ABSTRACT
INTRODUCTION: The diagnostic and classificatory performances of all combinations of three core (amyloid ß peptide [i.e., Aß1-42], total tau [t-tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation. METHODS: The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified. RESULTS: The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination [amyloid ß peptide + phosphorylated tau + neurofilament light chain] for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78). CONCLUSIONS: Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Aged , Alzheimer Disease/classification , Amyloid beta-Peptides/cerebrospinal fluid , Area Under Curve , Biomarkers/cerebrospinal fluid , Chitinase-3-Like Protein 1/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/classification , Cross-Sectional Studies , Diagnosis, Differential , Female , Frontotemporal Dementia/cerebrospinal fluid , Frontotemporal Dementia/classification , Humans , Male , Middle Aged , Neurofilament Proteins/cerebrospinal fluid , Nuclear Proteins/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , RNA-Binding Proteins , ROC Curve , Retrospective Studies , tau Proteins/cerebrospinal fluidABSTRACT
OBJECTIVE: To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife. METHODS: We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal. Sleep quality was measured with the Medical Outcomes Study Sleep Scale. CSF was assayed for biomarkers of amyloid metabolism and plaques (ß-amyloid 42 [Aß42]), tau pathology (phosphorylated tau [p-tau] 181), neuronal/axonal degeneration (total tau [t-tau], neurofilament light [NFL]), neuroinflammation/astroglial activation (monocyte chemoattractant protein-1 [MCP-1], chitinase-3-like protein 1 [YKL-40]), and synaptic dysfunction/degeneration (neurogranin). To adjust for individual differences in total amyloid production, Aß42 was expressed relative to Aß40. To assess cumulative pathology, CSF biomarkers were expressed in ratio to Aß42. Relationships among sleep scores and CSF biomarkers were assessed with multiple regression, controlling for age, sex, time between sleep and CSF measurements, and CSF assay batch. RESULTS: Worse subjective sleep quality, more sleep problems, and daytime somnolence were associated with greater AD pathology, indicated by lower CSF Aß42/Aß40 and higher t-tau/Aß42, p-tau/Aß42, MCP-1/Aß42, and YKL-40/Aß42. There were no significant associations between sleep and NFL or neurogranin. CONCLUSIONS: Self-report of poor sleep was associated with greater AD-related pathology in cognitively healthy adults at risk for AD. Effective strategies exist for improving sleep; therefore sleep health may be a tractable target for early intervention to attenuate AD pathogenesis.
Subject(s)
Sleep Wake Disorders/cerebrospinal fluid , Sleep/physiology , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Chemokine CCL2/cerebrospinal fluid , Chitinase-3-Like Protein 1/cerebrospinal fluid , Female , Humans , Longitudinal Studies , Male , Mental Status Schedule , Middle Aged , Neurofilament Proteins/cerebrospinal fluid , Nuclear Proteins/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Phosphorylation , RNA-Binding Proteins , Self Report , Sleep Wake Disorders/psychology , tau Proteins/cerebrospinal fluidABSTRACT
INTRODUCTION: Pathogenesis of Alzheimer's disease (AD) in apolipoprotein E ε4 (APOE ε4) carriers remains unclear. We hypothesize that APOE isoforms have differential effects on synaptic function. METHODS: We compared levels of CSF neurogranin (Ng) between APOE ε4 carriers and noncarriers in 399 subjects with normal cognition, mild cognitive impairment (MCI), and AD. We examined associations between Ng levels and age, education, gender, CSF-Aß42, and tau protein. RESULTS: Neurogranin levels were significantly higher in APOE ε4 carriers compared to APOE ε4 noncarriers with MCI. Levels of Ng between the APOE ε4 carriers and APOE ε4 noncarriers with AD did not differ. Ng levels were correlated with MMSE and levels of tau and Aß42. DISCUSSION: Significantly higher CSF Ng levels in APOE ε4 carriers with MCI may reflect synaptic injury underlying early cognitive impairment. Neurogranin may be an early biomarker of AD and important for disease diagnosis and timing of intervention in APOE ε4 carriers.
Subject(s)
Apolipoprotein E4/genetics , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/genetics , Nuclear Proteins/cerebrospinal fluid , Age Factors , Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Cohort Studies , Cross-Sectional Studies , Disease Progression , Educational Status , Female , Heterozygote , Humans , Male , Mental Status and Dementia Tests , Peptide Fragments/cerebrospinal fluid , RNA-Binding Proteins , Risk , Sex Factors , Synapses/metabolism , tau Proteins/cerebrospinal fluidABSTRACT
Cerebrospinal fluid amyloid-beta 1-42 (Aß1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aß1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aß1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aß1-42.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Apolipoprotein E4/genetics , Nuclear Proteins/genetics , Peptide Fragments/genetics , Polymorphism, Single Nucleotide , RNA-Binding Proteins/genetics , tau Proteins/genetics , Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/pathology , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoprotein E4/cerebrospinal fluid , Cognition , Female , Gene Expression Regulation , Genome-Wide Association Study , Humans , Male , Nuclear Proteins/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Phosphorylation , RNA-Binding Proteins/cerebrospinal fluid , Serine-Arginine Splicing Factors , Signal Transduction , tau Proteins/cerebrospinal fluidABSTRACT
We present the case of a 1-year-old female with stage-4 neuroblastoma with MYCN amplification; she was treated with five chemotherapy courses, resulting in normalization of elevated serum levels of tumor markers. Complete remission was achieved after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. Nine months later, however, the tumor relapsed in the central nervous system (CNS). The serum and cerebrospinal fluid (CSF) levels of the tumor markers were normal, but the MYCN copy number was high only in the CSF DNA, suggesting an isolated CNS recurrence. The MYCN copy number in the CSF DNA was reflective of response to treatment.
Subject(s)
Central Nervous System Neoplasms/cerebrospinal fluid , Central Nervous System Neoplasms/diagnosis , DNA, Neoplasm/cerebrospinal fluid , Neuroblastoma/complications , Nuclear Proteins/cerebrospinal fluid , Nuclear Proteins/genetics , Oncogene Proteins/cerebrospinal fluid , Oncogene Proteins/genetics , Central Nervous System Neoplasms/etiology , DNA, Neoplasm/blood , Female , Humans , Infant , Magnetic Resonance Imaging , N-Myc Proto-Oncogene Protein , Neuroblastoma/pathology , Nuclear Proteins/blood , Oncogene Proteins/blood , PrognosisABSTRACT
Reissner's fibre (RF) is formed by the polymerization of the glycoprotein secreted by the subcommissural organ (SCO). The SCO also secretes soluble glycoprotein into the cerebrospinal fluid (CSF); variations in RF and SCO have been reported in hydrocephalus. On the other hand, hydrocephalus and other brain alterations have been described in p73 mutant mice. The p73 belongs to the tumour suppressor p53 protein family and has two isoforms: the TAp73 with apoptotic activity and DeltaNp73 with anti-apoptotic function. Moreover, the TAp73 isoform is glycosylated and secreted into the CSF. In the present work, we analysed the variations in RF and p73 proteins in the CSF and SCO of spontaneously hydrocephalic rats. Brains from control rats and spontaneously hydrocephalic rats of 12 months of age were used. The SCO sections were immunohistochemically processed with anti-TAp73 and anti-Reissner fibre (AFRU). The spontaneous hydrocephalus presents a decrease in the AFRU immunoreactive material in the SCO and an absence of RF. The anti-TAp73 was also present, slightly decreased, in the hydrocephalic SCO. AFRU and p73 bands were also detected in the CSF by western blot and six AFRU and p73 protein bands of a similar molecular weight were found in the CSF of the control rats. The number of AFRU and p73 bands was lower in the hydrocephalic rats than in the control rats. In conclusion, hydrocephalus produces a decrease in the secretions of the SCO and an absence of RF and a decrease in p73 and RF proteins in the CSF.