In this longitudinal study, we evaluate the sensitivity of cognitive-neurophysiological parameters for documenting disease progression in pre-HD. The results show that parallel monitoring of conflict and flexible adaptation of actions became increasingly compromised in pre-HD subjects during a 15-month period from baseline as well as during the subsequent 6-month period. To the best of our knowledge, this is the first study to show declines in premanifest disease progression over a period of just 6 months. Other studies on cognition have not shown changes in cognitive function in pre-HD subjects22
or, alternatively, the pre-HD subjects did not differ from controls23
. The effect sizes show the high sensitivity of the measures we use (). Two pre-HD subjects revealed phenoconversion between the 15 and 21-month endpoint. Excluding these subjects did not affect the pattern of results or the effect sizes obtained. The effect sizes are greater than those obtained from longitudinal neuropsychological data in the TRACK-HD study21
Schematical overview of the experimental paradigm to assess parallel execution of response selection and conflict monitoring.
In particular, the results show increases in RTs in incompatible switch trials that are paralleled by reduction of the N2 ERP component and evoked wavelet power in the delta frequency band. The N2 ERP reflects conflict monitoring, response selection processes, and inhibition of responses24,25
. The N2 ERP data, together with the behavioural effects, most likely reflect an increasing inability to inhibit processes related to the irrelevant task set from the previous trial26
and to select the appropriate response in the current trial19,24
. In contrast, the P3 ERP component is related to working memory processes, and in particular to the updating, organization, and implementation processes involved in a new task set27
. Since this neurophysiological parameter does not show longitudinal changes in pre-HD subjects, working memory processes may not contribute to the longitudinal changes we observed.
N2-related processes are mediated via the fronto-striatal networks, including the anterior cingulate cortex (ACC)25
. Processes reflected by the P3 component are mediated largely via parietal cortical networks28
. As opposed to the parietal areas, the ACC is closely connected to the striatum. It is possible that differences in the strength of connectivity between the striatal areas and the frontal or parietal areas underlie the differences we observed during premanifest disease progression. The dependence on N2-related processes in fronto-striatal circuits, together with the fact that the parallel execution of cognitive processes (i.e., conflict monitoring and flexible adaptation) depends on the fronto-striatal networks, may explain the high sensitivity across the longitudinal endpoints that we observed in this study. This is underlined by the finding that no longitudinal changes were observed in other trials in which conflict processing and set-shifting did not coincide.
A disease progression biomarker should be sensitive enough to vary with disease progression in pre-HD subjects, should not vary in controls, and should correlate with clinically important parameters2,11
. The measures presented here fulfil all these requirements. In both longitudinal periods, disease progression, as tracked by behavioural and neurophysiological parameters, reveal substantial correlations with clinically relevant parameters such as “disease burden score” (DBS), also called the “toxic load,” and with the probability of disease manifestation in the next 5 years. Systematic changes were not detected at the longitudinal endpoints in controls, but were detected in pre-HD subjects and showed considerable sensitivity as indicated by the Cohen's d effect sizes in pre-HD subjects over a 6-month period of premanifest disease progression. As shown in , the effect sizes as estimated by Cohen's d for the behavioural and neurophysiological parameters in the current study were considerably greater than the effect sizes obtained from standard neuropsychological tests. However, when we used neuropsychological tests similar to those used in the TRACK-HD study21
and looked at effect sizes obtained from structural MRI data, the effect sizes were similar to those obtained in the current study. Compared to these measures, effect sizes obtained from the time-frequency decomposed neurophysiological data were higher. This is likely due to the fact that the way the test was applied allowed us to conduct a series of trials, and this considerably increased the reliability of the behavioural and neurophysiological measures. The measures we used have been shown to be sensitive to disease-modifying therapy in Parkinson's disease29
and may also be sensitive enough to monitor the effects of a potential disease-modifying therapy for HD. In contrast to the TRACK-HD study, the current study was not a multi-centre study, which is clearly a limitation. Further studies are needed to evaluate whether the parameters identified here are suitable for use in larger multi-centre studies and can be used as outcome parameters in clinical trials that assess potential neuroprotective treatments for HD.
In summary, this study showed that behavioural and neurophysiological measures of cognitive response selection processes are sensitive enough to detect changes in premanifest disease progression over a short 6-month period. The effect sizes in pre-HD subjects, correlations with clinically relevant parameters, and a lack of similar changes in control subjects suggest that the measures have potential as a novel cognitive-neurophysiological state biomarker and merit further evaluation in larger multi-centre studies.