In the present study, we analyzed and compared the plasma concentration of NfL as well as the volume differences in hippocampus and amygdala among patients with AD, patients with aMCI and normal elderly. Finally, we reached some interesting conclusions: a) the concentration of plasma NfL in aMCI group and normal group were lower (p < 0.05)than that in AD group, but there was no significant difference(p > 0.05) between aMCI group and normal group; b) the volume(both left and right) of hippocampus and amygdala in aMCI group and normal group were larger (p < 0.05)than that in AD group, but there was no significant difference(p > 0.05) between aMCI group and normal group; c) plasma NfL was negatively correlated (p < 0.05)with MoCA total score (r=-0.415, p = 0.013), right hippocampal volume(r=-0.335,p = 0.036) and right amygdala volume(r=-0.337, p = 0.048).
NfL is an important cytoarchitectural protein present primarily in large-caliber myelinated axons31,and increased NfL in CSF will indicate damage or degeneration of these axons. This protein appears to be relatively independent of tau and amyloid levels, and might correlate with symptomology, progression, and survival32. Now NfL has been considered as an especially promising biomarker for neurodegeneration because it can be measurable in plasma33. Single molecule array (SiMoA) digital immunoassay platform can offer heightened sensitivity by miniaturizing the reaction volume34, and several biomarkers indicative of peptide fragmentation and neuronal dysfunction can be accurately quantified in peripheral blood. In our study, we used this Simoa technology to compare the plasma NFL concentrations of AD, aMCI and normal elderly people(their gender, age and education are matched), and found the concentration of plasma NfL in AD group were significantly higher(p < 0.05) than that in aMCI group and normal group. Previous studies had confirmed that AD was associated with elevated NFL in plasma, so our findings were consistent8,9. However, we did not find any difference in plasma NfL between patients with aMCI and normal elderly, which was inconsistent with the conclusion of Zhow W7 et al. So the relationship between NfL and aMCI needs to be further verified.
Atrophy of the medial temporal lobe, a critical region involved in memory formation, is considered as a recognized marker for AD35. The hippocampus and amygdala, both residing in the medial temporal lobe, are proved to be associated with declarative memory and emotional processing, respectively36. As the atrophy of hippocampal and amygdalar are already evident in the prodromal stage of AD37, the volumetric measurements of hippocampus and amygdala have been used to assist the clinical diagnosis of AD38 and to predict the cognitive status of the elderly39. As expected, the volume of hippocampus and amygdala in AD patients was significantly smaller than that in aMCI and normal old people, in concordance with previous publications39–41. Then by using partial correlation analysis (adjusting hypertension), we found plasma NfL was negatively correlated with MoCA total score (r=-0.415, p = 0.013), right hippocampal volume(r=-0.335,p = 0.036) and right amygdala volume(r=-0.337, p = 0.048).
Parbo P42 et al pointed that plasma NfL levels were inverse correlated with levels of inflammation in cortical areas in AD. Mattsson N33 et al found that faster increase in plasma NfL levels correlated with faster rates of atrophy and hypometabolism, and faster worsening in global cognition in aMCI and AD. And Weston PSJ43 et al also found that serum NfL correlated with baseline brain volume and whole-brain atrophy rate in patients with familial Alzheimer disease. So we had jointly confirmed that there was a certain correlation between plasma NfL and cognitive related brain regions. However, we only found that plasma NfL was related to the right hippocampus and right amygdala, but not to the left. Wang L44 et al found that the functional connectivity between the right hippocampus and a set of regions(such as medial prefrontal cortex, right inferotemporal cortex, right cuneus extending into precuneus, ventral anterior cingulate cortex, left cuneus, right superior and middle temporal gyrus and posterior cingulate cortex)was disrupted in AD. Sohn WS45 et al also believed that the right hippocampal connectivity was relatively by AD progression. And López-Jaramillo C46 et also found that lithium-treated bipolar I disorder patients had larger right thalamus than unmedicated patients and controls. Therefore, we speculated that plasma NFL had some intrinsic relationship with the right hippocampus and the right amygdala, although the mechanism was not fully understood.
Our study has certain limitations: first, it’s just a cross-sectional study that could not establish a causal link; second, the relatively small sample size reduced the reliability of the study; third, we lacked the gold standard to diagnose AD and aMCI.