MRI detects brain changes before hATTR-PN symptoms begin
Multimodal MRI has potential as early detector of CNS involvement
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MRI scans detect brain changes in adults with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) before symptoms appear, according to a study.
While these changes were not associated with cognitive problems in early-stage hATTR-PN patients not yet showing signs of peripheral nerve damage, a hallmark of the disease where nerves outside the brain and spinal cord are damaged, people who did have symptoms scored significantly lower on cognitive assessment.
“MRI serves as an accurate, non-invasive tool for detecting CNS [central nervous system] damage, improving our understanding of the disease spectrum,” the researchers wrote. “This study highlights the need for ongoing research to validate multimodal MRI as a sensitive biomarker for early identification of CNS involvement in hereditary transthyretin amyloidosis, advancing future clinical trials and treatment strategies.” CNS refers to the brain and spinal cord.
The study, “Early Detection of Central Nervous System Involvement in ATTRv Using Multimodal MRI and Cognitive Assessments,” was published in the European Journal of Neurology.
Hereditary transthyretin amyloidosis, a group of conditions including hATTR-PN, is caused by mutations in the TTR gene. This leads to the production of a misfolded transthyretin protein that forms toxic aggregates, called amyloid deposits, that accumulate in tissues and organs. In hATTR-PN, also known as familial amyloid polyneuropathy (FAP), amyloid deposits accumulate primarily in peripheral nerves extending from the spinal cord to the extremities, causing damage. Such damage results in symptoms such as balance problems, muscle weakness, burning pain, and numbness.
Looking for ‘clinically useful tools’
Emerging research suggests that amyloid fibrils can also cause damage in the central nervous system (CNS, or the brain and spinal cord), including in patients carrying Val30Met, the most common hATTR-PN-causing mutation.
However, “no clinically useful tools are available to detect this impairment in its early stages of CNS damage,” wrote the team of researchers in Brazil, who used cognitive assessments and MRI techniques to identify early CNS involvement in hATTR-PN.
The team enrolled 49 adults with hATTR-PN (29 women and 20 men), 19 of whom were classified as pre-hATTR-PN because they showed no signs or symptoms of peripheral neuropathy (damage to the peripheral nerves). The hATTR-PN group, those showing symptoms, had a mean age of 51, while the pre-hATTR-PN group had a mean age of 41.
A group of 44 healthy participants, matched in sex and age with the patients, served as controls.
More than 70% of patients carried the Val30Met mutation, and 86.7% were receiving treatment.
All participants underwent a cognitive assessment using the Addenbrooke’s Cognitive Examination-Revised (ACE-R) test, which evaluated six cognitive domains: attention and orientation, memory, verbal fluency, language, and visuospatial ability.
Results showed that the cognitive abilities of hATTR-PN patients were worse than those of pre-hATTR-PN patients, as indicated by significantly lower overall ACE-R scores. Memory and verbal fluency (the ease and speed with which words are accessed and articulated) were particularly affected.
Even so, MRI scans of the brain revealed alterations in the microstructure of the white matter — the nerve fibers that facilitate communication among brain regions — in both hATTR-PN and pre-hATTR-PN patients relative to controls.
In hATTR-PN patients, there were noticeable changes on both sides of the brain, especially in regions related to memory, thinking, and planning (the temporal and frontal lobes). These changes were slightly more pronounced on the right side of the brain.
People with pre-ATTRv-PN showed similar but milder changes, primarily in deep regions of the temporal lobes, demonstrating that subtle brain changes begin before symptoms appear.
No decrease in the thickness of the brain’s outer layer, composed of gray matter or nerve cell bodies, was observed in any of the patient groups when compared with healthy controls.
Changes indicative of brain microbleeds were uncommon and minimal, detected in six people with ATTRv-PN, one healthy control, and none of those with pre-ATTRv-PN.
Detected abnormalities “had a rather typical pattern—diffuse and severe at [white matter], but none at [gray matter], indicating selective vulnerability of some regions to [transthyretin-mediated] damage,” the researchers wrote.
No significant associations were identified between cognitive assessments and MRI-based parameters after adjustment for multiple comparisons.
“We have shown that [hATTR-PN] involves not only the peripheral, but also the central nervous system since early disease stages,” the team wrote. “Indeed, subjects deemed pre-symptomatic from the perspective of the peripheral nervous system already presented structural [brain] abnormalities.”
Multimodal MRI “demonstrates promise in revealing early CNS structural changes in patients with [hATTR-PN],” the researchers concluded.
