I don't even know if any apps of this category EXIST, but I know that it would be rather useful. What I've got in mind is something that tracks processes - particularly apps from the Portableapps folder - and acts like a firewall for the registry. That way, if someone finds an app that works without the registry but wants to use it anyway (Looking at you, scirra.com team!) you can use it anyway.
I know that the stuff here wouldn't need the registry blocker, but there are some "portable" apps that aren't portable (like construct 2 by scirra 
) that technically work but just have the registry problem. BUT if someone made an app that basically firewalls the registry, problem solved! I've tested it, if you clean those files out of the registry (or bounce them with the app I'm thinking of) Construct works just fine. If that one works, there have to be others that can be portable-ized like that.
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I'm not entirely sure what you're after, but I use MJ Registry Watcher quite a lot - http://www.jacobsm.com/mjsoft.htm#rgwtchr
It runs in your systray and alerts you to any registry changes (and system files too if you wish) and allows you to block them if you want to, or just to log them. Works well for me and has various configurations and settings to choose from.
I'm not sure how well it catches x64 reg changes though.
That sounds right from the description on the site... but I'm confused. I can't figure out how it works! But if I can get it to work, that'd be perfect. The only thing missing would be a system that compares newly placed registry files and removes the ones that were written by "stranger" programs coming from a flash drive.