Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study

作者：Reiman, Eric M.^*; Quiroz, Yakeel T.; Fleisher, Adam S.; Chen, Kewei; Velez-Pardo, Carlos; Jimenez-Del-Rio, Marlene; Fagan, Anne M.; Shah, Aarti R.; Alvarez, Sergio; Arbelaez, Andres; Giraldo, Margarita; Acosta-Baena, Natalia; Sperling, Reisa A.; Dickerson, Brad; Stern, Chantal E.; Tirado, Victoria; Munoz, Claudia; Reiman, Rebecca A.; Huentelman, Matthew J.; Alexander, Gene E.; Langbaum, Jessica B. S.; Kosik, Kenneth S.; Tariot, Pierre N.; Lopera, Francisco

来源：Lancet Neurology, 2012, 11(12): 1048-1056.

DOI：10.1016/S1474-4422(12)70228-4

• AMYLOID-BETA
• IN-VIVO
• EPSILON-4 ALLELE
• APOLIPOPROTEIN-E
• GAMMA-SECRETASE
• MILD
• DEPOSITION
• DEMENTIA
• CARRIERS
• MEMORY

Background We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. @@@ Methods Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellin Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF A beta(1-42), total tau and phospho-tau, concentrations, and plasma A beta(1-42) concentrations and A beta(1-42):A beta(1-40) ratios. Structural and functional Mill data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. @@@ Findings 44 participants were included: 20 P SEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) epsilon 4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0.001 and p<0.014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0.010 after correction), and less grey matter in several parietal regions (all p<0.002 uncorrected and corrected p=0.009 in the right parietal search region). In the 20 participants (ten P SEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF A beta(1-42) concentrations (p=0.008) and plasma A beta(1-42) concentrations (p=0.01) than non-carriers. @@@ Interpretation Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with A beta(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease.

• 出版日期2012-12