Suzanne E. Schindler

Photo-activatable Cre recombinase regulates gene expression in vivo

Techniques allowing precise spatial and temporal control of gene expression in the brain are needed. Herein we describe optogenetic approaches using a photo-activatable Cre recombinase (PA-Cre) to stably modify gene expression in the mouse brain. Blue light illumination for 12 hours via optical fibers activated PA-Cre in the hippocampus, a deep brain structure. Two-photon illumination through a thinned skull window for 100 minutes activated PA-Cre within a sub-millimeter region of cortex. Light activation of PA-Cre may allow permanent gene modification with improved spatiotemporal precision compared to standard methods.

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

Administration of an anti-tau antibody to transgenic mice expressing human tau and to patients with tauopathy increased the concentration of tau in plasma. Tracking tau in mice and humans Tauopathies, such as progressive supranuclear palsy and Alzheimer’s disease, are a group of neurodegenerative diseases characterized by the accumulation of aggregated forms of tau protein in the brain. Administration of anti-tau antibodies is a new treatment approach being tested for these diseases. Tau is present at high levels in the brain and low levels in the plasma. Peripheral administration of an anti-tau antibody markedly increased tau in the plasma of both transgenic mice expressing human tau and patients with tauopathy (Yanamandra et al.). The increase in plasma tau in mice correlated with an increase in brain extracellular and soluble tau. Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.

Autosomal dominant Alzheimer disease: a unique resource to study CSF biomarker changes in preclinical AD

Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

Upward drift in cerebrospinal fluid amyloid β 42 assay values for more than 10 years

The best‐established cerebrospinal fluid (CSF) biomarkers for Alzheimers disease are levels of amyloid β 42 (Aβ42), total tau (tau), and phosphorylated tau 181 (ptau). We examined whether a widely used commercial immunoassay for CSF Aβ42, tau, and ptau provided stable measurements for more than 10 years.

Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging.

Levels of amyloid β peptide 42 (Aβ42), total tau, and phosphorylated tau‐181 are well‐established cerebrospinal fluid (CSF) biomarkers of Alzheimers disease, but variability in manual plate‐based assays has limited their use. We examined the relationship between CSF biomarkers, as measured by a novel automated immunoassay platform, and amyloid positron emission tomography.

CSF sTREM2: marking the tipping point between preclinical AD and dementia?

Biomarkers for Alzheimers disease (AD) have improved our understanding of the temporal sequence of biological events that lead to AD dementia (Jack et al, ). AD is characterized neuropathologically by amyloid plaques comprised of the amyloid‐β peptide and neurofibrillary tangles comprised of tau. Brain amyloid deposition, as evidenced by a decline in amyloid‐β peptide 42 (Aβ42) in the cerebrospinal fluid (CSF) or by binding of amyloid PET ligands, is thought to be a key initiating event in AD and begins many years prior to the onset of dementia. A rise in CSF tau and phosphorylated tau in the setting of Aβ deposition appears to reflect neurodegeneration and also begins years prior to the onset of dementia but after Aβ deposition has begun to accumulate. Individuals with “preclinical AD,” that is, normal cognition but abnormal AD biomarkers, have a much higher risk for developing AD dementia but may remain cognitively normal for years (Vos et al, ). While deposition of amyloid and formation of tau tangles are necessary for AD to occur, it is likely that additional events involving inflammation or other processes contribute to crossing the tipping point from preclinical AD to AD dementia. Current efforts are aimed at defining the biomarker(s) that best predict the transition from cognitive normality to abnormality. A biomarker that is closely associated with the onset of cognitive decline could help us to understand the biological events that connect amyloid deposition and tangle formation to cognitive decline and could have significant practical value in AD diagnosis and clinical trial design.

Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers

Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-β42, tau, ptau181, tau/amyloid-β42, ptau181/amyloid-β42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ∼70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE ɛ in modulating amyloid accumulation in CDR > 0 with APOE ɛ4 being deleterious and APOE ɛ2 protective.

THE EMERGING CEREBROSPINAL FLUID BIOMARKER SNAP-25 IS ELEVATED IN APOEε4 CARRIERS IN COGNITIVELY NORMAL INDIVIDUALS

With respect to CSFAD biomarkers, therewas a significant positive relationship between CSF TMAO and p-tau (b1⁄40.09, p1⁄40.006) and p-tau/Ab42 (b1⁄40.11, p1⁄40.013; Figure 1B). There was no significant relationship between CSF TMAO and Ab42/Ab40 (b1⁄4-0.003, p1⁄40.13). Conclusions:CSF TMAO, a gut microbial-derived metabolite, is higher in individuals with MCI and dementia due to AD, and higher CSF TMAO is associated with elevated AD pathology as measured by CSF biomarkers. While these findings suggest a potential role for TMAO in AD, additional studies are needed to further characterize this relationship and potential mechanisms.

NOVEL CSF BIOMARKERS OF NEURONAL INJURY, SYNAPTIC DYSFUNCTION AND NEUROINFLAMMATION IN AUTOSOMAL DOMINANT ALZHEIMER DISEASE: VILIP-1, NEUROGRANIN, SNAP-25 AND YKL-40 IN THE DOMINANTLY INHERITED ALZHEIMER NETWORK (DIAN)

O3-14-01 NOVEL CSF BIOMARKERS OF NEURONAL INJURY, SYNAPTIC DYSFUNCTION AND NEUROINFLAMMATION IN AUTOSOMAL DOMINANTALZHEIMER DISEASE: VILIP-1, NEUROGRANIN, SNAP-25 AND YKL-40 IN THE DOMINANTLY INHERITED ALZHEIMER NETWORK (DIAN) Anne M. Fagan, Yan Li, Kaitlin Todd, Elizabeth M. Herries, Rachel L. Henson, Suzanne E. Schindler, Julia D. Gray, GuoqiaoWang, Danielle Graham, Leona Fields, Leslie M. Shaw, Jack H. Ladenson, Jason Hassenstab, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Chengjie Xiong, Washington University School of Medicine, Saint Louis, MO, USA; Washington University School of Medicine, St. Louis, MO, USA; Biogen, Cambridge, MA, USA; University of Pennsylvania, Philadelphia, PA, USA; Washington University in St. Louis School of Medicine, St. Louis, MO, USA. Contact e-mail: fagana@ wustl.edu

Double Monoclonal Immunoassay for Quantifying Human Visinin-Like Protein-1 in CSF

To the Editor: Alzheimer disease (AD)1 is thought to account for up to 70% of all dementia cases and is estimated to be the third leading cause of death in the US (1). To date, clinical trials of potential drug therapies have had little success when cognitive defects are present before the start of the clinical trial. Tau protein, phosphorylated tau protein, and Aβ 42/Aβ40 amyloid peptide are implicated in the neuropathology of AD but could be altered by potential drug candidates. Thus, there is an expanding search for additional biomarkers to identify subjects at a high risk of developing symptomatic AD in the future. Visinin-like protein-1 (VILIP-1) in the cerebrospinal fluid (CSF) has shown promise to predict cognitive symptoms of AD years before they occur (2, 3). Our initial VILIP-1 assay used a murine monoclonal capture antibody and an affinity-purified rabbit (4), and then later an affinity-purified sheep antibody for detection (2, 3). Here, we describe a new 2–monoclonal antibody (mAb) VILIP-1 assay and evaluation of different recombinant forms of VILIP-1 as standards with the various assays. We also assessed antibody cross-reactivity to other neuronal calcium sensor proteins. mAbs 3A8.1 (IgG1k) and 2B9.3 (IgG2ak) were obtained from fusions 4399 …