Blood NfL levels linked to cognitive deficits in IOPD

Study examines IOPD patients given enzyme replacement therapy

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Blood levels of neurofilament light chain (NfL) — a marker of nerve cell damage — are increased from infancy to young adulthood in classic infantile-onset Pompe disease (IOPD) patients given enzyme replacement therapy (ERT), a study shows.

This contrasted significantly with the blood NfL level reduction seen in healthy people over time. In addition, among IOPD patients, higher blood NfL levels were associated appreciably with worse cognitive function.

Given that it cannot reach the brain, these findings confirm ERT’s inability to prevent neurocognitive deficits and cognitive decline over time in these patients and further support the need for brain-targeting treatments, the researchers noted.

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“NfL is a promising biomarker for [brain and spinal cord] involvement in classic infantile Pompe disease and deserves additional research as a biomarker to monitor the effect of emerging treatments targeting the brain,” the researchers wrote.

The study, “Neurofilament Light and Its Association With CNS Involvement in Patients With Classic Infantile Pompe Disease,” was published in the journal Neurology.

Pompe disease is a genetic disease characterized by the toxic accumulation of a complex sugar molecule called glycogen inside cells due to a deficiency in the acid alpha-glucosidase (GAA) enzyme. Glycogen builds up most prominently in muscle cells, and to a lesser extent in cells of the central nervous system (CNS, the brain and spinal cord).

People with IOPD have very low or no GAA activity and manifest the most severe form of the disease, with symptoms appearing in the first few months of life.

ERT is an approved Pompe treatment that works by providing a working GAA enzyme to cells. For IOPD patients, it can enable the achievement of motor milestones and prolong survival, particularly when begun very early after birth.

However, because ERT cannot access the brain, extended survival has revealed that the disease increasingly affects the CNS and leads to neurocognitive problems.

Currently, biomarkers that reflect CNS involvement and the effect of future brain-targeting therapies are lacking. One such potential biomarker is NfL, a protein that reflects nerve fiber damage and that has been shown to “correlate with disease activity in many pediatric neurological diseases,” the researchers wrote.

Linking NfL to cognitive deficits

To learn more about the potential association between blood NfL levels and CNS involvement in IOPD, a team of researchers in the Netherlands analyzed data from 17 ERT-treated IOPD patients who had a brain MRI scan between 1999 and September 2020.

Patients’ age ranged from 22 days to 21.2 years, and their median age at diagnosis was 2.3 months (range, 3 days-5.7 months).

A total of four patients (24%) were cross-reactive immunologic material (CRIM)-negative, meaning they don’t produce any GAA enzyme and are more likely to develop anti-ERT antibodies, which limits the treatment’s effectiveness. Most patients (71%) were CRIM positive, while the CRIM status of one patient was unknown.

Patients started on ERT at a median age of 2.6 months, ranging from 4 days to 5.8 months.

A total of 74 blood samples to analyze NfL levels (one to eight samples per patient) were collected at ages below 1 year, 5 years, and 10 years, and around the time of MRI scans. These were compared with blood samples from 71 age- and sex-matched healthy children (age range 1.8 months-16.1 years), used as a control group.

Differences noticed at age 5

The researchers found that in the first year of life, blood NfL levels were similar in both groups, while differences were noticeable from year 5 onward. Blood NfL levels decreased by 8.8% yearly in the control group, while they increased by 6% yearly in IOPD patients — a group difference that was statistically significant.

While CRIM-negative patients are thought to have a poorer prognosis, their blood NfL levels were 45% lower than those of CRIM-positive patients. Still, “this finding should be interpreted with caution,” the researchers wrote, noting that the small number and young age of CRIM-negative patients in this study may have influenced this result.

The team then paired 43 brain MRI scans of 16 patients (one to six MRIs per patient) with blood samples taken around the same time. MRI scans were graded as stages 0-3 of brain involvement, with higher stages indicating more damage to the brain’s white matter, which contains nerve fibers.

Results showed that median NfL levels were increasingly higher with greater brain involvement: 4.4 picograms (pg)/mL in a patient with no brain involvement, 9.3 pg/mL in patients graded as stage 1, 16.6 pg/mL in those graded stage 2, and 21.3 pg/mL in those graded stage 3. However, these differences could not be tested statistically.

Patients’ cognitive function was assessed with neuropsychological tests that measured intelligence quotients (IQ) and processing speed, or the speed with which the brain receives, understands, and responds to information.

The researchers found that higher blood NfL levels were significantly associated with more cognitive deficits, with a doubling of NfL levels corresponding to a decrease of 7.7 IQ points and 13.9 processing speed score points.

“Since the CNS involvement in Pompe disease is much slower, and NfL increased in our study over time from childhood through young adulthood in the absence of CNS-targeting therapy, we conclude that NfL holds promise as a biomarker to evaluate the effects of innovative future treatments targeting the brain,” the researchers wrote.

They noted, however, that larger studies are needed to confirm these results and provide additional information about the role of factors such as CRIM status in this patient population.