David S Knopman1, Clifford R Jack2, Emily S Lundt3, Heather J Wiste3, Stephen D Weigand3, Prashanthi Vemuri4, Val J Lowe5, Kejal Kantarci5, Jeffrey L Gunter5, Matthew L Senjem5, Michelle M Mielke6, Mary M Machulda7, Rosebud O Roberts6, Bradley F Boeve1, David T Jones8, Ronald C Petersen9. 1. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota2Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota. 2. Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota3Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota. 3. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota. 4. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota. 5. Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota. 6. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota5Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota. 7. Division of Psychology, Department of Psychiatry, Mayo Clinic and Foundation, Rochester, Minnesota. 8. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota2Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota3Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota. 9. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota2Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota5Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic and F.
Abstract
IMPORTANCE: To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI). OBJECTIVE: To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography. MAIN OUTCOMES AND MEASURES: Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions. RESULTS: In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups. CONCLUSIONS AND RELEVANCE: Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.
IMPORTANCE: To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI). OBJECTIVE: To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or MayoAlzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography. MAIN OUTCOMES AND MEASURES: Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions. RESULTS: In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups. CONCLUSIONS AND RELEVANCE: Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.
Authors: P Vemuri; H J Wiste; S D Weigand; L M Shaw; J Q Trojanowski; M W Weiner; D S Knopman; R C Petersen; C R Jack Journal: Neurology Date: 2009-07-28 Impact factor: 9.910
Authors: Gaël Chételat; Victor L Villemagne; Pierrick Bourgeat; Kerryn E Pike; Gareth Jones; David Ames; Kathryn A Ellis; Cassandra Szoeke; Ralph N Martins; Graeme J O'Keefe; Olivier Salvado; Colin L Masters; Christopher C Rowe Journal: Ann Neurol Date: 2010-03 Impact factor: 10.422
Authors: W J P Henneman; J D Sluimer; J Barnes; W M van der Flier; I C Sluimer; N C Fox; P Scheltens; H Vrenken; F Barkhof Journal: Neurology Date: 2009-03-17 Impact factor: 9.910
Authors: J L Whitwell; K A Josephs; M E Murray; K Kantarci; S A Przybelski; S D Weigand; P Vemuri; M L Senjem; J E Parisi; D S Knopman; B F Boeve; R C Petersen; D W Dickson; C R Jack Journal: Neurology Date: 2008-09-02 Impact factor: 9.910
Authors: Rosebud O Roberts; Yonas E Geda; David S Knopman; Ruth H Cha; V Shane Pankratz; Bradley F Boeve; Robert J Ivnik; Eric G Tangalos; Ronald C Petersen; Walter A Rocca Journal: Neuroepidemiology Date: 2008-02-07 Impact factor: 3.282
Authors: Rachel L Nosheny; Philip S Insel; Niklas Mattsson; Duygu Tosun; Shannon Buckley; Diana Truran; N Schuff; Paul S Aisen; Michael W Weiner Journal: Neurobiol Aging Date: 2019-07-22 Impact factor: 4.673
Authors: David S Knopman; Clifford R Jack; Emily S Lundt; Stephen D Weigand; Prashanthi Vemuri; Val J Lowe; Kejal Kantarci; Jeffrey L Gunter; Matthew L Senjem; Michelle M Mielke; Mary M Machulda; Rosebud O Roberts; Bradley F Boeve; David T Jones; Ronald C Petersen Journal: Neurobiol Aging Date: 2016-06-16 Impact factor: 4.673
Authors: Mekala R Raman; Christopher G Schwarz; Melissa E Murray; Val J Lowe; Dennis W Dickson; Clifford R Jack; Kejal Kantarci Journal: J Neuroimaging Date: 2016-03-28 Impact factor: 2.486
Authors: Rizwan S Akhtar; Sharon X Xie; Yin J Chen; Jacqueline Rick; Rachel G Gross; Ilya M Nasrallah; Vivianna M Van Deerlin; John Q Trojanowski; Alice S Chen-Plotkin; Howard I Hurtig; Andrew D Siderowf; Jacob G Dubroff; Daniel Weintraub Journal: PLoS One Date: 2017-05-25 Impact factor: 3.240
Authors: Katie E Osborn; Omair A Khan; Hailey A Kresge; Corey W Bown; Dandan Liu; Elizabeth E Moore; Katherine A Gifford; Lealani Mae Y Acosta; Susan P Bell; Timothy J Hohman; Kaj Blennow; Henrik Zetterberg; Angela L Jefferson Journal: Alzheimers Dement (Amst) Date: 2019-10-22
Authors: L E M Wisse; S R Das; C Davatzikos; B C Dickerson; S X Xie; P A Yushkevich; D A Wolk Journal: Neuroimage Clin Date: 2018-02-08 Impact factor: 4.881
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