Abstract and Introduction
Background: In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD).
Methods: 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).
Results: 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.
Conclusions: Our findings support the use of CSF neurogranin as a biomarker of synapsis damage in patients with AD.
Alzheimer disease (AD), one of the most prevalent neurodegenerative disorders worldwide, is characterized by memory loss and cognitive impairment. The pathological hallmarks of the disease are the extracellular amyloid-β (Aβ) peptides deposition, the intracellular neurofibrillary tangles consisting of phosphorylated tau (pTau) protein, the loss of synapses, and neuroinflammation.[1,2]
Cognitive decline is closely associated with synapse loss and neuropathological lesions in many brain regions as a consequence of direct effects of Aβ and tau proteins on synaptic structural plasticity, as well as indirect effects of the inflammatory response on the neuronal process. AD has a slowly progressive clinical course which, based on the symptoms, can generally be divided into 3 phases: initial, intermediate, and terminal. Dementia represents the end stage of the disease. Also, a preclinical stage and a prodromal stage, the latter of which is also referred to as mild cognitive impairment (MCI) due to AD, can be identified, especially in the field of clinical research.
The preclinical stage is defined by the presence of typical AD alterations detected by cerebrospinal fluid (CSF) biomarkers in the absence of signs and/or symptoms of the disease. MCI due to AD, however, is characterized by the presence of an initial memory disorder but no significant impact on the life of the patient. We note that neuropathological alterations in AD occur several years before the onset of cognitive decline, making CSF biomarkers a useful tool for supporting the early diagnosis of the disease and the differential diagnosis between AD and other forms of dementia.[6,7]
Currently, 3 CSF molecules, known as core CSF biomarkers, including total tau (tTau), pTau, and Aβ42 peptide, have been internationally recognized as research clinical diagnostic tools for AD.[8–10] Specifically, the typical AD biochemical profile is defined by decreased Aβ42 levels associated with increased tTau and pTau levels.[11,12] Alterations of such biomarkers reflect the main pathophysiological mechanisms of the disease. Specifically, the decrease in Aβ42 levels is the consequence of amyloid-plaque deposition, whereas the increase in pTau and tTau levels reflects the formation of neurofibrillary tangles and related neuronal damage.
Although Aβ42 changes are typically observed only in AD, tau changes are not characteristic of the disease. Indeed, elevated tau levels can be detected in several neurodegenerative disorders, such as Creutzfeldt-Jacob disease, Wernicke encephalopathy, severe malaria, hydrocephalus, and brain cancer,[13–16] referred to collectively as "tauopathies". Therefore, additional specific biomarkers reflecting synaptic plasticity are needed; several molecules have been studied as possibilities.[18–22] Among molecules involved in synaptic dysfunction or neurodegeneration,[23–25] neurogranin and α-synuclein seem to be promising as novel molecular biomarkers for AD.
The aim of the present study is to assess the diagnostic value of CSF neurogranin and α-synuclein in a cohort consisting of patients with and without AD. Also, we evaluated the relationship of these analytes with CSF core biomarkers. The combination of these biomarkers may increase the diagnostic accuracy of AD testing, as well as allowing us to better understand the pathogenesis of the disease, to identify potential drug targets, design clinical trials, and improve clinical practice in AD diagnostic workup.
Lab Med. 2021;52(2):188-196. © 2021 American Society for Clinical Pathology