Elizabeth M. Herries

Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease

IMPORTANCE Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse. OBJECTIVE To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic-based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014. MAIN OUTCOME AND MEASURE Levels of NGRN in CSF samples. RESULTS Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD. CONCLUSIONS AND RELEVANCE Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss.

Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.

IMPORTANCE Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. OBJECTIVE To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. MAIN OUTCOMES AND MEASURES Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. RESULTS A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: β estimate, 0.29; P = .001; global composite scores: β estimate, -0.11; P = .001; episodic memory scores: β estimate, -0.18; P < .001; and semantic memory scores: β estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181. CONCLUSIONS AND RELEVANCE The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.

Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid.

We hypothesized that one mechanism underlying the association between obstructive sleep apnea (OSA) and Alzheimers disease is OSA leading to decreased slow wave activity (SWA), increased synaptic activity, decreased glymphatic clearance, and increased amyloid‐β. Polysomnography and lumbar puncture were performed in OSA and control groups. SWA negatively correlated with cerebrospinal fluid (CSF) amyloid‐β‐40 among controls and was decreased in the OSA group. Unexpectedly, amyloid‐β‐40 was decreased in the OSA group. Other neuronally derived proteins, but not total protein, were also decreased in the OSA group, suggesting that OSA may affect the interaction between interstitial and cerebrospinal fluid. Ann Neurol 2016;80:154–159

Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease

Individuals in early stages of Alzheimers disease are a targeted population for secondary prevention trials aimed at preserving normal cognition. Understanding within‐person biomarker(s) change over time is critical for trial enrollment and design.

Neurogranin as Cerebrospinal Fluid Biomarker for Alzheimer Disease: An Assay Comparison Study

BACKGROUND Neurogranin in cerebrospinal fluid (CSF) correlates with cognitive decline and is a potential novel biomarker for Alzheimer disease (AD) dementia. We investigated the analytical and diagnostic performance of 3 commonly used neurogranin assays in the same cohort of patients to improve the interpretability of CSF neurogranin test results. METHODS The neurogranin Erenna® assay from Washington University, St. Louis, MO (WashU); ELISA from ADx Neurosciences; and ELISA from Gothenburg University, Mölndal, Sweden (UGot), were compared using silver staining and Western blot after gel electrophoresis. Clinical performance of the 3 assays was compared in samples from individuals diagnosed with subjective cognitive decline (n = 22), and in patients with AD (n = 22), frontotemporal dementia (n = 22), dementia with Lewy bodies (n = 22), or vascular dementia (n = 20), adjusted for sex and age. RESULTS The assays detected different epitopes of neurogranin: the WashU assay detected the N-terminal part of neurogranin (S10-D23) and a C-terminal part (G49-G60), the ADx assay detected C-terminal neurogranin truncated at P75, and the UGot assay detected the C-terminal neurogranin with intact ending (D78). Spearman ρ was 0.95 between ADx and WashU, 0.87 between UGot and WashU, and 0.81 between UGot and ADx. ANCOVA (analysis of covariance) showed group differences for ranked neurogranin concentrations in each assay (all P < 0.05), with specific increases in AD. CONCLUSIONS Although the 3 assays target different epitopes on neurogranin and have different calibrators, the high correlations and the similar group differences suggest that the different forms of neurogranin in CSF carry similar diagnostic information, at least in the context of neurodegenerative diseases.

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

QUANTIFYING CSF BIOFLUID BIOMARKERS OF NEURONAL INJURY, NEUROINFLAMMATION AND NEUROTRANSMISSION IN ANTIBODY-MEDIATED ENCEPHALITIS

LEARN 34.00 420.22 59.54 0.7077 A4 26.00 414.86 50.64 All 60.00 417.90 55.47 Wake after Sleep Onset (WASO) (minutes) N Mean SD t-Test P LEARN 34.00 37.19 14.24 0.7931 A4 26.00 38.22 15.48 All 60.00 37.63 14.67 Average Wake Bout Length (minutes) N Mean SD t-Test P LEARN 34.00 1.31 0.29 0.9011 A4 26.00 1.32 0.31 All 60.00 1.32 0.29 Sleep Efficiency (%) N Mean SD t-Test P LEARN 34.00 86.82 5.52 0.9329 A4 26.00 86.93 4.95 All 60.00 86.86 5.24 Fragmentation Index N Mean SD t-Test P LEARN 34.00 19.61 6.97 0.2781 A4 26.00 18.06 3.85 All 60.00 18.94 5.83 Time in Bed (minutes) N Mean SD t-Test P LEARN 34.00 483.36 54.29 0.6267 A4 26.00 476.47 53.91 All 60.00 480.38 53.78 Sleep Onset Latency (minutes) N Mean SD t-Test P LEARN 34.00 12.83 17.29 0.5661 A4 26.00 10.79 9.81 All 60.00 11.94 14.46 Interdaily Stability

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 …

EMERGING CSF BIOMARKERS AS PREDICTORS OF ALZHEIMER DISEASE DEMENTIA

APL1b28 peptide in plasma. The concentration of APL1b28 is w0.4pM, which is much less than that in CSF (w500pM). Currently, we are analyzing the APL1b28 ratio in CSF and plasma paired samples. We are also investigating correlation between plasma APL1b28 ratio and CSF Ab42 ratio. Conclusions:We have tried to develop an Ab42 surrogate marker in peripheral blood. We intend to show how and to what degree the plasma APL1b28 ratio correlates with CSF Ab42 ratio.