Beyond diagnosis: what biomarkers are teaching us about the "bio"logy of Alzheimer disease.
Beyond diagnosis: what biomarkers are teaching us about the "bio"logy of Alzheimer disease.
复制标题
超越诊断：哪些生物标志物正在告诉我们阿尔茨海默病的“生物学”知识。
DOI：
10.1002/ana.22020
复制
发表时间：
2010
影响因子：
11.2
通讯作者：
Roberson,ErikD
中科院分区：
文献类型：
--
作者：
Rabinovici,GilD;Roberson,ErikD
The development of biological markers for in vivo assessment of amyloid-beta (Aβ) and tau, the proteins that define Alzheimer disease (AD) histopathology, promises to revolutionize the diagnosis of this devastating disease. Senile plaques, once visible only at autopsy, can now be imaged during life with positron emission tomography (PET) using Aβ-specific ligands such as [11C] Pittsburgh compound B (PiB). 1 AD also leaves a molecular signature in the cerebrospinal fluid (CSF) in the form of decreased Aβ1–42 and increased total and phosphorylated tau levels. 2, 3 Major interinstitutional initiatives, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and its “down under” counterpart, the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL), are optimizing the integration of biomarkers into clinical trials and demonstrating their potential utility for early, even presymptomatic, diagnosis of AD. At the same time, these large collaborative studies are also yielding another dividend, as they begin to proffer interesting insights into the biology of AD. Two reports in this issue of Annals of Neurology demonstrate how in vivo measures of Aβ and tau not only can serve as diagnostic markers, but—in conjunction with genetics, clinical characterization, and structural neuroimaging—can help address important, unanswered questions regarding the mechanisms underlying AD. One such question has been the significance of AD-like plaque burden found at autopsy in as many as onethird of elderly individuals without discernable cognitive impairment. 4 Do plaques in these individuals represent a benign accompaniment to normal aging, or are they indicative of preclinical disease? Resolving this fundamental question about the relationship between Aβ and AD has become even more pressing in light of disappointing results from clinical trials of Aβ-directed therapies, 5, 6 which so far have failed to produce a clinical benefit even when amyloid burden is dramatically reduced. 7 Data from Chételat and colleagues8 in this issue strongly suggest that Aβ accumulation in nondemented elderly is a harbinger of clinical decline. Using PiB-PET to study the association between amyloid burden and gray matter atrophy (measured by magnetic resonance imaging [MRI]) in 163 AIBL participants spanning the clinical spectrum from normal cognition to AD, the authors found that global PiB binding was negatively correlated with gray matter volume in participants with subjective cognitive impairment (SCI; those who complained of memory problems but had no objective deficits on cognitive testing). 8 No correlations were found between PiB binding and gray matter volumes in subjects with mild cognitive impairment (MCI) or AD, consistent with longitudinal observations that PiB uptake reaches a relative plateau by MCI or early AD, whereas clinical decline and neurodegeneration (as measured by MRI or [18F] fluorodeoxyglucose PET) accelerate independent of further amyloid accumulation. 9, 10 Gray matter regions inversely correlated with global PiB in SCI included hippocampus, precuneus, lateral temporoparietal cortex, and cingulate cortex, replicating the atrophy pattern seen in AD. This study thus contributes to a converging literature suggesting that amyloid accumulation in cognitively normal (CN) individuals is associated with AD-like functional and structural brain changes. 11–16 Although longitudinal data on PiB-positive normal controls are still sparse, a recent study found that high PiB binding at baseline was associated with a 5-fold increased risk of cognitive decline, 17 supporting the notion that many of these individuals have preclinical AD.Two …
