The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease
Martí Colom‐CadenaTara L. Spires‐JonesHenrik ZetterbergKaj BlennowAnthony CaggianoSteven T. DeKoskyHoward FillitJohn HarrisonLon S. SchneiderPhilip ScheltensWillem de HaanMichael GrundmanChristopher H. van DyckNicholas J. IzzoSusan M. Catalano
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Abstract Background Synapse damage and loss are fundamental to the pathophysiology of Alzheimer’s disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD. Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance. Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD. Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs. The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. Conclusion A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.Keywords:
Tauopathy
Neurogranin
Cognitive Decline
Abstract Background Synapse damage and loss are fundamental to the pathophysiology of Alzheimer’s disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD. Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance. Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD. Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs. The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. Conclusion A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.
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In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD).The study was performed in a cohort consisting of patients with AD and those without AD, including individuals with other neurological diseases. Cerebrospinal fluid (CSF) neurogranin and α-synuclein levels were measured by sensitive enzyme-linked immunosorbent assays (ELISAs).We found significantly increased levels of CSF neurogranin and α-synuclein in patients with AD than those without AD. Neurogranin was correlated with total tau (tTau) and phosphorylated tau (pTau), as well as with cognitive decline, in patients with AD. Receiver operating characteristic (ROC) curve analysis showed good diagnostic accuracy of neurogranin for AD at a cutoff point of 306 pg per mL with an area under the curve (AUC) of 0.872 and sensitivity and specificity of 84.2% and 78%, respectively.Our findings support the use of CSF neurogranin as a biomarker of synapsis damage in patients with AD.
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Synapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease.
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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.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.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.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.
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Neurogranin is a postsynaptic protein elevated in cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients. The correlation with cognitive decline evokes promise to use CSF Neurogranin to monitor disease progression. Current assays report divergent ranges of Neurogranin concentrations, and differ in which form of Neurogranin is being measured. This study compares the analytical and clinical performance of three commonly used Neurogranin assays in the same cohort of patients. Intra-assay and inter-assay CV, LLOD, calibrators of the other assays, and Neurogranin in brain lysate were measured in: Neurogranin immunoassay performed on an Erenna instrument from WashU (St. Louis, MO), Neurogranin ELISA from ADx NeuroSciences (Ghent, Belgium), and Neurogranin ELISA from UGot (Gothenburg, Sweden). 108 CSF samples from 22 controls with subjective cognitive decline, 22 AD, 22 frontotemporal dementia, 22 dementia with Lewy Bodies, and 20 vascular dementia were selected. Passing-Bablok regression was used to compare the three assays and Kruskal-Wallis was used for Neurogranin group comparisons. Calibrators and antibodies of the three immunoassays were also tested for their reciprocal affinities on Western blot. All immunoassays had good technical performance and targeted different epitopes of Ng. Absolute Neurogranin ranged from (median+range) 1881 (330–8320) pg/mL for WashU, 372 (71–1191) pg/mL for ADx, and 416 (115–1481) pg/mL for UGot. Spearman correlations between assays were 0.95 (ADx-WashU), 0.87 (UGot-WashU), 0.81 (UGot-ADx). Proportional differences were found between all assays and a systematic difference was found only between WashU and ADx. The assays showed similar Neurogranin distribution patterns for dementia diagnoses – being high in AD compared to the other dementias and controls. Differences in absolute Neurogranin concentrations between the immunoassays were also evaluated by comparisons of the calibrators by SDS-PAGE gels and by Western blot. Results of all three assays are highly correlated. Clinical value of all Neurogranin assays is comparable, while the targeting of different epitopes per assay enables in-depth studies into Neurogranin's role in AD pathology.
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Aging is a major risk factor for Alzheimer’s disease (AD) and related dementias. We used viral vectors to initiate tau over-expression in mice of different ages. Delivery of tau containing the FTD-associated mutation P301L produced tauopathy in nontransgenic C57BL/6Nia mice, including increased phosphorylated tau and formation of neurofibrillary tangles. Surprisingly, tauopathy was only modestly increased in aged mice, and these increases seem insufficient to account for the exponential increase in risk of AD in the aged. Using viral constructs over-expressing different tau variants, we observed that 4R2N tau (without mutations) was neurotoxic, while P301L tau aggregated more. Rapamycin was used to slow the rate of biological aging, then tauopathy was induced by viral over-expression of P301L tau. The magnitude of the tauopathy produced was not affected by prior long-term treatment with rapamycin. Finally, we used viral constructs with capsids allowing uptake across the blood brain barrier to deliver P301L tau intravenously, producing modest 2-fold tau over-expression. Nontransgenic mice developed tauopathy (increased phosphorylated and aggregated tau). However, mice with pre-exising amyloid deposits developed greater tauopathy. This model will be useful to explore mechanisms of and treatments for amyloid- induced tauopathy.
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The developmental expression and the cellular localization of neurogranin (formerly designated p17), a brain-specific protein kinase C (PKC) substrate, were investigated. The developmental expression of neurogranin was studied by immunoblotting of rat brain and neuronal cell-culture extracts using neurogranin polyclonal antibodies. Neurogranin synthesis was found to be developmentally regulated, with no expression in the embryonic and neonatal period and an abrupt increase between 2 and 3 weeks of age. By immunohistochemistry, neurogranin was found essentially in the adult rat telencephalon, specifically located in the cell bodies and dendritic processes of neurons of the cerebral cortex, hippocampus, striatum, and a few other discreet areas. Neurogranin immunoreactivity was nearly absent in the thalamus, cerebellum, and brain stem. The late developmental expression and the dendritic localization of neurogranin in neurons are 2 features that also characterize the type I PKC isozyme. The specific localization of the protein in integrative areas of the rat brain suggests a highly specialized function of neurogranin in the CNS. A possible role for neurogranin in the transduction of the PKC activation signals at the postsynaptic level is suggested.
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