title: Cortical thickness in relation to clinical symptom onset in preclinical AD.
abstract: Mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia are preceded by a phase of disease, referred to as 'preclinical AD', during which cognitively normal individuals have evidence of AD pathology in the absence of clinical impairment. This study examined whether a magnetic resonance imaging (MRI) measure of cortical thickness in brain regions, collectively known as 'AD vulnerable' regions, predicted the time to onset of clinical symptoms associated with MCI and whether cortical thickness was similarly predictive of clinical symptom onset within 7 years post baseline versus progression at a later point in time. These analyses included 240 participants from the BIOCARD study, a cohort of longitudinally followed individuals who were cognitively normal at the time of their MRI (mean age = 56 years). Participants have been followed for up to 18 years (M follow-up = 11.8 years) and 50 participants with MRIs at baseline have developed MCI or dementia over time (mean time to clinical symptom onset = 7 years). Cortical thickness in AD vulnerable regions was based on the mean thickness of eight cortical regions. Using Cox regression models, we found that lower mean cortical thickness was associated with an increased risk of progression from normal cognition to clinical symptom onset within 7 years of baseline (p = 0.03), but not with progression > 7 years from baseline (p = 0.30). Lower cortical thickness was also associated with higher levels of phosphorylated tau, measured in cerebrospinal fluid at baseline. These results suggest that cortical thinning in AD vulnerable regions is detectable in cognitively normal individuals several years prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI, and that the changes are more likely to be evident in the years proximal to clinical symptom onset, consistent with hypothetical AD biomarker models.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Pettigrew
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Anja
authors.initials: A
authors.lastname: Soldan
authors.affiliation: Department of Biostatistics, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biostatistics, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Mei-Cheng
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Abhay
authors.initials: A
authors.lastname: Moghekar
authors.affiliation: Center for Imaging Science, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Brown
authors.affiliation: Center for Imaging Science, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Albert
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000150:complications / Q000000981:diagnostic imaging* / Q000473:pathology*; D015415:Biomarkers; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000150:complications / Q000000981:diagnostic imaging* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D015415:Biomarkers
keywords: Alzheimer's disease; Cerebrospinal fluid; Cortical thickness; Magnetic resonance imaging; Phosphorylated tau; Preclinical AD