Changes in the amount of grey matter in specific regions of the brain appear to occur early in relapsing multiple sclerosis (MS), while structural changes in white matter happen late in disease progression.
These were among the findings of a recent study that tracked the sequence of events in the progression of relapsing MS, as related to different aspects of the disorder. Researchers say such data on brain changes can help in better understanding the development of the neurodegenerative disease.
The study, “The sequence of structural, functional and cognitive changes in multiple sclerosis,” was published in the journal NeuroImage: Clinical.
Understanding the order of events in MS progression could help researchers interpret study results based on single biomarkers, shed light on the biological mechanisms driving progression, and help physicians more precisely monitor patients.
Thus, scientists from the MS Center Amsterdam, in the Netherlands, and other institutions examined the records of 295 relapsing MS patients — 243 with relapsing-remitting MS (RRMS) and 52 with secondary progressive MS (SPMS) — and 96 healthy people (controls).
“The primary aim was to build a model that reflects a sequence of events in disease evolution in MS patients with a relapse onset,” the researchers wrote.
“The secondary aim was to explore the event sequence for patients in relation to worsening physical and cognitive burden separately, because underlying disease processes could be different,” they wrote.
The sequence of events involved in relapsing MS was modeled as it related to three factors: disease progression, changes from low to high disability, and cognitive decline.
With respect to disease progression, data showed that relapsing MS tended to begin with neuron loss in the corticospinal tract — a part of the central nervous system running from the brain’s base down the spinal cord. Wasting, or atrophy, of the cerebellum and thalamus brain regions followed.
Of note, the cerebellum is broadly involved in balance, coordination, and posture, while the thalamus plays a role in cognitive and sensorimotor functions.
Neurodegeneration appeared to spread from there, involving the occipital and parietal lobes of the brain before moving into the temporal lobe, the spinal cord, and the basal ganglia, which is the region primarily responsible for motor control. It later on affected the cingulate — key to emotion formation and processing, learning, and memory — and the insula, which is the region involved in basic emotions and self-awareness.
Nerve loss within the cingulum, a tract of nerves running through the brain’s interior, and non-specific white matter tracts started to appear in between the loss of volume of the basal ganglia and cingulate.
Thalamic atrophy is associated with declines in visuospatial cognition, encompassing tasks such as locating objects, shifting spatial attention, and holding items in visual memory. Declines in verbal fluency, verbal memory, and information processing tended to occur next, with other cognitive domains following.
Regarding disability, grey matter in the cerebellum and insula appeared to atrophy early on in the shift from low to high disability, while occipital and frontal lobe atrophy occurred relatively late.
As disability increased, abnormal brain lesions appeared in the inner brain regions, followed by deep white matter, and then the outer regions. Changes related to attention, working memory, and executive function were the last to be affected as disability grew.
Concerning cognitive decline, data showed early atrophy of the insula, followed by the hippocampus and then the cervical cord, then the frontal, parietal, occipital, and temporal lobes. Atrophy of the thalamus followed, and lastly that of the basal ganglia. Lesions in the brain appeared to occur soon after most atrophy measures.
Finally, changes in white matter density occurred toward the end of cognitive decline, with the white matter of the corticospinal tract being affected earlier than the rest.
Although the data behind these models suggest a general order to relapsing MS progression, the researchers stressed that MS manifests and develops differently from one person to the next. The investigators saw evidence for this in how their data varied, and suggested that the precise sequence of events may change for different MS subgroups.
In general, reductions in grey matter, especially within the thalamus, insula, hippocampus, and cerebellum, were the earliest to occur, alongside physical disability and cognitive decline.
“We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM [white matter] tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events,” the researchers wrote.
Small changes in white matter generally occurred later, which, according to the team, deserves further investigation.
“It appears to contradict the early occurrence of focal white matter lesions in many tracts, possibly indicating that overall tract integrity is maintained for a longer period of time,” they wrote.
The team also emphasized that future studies “should also include patients soon after first symptoms arise (i.e., CIS [clinically isolated syndrome]) to determine the earliest disease pathologies in MS with high certainty.”
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