CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer's disease

Remnestål, Julia; Just, David R.; Mitsios, Nicholas; Fredolini, Claudia; Mulder, Jan; Schwenk, Jochen M.; Uhlén, Mathias; Kultima, Kim; Ingelsson, Martin; Kilander, Lena; Lannfelt, Lars; Svenningsson, Per; Nellgård, Bengt; Zetterberg, Henrik; Blennow, Kaj; Nilsson, Peter; Häggmark-Månberg, Anna

doi:10.1002/prca.201500150

Cited by 69 publications

(70 citation statements)

References 56 publications

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“…As Ng is expressed in dendrites and as CSF Ng concentrations correlate with memory impairment and reduced cerebral glucose metabolism in ADD-affected brain regions [39], this biomarker has been proposed to reflect synaptic dysfunction in ADD. Importantly, CSF Ng appears to be an ADD-specific biomarker; its concentration is unaltered or even reduced in several neurodegenerative diseases, including FTD, PD and atypical parkinsonian disorders [25, 41, 53]. Here, we re-examine the ADD specificity of CSF Ng in a large cross-sectional serie of neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 98%

“…Since the discovery that Ng is present in CSF [8], and that levels are increased in ADD [50], several recent studies have reported higher cerebrospinal fluid (CSF) Ng concentration in ADD and mild cognitive impairment (MCI) patients compared to cognitively unimpaired elderly subjects [26–28, 43]. Further, other studies suggest that increased CSF Ng concentrations may be specific for ADD [25, 41, 53]. …”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1851-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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“…Moreover, neurogranin predicts progression from MCI to AD dementia [13,17,18] and rate of cognitive decline [13], and correlates longitudinally with rates of hippocampal atrophy [18,19] as well as with reduced regional cortical glucose metabolism assessed by 18 F-Fluorodeoxyglucosepositron emission tomography ( 18 F-FDG-PET) [18]. Very recently, CSF profiling of the human brain enriched proteome has confirmed a significant association between increased neurogranin concentrations and AD [20].…”

Section: Introductionmentioning

confidence: 98%

Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study

Lista¹,

Toschi

Baldacci

et al. 2017

JAD

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Abstract. We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n = 35) S. Lista et al. / CSF Neurogranin in Neurodegenerative Diseasescognitively HC (n = 23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-␤ peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases.

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“…Furthermore, similar distribution patterns were observed for myristoylated alanine-rich C kinase substrate (MARCKS) and neuromodulin. These two presynaptic proteins, which are both involved in regulating the dynamics of the actin cytoskeleton at the synaptic membrane (Laux et al 2000) and are considered of diagnostic value for neurodegenerative diseases (Remnestal et al 2016), showed a distinct absence in layer IV and, therefore, differentiated V1 from V2. Both MARCKS mRNA and neuromodulin mRNA were co-expressed in monkey V1 (Higo et al 2002, 2004).…”

Section: Discussionmentioning

confidence: 99%

Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging

et al. 2018

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The primary visual cortex (area V1) is an extensively studied part of the cerebral cortex with well-characterized connectivity, cellular and molecular architecture and functions (for recent reviews see Amunts and Zilles, Neuron 88:1086–1107, 2015; Casagrande and Xu, Parallel visual pathways: a comparative perspective. The visual neurosciences, MIT Press, Cambridge, pp 494–506, 2004). In humans, V1 is defined by heavily myelinated fibers arriving from the radiatio optica that form the Gennari stripe in cortical layer IV, which is further subdivided into laminae IVa, IVb, IVcα and IVcβ. Due to this unique laminar pattern, V1 represents an excellent region to test whether multimodal mass spectrometric imaging could reveal novel biomolecular markers for a functionally relevant parcellation of the human cerebral cortex. Here we analyzed histological sections of three post-mortem brains with matrix-assisted laser desorption/ionization mass spectrometry imaging and laser ablation inductively coupled plasma mass spectrometry imaging to investigate the distribution of lipids, proteins and metals in human V1. We identified 71 peptides of 13 different proteins by in situ tandem mass spectrometry, of which 5 proteins show a differential laminar distribution pattern revealing the border between V1 and V2. High-accuracy mass measurements identified 123 lipid species, including glycerolipids, glycerophospholipids and sphingolipids, of which at least 20 showed differential distribution within V1 and V2. Specific lipids labeled not only myelinated layer IVb, but also IVa and especially IVc in a layer-specific manner, but also and clearly separated V1 from V2. Elemental imaging further showed a specific accumulation of copper in layer IV. In conclusion, multimodal mass spectrometry imaging identified novel biomolecular and elemental markers with specific laminar and inter-areal differences. We conclude that mass spectrometry imaging provides a promising new approach toward multimodal, molecule-based cortical parcellation.Electronic supplementary materialThe online version of this article (10.1007/s00429-018-1660-y) contains supplementary material, which is available to authorized users.

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CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer's disease

Cited by 69 publications

References 56 publications

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study

Molecular composition of the human primary visual cortex profiled by multimodal mass spectrometry imaging

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