Genetic and Environmental Contributors to Neurodegeneration: An Exploration of the Effects of Alcohol on Clinical Features of Huntington’s Disease Using the Enroll-HD Global Platform

Abstract

Huntington’s disease (HD) is a neurodegenerative dementia with a well recognised genetic cause. Alcohol misuse is a major environmental factor relevant to numerous neurological presentations, including HD. We explored the effects of alcohol intake on clinical features of HD by means of data from the Enroll-HD, which is a global registry study. A retrospective observational study making use of the Enroll-HD periodic dataset up to 2020 (in accordance with the Enroll-HD guidelines, encompassing 16,120 subjects with the HD gene (CAG expansion > 36), was carried out. This included 180 sites in 21 countries. The study looked at the association of alcohol use with the clinical presentation of HD, specifically looking into the age of first symptoms and HD severity. We also describe a specific case with manifest HD, a participant in the Enroll-HD study, whereby the patient’s obsessionality was central to her pattern of high alcohol intake and to her successful avoidance of alcohol thereafter. A record of past problems with high alcohol intake was more common in the group with manifest HD (9.0%, n = 1121) when compared with the pre-manifest carriers of the HD genetic abnormality (2.3%, n = 339). Age at onset of symptoms was not significantly influenced by current alcohol misuse, or past misuse. The severity of clinical impairments in HD was influenced by alcohol. Patients who reported high alcohol intake in the past had a statistically significant increase in motor impairments, by the Unified Huntington’s Disease Rating Scale total motor score (Kruskal–Wallis, post hoc Dunn’s, p < 0.001), and a significantly higher burden of psychiatric symptoms by the Problem Behaviours Assessment score (Kruskal–Wallis, post hoc Dunn’s, p < 0.01) compared with those not reporting high alcohol use. However, the past alcohol group did not have a lower Mini Mental State Examination score (Kruskal–Wallis, post hoc Dunn’s, p > 0.05) The first symptom of HD, as determined by the assessing clinician, was more likely to be psychiatric disturbance in patients currently misusing alcohol or those with prior history of alcohol misuse (55% and 31% respectively) when compared with controls (5%). Individual case experience, such as that presented in this study, shows that HD and alcohol, two major genetic and environmental contributors to neurodegeneration, interact in producing clinical problems. However, the complexities of these interactions are difficult to define, and may require larger studies dedicated to exploring the various factors in this interaction.

Associations between Sleep Quality and Serum Levels of Neurofilament Light in Individuals with Premanifest Huntington Disease

“…Moreover, future studies should include larger samples of individuals with premanifest HD, as neurodegeneration in this population can be influenced by several variables other than sleep, such as medication use and alcohol consumption. 14 Larger sample sizes would also enable moderation analyses on the role of the CAG expansion on associations between NfL and sleep quality.…”

Huntington's disease: A clinical primer for acute and general physicians

“…Rates of substance misuse, self-harm and suicide are higher in the HD population than in the general population and rates of addiction often increase with disease progression. 8 …”

Modifiable factors associated with Huntington's disease progression in presymptomatic participants

“…Despite considerable research into disease‐modifying drugs, only environmental factors have been shown to impact disease progression. 6 , 7 , 8 Moreover, disease trajectories differ between individuals with similar genotypic profiles and age at onset, 9 , 10 suggesting an influence of sociodemographic factors, 11 , 12 , 13 , 14 , 15 health behaviors, 11 , 16 , 17 , 18 , 19 or health history 11 , 20 , 21 , 22 on which intervention might have a positive impact. Identifying modifiable factors on which to act as early as possible is important to ensure the maximum effect of interventions and preserve a good quality of life for as long as possible.…”

“…For instance, a high educational level is associated with an early diagnosis 12 but also slower disease progression. 13 Health behaviors such as high alcohol consumption, 16 tobacco use, 18 coffee consumption, 23 and low body mass index (BMI) 19 are associated with more rapid disease progression as are musculoskeletal, 24 cardiovascular, 25 , 26 neurological, 27 or psychiatric comorbidities, 20 and a history of depression and anxiety. 21 However, these associations remain unclear, and the evidence contrasted.…”

“…First, reverse causality, that is, when behaviors (e.g., smoking or drinking alcohol) or sociodemographic changes (e.g., work) are interpreted as causes of the disease when they are its consequence, or vice versa, as has already been observed in other conditions, 28 , 29 therefore studying modifiable factors before the disease manifest itself might address the reverse causality effect. Second, interactions between multiple factors are difficult to account for during disease progression, 16 particularly because of the already described impact of the interaction between age and CAG repeat number. Third, factors such as BMI, alcohol consumption, or smoking have shown differential effects on function, mortality, or morbidity by age range, gender, or educational level in other populations, 30 , 31 , 32 , 33 but in HD these interactions remain unknown.…”