To our knowledge, this is the first study to investigate the frequency of both psychiatric symptoms and cognitive impairment in a national clinical cohort of premanifest to moderately affected HD gene-expansion carriers. In this cross-sectional study the triad of motor symptoms, neuropsychiatric symptoms, and cognitive impairment was found in 51.8% of all motor manifest HD gene-expansion carriers. Further, we showed that among the premanifest HD gene-expansion carriers, 39.2% had neuropsychiatric symptoms, cognitive impairment, or both.
In the motor manifest group, 76.8% of the patients fulfilled the criteria for cognitive impairment. The results show that cognitive deficits are found in the large majority of the motor manifest patients seen in the clinic (even in the early stages of HD). In addition, the results imply that cognitive evaluation is very important in HD motor manifest patients, since such deficits could have a negative effect on the patient’s ability to, for example, maintain a job, manage household finances, or drive a car.
In the premanifest group, 13.7% were classified as cognitively impaired. The premanifest gene-expansion carriers are generally considered to be healthy and are treated as such; however, the results show that neuropsychological assessment and follow-up may be relevant, e.g. to try to prevent financial stagnation and social exclusion. The frequency of cognitive impairment in HD has been investigated in a previous study, and the frequency of MCI in “prediagnosed” HD gene-expansion carriers was examined using standard criteria for MCI (test performance in one of four tests below 1.5 standard deviations on age- and education-adjusted normative data). MCI was found in 39.8% and multiple-domain MCI (two or more tests below 1.5 standard deviations) in 13.9% of the “prediagnosed” HD gene-expansion carriers . The methodology of our study compared to the MCI study is different, and we used a more conservative classification of cognitive impairment and the premanifest status. Importantly, both studies show that cognitive impairment is present in some presymptomatic HD gene-expansion carriers. Our study further suggests that cognitive symptoms in premanifest HD are not only mild, but also that premanifest HD gene-expansion carriers may have cognitive deficits to an extent where they may be classified as cognitively impaired.
According to our predefined criteria, 66.1% in the motor manifest group and 29.4% in the premanifest group were classified to the neuropsychiatric group. Previous studies have reported very different lifetime prevalence of psychiatric symptoms in HD gene-expansion carriers that varies from 24.7% to 76.0% in manifest patients . A recent study reported a 12-month prevalence of psychiatric symptoms of 24.7% in manifest and of 27.3% in premanifest HD gene-expansion carriers . The frequencies in our study are markedly higher as compared to Van Duijn et al’s study . We chose an all or none approach in our study. If the participants had an intake of psychotropic medication, they were classified in the neuropsychiatric group, without regard to their current psychiatric symptoms. Psychotropic medication is prescribed by physicians who have found indication for the treatment. Moreover, we assume that the participants taking psychotropic medication do so because they have an underlying psychiatric disorder and the majority of these patients would probably have affective or other psychiatric symptoms if their medication were paused. Therefore, not classifying patients on psychotropic medication in the neuropsychiatric group seems, in our opinion, counterintuitive. However, the frequency of psychiatric symptoms according to the SCL-90-R in our cohort was 35.7% in the motor manifest group and 19.6% in the premanifest group, which is in accordance with the Van Duijn et al’s study .
It is important to recognise that both psychiatric symptoms and/or cognitive dysfunction may be stress disorders, reactive to life events, and in the case of HD, a transient reaction to receiving the genetic test result , and therefore not necessarily a consequence of neurodegeneration. However, the majority of our premanifest participants completed the genetic counseling procedure more than one year prior to inclusion in this study, which makes a test-related reactive disorder less likely. The criteria for cognitive impairment in our study are consistent with severe impairment, and the cognitive deficits in depression in general are described as mild to moderate in group comparisons , a pattern which was equally found in prodromal HD in the PREDICT-HD study . Therefore, cognitive impairment may not solely be attributed to depression or other psychiatric symptoms but a consequence of the neuropathological changes as well.
Antidepressants exert more positive than negative effects on cognitive dysfunction in patients with depression . The effect of antidepressants on cognitive performance has not been studied in HD; however, it seems likely that treatment may also improve cognitive function due to depression in HD gene-expansion carriers.
When applying our predefined criteria of cognitive impairment and neuropsychiatric symptoms to a Danish control cohort of 40 healthy HD gene-expansion negative individuals, the frequency of cognitive impairment was, as expected, 5%. The frequency of psychiatric symptoms was, however, lower than the expected 10% , confirming that our criteria for cognitive impairment and neuropsychiatric symptoms are suitable and adequately conservative for use in the Danish population.
The patients included in this study all had an MMSE score ≥24, a MoCA score ≥19 and a UHDRS motor ≤55. These cut-off scores for inclusion were applied because patients with lower scores would not be capable of doing a meaningful neuropsychological testing in this study. This selection has important implications because the frequency of cognitive deficits and neuropsychiatric symptoms in this selected group of HD gene-expansion carriers cannot be generalised to the entire HD population. A small subgroup of invited participants either declined participation or did not meet for arranged trial dates. Evaluating the patient files of this patient group showed that the majority of these patients would have been classified in the neuropsychiatric group. We therefore hypothesise that both cognitive impairments and psychiatric symptoms are more frequent in the “general” HD population.
Despite these limitations, we demonstrate the importance of the assessment of all HD gene-expansion carriers with motor, neuropsychiatric, and cognitive measures regularly to ensure sufficient and early treatment and social intervention.