Apathy begins early, worsens over time in Huntington’s disease: Study
Findings underscore variable nature of progression of this symptom
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Apathy, a common symptom of Huntington’s disease, may present even before the development of hallmark motor symptoms and worsens gradually over time, according to a six-year study of people carrying a Huntington’s-causing mutation.
Data also showed that in those without clear Huntington’s symptoms, apathy worsening over time was mainly driven by increasing difficulty in initiating actions. In contrast, apathy changes in people with manifest disease were broader and more variable, reflecting greater clinical complexity at later disease stages.
“These findings underscore the [variable] nature of apathy progression and the value of multidimensional assessment in longitudinal studies,” researchers wrote.
The study, “Longitudinal trajectories of apathy in Huntington’s disease: a 6-year follow-up study,” was published in the Journal of Neurology by a team of researchers in Denmark.
Apathy one of the most common, distressing Huntington’s symptoms
Huntington’s disease is caused by a mutation in the HTT gene that results in the production of an abnormally long huntingtin protein, which forms toxic clumps in nerve cells, leading to their dysfunction and death. This ultimately results in hallmark movement problems, as well as other symptoms such as cognitive decline and mental health issues.
Among these, apathy is one of the most common and distressing symptoms, affecting up to 50% to 99% of patients across disease stages. It is generally defined as a reduction in goal-directed behavior, “yet researchers debate whether it reflects diminished interest and motivation or a multidimensional construct encompassing emotional, cognitive, and behavioral components,” the team wrote.
In Huntington’s, apathy has emerged as a potential marker of disease progression, with studies suggesting it can appear before hallmark Huntington’s symptoms develop and worsen over time. However, how apathy evolves over longer periods remains poorly understood.
To address this gap, the researchers followed 82 people carrying a Huntington’s-causing mutation over six years. These carriers, enrolled at a clinic in Copenhagen between 2018 and 2019, included 40 individuals not yet showing symptoms (premanifest Huntington’s) and 42 with manifest disease. A group of 32 relatives who did not carry a disease-causing mutation was also included for comparison.
All participants underwent an initial assessment of apathy, along with an evaluation of motor, cognitive, and other mental health symptoms.
Participants with manifest Huntington’s showed more severe apathy
Apathy was measured using the Lille Apathy Rating Scale (LARS), which assesses different aspects of goal-directed behavior, with higher scores indicating greater apathy. The Problem Behaviors Assessment-short (PBA-s), which assesses behavioral symptoms, was also used to examine apathy and depression.
After a mean of six years, 25 of the carriers with premanifest Huntington’s, 30 of the carriers with manifest Huntington’s, and 27 of the healthy relatives also completed follow-up evaluations.
As expected, participants with manifest Huntington’s showed significantly more severe motor and cognitive impairment, depression, and apathy than those with premanifest Huntington’s or healthy relatives at both time points. People in the premanifest stage of the disease showed significantly worse motor scores than healthy relatives at the two time points.
Across all carriers, apathy showed a modest but significant increase over the six years. Scores on LARS rose significantly by 1.38 points, indicating worsening apathy. This score worsening was largely driven by increasing difficulty with action initiation, or the ability to start tasks or activities, which was assessed with a LARS subscale.
Similarly, PBA-s apathy scores increased by 1.11 points, further supporting a worsening in apathy across participants.
These findings highlight the importance of long-term follow-up and multidimensional assessment when studying apathy progression and underscore the need to account for individual variability in both research and clinical practice.
Across disease stages, distinct patterns of apathy progression emerged based on LARS scores. People with premanifest Huntington’s showed a significant increase in difficulty initiating actions, suggesting that early motivational changes may occur before hallmark motor symptoms become evident.
In contrast, those with manifest Huntington’s showed a significant increase in LARS global scores over time, but no significant changes in subscales.
“This pattern is consistent with previous findings suggesting that apathy in earlier stages may be more closely linked to specific motivational and executive processes, whereas in later stages apathy becomes more multifactorial as motor, cognitive, and psychiatric symptoms accumulate and contribute to functional decline,” the researchers wrote.
Moreover, individual trajectories varied considerably, with some participants showing worsening apathy over time while others remained stable or even improved. Variability appeared to be greatest among those with manifest Huntington’s, consistent with greater differences between individuals at later disease stages, the researchers noted.
Still, the overall rate of apathy progression did not differ significantly between individuals with premanifest and manifest Huntington’s.
“This suggests that apathy progression may begin already in the premanifest stage and continue across disease progression, although the sample size may have limited statistical power to detect small differences between groups,” the team wrote.
When the researchers examined whether worsening apathy was linked to changes in other symptoms, they found that only increases in depressive symptoms appeared to play a role.
“These findings highlight the importance of long-term follow-up and multidimensional assessment when studying apathy progression and underscore the need to account for individual variability in both research and clinical practice,” the researchers concluded.
