I suspect that there may be a problem with the file system. I wonder if there might be cross-linkages or orphaned file fragments that are generated in use and then removed by the defragmentation process.
What I suggest is a full backup, preferably a disk clone as well, and then run chkdsk - you'll find that the system disk (presumably C:) can only be analysed by chkdsk after a reboot, so allow for that.
Be warned that this may find and fix corrupted files, index entries etc. and the repair can affect system files, requiring recovery work (hence the full backup and disk clone).
You can run it just to investigate, but since it won't tell you what files are affected if it finds disk errors, you have no way of knowing what damage may be caused by repairing anyway.
Of course you could just wipe the disk and start with a clean format and re-install, but it's much less fun! :)
Another approach would be to use software like WinINSTALL / LE (free) to take a snapshot of your system, then another snaphsot some time later (in your case it might be days or weeks later). The software automatically compares the two snapshots and can generate a report of the differences (files and registry entries). It's geared towards package installation, but it might be helpful for you to analyse the changes.
SD