Preheat oven to 375°F. Butter a 9x13 inch baking dish and set aside on cutting board.
Cook pasta in salted boiling water until al dente (2 minutes less than package directions). Drain and return to pot. Do not rinse.
While pasta cooks, make cheese sauce: Melt 4 tablespoons butter in grill or cast iron skillet over medium heat. Whisk in flour and cook for 2 minutes, stirring constantly with whisk, until golden and bubbling.
Gradually add warm milk and cream, whisking constantly to prevent lumps. Bring to a gentle simmer and cook for 5 minutes, stirring occasionally, until sauce thickens enough to coat the back of a spoon.
Remove from heat. Stir in Dijon mustard, garlic powder, onion powder, cayenne if using, salt, and pepper using a wooden spoon.
Add cheddar, gruyere, and mozzarella cheese, stirring until completely melted and smooth. Taste and adjust seasoning.
Pour cheese sauce over cooked pasta in the pot. Stir with tongs until pasta is completely coated.
Transfer mac and cheese to prepared baking dish, spreading evenly.
Make topping: In a small mixing bowl, combine panko breadcrumbs, melted butter, parmesan cheese, and parsley. Sprinkle evenly over mac and cheese.
Bake for 20-25 minutes until bubbly and golden brown on top. Let rest for 5 minutes on cutting board before serving.