15 Sep 2015

When it comes to tracking Alzheimer’s disease, a marker of synaptic degeneration ranks high on the collective wish list. Postmortem studies show that synapse loss occurs early in AD and correlates well with cognitive deficit, but how to monitor synaptic degeneration in living subjects? A study in the 14 September JAMA Neurology suggests that levels of neurogranin in the cerebrospinal fluid may help. Alzforum reported on these data from this year's Alzheimer’s Association International Conference (AAIC) (see July 2015 conference news).

Neurogranin is a post-synaptic protein that abounds in dendritic spines. Scientists believe neurons release it into the CSF when their synapses degenerate. In cross-sectional studies, AD patients have more CSF neurogranin than cognitively healthy controls (Thorsell et al., 2010; de Vos et al., 2015). Among people with mild cognitive impairment, high baseline levels of neurogranin predict progression to AD (Kvartsberg 2014; Jan 2015 news).

In the new study, researchers led by Maartje Kester at the VU University Medical Center, Amsterdam, confirmed these findings in 163 patients from the Amsterdam Dementia Cohort. Their results include the first within-subject longitudinal data for CSF neurogranin, and hint that the protein may be elevated even before MCI, when cognition is demonstrably intact. Working in collaboration with Anne Fagan and colleagues at Washington University, St. Louis, Kester used an ELISA to quantify neurogranin levels in the CSF of people with AD (n=65), MCI (n=61), and those classified as cognitively normal (n=37), most of whom reported subjective memory complaints (n=31). All participants provided two CSF samples an average of two years apart and were followed clinically for about four years.

The researchers found that baseline neurogranin levels were higher in the AD and MCI groups than controls. Two years later, levels were unchanged in the AD and MCI groups, but increased significantly in the cognitively normal group.

Why did neurogranin levels rise specifically in the cognitively normal group? The researchers point out that synaptic changes occur very early in pathogenesis, and that the longitudinal increase may reflect active synaptic degeneration in people on the path to AD.  That 10 of the 37 participants who were classified as cognitively normal at baseline then progressed to MCI or dementia within the four-year follow-up period supports this hypothesis. 

“We now know from several independent studies that CSF neurogranin is indeed a promising CSF biomarker for AD,” wrote Henrik Zetterberg and Kaj Blennow, University of Gothenburg, Sweden, in an accompanying JAMA Neurology editorial. They added that it will be important to further characterize longitudinal changes in neurogranin during AD, especially in the preclinical phase, and to correlate CSF levels of the protein with other putative markers of synaptic injury, such as hippocampal atrophy.—Kelly Dakin

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References

News Citations

1. At AAIC, Researchers Debate Neurogranin's Measure as a Marker 21 Aug 2015
2. New Biomarkers? Synaptic Proteins in Spinal Fluid Predict Cognitive Decline 16 Jan 2015

Paper Citations

1. Thorsell A, Bjerke M, Gobom J, Brunhage E, Vanmechelen E, Andreasen N, Hansson O, Minthon L, Zetterberg H, Blennow K. Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease. Brain Res. 2010 Nov 29;1362:13-22. Epub 2010 Sep 25 PubMed.
2. De Vos A, Jacobs D, Struyfs H, Fransen E, Andersson K, Portelius E, Andreasson U, De Surgeloose D, Hernalsteen D, Sleegers K, Robberecht C, Van Broeckhoven C, Zetterberg H, Blennow K, Engelborghs S, Vanmechelen E. C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer's disease. Alzheimers Dement. 2015 Jun 16; PubMed.
3. Kvartsberg H, Duits FH, Ingelsson M, Andreasen N, Öhrfelt A, Andersson K, Brinkmalm G, Lannfelt L, Minthon L, Hansson O, Andreasson U, Teunissen CE, Scheltens P, Van der Flier WM, Zetterberg H, Portelius E, Blennow K. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. Alzheimers Dement. 2015 Oct;11(10):1180-90. Epub 2014 Dec 19 PubMed.

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