番茄社区

A blood test predicted disease progression and brain neurodegeneration at very early stages of familial Alzheimer's disease, researchers reported.

Serum neurofilament light chain (NfL) levels correlated with NfL levels in the cerebrospinal fluid (CSF) and were elevated at pre-symptomatic stages of familial Alzheimer's disease, according to Mathias Jucker, PhD, of the German Center for Neurodegenerative Diseases in Tübingen, Germany, and colleagues.

Up to 16 years before the calculated onset of dementia symptoms, there were noticeable changes in blood, they reported in .

The rate of change of serum NfL was key: "It is not the absolute neurofilament concentration but its temporal evolution which is meaningful and allows predictions about the future progression of the disease," Jucker said in a statement.

These findings add to a growing body of evidence suggesting NfL might be used clinically as a blood biomarker for Alzheimer's and other neurodegenerative diseases.

"This is something that would be easy to incorporate into a screening test in a neurology clinic," co-author Brian Gordon, PhD, of Washington University in St. Louis, said in a statement. "We validated it in people with Alzheimer's disease because we know their brains undergo lots of neurodegeneration, but this marker isn't specific for Alzheimer's. High levels could be a sign of many different neurological diseases and injuries."

When brain neurons are damaged or dying, they release the NfL protein, which leaks into CSF and blood. Rising levels of NfL in CSF signal neuron loss in stroke, traumatic brain injury, Alzheimer's, multiple sclerosis, and other neurodegenerative conditions.

This study assessed 405 people from the (DIAN), a consortium led by Washington University. Participants in DIAN carry one of the gene mutations (APP, PSEN1, PSEN2) known to cause dominantly inherited Alzheimer's disease. The cohort offers a unique opportunity for researchers to develop accurate predictions about whether and when a family member will develop dementia: a parent with one of these mutations has a 50% chance of passing the genetic error to a child, and a child who inherits a variant is all but guaranteed to develop symptoms of dementia around the same age as the parent.

The researchers examined 243 DIAN participants who carried an early-onset genetic variant and 162 unaffected relatives as controls. DIAN participants were evaluated at baseline and at subsequent follow-up visits (annually to every third year) with blood and CSF tests, imaging, and cognitive tests.

NfL levels in CSF (n=187) and serum (n=405) correlated with one another and were elevated before dementia symptoms occurred. Longitudinal, within-person analysis of serum NfL (n=196) confirmed this elevation, and showed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels -- 16.2 versus 6.8 years before the estimated symptom onset.

The serum NfL rate of change peaked in participants converting from the pre-symptomatic to the symptomatic stage of Alzheimer's and was associated with cortical thinning on MRI. Serum NfL also predicted cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test over a 2-year period.

"These results suggest that in the context of Alzheimer's disease pathology -- currently measured by CSF amyloid or amyloid PET, but potentially in the future by blood amyloid -- serum NfL could prognosticate the rate of disease progression and potentially be utilized in clinical trials as a surrogate endpoint," observed Michelle Mielke, PhD, of the Mayo Clinic in Rochester, Minnesota, who was not involved in the research.

"The authors correctly point out that additional studies are needed over the clinical and pathological course of sporadic Alzheimer's patients, especially because sporadic Alzheimer's patients are older and are more likely to have co-existent vascular and other brain pathology which can also impact serum NfL levels," Mielke told 番茄社区.

"Regardless, the current findings are promising and elegantly highlight the potential clinical use of this blood-based marker," she said.

Future analyses are needed to more accurately pinpoint when serum NfL rate of change is a better predictor of neurodegeneration and cognitive decline than absolute NfL, Jucker noted. And because neurofilaments also accumulate in the blood during the course of other neurodegenerative disorders, this test is only conditionally suitable for diagnosing Alzheimer's. "However, the test accurately shows the course of the disease and is therefore a powerful instrument for investigating novel Alzheimer's therapies in clinical trials," he said.

Comment