TY - JOUR
T1 - Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia
AU - Merluzzi, Andrew P.
AU - Carlsson, Cynthia M.
AU - Johnson, Sterling C.
AU - Schindler, Suzanne E.
AU - Asthana, Sanjay
AU - Blennow, Kaj
AU - Zetterberg, Henrik
AU - Bendlin, Barbara B.
N1 - Funding Information:
This project was supported by NIH grants R01AG037639 (B. B.B.), AG027161 (S.C.J.), and P50 AG033514 (S.A.); the University of Wisconsin Institute for Clinical and Translation Research grant 1UL1RR025011; the Geriatric Research, Education, and Clinical Center of the William S. Middleton Memorial Veterans Hospital; the Swedish Alzheimer Foundation (Nos. AF-553101 and AF-646211); the Torsten Söderberg Foundation (K.B.); the Research Council of Sweden (project 14002) (K.B.); the Swedish Brain Foundation (project FO2015-0021) (K.B.); LUA/ALF Västra Götalandsregionen Sweden (project ALFGBG-139671) (K.B.); the European Research Council (No. 681712) (H.Z.); Swedish State Support for Clinical Research (No. ALFGBG-441051) (H.Z.); the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow 2013) (H.Z.); and the National Science Foundation Graduate Research Fellowship under grant DGE-1256259 (A.P.M.). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation.
Publisher Copyright:
© 2018 American Academy of Neurology
PY - 2018/7/31
Y1 - 2018/7/31
N2 - Objective To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. Methods In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). Results In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. Conclusions These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.
AB - Objective To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. Methods In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). Results In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. Conclusions These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.
UR - http://www.scopus.com/inward/record.url?scp=85054024428&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000005901
DO - 10.1212/WNL.0000000000005901
M3 - Article
C2 - 29959263
AN - SCOPUS:85054024428
SN - 0028-3878
VL - 91
SP - E436-E443
JO - Neurology
JF - Neurology
IS - 5
ER -