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Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings.

ABSTRACT: We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (? = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.

SUBMITTER: Jack CR

PROVIDER: S-EPMC4655341 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings.

Jack Clifford R CR Wiste Heather J HJ Weigand Stephen D SD Knopman David S DS Mielke Michelle M MM Vemuri Prashanthi P Lowe Val V Senjem Matthew L ML Gunter Jeffrey L JL Reyes Denise D Machulda Mary M MM Roberts Rosebud R Petersen Ronald C RC

Brain : a journal of neurology 20150930 Pt 12

We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. Th ...[more]

PMID: 26428666

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Project description:In a 2014 cross-sectional analysis, we showed that amyloid and neurodegeneration biomarker states in participants with no clinical impairment varied greatly with age, suggesting dynamic within-person processes. In this longitudinal study, we aimed to estimate rates of transition from a less to a more abnormal biomarker state by age in individuals without dementia, as well as to assess rates of transition to dementia from an abnormal state.Participants from the Mayo Clinic Study of Aging (Olmsted County, MN, USA) without dementia at baseline were included in this study, a subset of whom agreed to multimodality imaging. Amyloid PET (with (11)C-Pittsburgh compound B) was used to classify individuals as amyloid positive (A(+)) or negative (A(-)). (18)F-fluorodeoxyglucose ((18)F-FDG)-PET and MRI were used to classify individuals as neurodegeneration positive (N(+)) or negative (N(-)). We used all observations, including those from participants who did not have imaging results, to construct a multistate Markov model to estimate four different age-specific biomarker state transition rates: A(-)N(-) to A(+)N(-); A(-)N(-) to A(-)N(+) (suspected non-Alzheimer's pathology); A(+)N(-) to A(+)N(+); and A(-)N(+) to A(+)N(+). We also estimated two age-specific rates to dementia: A(+)N(+) to dementia and A(-)N(+) to dementia. Using these state-to-state transition rates, we estimated biomarker state frequencies by age.At baseline (between Nov 29, 2004, to March 7, 2015), 4049 participants did not have dementia (3512 [87%] were clinically normal and 537 [13%] had mild cognitive impairment). 1541 individuals underwent imaging between March 28, 2006, to April 30, 2015. Transition rates were low at age 50 years and, with one exception, exponentially increased with age. At age 85 years compared with age 65 years, the rate was nearly 11-times higher (17.2 vs 1.6 per 100 person-years) for the transition from A(-)N(-) to A(-)N(+), three-times higher (20.8 vs 6.1) for A(+)N(-) to A(+)N(+), and five-times higher (13.2 vs 2.6) for A(-)N(+) to A(+)N(+). The rate of transition was also increased at age 85 years compared with age 65 years for A(+)N(+) to dementia (7.0 vs 0.8) and for A(-)N(+) to dementia (1.7 vs 0.6). The one exception to an exponential increase with age was the transition rate from A(-)N(-) to A(+)N(-), which increased from 4.0 transitions per 100 person-years at age 65 years to 6.9 transitions per 100 person-years at age 75 and then plateaued beyond that age. Estimated biomarker frequencies by age from the multistate model were similar to cross-sectional biomarker frequencies.Our transition rates suggest that brain ageing is a nearly inevitable acceleration toward worse biomarker and clinical states. The one exception is the transition to amyloidosis without neurodegeneration, which is most dynamic from age 60 years to 70 years and then plateaus beyond that age. We found that simple transition rates can explain complex, highly interdependent biomarker state frequencies in our population.National Institute on Aging, Alexander Family Professorship of Alzheimer's Disease Research, the GHR Foundation.

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Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings.

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Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings.

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