD biomarkers on a (semi-)continuous scale with respect to the post-test probability of AD across different assays and cohorts.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Probabilidad , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Humanos , Biomarcadores/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Funciones de Verosimilitud , Persona de Mediana Edad , Proteínas tau/líquido cefalorraquídeo , Estudios Retrospectivos , Fragmentos de Péptidos/líquido cefalorraquídeo , Estudios de CohortesRESUMEN
OBJECTIVES: Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. ß-Amyloid (Aß) accumulation evidenced by amyloid PET positivity or CSF Aß decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aß and tau in iCAA and sCAA cohorts. METHODS: Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aß40, Aß42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. RESULTS: 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aß40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aß42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aß40 (p = 0.08, 95% CI 181-222), Aß42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aß40, 95% CI 153-193; Aß42, 95% CI 6-7 and total tau, 95% CI 2-4). DISCUSSION: Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aß and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.
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Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral , Enfermedad Iatrogénica , Fragmentos de Péptidos , Proteínas tau , Humanos , Masculino , Femenino , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/sangre , Anciano , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Estudios Prospectivos , Anciano de 80 o más AñosRESUMEN
BACKGROUND AND OBJECTIVES: There is a clear need to characterize and validate molecular biomarkers of cerebral amyloid angiopathy (CAA), in an effort to improve diagnostics, especially in the context of patients with Alzheimer disease (AD) receiving immunotherapies (for whom underlying CAA is the driver of amyloid-related imaging abnormalities). We performed an updated meta-analysis of 5 core CSF biomarkers (Aß42, Aß40, Aß438, total tau [T-tau], and phosphorylated tau [P-tau]) to assess which of these are most altered in sporadic CAA. METHODS: We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting APP metabolism (Aß42, Aß40, Aß38), neurodegeneration (T-tau), and tangle pathology (P-tau), in symptomatic sporadic CAA cohorts (based on the Boston criteria) vs control groups and/or vs patients with AD. Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations in (1) patients with CAA to controls and (2) CAA to patients with AD. RoM >1 indicates higher biomarker concentration in CAA vs comparison population, and RoM <1 indicates higher concentration in comparison groups. RESULTS: 8 studies met inclusion criteria: a total of 11 CAA cohorts (n = 289), 9 control cohorts (n = 310), and 8 AD cohorts (n = 339). Overall included studies were of medium quality based on our assessment tools. CAA to controls had lower mean level of all amyloid markers with CSF Aß42, Aß40, and Aß38 RoMs of 0.46 (95% CI 0.38-0.55, p < 0.0001), 0.70 (95% CI 0.63-0.78, p < 0.0001), and 0.71 (95% CI 0.56-0.89, p = 0.003), respectively. CSF T-tau and P-tau RoMs of patients with CAA to controls were both greater than 1: 1.56 (95% CI 1.32-1.84, p < 0.0001) and 1.31 (95% CI 1.13-1.51, p < 0.0001), respectively. Differentiation between CAA and AD was strong for CSF Aß40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001) and Aß38 (RoM 0.55, 95% CI 0.38-0.81, p < 0.0001), but not Aß42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For T-tau and P-tau, average CSF ratios in patients with CAA vs AD were 0.64 (95% CI 0.58-0.71, p < 0.0001) and 0.64 (95% CI 0.58-0.71, p < 0.0001), respectively. DISCUSSION: Specific CSF patterns of Aß42, Aß40, Aß38, T-tau, and P-tau might serve as molecular biomarkers of CAA, in research and clinical settings, offering the potential to improve the clinical diagnostic approach pathway in specific scenarios.
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Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral , Proteínas tau , Humanos , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnósticoRESUMEN
OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies. METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA). RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient. DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.
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Acuaporina 4 , Astrocitos , Biomarcadores , Proteína Ácida Fibrilar de la Glía , Inmunoglobulina G , Humanos , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Proteína Ácida Fibrilar de la Glía/inmunología , Femenino , Masculino , Acuaporina 4/inmunología , Persona de Mediana Edad , Astrocitos/inmunología , Astrocitos/metabolismo , Astrocitos/patología , Estudios Retrospectivos , Adulto , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Anciano , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Adulto Joven , AdolescenteRESUMEN
BACKGROUND AND OBJECTIVES: There is an urgent need to discover blood-based biomarkers of multiple sclerosis (MS) to better define the underlying biology of relapses and monitor disease progression. The main goal of this study is to search for candidate biomarkers of MS relapses associated with circulating extracellular vesicles (EVs), an emerging tool for biomarker discovery. METHODS: EVs, purified from unpaired plasma and CSF samples of RRMS patients by size-exclusion chromatography (SEC), underwent proteomic analysis to discover novel biomarkers associated with MS relapses. The candidate biomarkers of disease activity were detected by comparison approach between plasma- and CSF-EV proteomes associated with relapses. Among them, a selected potential biomarker was evaluated in a cohort of MS patients, using a novel and highly reproducible flow cytometry-based approach in order to detect low abundant EV subsets in a complex body fluid such as plasma. RESULTS: The proteomic profiles of both SEC-purified plasma EVs (from 6 patients in relapse and 5 patients in remission) and SEC-purified CSF EVs (from 4 patients in relapse and 3 patients in remission) revealed a set of proteins associated with MS relapses significant enriched in the synaptic transmission pathway. Among common proteins, excitatory amino-acid transporter 2, EAAT2, responsible for the majority of the glutamate uptake in CNS, was worthy of further investigation. By screening plasma samples from 110 MS patients, we found a significant association of plasma EV-carried EAAT2 protein (EV-EAAT2) with MS relapses, regardless of disease-modifying therapies. This finding was confirmed by investigating the presence of EV-EAAT2 in plasma samples collected longitudinally from 10 RRMS patients, during relapse and remission. Moreover, plasma EV-EAAT2 levels correlated positively with Expanded Disability Status Scale (EDSS) score in remitting MS patients but showed a negative correlation with age in patients with secondary progressive (SPMS). CONCLUSION: Our results emphaticize the usefulness of plasma EVs as a source of accessible biomarkers to remotely analyse the CNS status. Plasma EV-EAAT2 showed to be a promising biomarker for MS relapses. Further studies are required to assess the clinical relevance of this biomarker also for disability progression independent of relapse activity and transition from RRMS towards SPMS.
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Transportador 2 de Aminoácidos Excitadores , Vesículas Extracelulares , Esclerosis Múltiple , Proteómica , Humanos , Vesículas Extracelulares/metabolismo , Masculino , Femenino , Adulto , Proteómica/métodos , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/sangre , Estudios de CohortesRESUMEN
BACKGROUND: We measured postoperative changes in cerebrospinal fluid (CSF) interleukin (IL)-6 levels in subarachnoid hemorrhage (SAH) due to aneurysm rupture and examined factors associated with outcomes and cerebral vasospasm. We used physiologic saline or artificial CSF as the intraoperative irrigation fluid and examined the differences. METHODS: The participants were 16 men and 41 women who were transported to our facility for SAH and underwent surgical treatment during the period from February 2012 through March 2015. In terms of severity, 31 cases were World Federation of Neurological Surgeons (WFNS) grade I-III and 26 cases were grade IV-V. All cases underwent clipping. Physiologic saline and artificial CSF were used as intraoperative irrigation fluid. We placed a ventricular drainage tube intraoperatively and collected CSF daily from postoperative day (POD) 1 through 10 or until drain removal. RESULTS: IL-6 level varied from 74 pg/mL to 407,936 pg/mL and peaked on PODs 1 and 5. Patients with favorable outcomes had significantly lower postoperative IL-6 levels. POD 1 IL-6 level significantly differed in relation to the presence of cerebral vasospasm but was not associated with its timing or severity. Use of artificial CSF was associated with a significantly lower incidence of cerebral vasospasm. Age and WFNS grade were significantly associated with outcome, and use of artificial CSF had a tendency toward favorable outcomes. CONCLUSIONS: Artificial CSF is a potentially useful intervention when managing subarachnoid hemorrhage.
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Interleucina-6 , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Hemorragia Subaracnoidea/cirugía , Hemorragia Subaracnoidea/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Masculino , Femenino , Persona de Mediana Edad , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/líquido cefalorraquídeo , Anciano , Resultado del Tratamiento , Biomarcadores/líquido cefalorraquídeo , Índice de Severidad de la Enfermedad , Adulto , Factores de Tiempo , Aneurisma Roto/cirugía , Aneurisma Roto/líquido cefalorraquídeo , Periodo PosoperatorioRESUMEN
OBJECTIVE: Coronary artery disease (CAD) is frequent, but coronary slow flow (CSF) is a less common cardiovascular disease with a significant risk of mortality and morbidity. Endocan is a proinflammatory glycopeptide that has been investigated in cardiovascular diseases as well as some inflammatory diseases in recent years. We planned to compare the levels of endocan in both CAD and CSF in a similar population and examine the relationship of endocan with additional clinical variables. MATERIALS AND METHODS: In the trial, we included 169 consecutive subjects having a coronary angiography indication. According to the results of coronary angiography, 58 people were included in the CAD group, 52 were in the CSF group, and 59 people were in the control group. The control group includes those who did not have any lesions in their epicardial coronary arteries. Thrombolysis in myocardial infarction (TIMI)-frame counts (TFC) were calculated for all patients. RESULTS: Notably, 2.6% of the population in our study had CSF. Both the CAD (555±223 pg/mL) and CSF (559±234 pg/mL) groups had higher endocan levels than the control group (331±252 pg/mL) (p<0.001). There were similar endocan levels between the CAD and CSF groups. Endocan levels were shown to be favorably associated with mean TFC (r=0.267; p0.001). Serum endocan levels (particularly those above 450 pg/mL) and the presence of hyperlipidemia were the most important predictors of both CAD and CSF. CONCLUSION: Endocan levels are higher in CAD and CSF patients than in those with normal coronary arteries.
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Biomarcadores , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Proteínas de Neoplasias , Proteoglicanos , Humanos , Proteoglicanos/sangre , Proteoglicanos/líquido cefalorraquídeo , Masculino , Femenino , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/líquido cefalorraquídeo , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/líquido cefalorraquídeo , Proteínas de Neoplasias/análisis , Estudios de Casos y Controles , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Anciano , Circulación Coronaria/fisiología , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
Cerebral malaria in young African children is associated with high mortality, and persisting neurological deficits often remain in survivors. Sequestered Plasmodium-infected red blood cells lead to cerebrovascular inflammation and subsequent neuroinflammation. Brain inflammation can play a role in the pathogenesis of neurologic sequelae. Therefore, we assessed a select set of proinflammatory analytes (IP10, IL23, MIP3α, GRO, MCP-1, and osteopontin in both the plasma and cerebrospinal fluid(CSF) of Zambian children with cerebral malaria and compared this with children with neurological symptoms that were negative for Plasmodium falciparum (non-cerebral malaria). Several similarities in plasma and CSF levels were found, as were some striking differences. We confirmed that IP10 levels were higher in the plasma of cerebral malaria patients, but this was not found in CSF. Levels of osteopontin were elevated in both the plasma and CSF of CM patients compared to the non-CM patients. These results show again a highly inflammatory environment in both groups but a different profile for CM when compared to non-cerebral malaria. Osteopontin may play an important role in neurological inflammation in CM and the resulting sequelae. Therefore, osteopontin could be a valid target for further biomarker research and potentially for therapeutic interventions in neuroinflammatory infections.
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Biomarcadores , Malaria Cerebral , Osteopontina , Humanos , Malaria Cerebral/líquido cefalorraquídeo , Malaria Cerebral/sangre , Malaria Cerebral/parasitología , Osteopontina/líquido cefalorraquídeo , Osteopontina/sangre , Masculino , Femenino , Preescolar , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Inflamación/líquido cefalorraquídeo , Inflamación/sangre , Niño , Plasmodium falciparum/patogenicidad , Lactante , Malaria Falciparum/líquido cefalorraquídeo , Malaria Falciparum/sangre , Malaria Falciparum/parasitologíaRESUMEN
AIM: To examine whether changes in biomarker concentrations in patients with idiopathic normal-pressure hydrocephalus (iNPH) during 72 h of external lumbar drainage (ELD) can differentiate between responders and non-responders. METHODS: Twenty patients with clinical and neuroradiological signs of iNPH underwent ELD over a period of 72 h. During this period, changes in cerebrospinal fluid (CSF) concentrations of biomarkers (amyloid-ß, total and phosphorylated tau proteins) and intracranial pressure were monitored, and the volume of drained CSF was measured. Changes in the concentrations of selected biomarkers at three time points (0, 36, and 72 h) during ELD were tested for association with changes in clinical condition. RESULTS: Ten patients showed significant clinical improvement after ELD, quantified as a difference of two or more points on the Mini-Mental State Examination and/or Japanese iNPH grading scale. The concentration of all tested biomarkers increased during the first 36 h. Respondents had higher Aß 1-42 at all time points, with a significant difference seen after 72 h. They also had a significantly higher Aß1-42/Aß1-40 ratio at all time points. CONCLUSION: A gradual increase in Aß 1-42 concentration during three-day ELD represents a possible positive prognostic factor for the placement of permanent CSF drainage in patients with iNPH.
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Péptidos beta-Amiloides , Biomarcadores , Drenaje , Hidrocéfalo Normotenso , Humanos , Hidrocéfalo Normotenso/líquido cefalorraquídeo , Hidrocéfalo Normotenso/diagnóstico , Hidrocéfalo Normotenso/cirugía , Masculino , Femenino , Proyectos Piloto , Biomarcadores/líquido cefalorraquídeo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Anciano de 80 o más Años , Proteínas tau/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Persona de Mediana Edad , Presión Intracraneal , Punción EspinalRESUMEN
Impaired clearance of amyloid ß (Aß) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aß clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aß-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aß-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aß levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aß-binding monocytes may play a role in CNS Aß clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Disfunción Cognitiva , Progresión de la Enfermedad , Ratones Transgénicos , Monocitos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/sangre , Humanos , Monocitos/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Femenino , Anciano , Masculino , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/líquido cefalorraquídeo , Ratones , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/metabolismo , Citometría de Flujo , Modelos Animales de Enfermedad , Fagocitosis , Persona de Mediana EdadRESUMEN
This study examines the emerging role of biomarkers in the prognosis and management of severe traumatic brain injury (sTBI). Key findings highlight the significance of serum RIP-3, STC1, Nrf2, and cerebrospinal fluid galectin-3 and cytokines in predicting disease severity, mortality, and functional outcomes in sTBI patients. Elevated levels of RIP-3 and STC1 were linked to poor prognosis and increased mortality, with RIP-3 associated with necroptosis and inflammation, and STC1 with neuroprotective properties. Nrf2 was found to correlate with oxidative stress and adverse outcomes, while elevated CSF galectin-3 and IL-6 indicated neuroinflammation and neurodegeneration. These biomarkers show promise not only as prognostic tools but also as potential therapeutic targets. The study suggests further validation through multicenter research to enhance clinical applications and improve treatment strategies for sTBI.
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Biomarcadores , Lesiones Traumáticas del Encéfalo , Humanos , Lesiones Traumáticas del Encéfalo/diagnóstico , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/terapia , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , PronósticoRESUMEN
The study by Ooi et al. (2022) systematically reviews the potential of Interleukin-6 (IL-6) as a prognostic biomarker for traumatic brain injury (TBI). By analyzing IL-6 levels in serum, cerebrospinal fluid (CSF), and brain parenchyma, the authors provide valuable insights into its role in predicting clinical outcomes. The study emphasizes the neuroinflammatory response and the mechanistic role of IL-6 in neuronal recovery, offering a strong rationale for its consideration as a biomarker. However, variability in IL-6 detection methods and timing of sample collection across studies highlights the need for standardization. Future research should focus on refining detection methods, exploring IL-6's temporal dynamics post-TBI, and accounting for interactions with other cytokines. Additionally, advanced statistical controls are recommended to better isolate IL-6's prognostic value. This research lays a solid foundation for future studies aimed at improving clinical prognostication in TBI.
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Biomarcadores , Lesiones Traumáticas del Encéfalo , Interleucina-6 , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/diagnóstico , Humanos , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Interleucina-6/sangre , Interleucina-6/líquido cefalorraquídeo , PronósticoRESUMEN
Background: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI, Nâ=â495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, Nâ=â619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pcâ=â0.017; 0.010, respectively) and total-tau (T-tau) (pcâ=â0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pcâ=â0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528â:â20.8%; Proportion of rs744373â:â24.8%) and T-tau (Proportion of rs7561528â:â36.5%; Proportion of rs744373â:â43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.
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Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer , Biomarcadores , Glicoproteínas de Membrana , Receptores Inmunológicos , Proteínas Supresoras de Tumor , Proteínas tau , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Femenino , Proteínas Supresoras de Tumor/genética , Masculino , Anciano , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Anciano de 80 o más Años , Proteínas NuclearesRESUMEN
BACKGROUND: There is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer's disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum. METHODS: Participants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism. RESULTS: Ng levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aß1-42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (ß=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (ß=-0.32, p = .358). CONCLUSIONS: In this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aß1-42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.
Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Degeneración Lobar Frontotemporal , Neurogranina , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/genética , Apolipoproteínas E/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Estudios Transversales , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Degeneración Lobar Frontotemporal/diagnóstico , Neurogranina/líquido cefalorraquídeo , Pruebas NeuropsicológicasRESUMEN
AIM: The availability of disease-modifying therapies and newborn screening programs for spinal muscular atrophy (SMA) has generated an urgent need for reliable prognostic biomarkers to classify patients according to disease severity. We aim to identify cerebrospinal fluid (CSF) prognostic protein biomarkers in CSF samples of SMA patients collected at baseline (T0), and to describe proteomic profile changes and biological pathways influenced by nusinersen before the sixth nusinersen infusion (T302). METHODS: In this multicenter retrospective longitudinal study, we employed an untargeted liquid chromatography mass spectrometry (LC-MS)-based proteomic approach on CSF samples collected from 61 SMA patients treated with nusinersen (SMA1 n=19, SMA2 n=19, SMA3 n=23) at T0 at T302. The Random Forest (RF) machine learning algorithm and pathway enrichment analysis were applied for analysis. RESULTS: The RF algorithm, applied to the protein expression profile of naïve patients, revealed several proteins that could classify the different types of SMA according to their differential abundance at T0. Analysis of changes in proteomic profiles identified a total of 147 differentially expressed proteins after nusinersen treatment in SMA1, 135 in SMA2, and 289 in SMA3. Overall, nusinersen-induced changes on proteomic profile were consistent with i) common effects observed in allSMA types (i.e. regulation of axonogenesis), and ii) disease severity-specific changes, namely regulation of glucose metabolism in SMA1, of coagulation processes in SMA2, and of complement cascade in SMA3. CONCLUSIONS: This untargeted LC-MS proteomic profiling in the CSF of SMA patients revealed differences in protein expression in naïve patients and showed nusinersen-related modulation in several biological processes after 10 months of treatment. Further confirmatory studies are needed to validate these results in larger number of patients and over abroader timeframe.
Asunto(s)
Aprendizaje Automático , Atrofia Muscular Espinal , Oligonucleótidos , Proteómica , Humanos , Proteómica/métodos , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/líquido cefalorraquídeo , Atrofia Muscular Espinal/metabolismo , Oligonucleótidos/uso terapéutico , Masculino , Femenino , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Estudios Retrospectivos , Lactante , Estudios Longitudinales , Preescolar , Cromatografía Liquida/métodos , NiñoRESUMEN
This chapter provides a comprehensive examination of a broad range of biomarkers used for the diagnosis and prediction of treatment outcomes in major depressive disorder (MDD). Genetic, epigenetic, serum, cerebrospinal fluid (CSF), and neuroimaging biomarkers are analyzed in depth, as well as the integration of new technologies such as digital phenotyping and machine learning. The intricate interplay between biological and psychological elements is emphasized as essential for tailoring MDD management strategies. In addition, the evolving link between psychotherapy and biomarkers is explored to uncover potential associations that shed light on treatment response. This analysis underscores the importance of individualized approaches in the treatment of MDD that integrate advanced biological insights into clinical practice to improve patient outcomes.
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Biomarcadores , Trastorno Depresivo Mayor , Medicina de Precisión , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Mayor/diagnóstico , Humanos , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Medicina de Precisión/métodos , Resultado del Tratamiento , Antidepresivos/uso terapéutico , Psicoterapia/métodos , Aprendizaje Automático , Neuroimagen/métodosRESUMEN
Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer's disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer's Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.
Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Trastornos Cerebrovasculares , Disfunción Cognitiva , Hidrocortisona , Saliva , Humanos , Femenino , Masculino , Hidrocortisona/metabolismo , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Anciano , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Persona de Mediana Edad , Saliva/química , Saliva/metabolismo , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/líquido cefalorraquídeo , Estudios de Cohortes , Ritmo Circadiano/fisiología , Enfermedades Neuroinflamatorias/líquido cefalorraquídeo , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Pruebas Neuropsicológicas , Quimiocina CXCL10/líquido cefalorraquídeo , Quimiocina CXCL10/metabolismoRESUMEN
Aim of the project was to evaluate the technical and clinical validity of plasma Lumipulse p-tau, Aß42 and Aß40 species and their correlation with CSF core Alzheimer's Disease (AD) markers; a method comparison with SIMOA was also performed. One-hundred-thirthy-three participants, namely 55 A+T+N+ AD, 28 Neurodegenerative disorders (NDD) and 50 controls were enrolled for the study. Lumipulse technical validity showed high stability for p-tau181, Aß42, and Aß40, with higher stability of p-tau to repeated freezing thaw cycles. p-tau181 levels detected by both techniques were higher in AD compared to both NDD/controls and exhibited a similar correlation with CSF p-tau levels, whereas Aß42 levels were slightly lower in AD with both methods. In the comparison between SIMOA and Lumipulse plasma markers, both techniques exhibited similar diagnostic accuracy for AD for p-tau181 (0.87; 95â¯%CI 0.81-0.94, vs 0.85; 95â¯%CI 0.78-0.93), whereas the best performance was reached by p-tau181/ Aß42 Lumipulse ratio (ROC AUC 0.915, 95â¯%CI 0.86-0.97). The study thus confirmed the construct validity of both Lumipulse and SIMOA techniques for the identification of CSF AD pattern in clinical settings.