Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [ ¹¹ C]PiB

Abstract

Objective: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (A␤) deposition in vivo in individuals without dementia. Method: [11 C]PiB images were obtained to measure fibrillar A␤ burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating ϭ 0.5. To measure [11 C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. Results: [11 C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. Conclusions:Higher A␤ deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early A␤ deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging. Postmortem studies of associations between amyloid-beta (A␤) burden and antemortem cognition yield conflicting findings. 1,2 We found that longitudinal cognitive trajectories were similar between cognitively normal individuals with and without Alzheimer disease (AD) neuropathology and that both groups differed from individuals with mild cognitive impairment (MCI) or AD, who showed marked cognitive decline. 3Radiotracers for in vivo imaging of fibrillar A␤ burden allow prospective investigation of relationships between cognitive performance and A␤. Consistent with postmortem studies, 20% to 30% of clinically normal individuals show A␤ deposition on imaging.4,5 Across the spectrum of cognitive function, lower memory correlates cross-sectionally with higher [ 11 C]PiB. 6,7 The only study investigating longitudinal changes in cognition in relation to A␤ e-Pub ahead of print on February 10, 2010, at www.neurology.org.

Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers

“…2 We again found an acceleration of memory decline in preclinical APOE 4 carriers beginning around age 55-60 years, but no similar acceleration of decline on any frontal/executive measure despite the greater amount of fibrillar amyloid in frontal than medial temporal regions. [1][2][3][4][5][6] The frontal/executive measures we used were age-sensitive, surveyed a wide range of relevant skills, and comprised a unique dataset in the extensive literature of cognitive aging. Although none demonstrated significant quadratic effects, several showed significant linear effects (uncorrected for multiple comparisons), particularly mental arithmetic tasks in 4 HMZ, the group with the heaviest frontal amyloid burden.…”

“…[2][3][4][5][6] Yet, in apparent contradiction to the amyloid cascade hypothesis, 7 cortical atrophy is maximal, not in A␤ rich regions, but in medial temporal structures. 5 Another recent challenge to A␤'s posited central role in AD pathogenesis, discussed by others, 5 comes from the clinical underperformance of A␤-modifying therapies including immunotherapy-mediated A␤ clearance that failed to halt the dementia progression.…”

“…5 Another recent challenge to A␤'s posited central role in AD pathogenesis, discussed by others, 5 comes from the clinical underperformance of A␤-modifying therapies including immunotherapy-mediated A␤ clearance that failed to halt the dementia progression. 8 Paralleling the lack of frontal atrophy is an apparent lack of frontally mediated cognitive dysfunction in preclinical and mild AD, [2][3][4][5][6] but this missing "frontal effect" might reflect insufficient study sensitivity due to small patient numbers and a limited range of frontal cognition measures. In patients with established dementia, cerebral A␤ deposition is widespread, but preclinically is more focally concentrated in the frontal lobe, temporal pole and neocortex, and posterior cingulate.…”

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

“…[3][4][5][6] Studies using amyloid PET in cognitively normal elderly individuals and individuals with mild cognitive impairment (MCI) and AD dementia have found significant relationships between cognitive deficits and increased brain fibrillar amyloid using both cross-sectional [7][8][9][10][11][12] and longitudinal data [13][14][15][16][17][18][19][20][21][22][23] ; however, other studies have not shown amyloid and cognitive correlations. [24][25][26] In autosomal dominant AD (ADAD), brain amyloid deposition is known to occur 15 years or more before the onset of clinical symptoms, 27,28 and estimated years from expected symptom onset (EYO) calculated from family history data can provide an objective biomarkerindependent estimate of an individual's relative point in the disease process.…”

Mild cognitive impairment (part 2): biological markers for diagnosis and prediction of dementia in Alzheimer's disease

“…103 Interestingly, retention of PiB was also observed in elderly subjects without cognitive symptoms, but higher PiB retention at baseline correlated with worse cognitive performance and faster cognitive decline upon follow-up. [108][109][110][111] These studies also showed that despite higher PiB retention, some individuals did not have significant brain atrophy. 112 In addition, PiB-positive patients with MCI had a higher rate of conversion to AD than PiB-negative patients with MCI.…”