Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease

Portelius, Erik; Zetterberg, Henrik; Skillbäck, Tobias; Törnqvist, Ulrika; Andréasson, Ulf; Trojanowski, John Q.; Weiner, Michael W.; Shaw, Leslie M.; Mattsson, Niklas; Blennow, Kaj

doi:10.1093/brain/awv267

Cited by 235 publications

(262 citation statements)

References 36 publications

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“…The elevated Ng in AD may not be specific to hippocampal atrophy and may represent more widespread global degeneration, perhaps in AD related areas including the parietal cortex. Our results may be a consequence of small sample size and the cross‐sectional nature of this study, noting that previous studies have reported no association between CSF Ng and hippocampal volumes in a similar cross‐sectional analysis6; it may be that rates of atrophy derived from longitudinal assessments would better reflect the rate of synaptic loss. Finally, the CSF levels of neuronal and synaptic proteins such as tau and Ng are believed to reflect the state (or intensity) of the degenerative process, while MRI measurements of cortical volumes reflect the stage of degeneration,29 and thus these measures may not be expected to correlate well.…”

Section: Discussionmentioning

confidence: 63%

“…It is a postsynaptic protein that is mainly expressed in the cortex and hippocampus, where it is concentrated in dendritic spines, and has a major role in regulating LTP and learning. Cerebrospinal (CSF) Ng is elevated in patients fulfilling clinical criteria for AD compared to mild cognitive impairment (MCI) patients as well as controls, a finding that has been replicated using different assays and across clinical sites 4, 5, 6, 7. Importantly, it has not yet been determined if it is also elevated in atypical forms of AD.…”

Section: Introductionmentioning

confidence: 99%

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CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Wellington¹,

Paterson

Suárez‐González

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease.MethodsImmunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls (n = 27), biomarker‐proven amnestic Alzheimer's disease (n = 68), and the atypical visual variant of Alzheimer's (n = 19) according to international criteria. CSF total‐tau, Aβ42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1‐weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total‐tau, Aβ42, and neurofilament light were assessed.ResultsMedian cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls (P < 0.001 and P = 0.005). Both neurogranin and total‐tau concentrations, but not neurofilament light and Aβ42, were higher in typical Alzheimer's compared to atypical patients (P = 0.004 and P = 0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger (P = 0.03) and smaller (P = 0.001 and P < 0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total‐tau (P < 0.001) and a weaker association with neurofilament light (P = 0.005).InterpretationThese results show significant differences in neurogranin and total‐tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total‐tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

Wellington¹,

Paterson

Suárez‐González

et al. 2018

Ann Clin Transl Neurol

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“…Owing to the cross-sectional nature of the study, it was not possible to differentiate stable-MCI subjects from those progressing and converting into dementia. Further studies are needed to confirm the potential value of neurogranin in predicting conversion from MCI to AD [17,18]. Extensive psychometric data were not available in our study, thus preventing the study of CSF neurogranin concentrations in relation to different cognitive dimensions.…”

Section: Discussionmentioning

confidence: 90%

“…Compared with healthy controls (HC), cerebrospinal fluid (CSF) neurogranin concentrations are increased in patients with AD [13][14][15] and subjects with mild cognitive impairment (MCI) as well as MCI progressors and converters to AD (MCI-AD) [13,16]. 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: 99%

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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“…[15][16][17] Furthermore, Ng can predict conversion from mild cognitive impairment to AD, as well as predict faster cognitive decline and hippocampal atrophy rates in amyloid-positive patients with prodromal AD. 15,18 Using a sensitive sandwich immunoassay with electrochemiluminescence detection to investigate the CSF from well-characterized patients with AD and a range of other neurodegenerative disorders associated with synapse dysfunction, we aimed to explore to what extent Ng increase is specific to AD.…”

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confidence: 99%

Increased CSF neurogranin concentration is specific to Alzheimer disease

et al. 2016

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Objective: To assess the specificity of the dendritic protein neurogranin (Ng) in CSF from patients with a broad range of neurodegenerative diseases including a variety of dementias, tauopathies, and synucleinopathies.Method: An optimized immunoassay was used to analyze CSF Ng in a retrospective cohort of 331 participants with different neurodegenerative diseases, including healthy controls (n 5 19), biomarker-proven Alzheimer disease (AD) (n 5 100), genetic AD (n 5 2), behavioral variant frontotemporal dementia (n 5 20), speech variant frontotemporal dementia (n 5 21), Lewy body dementia (n 5 13), Parkinson disease (n 5 31), progressive supranuclear palsy (n 5 46), multiple system atrophy (n 5 29), as well as a heterogeneous group with non-neurodegenerative cognitive impairment (n 5 50). CSF Ng concentrations and correlations of CSF Ng with total tau, phosphorylated tau, and b-amyloid 42 concentrations, Mini-Mental State Examination score, and disease duration in the different groups were investigated.Results: Median CSF Ng concentration was higher in patients with AD compared to both controls (p , 0.001) and all other disease groups (all p , 0.001) except speech variant frontotemporal dementia. There were no significant differences in CSF Ng concentrations between any other neurodegenerative groups and controls. In addition, we found strong correlations between Ng and total tau (p , 0.001) and phosphorylated tau (p , 0.001). Conclusions:These results confirm an increase in CSF Ng concentration in patients with AD as previously reported and show that this is specific to AD and not seen in a range of other neurodegenerative diseases. There is substantial evidence that synapse loss is an early event in Alzheimer disease (AD) preceding neuronal cell death and cognitive decline.1-3 Furthermore, synapse loss is a better correlate of cognitive decline than both plaque and tangle pathology.2,4,5 Neurogranin (Ng) is a neuron-specific postsynaptic protein that is mainly expressed in the cortex, hippocampus, and amygdala by excitatory neurons, 6,7 i.e., the same brain regions that are affected in AD. It has a key role in synaptic plasticity, enhancing synaptic strength by regulating the availability of calmodulin. [8][9][10][11] It has previously been shown that Ng levels are significantly lower in the cortex and hippocampus of patients with AD compared to controls. 12,13 In a pilot study, CSF concentration of Ng was found to be increased in patients with AD, using a semiquantitative immunoprecipitation and Western blot method.14 The production of novel anti-Ng monoclonal antibodies has enabled quantification of low concentrations of Ng C-terminal peptides found in CSF.15 Consequently, Ng concentration was shown to be

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Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease

Cited by 235 publications

References 36 publications

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease

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

Increased CSF neurogranin concentration is specific to Alzheimer disease

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