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Neurogranin, a CSF Biomarker for Synaptic Loss, Is Found to Predict Progression from MCI to Alzheimer's Disease

ARTICLE IN BRIEF

Researchers reported that levels of neurogranin, a cerebrospinal fluid biomarker for synaptic loss, were elevated in patients with Alzheimer's disease compared with cognitively normal individuals.

WASHINGTON — Levels of neurogranin, a cerebrospinal fluid (CSF) biomarker for synaptic loss, were elevated in patients with Alzheimer's disease (AD) compared with cognitively normal individuals. Neurogranin levels also predicted progression from mild cognitive impairment (MCI) to AD dementia, researchers reported here in July at the Alzheimer's Association International Conference (AAIC).

“In Alzheimer's disease, synaptic loss is an early pathologic event and is correlated to cognitive decline. With this study we hoped to find a biomarker that reflects early Alzheimer's disease and correlates with disease progression,” study author Maartje Kester, MD, PhD, of the department of neurology and the Alzheimer Center at VU University Medical Center in Amsterdam, the Netherlands, told Neurology Today.

STUDY METHODOLOGY, RESULTS

The researchers measured CSF levels of neurogranin in 37 cognitively normal individuals with a mean age of 64, 61 people with MCI with a mean age of 68, and 65 patients with AD with a mean age of 65. The patients were enrolled in the Amsterdam Dementia Cohort and received two lumbar punctures two years apart. They were followed for approximately 3.8 years.

Among the findings, baseline levels of neurogranin were higher in AD patients than in cognitively normal individuals (p=0.04) and were strongly correlated with levels of tau and phosphorylated tau (p<0.001), but not with amyloid-beta. People with MCI who progressed to AD had higher baseline levels of neurogranin than those with stable MCI (p=0.004). Neurogranin levels were predictive of progression from MCI to AD (hazard ratio [HR] 1.8; 95% confidence interval [CI], 1.1-2.9; tertiles), the researchers reported.

Based on the findings, neurogranin “could have a future role in the diagnostic process, probably in combination with the core CSF biomarkers [amyloid and tau],” Dr. Kester said. “Furthermore, it could have a role in the monitoring of disease progression in treatment trials.”

She added, “We hope that our study will be replicated in other cohorts. In addition, studies on associations between this novel CSF biomarker and other functional measures, like repeated neuropsychological examination or EEG, are needed to increase the understanding of neurogranin in the pathogenesis of AD.”

EXPERTS COMMENT

Experts who spoke with Neurology Today said that neurogranin is a novel CSF biomarker for determining which patients with MCI have a higher risk of progressing to AD, and may help inform clinicians' understanding of the pathologic progression of AD. But they cautioned that more research is needed to fully elucidate neurogranin's utility as a biomarker and potential diagnostic tool.

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DR. MAARTJE KESTER said that based on the findings, neurogranin “could have a role in the diagnostic process, probably in combination with the core CSF biomarkers [amyloid and tau]. Furthermore, it could have a role in the monitoring of disease progression in treatment trials.”

Commenting on the findings, David Gill, MD, a cognitive and behavioral neurologist at Unity Rehabilitation & Neurology in Rochester, NY, and a member of the Neurology Today editorial advisory board, said that because of its association with tau but not amyloid-beta, neurogranin “could help inform our understanding of the Alzheimer's disease process.”

He added: “The study identifies a novel biomarker that could play a role not only in the diagnosis of Alzheimer's disease, but also the prediction of which patients with mild cognitive impairment will progress to Alzheimer's. The use of CSF biomarkers to diagnose and/or predict Alzheimer's disease is well established; this provides another CSF marker that can be studied.”

But Steven T. DeKosky, MD, FAAN, deputy director of the McKnight Brain Institute and a professor of neurology in the University of Florida College of Medicine, said it's unclear what neurogranin adds to the existing, validated CSF biomarkers for progression from MCI to AD.

“If you're going to do a spinal tap and you're looking for signs of Alzheimer's disease, you're going to run screens for tau, phosphorylated tau, and amyloid-beta. We already have good data on their predictability,” he said. “If you look at people who have MCI and they have low amyloid and high tau, we already know that 90 percent of them are probably going to get AD within five years. So how much more neurogranin adds to that, I don't know.”

However, he agreed with Dr. Gill that neurogranin may be useful “to tell us something more about the pathology of the disease. It's a solid marker, statistically, that synapses are being lost in the course of the disease, even without manifest evidence of cognitive loss,” he said. “So I see it more as a marker for helping us understand the timing of the pathology, rather than a diagnostic marker. These data may teach us about the nature and timing of synaptic degeneration.”

Future research into neurogranin's utility as a CSF biomarker should include studies to evaluate its use both for prediction and diagnosis of Alzheimer's disease, Dr. Gill said. “It would also be interesting to note if neurogranin is present in blood, and if so, if a blood test of neurogranin could be studied.”

LINK UP FOR MORE INFORMATION:

•. Amsterdam Dementia Cohort http://bit.ly/Amsterdam-dementia