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    Online Resource
    Levels of the synaptic proteins PSD‐95, SNAP‐25, and neurogranin are selectively increased in the cerebrospinal fluid of patients with Alzheimer’s disease
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S5 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S5 ( 2021-12)
    Abstract: Synaptic dysfunction and loss occur early in Alzheimer’s Disease (AD) dementia and are closely linked to cognitive decline. Levels of both pre‐ and post‐synaptic proteins are reduced in AD brains while recent studies have shown increased levels of synaptic proteins in the cerebrospinal fluid (CSF) already in the early stages of AD, presumably due to release from degenerating synapses. We measured CSF levels of the novel post‐synaptic marker PSD‐95 together with levels of SNAP‐25 (pre‐synaptic) and neurogranin (post‐synaptic), two emerging synaptic biomarkers, in subjects with AD, other neurodegenerative diseases (OND), and controls. Method CSF samples from 158 patients undergoing diagnostic lumbar punctures were selected from banked samples. Clinical diagnoses were established by chart review and AD status was verified by CSF ATN biomarkers. 30 subjects had mild cognitive impairment or dementia due to AD, 69 had OND, and 59 were neurological controls (NC). In addition, 30 CSF samples were obtained from healthy subjects (HC) participating in a research study. Levels of PSD‐95 and SNAP‐25 were measured by Quanterix SIMOA assays and neurogranin by an automated Euroimmun ELISA assay. Result All subjects had detectable CSF levels of PSD‐95, SNAP‐25, and neurogranin. Levels of all three synaptic markers were higher in AD subjects compared to subjects with OND (p=0.04, p 〈 0.001, and p 〈 0.001, respectively) and both control groups, while levels of SNAP‐25 and neurogranin were lower in OND subjects compared to NC (p=0.005, and p=0.025, respectively). There were tight correlations between levels of PSD‐95, SNAP‐25, and neurogranin with the strongest correlation between SNAP‐25 and neurogranin (r=0.87; r 2 =0.76; p 〈 0.0001). Conclusion Our data suggest that PSD‐95 and other emerging synaptic markers are selectively increased in the CSF of subjects with AD and that levels of both pre‐ and post‐synaptic markers are tightly correlated. Specific biomarkers for AD‐associated synaptic pathology may hold promise to discriminate AD from other neurodegenerative disorders, to correlate with cognitive decline, and to monitor responses to disease‐modifying drugs reducing synaptic degeneration.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S5
    DOI: 10.1002/alz.056339
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 2
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    Online Resource
    Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer’s disease
    Springer Science and Business Media LLC ; 2022
    In:  Alzheimer's Research & Therapy Vol. 14, No. 1 ( 2022-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2022-12)
    Abstract: There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer’s disease (AD). Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development. Methods We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. CSF samples from two well-characterized cohorts ( n =178 and n =156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC). Results All subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders. Conclusion The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration.
    Type of Medium: Online Resource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-022-01002-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2506521-X
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