Zetterberg, Henrik

AbstractIntroductionThis study investigated the comparability of potential Alzheimer's disease (AD) biomarkers across blood fractions and assay platforms.MethodsNonfasting serum and plasma samples from 300 participants (150 AD patients and 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots.ResultsOn the Meso Scale Discovery multiplex platform, 10 of the 21 markers shared >50% of the variance across blood fractions (serum amyloid A R2 = 0.99, interleukin (IL)10 R2 = 0.95, fatty acid‐binding protein (FABP) R2 = 0.94, I309 R2 = 0.94, IL‐5 R2 = 0.94, IL‐6 R2 = 0.94, eotaxin3 R2 = 0.91, IL‐18 R2 = 0.87, soluble tumor necrosis factor receptor 1 R2 = 0.85, and pancreatic polypeptide R2 = 0.81). When examining protein concentrations across platforms, only five markers shared >50% of the variance (beta 2 microglobulin R2 = 0.92, IL‐18 R2 = 0.80, factor VII R2 = 0.78, CRP R2 = 0.74, and FABP R2 = 0.70).DiscussionThe current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers.

AbstractIntroductionWe 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.MethodsReview 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.ResultsCSF 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.DiscussionFurther studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease‐modifying therapeutic trials.

Background and purposeHereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported.MethodsCSF1R exons 12−22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced.ResultsOne patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS.ConclusionsOur study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.

AbstractTraumatic brain injury (TBI) and post‐traumatic stress disorder (PTSD) are signature injuries of the wars in Iraq and Afghanistan and have been linked to an increased risk of Alzheimer's disease (AD) and other dementias. A meeting hosted by the Alzheimer's Association and the Veterans' Health Research Institute (NCIRE) in May 2012 brought together experts from the U.S. military and academic medical centers around the world to discuss current evidence and hypotheses regarding the pathophysiological mechanisms linking TBI, PTSD, and AD. Studies underway in civilian and military populations were highlighted, along with new research initiatives such as a study to extend the Alzheimer's Disease Neuroimaging Initiative (ADNI) to a population of veterans exposed to TBI and PTSD. Greater collaboration and data sharing among diverse research groups is needed to advance an understanding and appropriate interventions in this continuum of military injuries and neurodegenerative disease in the aging veteran.

BackgroundThe cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.MethodsThe program is open for laboratories using commercially available kits for Aβ, T‐tau, or P‐tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.ResultsForty laboratories participated. Twenty‐six used INNOTEST enzyme‐linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO‐BIA AlzBio3 kit (both measure Aβ‐(1‐42), P‐tau(181P), and T‐tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN‐42, AβN‐40, and AβN‐38) or T‐tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within‐laboratory precisions differed considerably between biomarkers within individual laboratories.ConclusionsMeasurements of CSF AD biomarkers show large between‐laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.