Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
Ann Neurol. 2011 Sep;70(3):465-76. doi: 10.1002/ana.22484.
The cellular and molecular mechanisms underlying magnetic resonance imaging-defined white matter (WM) changes associated with age-related cognitive decline remain poorly defined. We tested the hypothesis that WM lesions in older adults, defined by diffusion tensor imaging (DTI), arise in the setting of vascular brain injury (VBI) and are characterized by increased free radical injury and aberrant oligodendrocyte lineage (OL) cell response to injury.
We undertook a multimodal analysis of prefrontal cortex (PFC) WM from 25 autopsies derived from a population-based cohort where VBI and Alzheimer disease (AD) frequently coincide. Ex vivo high field strength DTI measurements of fractional anisotropy (FA), apparent diffusion coefficient, and axial and radial (D(⊥) ) diffusivity were measured at high magnetic field strength (11.7T) and analyzed relative to quantitative in vivo biomarkers of free radical injury, an OL-specific marker Olig2, and histologic evaluation of hyaluronan (HA), an inhibitor of OL maturation.
Coincident AD and VBI showed significant association with lower FA and a robust relationship between decreasing FA and increasing D(⊥) . Free radical injury to docosahexaenoate and adrenate in PFC WM was significantly elevated in cases with VBI independent of AD, and was inversely correlated with FA. Similarly, increased density of Olig2-immunoreactive cells in PFC WM was significantly associated with VBI independent of AD and colocalized with regions enriched in HA.
DTI-defined PFC WM lesions in older individuals are characterized by free radical injury to myelin and neuroaxonal elements that coincides with pronounced expansion of the pool of OL cells in HA-rich regions.
与年龄相关的认知能力下降相关的磁共振成像定义的白质（WM）变化的细胞和分子机制仍未得到很好的定义。我们检验了以下假设：在老年人中，通过弥散张量成像（DTI）定义的 WM 病变是在血管性脑损伤（VBI）的背景下发生的，其特征是自由基损伤增加和少突胶质细胞谱系（OL）细胞对损伤的异常反应。
我们对来自基于人群的队列的 25 例尸检的前额叶皮层（PFC）WM 进行了多模态分析，其中 VBI 和阿尔茨海默病（AD）经常同时发生。在高场强（11.7T）下测量了 WM 的分数各向异性（FA）、表观扩散系数以及轴向和径向（D（⊥））扩散系数的体外高场强 DTI 测量值，并相对于自由基损伤的定量活体生物标志物、OL 特异性标志物 Olig2 以及透明质酸（HA）的组织学评估进行了分析，HA 是 OL 成熟的抑制剂。
同时发生的 AD 和 VBI 与 FA 降低显著相关，并且 FA 降低与 D（⊥）增加之间存在强相关性。PFC WM 中的二十二碳六烯酸和肾上腺素的自由基损伤在 VBI 病例中显著升高，与 AD 无关，并且与 FA 呈负相关。同样，PFC WM 中 Olig2 免疫反应性细胞的密度增加与 VBI 显著相关，与 AD 无关，并且与富含 HA 的区域重叠。
在年龄较大的个体中，DTI 定义的 PFC WM 病变的特征是髓鞘和神经轴突元素的自由基损伤，这与富含 HA 的区域中 OL 细胞池的显著扩张相一致。
