Evidence for ordering of Alzheimer disease biomarkers - PubMed (original) (raw)

Comparative Study

Evidence for ordering of Alzheimer disease biomarkers

Clifford R Jack Jr et al. Arch Neurol. 2011 Dec.

Abstract

Objective: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.

Design: Validation sample.

Setting: Multisite, referral centers.

Participants: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.

Main outcome measures: Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume).

Results: Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.

Conclusions: A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

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Figures

Figure 1

Figure 1

Box plots and superimposed data points showing the distribution of biomarkers by baseline diagnosis and visit. Boxes indicate the quartiles and have whiskers extending to the furthest data point within 1.5 inter-quartile ranges of the box. T-tau is shown on the log scale. In subjects with both baseline and 12 month data, CSF Aβ42 is not changing from baseline to 12 months (CN, p=0.52; MCI, p=0.13; AD, p=0.51). T-tau is increasing from baseline to 12 months in CN subjects (p=0.002) but not in MCI or AD (p=0.12, p=0.36). HVa is decreasing in all clinical groups (p<0.001).

Figure 2

Figure 2

Estimated percentages of abnormality for each biomarker in all subjects (n=401) and within the subset of subjects with abnormal baseline CSF Aβ (n=274). Panels A & C show abnormality by clinical diagnosis and panels B & D show abnormality by MMSE score. Cutoffs used are 192 pg/mL for Aβ1–42, 93 for total tau, and 0.48 for HVa.

Figure 3

Figure 3

Estimated percentages of abnormality for each biomarker at baseline and 12 months by baseline clinical diagnosis for the subset of subjects with serial data (panel A, n=298) and those with serial data who were CSF Aβ positive at baseline (panel B, n=209). Values are shifted slightly along the x-axis for the middle biomarker to reduce overlap in lines. Cutoffs used are 192 pg/mL for Aβ1–42, 93 for total tau, and 0.48 for HVa.

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References

    1. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010 - PubMed
    1. Jack CR, Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging and the Alzheimer Association workgroup on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 (Epub ahead of print) - PMC - PubMed
    1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging and the Alzheimer’s Assocation Workgroup. Alzheimers Dement. 2011 (Epub ahead of print) - PMC - PubMed
    1. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging and the Alzheimer Assocation Workgroup. Alzheimers Dement. 2011 (Epub ahead of print) - PMC - PubMed
    1. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging and Alzheimer’s Association Workgroup. Alzheimers Dement. 2011 (Epub ahead of print) - PMC - PubMed

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