Cerebrospinal Fluid Neurogranin Correlates with Markers of Neurodegeneration
Since they first observed neurogranin in the cerebrospinal fluid (CSF) of Alzheimer’s disease patients, researchers have suspected that the synaptic protein may be a useful surrogate for measuring synapse loss in the brain. Now, a paper published September 15 in Brain reports that CSF neurogranin correlates with glucose hypometabolism and hippocampal atrophy, markers of neurodegeneration. The findings follow hot on the heels of a report linking CSF neurogranin to impending cognitive decline (see Sept 2015 news).
Markers of Neurodegeneration? Baseline neurogranin levels associate with hippocampal atrophy and glucose hypometabolism, two measures of neurodegeneration. [Courtesy of Erik Portelius and Brain. © Oxford University Press.]
Erik Portelius and colleagues at University of Gothenburg, Sweden, used their in-house immunoassay to measure CSF neurogranin levels in a well-characterized cohort from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). It included 95 people with AD, 173 with mild cognitive impairment, and 110 cognitively healthy controls. Participants were followed clinically for six months or more, and were repeatedly scanned by FDG-PET and MRI over a period of six months to nine years.
Neurogranin levels were not associated with baseline hippocampal volume or FDG-PET in any group. However, high baseline CSF neurogranin did correlate with future loss of hippocampal volume and reduction in cortical glucose metabolism in MCI patients. Neurogranin levels also correlated with cognitive decline in this group.
“In CSF neurogranin, we now have an independent marker of synaptic integrity, which previously has been very difficult to assess in living patients,” said Portelius. He added that the link between neurogranin and brain imaging measures needs to be replicated in other cohorts, particularly in large preclinical populations.
Maartje Kester, VU University Medical Center, Amsterdam, who was not involved in this study, noted that its neurogranin results align with those reported by her group earlier this week (Kester et al., 2015). Studying the Amsterdam Dementia Cohort, they found neurogranin levels to be elevated by the MCI stage of AD, possibly earlier, as suggested by the longitudinal increase in CSF neurogranin among those with subjective memory complaint. “Taken together, these results confirm the value of neurogranin as a promising early biomarker reflecting functional decline,” Kester wrote to Alzforum.
Consistent results observed in different cohorts using different assays are encouraging, but even so, questions remain before neurogranin is promoted from “promising biomarker” to being useful for diagnosis and/or prognosis, said co-author Kaj Blennow, also from Gothenburg. “We now need to understand the mechanism behind the increase of CSF neurogranin in AD, and whether it is specific for AD or also occurs in other neurodegenerative disorders that have synapse loss,” Blennow said.—Kelly Dakin
The findings of Portelius and colleagues are in line with our recent results (Kester et al,. 2015) and confirm the value of neurogranin as a CSF biomarker for AD. Both studies show the predictive value of neurogranin for disease progression in the MCI phase of AD. In addition, Portelius and colleagues report that baseline levels of neurogranin associate with longitudinal imaging biomarkers, MRI and PET. These associations strengthen the hypothesis that CSF neurogranin is an early biomarker for AD that reflects synaptic degeneration. Further studies are needed to confirm the association between neurogranin and these, and other, biomarkers.
Miguel de Cervantes European University (UEMC)
Neurogranin is a protein found at high concentrations in the specialized regions of nerve cells that enable them to receive synaptic signals (the postsynaptic terminal). The function of neurogranin is not yet well understood, but it is known to bind to another protein called calmodulin, which mediates some forms of synaptic plasticity. Levels of neurogranin have been recently found to be increased in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), potentially serving as an early biomarker of synaptic damage and/or pathology.
This new study by Portelius and colleagues confirmed the presence of higher CSF neurogranin levels in both AD and MCI subjects compared with heathy controls. More importantly, the authors demonstrated that CSF neurogranin could distinguish MCI subjects who progressed to dementia from those who remained stable. Additionally, high baseline CSF neurogranin levels predicted longitudinal cognitive decline, longitudinal reductions in cortical glucose metabolism and hippocampal volume at clinical follow-up. Taken together, these data suggest that neurogranin in the CSF of individuals newly diagnosed with MCI may inform physicians about the patient’s risk of future cognitive decline and structural/functional brain changes.
The main findings of this study remind us that MCI is a heterogeneous concept. Many subjects with MCI may stay clinically stable for years while others can be subject to a rapid decline. Physicians need a way to identify subjects at the greatest risk of progression as early as possible. The results shown here hold promise that systematic measurement of neurogranin in the CSF will support risk evaluation for metabolic, structural, and cognitive disease progression and monitor response to therapy of MCI subjects in future treatment trials.
However, some issues are slowing the development of robust biomarkers, and the need for standardization remains one of the main challenges. To confirm neurogranin as a reliable marker of disease progression, investigators need large sets of samples that have been all collected in a standardized manner and investigated, multicentric, in independent samples by independent expert research groups. Thus, Portelius and colleagues' use of samples collected in a biorepository managed by an internationally established large-scale consortium such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) should be clearly appreciated.
In the setting of MCI or prodromal AD, neurogranin may be useful as a biomarker for drugs specifically targeting synaptic dysfunction. Once standardization issues have been definitively overcome, the best proof of concept for neurogranin in MCI would be to show its correlation with cognitive benefits during a successful drug trial. Perhaps neurogranin could be a promising candidate for surrogate marker development.
University of California, San Diego
Neurogranin appears to be an interesting and novel marker that appears to reflect post-synaptic damage. There are multiple proteolytically cleaved forms of neurogranin in CSF; this is reminiscent of tau, with which neurogranin correlates. It is possible that similar proteolytic events release at least some forms of tau that are detected in CSF as well as neurogranin, which would account for the high correlation between the two.
The correlation between baseline neurogranin levels and progressive changes that reflect neuodegeneration, such as MRI atrophy and FDG PET, suggests that the tempo of synaptic damage carries some predictive value for progression of AD.
Further studies should be aimed at identifying how early in the course of AD neurogranin levels change in the CSF. Also, it would be interesting to evaluate levels in acute situations such as stroke and TBI (where CSF tau is increased) and after seizures.
The development of neurogranin as a synaptic damage biomarker adds to the repertoire of biomarkers in AD. It will be interesting to see it routinely applied to clincial trials as an outcome measure.
The recent report of Portelius and colleagues demonstrating patterns of CSF neurogranin in a relatively large ADNI cohort adds important information to what has already been published about this promising biomarker, notably its relationship with structural imaging measures, cortical glucose metabolism and cognitive performance. As has been found with many CSF biomarkers, abnormalities are observed in the MCI stage, prior to the onset of dementia, and track with clinical and pathologic disease progression.
The question, of course, remains as to whether changes are taking place even earlier than MCI, prior to any cognitive symptoms (preclinical AD), and what the relationships are between levels of neurogranin and the other biomarkers within individuals over time.
In terms of potential clinical use, we need to know whether analysis of neurogranin (or other synaptic markers) adds information beyond what CSF tau and phospho-tau already provide. One hypothesis is that changes in synaptic markers will be detectable earlier than tau-related measures of neurodegeneration. However, given that synaptic dysfunction/loss is not unique to AD, it is likely that other markers, such as those for amyloid, will also need to be included in order to establish AD as the underlying pathologic disorder. Longitudinal evaluation of large cohorts of cognitively normal individuals who undergo CSF collection and imaging and cognitive follow-up will be necessary to test this hypothesis; these studies are currently ongoing.
Co-founder of ADx NeuroSciences and founder of Key4AD