Seven-year clinical follow-up of premanifest carriers of Huntington's disease.

Detecting subtle clinical abnormalities in the 'premanifest' phase of Huntington's disease (HD) is of importance in the development of instruments to monitor early therapeutic intervention trials. The current study examined changes in motor function, cognition and behaviour over a period of seven years in premanifest carriers of the HD gene mutation. Twenty-nine carriers without unequivocal motor signs of HD and 43 non-carrier controls were prospectively examined four times. The assessments consisted of the Unified Huntington's Disease Rating Scale (UHDRS) and an extensive neuropsychological test battery addressing global cognitive function, memory, language and executive function. Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic). Over the years, carriers showed a decline in memory and concentration function (Wechsler Memory Scale (WMS)) and in motor function (UHDRS motor scale). Changes over time could be particularly ascribed to carriers converting to manifest HD. These results demonstrate that standardized motor assessments and objective memory and concentration tasks are sensitive to change over a period of 7 years, specifically in carriers converting to manifest HD. Executive tasks also showed subtle cognitive abnormalities in premanifest HD, but a decline over time could not be demonstrated.

Introduction

Huntington’s disease (HD) is a hereditary neurodegenerative disease that becomes manifest in midlife and is characterised by motor disturbances, cognitive decline and behavioural dysfunction. HD is caused by the abnormal expansion of a trinucleotide (CAG) repeat in the gene for the protein huntingtin [1]. The genetic defect leads to cerebral cell death, especially in the basal ganglia. Although the clinical diagnosis of HD is based on the first appearance of motor signs, a positive family history and confirmation by DNA-testing, subtle changes in motor function, cognition and behaviour are known to precede manifest disease. Detecting these very early changes is of importance in the development of instruments to monitor early therapeutic intervention trials and to obtain more insight into the phase of clinical disease onset.

Cross-sectional reports showed that carriers of the HD gene mutation without manifest motor signs (further labelled as carriers) perform significantly worse than non-carriers on certain motor scores, neuropsychological tests and behavioural assessments [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. Furthermore, some studies showed relationships between fewer years to estimated onset of diagnosable clinical disease and worse motor and cognitive function [2] [7] [12] [13] [14].

Longitudinal follow-up is however necessary to really understand the pattern of evolving motor, cognitive and behavioural abnormalities in the phase of HD clinical onset. First of all, to find out if clinical markers that are sensitive in detecting premanifest abnormalities show a decline over time and might be suitable as outcome measures in future therapeutic trials. Secondly, to monitor whether carriers, converting to manifest HD, display specific clinical changes.  
    To date, several longitudinal studies have been undertaken. The duration of follow-up however has been brief in the vast majority of longitudinal studies and results show discrepancies. In accordance with other studies we failed to demonstrate clinical markers for premanifest HD in our previous 3-year follow-up study [15] [16] [17]. Others did detect a significant decline over time in motor function, executive function, attention and memory [18] [19] [20] [21]. The longest follow-up study to date (10 years) demonstrated that the most rapid decline on motor and cognitive domains was found in individuals approaching clinical disease onset [13].  
    With the present observational study we aim to give more insight in the clinical onset phase of the disease as the number of reports on clinical decline in premanifest HD using long-term follow-up with a comprehensive assessment battery is limited. The objective was to follow a premanifest HD carrier group for 7 years in order to determine if our assessment battery detects subtle clinical changes preceding diagnosable clinical HD. Furthermore, we examined whether the rate of decline on motor, cognitive and behavioural measures could be related to estimated proximity to diagnosable clinical disease.

Methods

In the original study, 134 participants were included (46 premanifest carriers, 88 non-carriers). They were referred to the Leiden University Medical Centre (LUMC) Department of Clinical Genetics, for predictive testing, and consented to participate in a three-year clinical follow-up study [17]. Non-carriers were at-risk individuals who, after predictive testing, proved to have a CAG-repeat lenght of fewer than 27. Carriers were considered to be premanifest in the absence of unequivocal motor signs on the Unified Huntington’s Disease Rating Scale (UHDRS) [22]. A neurologist who was blind to genetic status and trained in the administration of the UHDRS performed the motor examination and filled in a score ranging from 0-3 (0= normal, 1= minor soft signs, 2= probable HD, 3= unquestionable HD). Carriers with a rating of 3 at baseline were diagnosed with HD and excluded from the study. One hundred six participants (33 carriers, 73 non-carriers) attended all follow-ups in the three-year period. Seven years after the start of the original study these participants were invited to take part in an additional follow-up. Twenty-nine carriers and 44 non-carriers consented to continue follow-up. Four carriers and 29 non-carriers did not re-enter the study after the original three year follow-up. One non-carrier was excluded for analyses since he had a minor stroke. This seven year follow-up study, therefore, reports on 29 carriers who were premanifest at baseline, and 43 non-carriers who served as controls. Carriers who where rated as unquestionable HD on the UHDRS after seven years were considered converters to manifest HD. The study was approved by the local Medical Ethical Committee. Written informed consent was obtained from all participants.

All participants were evaluated with the UHDRS, including motor and behavioural assessment, and an extensive set of neuropsychological tests covering global cognitive function, memory, language and executive function (Tables 2 and 3) [17] [22]. The number of estimated years to clinical diagnosis (EYTD) was calculated using a CAG- and age-based predictive model designed by Langbehn et al. [23].

Motor assessment

The UHDRS motor rating was filled in by a neurologist (range 0-3). A Total Motor Score (TMS) was calculated by summing all motor items of the UHDRS [17]. Analysis of TMS subscales was restricted to eye movement, voluntary movement and chorea [22].

Neuropsychological assessment

Neuropsychological tests included Mini Mental State Examination (MMSE) [24]; Wechsler Adult Intelligence Scale-Revised (WAIS-R) [25] subtests Information, Digit span, Arithmetic, Picture arrangement, Block design; Wechsler Memory Scale (WMS) [26];Verbal fluency (FAS) [27]; Boston naming test [28]; Symbol Digit Modalities Test (SDMT) [29]; Trail Making Test, consisting of a simple (TMT-A) and a more complex (TMT-B) version [30];Stroop colour-word test [31]. Reaction time measures were both derived from a simple reaction time paradigm and a complex ‘choice’ reaction time paradigm (go/no go paradigm) [32]. A psychologist administered the cognitive tests [17].

Behavioural assessment

Behavioural and mood complaints were limited to the total behavioural score (TBS) that was obtained by adding the products of the frequency and severity for each item from the behavioural assessment of the UHDRS, administered by a psychologist [11]. Analysis of individual items from the behavioural assessment were restricted to four frequently reported neuropsychiatric symptoms; sadness, anxiety, aggression and irritability [33].

Statistical analysis

SPSS for Windows (release 16.0) was used for data analysis. Cross-sectional group differences at baseline and after 7 years were analysed with parametric or non-parametric tests when appropriate. Clinical group comparisons were corrected for age at assessment using ANCOVA. For longitudinal analyses we used the method reported by Solomon et al. (2008) since it accounts for slight differences in follow-up period (Solomon et al., 2008). For each clinical score the change over the 7-year period was calculated for each participant. This Rate of Change (further labelled as RoC) was computed as follows: RoC= (score2- score1)/ (age2-age1).  Differences in RoC between carriers and non-carriers were analysed using ANCOVA with correction for age at baseline. To assess the relationship between EYTD and RoC, Pearson correlation coefficients were calculated. The level of statistical significance was set at p≤ 0.01. A more liberal level of significance of 0.01