title: 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 (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.
authors.affiliation: 1 Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA jack.clifford@mayo.edu.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: 2 Department of Health Sciences Research, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Wiste
authors.affiliation: 2 Department of Health Sciences Research, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: 3 Department of Neurology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: 2 Department of Health Sciences Research, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Mielke
authors.affiliation: 1 Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Prashanthi
authors.initials: P
authors.lastname: Vemuri
authors.affiliation: 1 Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Val
authors.initials: V
authors.lastname: Lowe
authors.affiliation: 1 Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Senjem
authors.affiliation: 1 Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gunter
authors.affiliation: 1 Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Reyes
authors.affiliation: 4 Department of Psychiatry and Psychology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Machulda
authors.affiliation: 2 Department of Health Sciences Research, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Rosebud
authors.initials: R
authors.lastname: Roberts
authors.affiliation: 3 Department of Neurology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D003430:Cross-Sectional Studies; D005260:Female; D059907:Functional Neuroimaging; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography
chemical_list: D015415:Biomarkers
keywords: Alzheimer’s disease; amyloid and neurodegeneration; amyloid imaging; cognitive ageing; preclinical Alzheimer’s disease