Older Age, Worse Disease Predict Cognitive Issues With FAP: Study

Researchers sought reasons for decline in patients given liver transplant

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Armed with a magnifying glass and a flashlight, two scientists study a giant model of the human brain.

Older age and worse disease were significantly associated with cognitive impairments in people with familial amyloid polyneuropathy (FAP) who underwent a liver transplant, a large study suggested.

Researchers noted these cognitive findings are consistent with the natural history of the disease.

“No distinct pattern was found for mild vs. moderate cognitive dysfunction” among patients who had a liver transplant, the team wrote.

Thus, while further studies are needed to investigate cognitive decline over time occurring in FAP patients who undergo a liver transplant, researchers said their findings confirm that “older age and higher severity of the disease are significantly associated and potentially predictors of cognitive dysfunction.

The study, “Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant,” was published in the journal Amyloid.

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FAP is a form of hereditary ATTR amyloidosis mainly characterized by the accumulation of harmful amyloid fibrils made up of a protein called transthyretin (TTR)  in peripheral nerves — those found outside the brain and spinal cord. This buildup results in nerve damage, or polyneuropathy. Other organs, such as the eyes, heart, and kidneys, also can be affected.

In FAP, these amyloid fibrils arise due to mutations in the TTR gene, which encodes the TTR protein. Because TTR is mainly produced in the liver, a liver transplant can slow FAP progression by preventing the formation of amyloid fibrils.

However, brain and spinal cord involvement have been reported in patients whose disease course was changed by a liver transplant. Yet, cognitive impairments in these patients has not been investigated.

Investigating cognitive impairments in FAP

The aim of this study, carried out by researchers in Portugal, was to explore the cognitive function of a large group of FAP patients who underwent a liver transplant so as to identify factors that could be associated with cognitive impairment. Participants included those carrying the most common disease-causing TTR mutation, called Val30Met.

“This is the largest study of cognitive dysfunction in [FAP-Val30Met] patients treated with [a liver transplant],” the team wrote.

The team recruited 269 patients who underwent a liver transplant from 1993 to 2018. More than half of the patients (55%) were male, and the median age was 45 (range: 28–75 years).

In 35 individuals (13%), cognitive impairment was documented. Of these patients, 14 had mild and 21 had moderate cognitive impairment.

Median age in the cognitive impairment group was higher than that seen in the group of patients who had no dysfunction — 50 vs. 45 years. Cognitively impaired patients also had fewer years of education, with a median of six verus eight years, and longer disease duration (median of 17 vs. 14 years).

The group with greater impairment also had a longer post-transplant duration, with a median of 13 years versus 10 years.

Cognitively impaired patients also experienced more focal neurological episodes (FNEs) than non-impaired patients (46% vs. 28%). FNEs are caused by damage to nerves at a specific location that can trigger a stroke or stroke-like symptoms, visual auras, and epileptic seizures.

Impairment also occurred more often in patients with higher modified polyneuropathy disability scores (mPND), indicative of higher disability.

Higher levels of the heart damage marker NT-proBNP and the kidney impairment marker cystatin C also were more frequently seen in patients from the cognitive dysfunction group.

“These findings are consistent with the results of our previous study in untreated [FAP-Val30Met] patients,” the researchers wrote.

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Patients with mild impairment had a longer disease duration than those with moderate cognitive difficulties (median of 21 vs. 15 years) and a more extended post-transplant period (median of 17 vs. 10 years).

Younger patients tended to experience milder cognitive deficits, but the differences between the two groups were marginal and non-significant. Elevated NT-proBNP and cystatin C levels were similar among those with mild or moderate impairment, as were sex, years of education, FNEs, cognitive complaints, and heart rhythm abnormalities.

Older age, severity are factors

Among the 35 individuals with cognitive impairment, 22 had undergone imaging assessments, with seven — three with mild and four with moderate impairments — having normal scans (31.8%).

On MRI, one patient with moderate cognitive impairment showed signs of amyloidosis in the brain. Other non-specific abnormalities detected in CT scans included brain shrinkage (atrophy), white matter loss, and blood vessel calcifications.

Subgroup analysis of the nine patients with late disease onset (starting at age 50 or older) showed that four had moderate cognitive dysfunction, while the remaining five had normal cognition.

Abnormal NT-proBNP values were observed in three patients with moderate cognitive dysfunction and in three of those with normal cognition. Abnormal cystatin C values were detected in almost all those with normal cognition or moderate dysfunction. None with normal cognition reported depression, whereas two of four cognitively impaired patients experienced depression.

Finally, patients with FNEs were older at assessment, but younger at disease onset, had fewer years of education, longer disease duration, and longer post-transplant duration. FNEs were not associated with sex, mPND score, elevated cystatin C, heart rhythm irregularities, anxiety, or depression.

“Study findings confirm that cognitive dysfunction is related to the severity of polyneuropathy,” the team wrote. “Older age at disease onset is statistically associate and potentially an important predictor of moderate cognitive dysfunction, whereas longer disease duration is necessary for the occurrence of mild cognitive dysfunction.”

“A longitudinal approach is necessary to understand the pattern of progression of cognitive dysfunction in [FAP-Val30Met] patients treated with [a liver transplant] or under newer therapeutic strategies for ATTR amyloidosis,” the team wrote.