Browsing by Subject "cerebrospinal fluid"
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Item The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans(Elsevier, 2015-07) Kang, Ju-Hee; Korecka, Magdalena; Figurski, Michal J.; Toledo, Jon B.; Blennow, Kaj; Zetterberg, Henrik; Waligorska, Teresa; Brylska, Magdalena; Fields, Leona; Shah, Nirali; Soares, Holly; Dean, Robert A.; Vanderstichele, Hugo; Petersen, Ronald C.; Aisen, Paul S.; Saykin, Andrew J.; Weiner, Michael W.; Trojanowski, John Q.; Shaw, Leslie M.; Alzheimer's Disease Neuroimaging Initiative; Department of Radiology and Imaging Sciences, School of MedicineINTRODUCTION: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. METHODS: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1-42, t-tau, and p-tau181 data. RESULTS: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. DISCUSSION: Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.Item Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects(Elsevier, 2014-02) Millard, Steven P.; Lutz, Franziska; Li, Ge; Galasko, Douglas R.; Farlow, Martin R.; Quinn, Joseph F.; Kaye, Jeffrey A.; Leverenz, James B.; Tsuang, Debby; Yu, Chang-En; Peskind, Elaine R.; Bekris, Lynn M.; Department of Neurology, IU School of MedicineLow cerebrospinal fluid (CSF) Aβ42 levels correlate with increased brain Aβ deposition in Alzheimer’s disease (AD), which suggests a disruption in the degradation and clearance of Aβ from the brain. In addition, APOE ε4 carriers have lower CSF Aβ42 levels than non-carriers. The hypothesis of this investigation was that CSF Aβ42 levels correlate with regulatory region variation in genes that are biologically associated with degradation or clearance of Aβ from the brain. CSF Aβ42 levels were tested for associations with Aβ degradation and clearance genes and APOE ε4. Twenty-four SNPs located within the 5′ and 3′ regions of 12 genes were analyzed. The study sample consisted of 99 AD patients and 168 cognitively normal control subjects. CSF Aβ42 levels were associated with APOE ε4 status in controls but not in AD patientsItem Choroid Plexus of the Fourth Ventricle: Review and Anatomic Study Highlighting Anatomical Variations(Elsevier, 2016-04) Tubbs, R. Shane; Shoja, Mohammadali M.; Aggarwal, Anjali; Gupta, Tulika; Loukas, Marios; Sahni, Daisy; Ansari, Shaheryar F.; Cohen-Gadol, Aaron A.; Department of Neurological Surgery, IU School of MedicineRelatively few studies have been performed that analyze the morphology of the choroid plexus of the fourth ventricle. Due to the importance of this tissue as a landmark on imaging and during surgical intervention of the fourth ventricle, the authors performed a cadaveric study to better characterize this important structure. The choroid plexus of the fourth ventricle of 60 formalin fixed adult human brains was examined and measured. The horizontal distance from the midline to the lateral most point of the protruding tip of the horizontal limbs was measured. In the majority of the 60 brain specimens, right and left horizontal limbs of the choroid plexus were seen extending from the midline and protruding out of their respective lateral apertures of the fourth ventricle and into the subarachnoid space. However, on 3.3% of sides, there was absence of an extension into the foramen of Luschka and in one specimen, this lack of extension into the foramen of Luschka was bilateral. On two sides, there was discontinuity between the midline choroid plexus and the tuft of choroid just outside the foramen of Luschka. For specimens in which the choroid plexus did protrude through the foramen of Luschka (96.7%), these tufts were located anterior to the flocculus and inferolateral to the facial/vestibulocochlear nerve complex and posterosuperior to the glossopharyngeal/vagal/accessory complex. A thorough understanding of the normal and variant anatomy of the fourth ventricular choroid plexus is necessary for those who operate in, or interpret imaging of, this region.Item Cognitive and Neuronal Link With Inflammation: A Longitudinal Study in People With and Without HIV Infection(Wolters Kluwer, 2020-12) Anderson, Albert M.; Jang, Jeong Hoon; Easley, Kirk A.; Fuchs, Dietmar; Gisslen, Magnus; Zetterberg, Henrik; Blennow, Kaj; Ellis, Ronald J.; Franklin, Donald; Heaton, Robert K.; Grant, Igor; Letendre, Scott L.; Biostatistics, School of Public HealthBackground: Across many settings, lack of virologic control remains common in people with HIV (PWH) because of late presentation and lack of retention in care. This contributes to neuronal damage and neurocognitive impairment, which remains prevalent. More evidence is needed to understand these outcomes in both PWH and people without HIV (PWOH). Methods: We recruited PWH initiating antiretroviral therapy and PWOH at 2 sites in the United States. One hundred eight adults were enrolled (56 PWOH and 52 PWH), most of whom had a second assessment at least 24 weeks later (193 total assessments). Tumor necrosis factor alpha, monocyte chemotactic protein-1 (MCP-1), neopterin, soluble CD14, and neurofilament light chain protein (NFL) were measured in plasma and cerebrospinal fluid (CSF). Using multivariate models including Bayesian model averaging, we analyzed factors associated with global neuropsychological performance (NPT-9) and CSF NFL at baseline and over time. Results: At baseline, higher CSF MCP-1 and plasma sCD14 were associated with worse NPT-9 in PWH, while CSF HIV RNA decrease was the only marker associated with improved NPT-9 over time. Among PWH, higher CSF neopterin was most closely associated with higher NFL. Among PWOH, higher CSF MCP-1 was most closely associated with higher NFL. After antiretroviral therapy initiation, decrease in CSF MCP-1 was most closely associated with NFL decrease. Conclusion: Monocyte-associated CSF biomarkers are highly associated with neuronal damage in both PWH and PWOH. More research is needed to evaluate whether therapies targeting monocyte-associated inflammation may ameliorate HIV-associated neurobehavioral diseases.Item Elevated Cerebrospinal Fluid Tau Protein Concentrations on Admission Are Associated With Long-term Neurologic and Cognitive Impairment in Ugandan Children With Cerebral Malaria(Oxford, 2020-03-15) Datta, Dibyadyuti; Conroy, Andrea L; Castelluccio, Peter F; Ssenkusu, John M; Park, Gregory S; Opoka, Robert O; Bangirana, Paul; Idro, Richard; Saykin, Andrew J; John, Chandy C; Pediatrics, School of MedicineBackground Elevated concentrations of cerebrospinal fluid (CSF) tau, a marker of axonal injury, have been associated with coma in severe malaria (cerebral malaria [CM]). However, it is unknown whether axonal injury is related to long-term neurologic deficits and cognitive impairment in children with CM. Methods Admission CSF tau concentrations were measured in 145 Ugandan children with CM and compared to clinical and laboratory factors and acute and chronic neurologic and cognitive outcomes. Results Elevated CSF tau concentrations were associated with younger age, increased disease severity (lower glucose and hemoglobin concentrations, malaria retinopathy, acute kidney injury, and prolonged coma duration, all P < .05), and an increased CSF:plasma albumin ratio, a marker of blood–brain barrier breakdown (P < .001). Admission CSF tau concentrations were associated with the presence of neurologic deficits at hospital discharge, and at 6, 12, and 24 months postdischarge (all P ≤ .02). After adjustment for potential confounding factors, elevated log10-transformed CSF tau concentrations correlated with worse cognitive outcome z scores over 2-year follow-up for associative memory (β coefficient, –0.31 [95% confidence interval [CI], –.53 to –.10]) in children <5 years of age, and for overall cognition (–0.69 [95% CI, –1.19 to –.21]), attention (–0.78 [95% CI, –1.34 to –.23]), and working memory (–1.0 [95% CI, –1.68 to –.31]) in children ≥5 years of age (all P < .006). Conclusions Acute axonal injury in children with CM is associated with long-term neurologic deficits and cognitive impairment. CSF tau concentrations at the time of the CM episode may identify children at high risk of long-term neurocognitive impairment.Item Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort(Elsevier, 2017) Li, Jin; Zhang, Qiushi; Chen, Feng; Meng, Xianglian; Liu, Wenjie; Chen, Dandan; Yan, Jingwen; Kim, Sungeun; Wang, Lei; Feng, Weixing; Saykin, Andrew J.; Liang, Hong; Shen, Li; Department of Radiology and Imaging Sciences, IU School of MedicineThe pathogenic relevance in Alzheimer’s disease (AD) presents a decrease of cerebrospinal fluid (CSF) amyloid-ß42 (Aß42) burden and an increase in CSF total-tau (T-tau) levels. In this work, we performed genome-wide association study (GWAS) and genome-wide interaction study (GWIS) of T-tau/Aß42 ratio as an AD imaging quantitative trait (QT) on 843 subjects and 563,980 single nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain “missing heritability”. Linear regression method was used to detect SNP-SNP interactions among SNPs with uncorrected p-value≤0.01 from the GWAS. Age, gender and diagnosis were considered as covariates in both studies. The GWAS results replicated the previously reported AD-related genes APOE, APOC1 and TOMM40, as well as identified 14 novel genes, which showed genome-wide statistical significance. GWIS revealed 7 pairs of SNPs meeting the cell-size criteria and with bonferroni-corrected p-value≤0.05. As we expect, these interaction pairs all had marginal main effects but explained a relatively high-level variance of T-tau/Aß42, demonstrating their potential association with AD pathology.Item Hydrocephalus: historical analysis and considerations for treatment(Springer, 2022) Hochstetler, Alejandra; Raskin, Jeffrey; Blazer-Yost, Bonnie L.; Biology, School of ScienceHydrocephalus is a serious condition that affects patients of all ages, resulting from a multitude of causes. While the etiologies of hydrocephalus are numerous, many of the acute and chronic symptoms of the condition are shared. These symptoms include disorientation and pain (headaches), cognitive and developmental changes, vision and sleep disturbances, and gait abnormalities. This collective group of symptoms combined with the effectiveness of CSF diversion as a surgical intervention for many types of the condition suggest that the various etiologies may share common cellular and molecular dysfunctions. The incidence rate of pediatric hydrocephalus is approximately 0.1–0.6% of live births, making it as common as Down syndrome in infants. Diagnosis and treatment of various forms of adult hydrocephalus remain understudied and underreported. Surgical interventions to treat hydrocephalus, though lifesaving, have a high incidence of failure. Previously tested pharmacotherapies for the treatment of hydrocephalus have resulted in net zero or negative outcomes for patients potentially due to the lack of understanding of the cellular and molecular mechanisms that contribute to the development of hydrocephalus. Very few well-validated drug targets have been proposed for therapy; most of these have been within the last 5 years. Within the last 50 years, there have been only incremental improvements in surgical treatments for hydrocephalus, and there has been little progress made towards prevention or cure. This demonstrates the need to develop nonsurgical interventions for the treatment of hydrocephalus regardless of etiology. The development of new treatment paradigms relies heavily on investment in researching the common molecular mechanisms that contribute to all of the forms of hydrocephalus, and requires the concerted support of patient advocacy organizations, government- and private-funded research, biotechnology and pharmaceutical companies, the medical device industry, and the vast network of healthcare professionals.Item The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review(Elsevier, 2018) Hansson, Oskar; Mikulskis, Alvydas; Fagan, Anne M.; Teunissen, Charlotte; Zetterberg, Henrik; Vanderstichele, Hugo; Molinuevo, Jose Luis; Shaw, Leslie M.; Vandijck, Manu; Verbeek, Marcel M.; Savage, Mary; Mattsson, Niklas; Lewczuk, Piotr; Batrla, Richard; Rutz, Sandra; Dean, Robert A.; Blennow, Kaj; Pathology and Laboratory Medicine, School of MedicineIntroduction Cerebrospinal fluid (CSF) biomarkers have the potential to improve the diagnostic accuracy of Alzheimer's disease, yet there is a lack of harmonized preanalytical CSF handling protocols. Methods This systematic review summarizes the current literature on the influence of preanalytical variables on CSF biomarker concentration. We evaluated the evidence for three core CSF biomarkers: β-amyloid 42, total tau, and phosphorylated tau. Results The clinically important variables with the largest amount of conflicting data included the temperature at which samples are stored, the time nonfrozen samples can be stored, and possible effects of additives such as detergents, blood contamination, and centrifugation. Conversely, we discovered that there is consensus that tube material has a significant effect. Discussion A unified CSF handling protocol is recommended to reduce preanalytical variability and facilitate comparison of CSF biomarkers across studies and laboratories. In future, experiments should use a gold standard with fresh CSF collected in low binding tubes.Item A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation(Elsevier, 2014-07-15) Nishida, Katsuya; Garringer, Holly J.; Futamura, Naonobu; Funakawa, Itaru; Jinnai, Kenji; Vidal, Ruben; Takao, Masaki; Department of Pathology & Laboratory Medicine, IU School of MedicineNeuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin deposition in the central nervous system. We report a family in which neuroferritinopathy begins with chronic headaches, later developing progressive orolingual and arm dystonia, dysarthria, cerebellar ataxia, pyramidal tract signs, and psychiatric symptoms. In the absence of classic clinical symptoms, the initial diagnosis of the disease was based on magnetic resonance imaging studies. Biochemical studies on the proband showed normal serum ferritin levels, but remarkably low cerebrospinal fluid (CSF) ferritin levels. A novel FTL mutation was identified in the proband. Our findings expand the genetic and clinical diversity of neuroferritinopathy and suggest CSF ferritin levels as a novel potential biochemical marker for the diagnosis of neuroferritinopathy.Item TERT Promoter Mutation Detection in Cell-Free Tumor-Derived DNA in Patients with IDH Wild-Type Glioblastomas: A Pilot Prospective Study(AACR, 2018-11) Juratli, Tareq A.; Stasik, Sebastian; Zolal, Amir; Schuster, Caroline; Richter, Sven; Daubner, Dirk; Juratli, Mazen A.; Thowe, Rachel; Hennig, Silke; Makina, Meriem; Meinhardt, Matthias; Lautenschlaeger, Tim; Schackert, Gabriele; Krex, Dietmar; Thiede, Christian; Radiation Oncology, School of MedicinePurpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)–mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients. Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp mutation in the CSF-tDNA was correlated with tumor features and patients’ outcome. Results: Thirty-eight patients had TERTp-mutant/IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 92.1% sensitivity (95% CI, 78.6–98.3%) (n = 35/38). In contrast, the sensitivity in the plasma-tDNA was far lower [n = 3/38, 7.9% (95% CI, 1.6–21.4%)]. We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared with patients with high VAF, irrespective of using the lower quartile VAF [11.45%; 14.0 mo. (95% confidence interval, CI, 10.3–17.6) vs. 8.6 mo. (95% CI, 4.1–13.2), P = 0.035], the lower third VAF [13%; 15.4 mo. (95% CI, 11.6–19.2) vs. 8.3 mo. (95% CI, 2.3–14.4), P = 0.008], or the median VAF [20.3%; 14.0 mo. (95% CI, 9.2–18.7) vs. 8.6 mo. (95% CI, 7.5–9.8), P = 0.062] to dichotomize the patients. Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients. Further studies are needed to complement the findings of our exploratory analysis.