Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

作者：Villemagne, Victor L.^*; Burnham, Samantha; Bourgeat, Pierrick; Brown, Belinda; Ellis, Kathryn A.; Salvado, Olivier; Szoeke, Cassandra; Macaulay, S. Lance; Martins, Ralph; Maruff, Paul; Ames, David; Rowe, Christopher C.; Masters, Colin L.

来源：Lancet Neurology, 2013, 12(4): 357-367.

DOI：10.1016/S1474-4422(13)70044-9

• ASSOCIATION WORKGROUPS
• DIAGNOSTIC GUIDELINES
• NATIONAL INSTITUTE
• HYPOTHETICAL MODEL
• IMPAIRMENT
• RECOMMENDATIONS
• ATROPHY
• INDIVIDUALS
• PROGRESSION
• BIOMARKERS

Background Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid beta (A beta) deposition, cerebral atrophy, and cognitive decline. @@@ Methods In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B (C-11-PiB) PET scan. We included participants with three or more C-11-PiB PET follow-up assessments. A beta burden was expressed as C-11-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1.5 was used to discriminate high from low A beta burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for A beta deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of A beta deposition to calculate the trajectory of each variable over time. @@@ Findings 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3-8 (95% CI CI 3.6-3-9) years. At baseline, significantly higher A beta burdens were noted in patients with AD (2.27, SD 0.43) and those with MCI (1.94, 0.64) than in healthy controls (1.38, 0.39). At follow-up, 163 (82%) of the 200 participants showed positive rates of A beta accumulation. A beta deposition was estimated to take 19.2 (95% CI 16.8-22.5) years in an almost linear fashion with a mean increase of 0.043 (95% CI 0.037-0.049) SUVR per year-to go from the threshold of C-11-PiB positivity (1.5 SUVR) to the levels observed in AD. It was estimated to take 12.0 (95% CI 10.1-14.9) years from the levels observed in healthy controls with low A beta deposition (1.2 [SD 0.1] SUVR) to the threshold of C-11-PiB positivity. As AD progressed, the rate of A beta deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which A beta deposition reaches our threshold of positivity at 17.0 (95% CI 14.9-19.9) years, hippocampal atrophy at 4.2 (3.6-5.1) years, and memory impairment at 3.3 (2.5-4.5) years before the onset of dementia (clinical dementia rating score 1). @@@ Interpretation A beta deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness.

• 出版日期2013-4