%0 Journal Article %J Lancet Neurol %D 2013 %T Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. %A Jack, Clifford R %A Knopman, David S %A Jagust, William J %A Petersen, Ronald C %A Weiner, Michael W %A Aisen, Paul S %A Shaw, Leslie M %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Lesnick, Timothy G %A Pankratz, Vernon S %A Donohue, Michael C %A Trojanowski, John Q %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognition Disorders %K Humans %K Models, Biological %K Nonlinear Dynamics %K tau Proteins %X

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

%B Lancet Neurol %V 12 %P 207-16 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23332364?dopt=Abstract %R 10.1016/S1474-4422(12)70291-0 %0 Journal Article %J Arch Neurol %D 2011 %T Evidence for ordering of Alzheimer disease biomarkers. %A Jack, Clifford R %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Aisen, Paul S %A Trojanowski, John Q %A Shaw, Leslie M %A Bernstein, Matthew A %A Petersen, Ronald C %A Weiner, Michael W %A Knopman, David S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Hippocampus %K Humans %K Longitudinal Studies %K Male %K Mild Cognitive Impairment %K tau Proteins %X

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.

%B Arch Neurol %V 68 %P 1526-35 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21825215?dopt=Abstract %R 10.1001/archneurol.2011.183