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Quiroz YT, Schultz AP, Chen K, Protas HD, Brickhouse M, Fleisher AS, Langbaum JB, Thiyyagura P, Fagan AM, Shah AR, Muniz M, Arboleda-Velasquez JF, Munoz C, Garcia G, Acosta-Baena N, Giraldo M, Tirado V, Ramírez DL, Tariot PN, Dickerson BC, Sperling RA, Lopera F, Reiman EM. Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study. JAMA Neurol. 2015 Aug;72(8):912-9. PubMed.
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Washington University School of Medicine
The authors should be congratulated on evaluating some of the youngest participants for Alzheimer’s biomarker changes. The findings reported on the Colombian kindred are of key interest and support prior findings in the Colombian kindred and in DIAN of increased plasma Aβ42 and Aβ42:40 ratios. Novel findings include a tantalizing report of increased functional connectivity in the posterior cingulate and increased gray matter volumes in the temporal lobe. These findings may also be seen in other dominantly inherited AD populations (Benzinger et al., 2013) and in presymptomatic sporadic AD. Replication of these studies and a better understanding of the earliest changes may be informative to understand the pathogenesis of Alzheimer’s disease and why these regions appear to be vulnerable for the disease.
References:
Benzinger TL, Blazey T, Jack CR Jr, Koeppe RA, Su Y, Xiong C, Raichle ME, Snyder AZ, Ances BM, Bateman RJ, Cairns NJ, Fagan AM, Goate A, Marcus DS, Aisen PS, Christensen JJ, Ercole L, Hornbeck RC, Farrar AM, Aldea P, Jasielec MS, Owen CJ, Xie X, Mayeux R, Brickman A, McDade E, Klunk W, Mathis CA, Ringman J, Thompson PM, Ghetti B, Saykin AJ, Sperling RA, Johnson KA, Salloway S, Correia S, Schofield PR, Masters CL, Rowe C, Villemagne VL, Martins R, Ourselin S, Rossor MN, Fox NC, Cash DM, Weiner MW, Holtzman DM, Buckles VD, Moulder K, Morris JC. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4502-9. Epub 2013 Nov 5 PubMed.
View all comments by Randall BatemanUniversity of Arkansas for Medical Sciences
This is a fascinating body of work. It should be noted that it is corroborated also by Sala-Llonch et al., 2015. That study had the additional strengths of being longitudinal and including initially asymptomatic carriers of nine different PSEN1 mutations from 11 different families. Though the subjects were much older (mean age 38.6), they also showed the same sort of trajectory, which the authors characterized as "nonlinear": greater cortical thickness initially, followed by accelerated thinning.
References:
Sala-Llonch R, Lladó A, Fortea J, Bosch B, Antonell A, Balasa M, Bargalló N, Bartrés-Faz D, Molinuevo JL, Sánchez-Valle R. Evolving brain structural changes in PSEN1 mutation carriers. Neurobiol Aging. 2015 Mar;36(3):1261-70. Epub 2014 Dec 24 PubMed.
View all comments by Steve BargerUniversity of Southern California; Imaging Genetics Center
The authors evaluated in 37 children and adolescents how the PSEN1 E280A mutation, which confers autosomal dominantly inherited Alzheimer’s disease (ADAD), was associated with plasma Aβ1-40 and Aβ1-42. They also examined associations of the mutation with structural and functional MRI measures. This is an exciting and important study in a relatively rare population. It serves as a step in identifying which differences seen in preclinical ADAD are progressive and which are developmental, potentially guiding future intervention studies.
Consistent with previous studies in cognitively intact young adult and middle-aged ADAD mutation carriers (Bateman et al., 2012; Fleisher et al., 2015), the authors found that plasma Aβ1-42 was elevated in mutation carriers. The previous cross-sectional work found that despite elevated plasma Aβ levels in mutation carriers, these levels were not significantly correlated with years until the expected age of disease onset. In contrast, cerebrospinal fluid (CSF) levels of Aβ and amyloid PET imaging signal in the brain were significantly correlated with the expected age of disease onset (Fleisher et al., 2015). This suggests that the elevated plasma Aβ levels in mutation carriers in the current study may represent a developmental rather than a progressive effect. However, it will be interesting to see whether future longitudinal studies are able to identify changes in plasma Aβ over time in preclinical ADAD mutation carriers. Platelets rather than neurons contribute to more than 90 percent of circulating Aβ, although most of that is Aβ1-40 (as reviewed in Evin and Li, 2012). Plasma Aβ1-42 levels largely have not reflected brain amyloid or CSF Aβ levels (as reviewed in Toledo et al., 2013). However, circulating Aβ may still contribute to amyloid deposits in the brain (Chen et al., 1995), and recognizing these differences so early in life is important to understanding how Alzheimer’s disease progresses in these mutation carriers.
The authors also found that the volumes of the parahippocampal gyrus and temporal pole were greater in mutation carriers compared with non-carriers. Although some previous studies of ADAD have found thinner regional cortices in preclinical mutation carriers (Mosconi et al., 2006; Knight et al., 2011), another with participants farther from their expected age of disease onset found regional cortical thickness increases in selected temporal and parietal regions in preclinical PSEN1 mutation carriers (Fortea et al., 2010). Together, these studies suggest that early increased regional brain volume, particularly in regions vulnerable to AD pathology, may precede typical AD-patterns of atrophy. Longitudinal study of these participants would help elucidate whether such effects are developmental and how changes in blood and CSF biomarker measures relate to changes in brain structure.
These results provide interesting insights into early AD-related vulnerabilities, and may reflect earliest disease changes. This study sets a strong foundation for future work.
References:
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. PubMed.
Chen M, Inestrosa NC, Ross GS, Fernandez HL. Platelets are the primary source of amyloid beta-peptide in human blood. Biochem Biophys Res Commun. 1995 Aug 4;213(1):96-103. PubMed.
Evin G, Li QX. Platelets and Alzheimer's disease: Potential of APP as a biomarker. World J Psychiatry. 2012 Dec 22;2(6):102-13. PubMed.
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W, Ayutyanont N, Lopez L, Moreno S, Muñoz C, Tirado V, Acosta-Baena N, Fagan AM, Giraldo M, Garcia G, Huentelman MJ, Tariot PN, Lopera F, Reiman EM. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015 Mar;72(3):316-24. PubMed.
Fortea J, Sala-Llonch R, Bartrés-Faz D, Bosch B, Lladó A, Bargalló N, Molinuevo JL, Sánchez-Valle R. Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. J Alzheimers Dis. 2010;22(3):909-22. PubMed.
Knight WD, Kim LG, Douiri A, Frost C, Rossor MN, Fox NC. Acceleration of cortical thinning in familial Alzheimer's disease. Neurobiol Aging. 2011 Oct;32(10):1765-73. PubMed.
Mosconi L, Sorbi S, de Leon MJ, Li Y, Nacmias B, Myoung PS, Tsui W, Ginestroni A, Bessi V, Fayyazz M, Caffarra P, Pupi A. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J Nucl Med. 2006 Nov;47(11):1778-86. PubMed.
Toledo JB, Shaw LM, Trojanowski JQ. Plasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker. Alzheimers Res Ther. 2013 Mar 8;5(2):8. PubMed.
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