Progranulin and neuropathological features of Alzheimer's disease: longitudinal study

Abstract

Background: Progranulin is an anti-inflammatory protein that plays an essential role in the synapse function and the maintenance of neurons in the central nervous system (CNS). It has been shown that the CSF level of progranulin increases in Alzheimer's disease (AD) patients and is associated with the deposition of amyloid-beta (Aβ) and tau in the brain tissue. In this study, we aimed to assess the longitudinal changes in cerebrospinal fluid (CSF) progranulin levels during different pathophysiological stages of AD and investigate associated AD pathologic features.

Methods: We obtained the CSF and neuroimaging data of 1001 subjects from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A + /TN + , A + /TN-, A-/TN + , and A-/TN-.

Results: Based on our analysis there was a significant difference in CSF progranulin (P = 0.001) between ATN groups. Further ANOVA analysis revealed that there was no significant difference in the rate of change of CSF-progranulin ATN groups. We found that the rate of change of CSF progranulin was associated with baseline Aβ-PET only in the A-/TN + group. A significant association was found between the rate of change of CSF progranulin and the Aβ-PET rate of change only in A-/TN + CONCLUSION: Our findings revealed that an increase in CSF progranulin over time is associated with faster formation of Aβ plaques in patients with only tau pathology based on the A/T/N classification (suspected non-Alzheimer's pathology). Together, our findings showed that the role of progranulin-related microglial activity on AD pathology can be stage-dependent, complicated, and more prominent in non-AD pathologic changes. Thus, there is a need for further studies to consider progranulin-based therapies for AD treatment.

Keywords: Alzheimer’s disease; Amyloid βeta; Microglia; Progranulin; Tau.

Figure1

Baseline level of CSF progranulin

Fig. 2

A longitudinal trajectories of CSF progranulin and B rate of change of CSF progranulin

Fig. 3

A association between baseline level of CSF progranulin and B rate of change of CSF progranulin with cognitive performance (ADNI-mem)

Fig. 4

Association between baseline CSF progranulin and tau and Aβ-PET rate of change (A) and baseline tau and Aβ-PET (B). association between rate of change of CSF progranulin and tau and Aβ-PET rate of change (C) and baseline tau and Aβ-PET (D)