Cerebrospinal Biomarkers in Alzheimer Disease-Potential Roles as Markers of Prognosis and Neuroplasticity.

Biomarkersasaids todiagnosis,prognosis, andeffective therapies have becomeholy grails of translational neuroscience. In neurodegenerative disorders, especially Alzheimer disease (AD), imagingandcerebrospinal fluid (CSF)biomarkers for the amyloid-β (Aβ) protein and tau have found their place in research and clinical trials, enabling much more accurate diagnosis. Despite these advances in diagnostic biomarkers, less progress has been made with respect to biomarkers of progression. Alzheimer disease progresses slowly and has a long preclinical stage prior to clinical manifestations; biomarkers of progression could provide invaluable information to assess the efficacy of potential disease-modifying agents in clinical trials. Ifmedicinesmodifydiseaseprogressionbyslowing neurodegeneration in the brain, the neurodegeneration biomarker should also be modified.1 More specifically, inAD, currentdiagnostic biomarkers includediminishedCSFAβ in combinationwith elevationof tau and phosphotau and the ratios between them. Alternatively, amyloid imaging with positron emission tomography (PET) with Pittsburgh Compound B (flutemetamol), florbetapir, or florbetaben in individuals with characteristic cognitive impairment enables the diagnosis of AD. Further, it is now well establishedthatalterations inCSFAβandtau levelsand/orpositive amyloid scans identify those cognitivelynormal individuals who are at risk for future development of AD and are candidates for prevention trials. Current markers of the neurodegenerative process2,3 include volume loss on magnetic resonance imaging, notably in the hippocampus and decreases in 18F-fluorodeoxyglucose (FDG) PET uptake, which reveals early losses of glucose use (driven predominantly by synaptic activity) in the posterior temporal and parietal lobes, as well as in the precuneus and posterior cingulate.4 While not highly specific, certain patterns of atrophy and decreased FDG-PET signal are characteristic of AD. Although CSF Aβ and tau levels are best viewed as diagnostic biomarkers, serial imaging studies can reveal either progressive accumulation of amyloid or tau or progressive volume loss or diminution of FDG-PET signal. Thus, some diagnostic imaging biomarkers may also be markers of progression in longitudinal studies. In contrast, neither CSF Aβ nor tau have shown utility as markers of progression. They are abnormal in early phases of the disease and do not appear to significantly change a great deal. Getting serial CSF levels in the same patient is essentially impossible, especially in the earliest prodromal stages of the disease, and this makes it very difficult, if not impossible, in practice to see any preclinical inflection points in these biomarkers. There is a great need to develop and validate new biomarkers of progression—not just for AD, but virtually all neurodegenerative disorders. In this issue of JAMA Neurology, Tarawneh and colleagues5 used multidimensional assessments of crosssectional and longitudinal diagnostic and neurodegeneration biomarkers; added a new one, neurogranin, to the mix of potential neurodegeneration markers; and bolstered data on another, visinin-like protein 1. Collectively, these data suggest that these novel CSF biomarkers are about as good as other biomarkers for distinguishing those with AD from control individuals even in the prodromal state of disease and may provide even better markers to track progression. They enable new inferences regarding the pathobiological changes underlying the course of AD, especially the preclinical stage, where we have very little data. Further, they confirm data from the Alzheimer Disease’s Neuroimaging Initiative, which also revealed strong associations of neurogranin levels with clinical progression in preclinical AD, mild cognitive impairment (MCI), and AD. In the present study,5 the authors used a wellcharacterized longitudinal cohort of cognitively normal older individuals, patients with a Clinical Dementia Rating score of 0.5 (essentially equivalent to MCI), and a number of patients with mild andmoderate AD, and they demonstrated that CSF neurogranin, a postsynaptic membrane component of synaptic structure, and visinin-like protein 1, a neuronal calcium-sensing protein, were elevated in preclinical AD and in the earliest stages of clinical AD, with some diminution of value (albeit from a smaller number of patients) in mild to moderate AD. By itself, neurogranin was as accurate as the well-established CSF Aβ and tau/phosphotau concentrations in differentiating cognitively normal control individuals from AD cases. It also added slightly to the power of the Aβ/tau CSF data to diagnose AD. Of course, neurogranin is a nonspecific biomarker because it might be predicted to rise in the CSF of any disorder associated with neuronal death and synaptic disruption or dysfunction. Indeed, with a number of other neurodegenerative disorders, there were some increases, but in only a few cases. So why was the finding of such particular interest in AD? Over the past decade, longitudinal clinical and cognitive data,neuroimagingwithmagnetic resonance imaging (includingvolumetricmagnetic resonance imaging), andamyloidPET, as well as CSF Aβ and tau/phosphotau, have been accumulated (notably via the Alzheimer’s Disease Neuroimaging Initiative)6 and led to a hypothesis of a proposed temporal sequence of progression, which has been heuristic as well as instructive.2 Decline in CSFAβ, reflecting its accumulation in amyloid plaques in the cortex as determined by amyloid PET imaging, is followed by a cascade of neurodegenerative changes. These data enabled the progression of AD to be dissected further intopreclinicalAD, early and late stageMCI, and mild tomoderateAD,with the termsbeingdefinedby thepresenceorabsenceofmarkersofneurodegeneration:volume loss, Related article page 561 Opinion Editorial