RYR2 and Cognitive impairment: RyR remodeling, in turn, results in impaired Ca2+ handling because of a pathological Ca2+ leak from the sarcoplasmic reticulum/ER (SR/ER) and is associated with multiple organ dysfunction, including cognitive impairment (54, 58), heart failure (59), and respiratory/locomotor muscle weakness (47, 58, 60–65).