Biomarkers and Brain Connectivity
Authors: William Jagust
Journal: JAMA Neurology (2013)

The investigation of Alzheimer disease (AD) with neuroimaging has often focused on 2 different brain regions. Researchers using positron emission tomographic (PET) imaging of glucose metabolism with fludeoxyglucose F 18 described hypometabolism in the lateral temporoparietal cortex and especially the medial parietal cortex encompassing the precuneus and posterior cingulate.1 Investigations using magnetic resonance imaging showed that patients with AD had substantial atrophy in the medial temporal lobes (MTLs), specifically the hippocampus and entorhinal cortex. Considerable work has extended these findings to individuals who may be in early stages of AD as reflected by mild cognitive impairment. Although subsequently it has become clear that involvement of these anatomical areas is not modality specific (that is, medial temporal hypometabolism and medial parietal atrophy are both reported in AD), the pathological relationship of degeneration in these 2 brain regions has been difficult to understand. Imagingbiomarkershave linked these regional changes to pathology, but this has raised more questions. Amyloid PET imaginghasmade it clear that theprecuneusandposterior cingulate are the site of relatively early deposition of β-amyloid (Aβ), thecentralprotein in the AD plaque. About a third of cognitively normal older people have brainAβdeposition, andwhen present, it almost invariably occurs in this region. However, the MTL, at least in early stages, is relatively devoid of Aβ, as seen at postmortem examination and with amyloid PET imaging. Postmortem studies, however, have linked theMTL strongly to the other key pathology of AD, the neurofibrillary tangle,2 reflectingpathological formsof the tau protein. This further establishes a major mystery of AD: how areamyloidpathology in themedial parietal cortexand taupathology in the MTL related? These 2 structures are linked through their participation inaneural systemknownas thedefaultmodenetwork (DMN). Thisnetworkhasbeenstudied invivousing resting-state functional connectivitymagnetic resonance imaging. By examiningthespontaneoussynchronyof thefunctionalmagnetic resonance imaging signal, functional network connections are detectedat rest thatparallel brainnetworks that areactiveduring specific types of cognitive tasks. The DMN is a tasknegative network that is deactivatedduring externally driven cognition but becomes active during introspective processes such as future planning and memory recall. It is also of particular interest because it becomes disconnected in patients withADand in cognitively normal older peoplewhohave evidence of brain Aβ on amyloid PET imaging. Thus, probing the functional connectivity of the DMN can provide insight into relationships between2major nodesof this network, theMTL andmedial parietal cortex. Wang et al3 examined changes in the DMN in 207 cognitively normal older people who had cerebrospinal fluid obtained for themeasurement of Aβ42 andphosphorylated tau. Lower levels of CSFAβ42 arewidely reported to parallel brain deposition of Aβ seenwith PET. Thus, it is not surprising that lower CSF Aβ42 in this study was associated with disconnection of the DMN since previous PET studies revealed similar findings. Within this network, however, Aβ42 affected connectivitybetween theposterior cingulate cortex (PCC) and the MTLmore thanconnectionsbetween thePCCandothernodes of the network. Biomarkers of tau are largely thought to indicate a stage later in the pathological progression of AD than Aβbecause theyare regardedas indicativeofAβ-initiatedneurodegeneration. In this study,phosphorylated taualso showed a relationshipwith connectivity such that higher levels of CSF phosphorylated tau were associated with PCC and MTL disconnection. In thesedata, the findings foreachbiomarkerwere present while controlling for the other, and the effects were not explained by age or atrophy of the relevant brain regions. Thiswork thusextendspreviousdataby showingnetworkdisconnection in asymptomatic individuals in a particularly important pathway and showing that this effect is seen for biomarkers reflecting both amyloid and neurodegenerative processes. It also provides hints about how these 2 pathological processes and anatomical regions might be related. Fromaclinical perspective, the results suggest that a relatively simple magnetic resonance imaging measure might be a reasonablebiomarker for earlyAD.Thecaveats, however, are substantial. Forexample, technical factors inassessing restingstate networks are crucial: small amounts of headmotion can produce artifacts that are difficult to detect, there are multiple approaches todata analysis, and reliability over timeand across centers has not been extensively established. Furthermore, validating this approach as a biomarker requires much stronger links todiseasephenotypes that include theprogression to AD dementia. Nevertheless, the appeal of this technique is that it can be performed on available clinical instruments, requires no particular cognitive task, and can be obtained in a fewminutes. Targeting 2brain regions for analysis—the PCC and the MTL—could be a simple and widely applicabledata-analytic approach to trackearlydisease if thedifficult technical issues, predictive value, sensitivity, and specificity can be worked out. Regardless of the clinical utility, the data presented by Wang et al3 show that changes in 2 different biomarkers reflectingdifferent aspects ofADpathological progressionaffect Related article page 1242 Opinion