Vemuri Prashanthi, Lesnick Timothy G, Przybelski Scott A, Knopman David S, Preboske Greg M, Kantarci Kejal, Raman Mekala R, Machulda Mary M, Mielke Michelle M, Lowe Val J, Senjem Matthew L, Gunter Jeffrey L, Rocca Walter A, Roberts Rosebud O, Petersen Ronald C, Jack Clifford R
1 Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
2 Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
Brain. 2015 Mar;138(Pt 3):761-71. doi: 10.1093/brain/awu393. Epub 2015 Jan 15.
Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-β load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-β load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was -0.02 if on neither pathway, -0.07 if on the vascular pathway, -0.08 if on the amyloid pathway and -0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.
我们的主要目标是研究一种生物标志物驱动的模型，用于探讨70至90岁认知正常的老年受试者中血管疾病病理、淀粉样蛋白病理和纵向认知衰退之间的相互关系。我们的次要目标是研究认知储备对这些相互关系的有益影响。我们使用匹兹堡化合物B正电子发射断层扫描测量的脑淀粉样β蛋白负荷作为淀粉样蛋白病理的标志物。使用液体衰减反转恢复磁共振成像测量白质高信号和脑梗死，作为血管病理的标志物。我们在基于人群的梅奥诊所衰老研究中，对393名认知正常的老年参与者进行了研究，这些参与者进行了基线3T液体衰减反转恢复磁共振成像评估、匹兹堡化合物B正电子发射断层扫描、基线认知评估、生活方式测量，以及至少一次额外的临床随访。如果受试者的全球皮质淀粉样β蛋白负荷≥1.5标准摄取值比率，我们将其分类为处于淀粉样蛋白途径；如果受试者有脑梗死和/或白质高信号负荷≥颅内总体积的1.11%（这对应于一个独立的非痴呆样本中白质高信号的前25%），则将其分类为处于血管途径。我们使用全球认知z评分作为认知的衡量指标。我们没有发现证据表明血管病理的存在与否会影响淀粉样蛋白病理的存在与否，反之亦然，这表明这两个过程似乎是独立的。在年龄较大的个体、男性、教育/职业程度较低的个体以及处于淀粉样蛋白途径的个体中，基线认知表现较低。年龄较大的个体（P < 0.001）以及患有淀粉样蛋白（P = 0.0003）或血管（P = 0.0037）病理的个体，其认知衰退率较高。在同时患有血管和淀粉样蛋白病理的受试者中，两种病理对认知的影响是相加的，而非协同的。对于一名79岁的受试者，如果其既不处于任何一条途径，预测的全球z评分年下降率为-0.02；如果处于血管途径，为-0.07；如果处于淀粉样蛋白途径，为-0.08；如果同时处于两条途径，则为-0.13。本研究的主要结论是：（i）淀粉样蛋白和血管病理似乎至少部分是独立的过程，它们都会对纵向认知轨迹产生不利影响，并且是老年人认知衰退的主要驱动因素；（ii）认知储备似乎可以抵消这两种病理对认知轨迹的有害影响。
