Central nervous system (CNS) damage in Friedreich’s ataxia (FA) starts in the spinal cord and specific brain areas in children, progressing to more widespread white and grey matter injury in adults, according to a new imaging study. The findings could lead to biomarkers for future studies and indicate that FA is not strictly a neurodegenerative disease, researchers said.
The study, “Developmental and Neurodegenerative Damage in Friedreich Ataxia,” appeared in the European Journal of Neurology.
Both the central and peripheral nervous systems of FA patients experience structural damage. The cerebellum — which plays a central role in motor coordination, balance, and speech — is the major target in the brain, but damage in other regions has also been seen.
Although some reports have suggested that damage in FA is progressive, others have challenged the strict neurodegenerative classification and indicated that FA may impair CNS development.
To assess whether FA might result from a combination of neurodegeneration and impaired development, magnetic resonance imaging (MRI) studies of patients in early stages of the disease are needed, the team from University of Campinas, in Brazil, observed. Such an approach would yield information about the earliest affected structures in FA, help predict prognosis, and establish biomarkers for clinical trials.
Aiming to address this gap, the scientists studied patients younger and older than 18 with classical FA (i.e. younger than 25 at onset). MRI was used to evaluate brain and spinal cord damage.
A total of 37 patients — 25 adults (mean age 28 years) and 12 pediatric patients (mean age 14 years) — were followed between 2009 and 2017. All patients, as well as 38 controls (25 adults, 10 males), underwent MRIs to assess grey and white matter. White matter is made of nerve fibers and connects grey matter areas, which include cell bodies, their projections and the sites where neurons communicate, called synapses.
Compared to the respective controls, pediatric patients had white matter damage in the spinal cord, inferior cerebellar peduncle — a thick strand that connects the cerebellum with the medulla oblongata — and in the red nucleus, which is implicated in motor coordination.
Adult FA patients showed more widespread damage, with bilateral volume loss in the hippocampus, critical in memory; the thalamus, which relays sensory and motor signals into the cortex; and red nucleus, as well as in the right substantia nigra, key in reward and movement; pons, which connects upper and lower parts of the brain; midbrain, also implicated in motor movement (particularly the eye); and in the medulla oblongata, which controls involuntary processes such as breathing and digestion.
Unlike pediatric patients, adults also showed cerebral cortical thinning, nerve fiber injury mostly in the cerebellum, decreased fractional anisotropy (FA) — a marker of white matter health — in several areas, as well as changed cerebellar mean diffusivity, which assesses grey matter. Another measure of white matter damage called increased radial diffusivity (RD) revealed more widespread alterations in adults than in pediatric patients. Neither pediatric nor adult patients showed cerebellar cortical damage.
Both patient groups showed reduction of cervical spinal cord area. Pediatric patients showed progressive spinal cord area decline with age. “Our data strongly support the concept of a developmental spinal cord abnormality, possibly followed later by progressive atrophy (shrinkage),” the scientists said.
The data further showed that, in the inferior cerebellar peduncle, values of FA in adult patients correlated with disease duration, while RD in pediatric patients was associated with FA severity, as assessed with the Friedreich’s Ataxia Rating Scale (FARS subscore III – Neurological Examination).
“Structural damage in [FA] begins in spinal cord, inferior cerebellar peduncle as well as red nucleus, and progresses to cerebral areas in adulthood,” the researchers said. “Our results favor for potential neuroimaging biomarkers and suggest that [FA] is not a purely neurodegenerative disease.”