Abstract
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.
Highlights
Synapses are the fundamental units that mediate neuronal communication
Incorporate samples previously analysed and increase the sample size: (1) Enzyme-linked immunosorbent assay (ELISA). 71 CSF samples from amnestic Alzheimer’s disease (AD) (n = 49), posterior cortical atrophy (PCA) (n = 14) and control participants (n = 8), were measured using an enzymelinked immunosorbent assays (ELISAs) assay for Ng; (2) MSD platform. 43 samples were run on an MSD platform (Meso Scale Discovery, Rockville, MD, USA), including amnestic AD (n = 19), PCA (n = 5) and controls (n = 19), to measure CSF Ng, as previously described.[9]
Median CSF neurofilament light (NFL) levels were higher in the amnestic AD and PCA groups (1408 and 1360 pg/mL, respectively) than controls (560 pg/mL) (P < 0.0001 for both comparisons with controls)
Summary
Synapses are the fundamental units that mediate neuronal communication Their plasticity underlies learning and memory, through mechanisms including long-term potentiation (LTP) and depression (LTD). There is substantial evidence that synapse loss is an early event in Alzheimer’s disease (AD), preceding neuronal cell death and cognitive decline and is found throughout the neuropil without any clear relation to amyloid plaques.[1,2,3] Biomarkers of synapse dysfunction or loss could potentially be useful in identifying Alzheimer’s disease patients in the predementia stage as well providing information about disease pathophysiology that could have utility in clinical drug trials. It might relate to the anatomical focus of the disease, noting that Ng is highly expressed in the amygdala, hippocampi and cortical regions,[10,11] areas typically and prominently involved in AD, there is prominent hippocampal involvement in some forms of frontotemporal dementia (FTD).[12] An alternative explanation is that it is specific to the pathological process that underpins AD. We hypothesized that patients with PCA due to AD would have lower concentrations of Ng than patients with typical AD, and that this would relate to the degree of medial temporal lobe involvement
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