Monitoring synaptic integrity

Alzheimer’s disease (AD) begins in the brain about 20 years prior to the appearance of symptoms of dementia. This “preclinical” period offers a potential therapeutic window. Existing biomarkers track two pathological hallmarks of disease—amyloid plaques and tau tangles—but until recently, there have been no markers for synaptic dysfunction, which is another key pathological component of AD that directly underlies cognitive deterioration. Neurogranin, a brain-specific postsynaptic protein, may be useful as a marker of synaptic integrity. Prior studies have reported elevated neurogranin in cerebrospinal fluid of symptomatic AD patients, and that higher neurogranin correlates with cognitive decline. Now, two separate groups further examine neurogranin in healthy controls, individuals with mild cognitive impairment (MCI), and AD patients. Portelius et al . examined cerebrospinal fluid from 110 healthy controls, 68 people with stable MCI, 105 with progressive MCI, and 95 with AD, all from the Alzheimer’s Disease Neuroimaging Initiative. Using an in-house immunoassay with a monoclonal antibody to the C-terminus of neurogranin (Ng7), the authors assessed the relationship of neurogranin to other markers of AD, to cognitive status, and to psychometric performance. Neurogranin was higher in AD and MCI individuals compared with healthy controls, and was also higher in those with progressive MCI compared with stable MCI. Neurogranin was higher in 32 healthy controls who progressed to MCI or AD, compared with stable healthy controls who did not. In all groups, there was strong correlation with amyloid plaque deposition as assessed by amyloid PET imaging, as well as with tau and phosphorylated tau in cerebrospinal fluid. There was no correlation between neurogranin and hippocampal volume or performance on cognitive tests, but higher neurogranin was predictive of change in performance on cognitive tests and rate of hippocampal tissue loss. Kester et al . report a longitudinal study of neurogranin, examining data from 37 cognitively normal individuals, 61 people with MCI, and 65 individuals with symptomatic AD, all of whom had two lumbar punctures to obtain cerebrospinal fluid. They measured neurogranin with a sandwich immunoassay using rabbit antibodies that recognize two epitopes, one at the C-terminus and one at the N-terminus. These investigators also found that neurogranin was higher in the AD group compared with healthy controls; however, there were no significant differences between the MCI and cognitively normal group. Among those with MCI, the 36 who progressed to AD had higher neurogranin in cerebrospinal fluid at baseline compared with those who did not progress; baseline neurogranin was predictive of progression from MCI to AD in a Cox regression analysis. Neurogranin was correlated with tau and phosphorylated tau in all groups but not with amyloid-β42. The longitudinal component of the study revealed that neurogranin increased over time in cognitively normal individuals but not in those with MCI or AD. A caveat is that, as with other AD markers, there is overlap between normal and “high” values. Furthermore, the two groups report cerebrospinal fluid neurogranin ranges that are substantially different—300 to 500 pg/mL in Portelius et al. and 1200 to 2800 pg/mL in Kester et al. —thus, further work is needed to standardize neurogranin assays and develop cutoffs for what would be classified as “normal.” Additionally, there are not yet convincing data that neurogranin adds to the diagnostic or prognostic information provided by existing biomarkers such as amyloid-β and tau. However, these two studies suggest that neurogranin should be further investigated as a potential marker of AD. Data from these two papers suggest that neurogranin increases in the preclinical stage of AD and may be useful for tracking synaptic integrity very early in the disease, prior to the appearance of symptoms. E. Portelius et al ., Cerebrospinal fluid neurogranin: Relation to cognition and neurodegeneration in Alzheimer’s disease. Brain 10.1093/brain/awv267 (2015). [[Abstract]][1] M. I. Kester et al ., Neurogranin as a cerebrospinal fluid biomarker for synaptic loss in symptomatic Alzheimer disease. JAMA Neurol. 10.1001/jamaneurol.2015.1867 (2015). [[Abstract]][2] [1]: http://brain.oxfordjournals.org/content/early/2015/09/14/brain.awv267 [2]: http://archneur.jamanetwork.com/article.aspx?articleid=2436595