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

• Published in: Brain (London, England : 1878) Vol. 138; no. 12; pp. 3747 - 3759
• Main Authors: Jack, Clifford R., Wiste, Heather J., Weigand, Stephen D., Knopman, David S., Mielke, Michelle M., Vemuri, Prashanthi, Lowe, Val, Senjem, Matthew L., Gunter, Jeffrey L., Reyes, Denise, Machulda, Mary M., Roberts, Rosebud, Petersen, Ronald C.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.12.2015
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - diagnosis; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloidosis - metabolism; Amyloidosis - pathology; Biomarkers - metabolism; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cross-Sectional Studies; Female; Functional Neuroimaging; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Middle Aged; Nerve Degeneration - diagnosis; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neuropsychological Tests; Original; Positron-Emission Tomography; amyloid imaging; Alzheimer’s disease; preclinical Alzheimer’s disease; cognitive ageing; amyloid and neurodegeneration
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awv283

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 (κ = 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.