Cherry Creek is a more of an upscale area. Lots of shops, but also good restaurants, some of them trendy. As someone pointed out the JW there is great. If the missus likes shopping boutiques and strolling through nice neighborhoods, it would be a good choice.

Downtown used to be one of those business districts that emptied out at night. There are lot more condos/apartments now, which means a lot more actual people around nights and weekends, and some good restaurants. The Curtis is a cool hotel and there other similar choices (Oxford, Crawford, Monaco).

LoDo blew up after Coors Field opened, and was sort of the main restaurant and bar scene in the late 90s and early 00s. Now, maybe not the area you want to spend a nice weekend with your wife. The new(ish) Union Station is really cool. That's where the Crawford Hotel is, mentioned above. Have a drink at the Terminal Bar.

LoHi, Ballpark, RiNo are more of the new(er) trendy areas. There's a Hilton Garden Inn right near Coors Field, that's between (walking distance) Ballpark and LoHi. Lots of breweries and beer gardens in the area. Also really close to Jackson's, where at last check the Denver Hokies watched games. RiNo is the newest hipster area, with some great restaurants and bars, but still relatively transitional. Personally I wouldn't stay there. Not because it's unsafe or anything; more because I'm too old (49) for the scene.

Bottom line: if you like shopping and a more upscale area, I'd do Cherry Creek, and Uber to some of the other areas. If you want a little more buzz and authenticity, I'd consider something like that Hilton Garden Inn.

@me when you get to restaurants and especially breweries.