Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment

Abstract

Objective: To determine whether clinical assessment methods that grade the severity of impairments within the spectrum of mild cognitive impairment (MCI) can predict clinical course, particularly among very mildly impaired individuals who do not meet formal MCI criteria as implemented in clinical trials.

Design: Cohort.

Setting: Community volunteers.

Participants: From a longitudinal study of normal (Clinical Dementia Rating [CDR] = 0; n = 77) and mildly impaired (CDR = 0.5; n = 167) participants with 5 or more annual clinical assessments, baseline level of cognitive impairment in daily life was graded using CDR sum of boxes (CDR-SB) and level of cognitive performance impairment was graded using neuropsychological test scores.

Main outcome measures: Five-year outcome measures included (1) probable Alzheimer disease (AD) diagnosis and (2) clinical "decline" (CDR-SB increase > or = 1.0). Logistic regression models were used to assess the ability of baseline measures to predict outcomes in the full sample and separately in the subjects who did not meet formal MCI criteria as implemented in a multicenter clinical trial (n = 125; "very mild cognitive impairment" [vMCI]).

Results: The presence of both higher CDR-SB and lower verbal memory and executive function at baseline predicted greater likelihood of probable AD and decline. Five-year rates of probable AD and decline in vMCI (20%, AD; 49%, decline) were intermediate between normal participants (0%, AD; 28%, decline) and participants with MCI (41%, AD; 62%, decline). Within vMCI, likelihood of probable AD was predicted by higher CDR-SB and lower executive function.

Conclusions: Even in very mildly impaired individuals who do not meet strict MCI criteria as implemented in clinical trials, the degree of cognitive impairment in daily life and performance on neuropsychological testing predict likelihood of an AD diagnosis within 5 years. The clinical determination of relative severity of impairment along the spectrum of MCI may be valuable for trials of putative disease-modifying compounds, particularly as target populations are broadened to include less impaired individuals.

Figure

Proportion of baseline clinical groups that met outcomes of probable Alzheimer disease (AD) diagnosis and clinical decline (increase in Clinical Dementia Rating sum of boxes ≥1.0) within 5 years of follow-up. Subjects with very mild cognitive impairment (vMCI) were more likely than normal subjects to decline (${\chi }_1^2=9.2$; P<.002) and be diagnosed with AD (${\chi }_1^2=17.6$; P<.001). Subjects with mild cognitive impairment (MCI) were more likely than normal subjects to decline (${\chi }_1^2=13.6$; P<.001) and to be diagnosed with AD (${\chi }_1^2=36.4$; P<.001) and were more likely than subjects with vMCI to be diagnosed with AD (${\chi }_1^2=7.0$; P<.01). For simplicity, the 7 individuals with non-AD dementia outcomes are not illustrated.