Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease

被引:182
作者
Dean, Douglas C., III [1 ]
Hurley, Samuel A. [2 ]
Kecskemeti, Steven R. [1 ]
O'Grady, J. Patrick [3 ]
Canda, Cristybelle [3 ]
Davenport-Sis, Nancy J. [3 ,4 ]
Carlsson, Cynthia M. [3 ,5 ]
Zetterberg, Henrik [6 ,7 ]
Blennow, Kaj [6 ]
Asthana, Sanjay [3 ,4 ,5 ]
Sager, Mark A. [3 ,4 ]
Johnson, Sterling C. [3 ,4 ,5 ]
Alexander, Andrew L. [1 ,8 ,9 ]
Bendlin, Barbara B. [3 ,5 ]
机构
[1] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA
[2] Univ Oxford, Oxford Ctr Funct Magnet Resonance Imaging Brain, Oxford, England
[3] Univ Wisconsin, Alzheimer Dis Res Ctr, Sch Med & Publ Hlth, Madison, WI 53706 USA
[4] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimer Inst, Madison, WI 53706 USA
[5] William S Middleton Mem VA Hosp, Geriatr Res Educ & Clin Ctr, Madison, WI USA
[6] Univ Gothenburg, Dept Psychiat & Neurochem, Clin Neurochem Lab, Inst Neurosci & Physiol, Molndal, Sweden
[7] UCL, Inst Neurol, Dept Mol Neurosci, London, England
[8] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, Madison, WI 53706 USA
[9] Univ Wisconsin, Dept Psychiat, Sch Med & Publ Hlth, Madison, WI 53706 USA
基金
美国国家卫生研究院; 瑞典研究理事会;
关键词
WHITE-MATTER DEVELOPMENT; CEREBROSPINAL-FLUID; BRAIN MYELINATION; WATER; TAU; MICROSTRUCTURE; CHILDHOOD; MARKERS; STATE;
D O I
10.1001/jamaneurol.2016.3232
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
IMPORTANCE The accumulation of aggregated beta-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. OBJECTIVE To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. DESIGN, SETTING, AND PARTICIPANTS Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including beta-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. MAIN OUTCOMES AND MEASURES Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. RESULTS The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/beta-amyloid 42, suggesting that phosphorylated tau 181/beta-amyloid 42 levels modulate age-related changes in myelin water fraction. CONCLUSIONS AND RELEVANCE These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.
引用
收藏
页码:41 / 49
页数:9
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