Profile of cognitive progression in early Huntington’s disease

Method.

Results.

All changes in performance over time referred to below are significant at at least the p < 0.05 level. For details of test results see tables E-1, E-2, and E-3 on the Neurology Web site (www.neurology.org).

Although general cognition as assessed by the MMSE did not change over time, the specific subscores for time orientation, place orientation, and delayed recall were progressively impaired, but the decline was slight, as reflected by the respective mean slopes (see table E-1 at www.neurology.org). In contrast, all tests of attention and executive function were found to deteriorate except for the WCST (where there was actually a decrease of the percentage of Milner perseverative errors). Measures such as Stroop (color naming and word reading) and Trails (A and B) showed a relatively marked decline over time as evidenced by a steeper regression slope, while verbal fluency (letter and semantic category), Symbol Digit Modalities, and Stroop interference declined to a lesser degree.

From the CAPIT-HD baseline tests, only Block Design and the Token Test deteriorated over time (see table E-2, www.neurology.org). CANTAB test measures that declined over time were the total accuracy score for the one-touch Tower of London, and mean latency for the set shifting task and pattern recognition memory (see table E-3, www.neurology.org).

When all the neuropsychological measures that decreased or increased over time were included in a MANCOVA to explore possible associations with demographic (sex, mode of inheritance, age at onset, duration of HD) and neurologic variables (linear regression slopes over consecutive assessments for the UHDRS motor score, Total Functional Capacity, and Independence Scale), two significant relationships emerged. First, duration of disease (estimated historically) was negatively associated with Pattern Recognition (CANTAB battery) mean latency (p < 0.01), such that longer duration of disease was accompanied by slower performance on this task. Secondly, Total Functional Assessment score was positively associated with the one-touch Tower of London (CANTAB battery) accuracy score (p < 0.01), such that poorer functional scores occurred together with poorer planning ability.

Discussion.

This study examined the pattern of cognitive decline in the largest cohort of patients with mild to moderate HD so far reported who received a comprehensive battery of neuropsychological tests.

Virtually all tests of attention and executive function deteriorated over a 3- to 6-year period, providing strong evidence for early and pervasive executive function decline over time as suggested in cross-sectional studies.1,2⇓ In addition, it consolidates previous longitudinal studies showing a decline in subsets of executive function tests using either smaller cohorts5,7,9⇓⇓ or fewer tests.8

An examination of the rate of decline (mean slopes from tables E-2, E-3, and E-4 at www.neurology.org) of various executive function tests revealed that this was not uniform. Specifically, tests that tapped psychomotor skill—i.e., Trails A (mean slope = 0.43), Stroop word reading (mean slope = −0.34), Stroop color naming (mean slope = −0.20), and Symbol digit modalities (mean slope = −0.12)—were prone to some of the highest levels of decline. Previously, timed psychomotor tests have been found to be particularly sensitive to longitudinal change3,7–9⇓⇓⇓ because they are affected by mental processing and motor function, which are necessary for accurate and fast performance. Nevertheless, it did not appear that tests more reliant on motor skill always suffered a greater degree of decline because the symbol digit substitution test was not as sensitive as Stroop word reading and color naming. These simpler Stroop measures may be sensitive to decline8,9⇓ owing to the basal ganglia contribution in the fluent generation of highly automatic over-learnt sequences.9 Trails B, which taps cognitive flexibility (in addition to psychomotor ability), showed an even greater degree of decline (mean slope = 2.02) than tests of psychomotor skill, suggesting that the additional requirement of holding and switching mental sets makes this test even more sensitive than purely psychomotor measures.

Next, more traditional tests of executive function that tapped planning showed the greatest rate of decline. Patients were increasingly impaired in their ability to correctly plan the minimum number of moves required to make the test array identical to a target array on the one-touch Tower of London test (strategy score mean slope = 0.08). While patients did not show a clearcut impairment in the ID/ED set shifting and Spatial Working Memory tasks, a decline in mental processing speed and psychomotor speed was suggested by the increased average response latency. The absence of a clearcut decline is not unexpected given that tasks that are dependent on the use of strategy often have limited test-retest reliability. Indeed, the results on the WCST (in which there was no change, apart from less Milner perseverative errors) reflected this, and supports previous research suggesting that this test is not ideal for longitudinal assessment in HD.7,9⇓

Next, tests of lexical retrieval showed smaller but significant rates of decline, with both phonemic (mean slope = −0.06) and semantic category (mean slope = −0.05) fluency being equally affected, suggesting a frontal access difficulty rather than an amnesic degradation of lexical storage.

Finally, tests of attentional span (i.e., spatial span, digit span forwards and backwards) declined at the lowest rate but still to a significant extent. Tests that tap immediate memory (therefore requiring adequate attention and concentration) also declined, such as the Token Test7 and some subsections of the MMSE (i.e., time orientation, place orientation, delayed recall). This latter subsection of the MMSE actually involves a very short delay of not more than a couple of minutes at the most, and is therefore strictly an immediate memory task. Likewise, the Token Test is reliant on immediate memory to correctly execute verbal instructions. This decline in immediate memory is likely to stem from an attentional impairment, in view of the concurrent attentional/executive deficits demonstrated in this cohort. In contrast, measures of delayed memory (over a longer period of time) generally remained stable (i.e., for a word list [HVLT] and narrative [RBMT]). Similarly, visuospatial (consistent with some studies1,31⇓ but not others2,32⇓) and semantic memory measures such as word naming and vocabulary showed no progressive decline (supporting some studies3,32,33⇓⇓ but not others7,8,34⇓⇓).

This consistent and selective deterioration of attentional/executive function is compatible with the frontostriatal pathology of patients at the mild to moderate stage of HD. In the earlier stages of HD, pathology begins in the dorsal caudate nucleus, which forms part of the dorsolateral prefrontal cortex loop, and from there gradually spreads throughout the frontostriatal system.35 Both structural and functional imaging studies have shown that impairments in executive function tasks early in HD relate to this frontostriatal neuropathology,36,37⇓ and this includes presymptomatic HD gene carriers. For example, impairment in accuracy on the one-touch Tower of London test of planning has been shown to correlate with loss of caudate and putamen D2 receptor binding potentials in HD.4 Therefore the selective attentional and executive function decline in patients with early to moderate HD found in this study is entirely consistent with the reported pathophysiologic changes described previously at this stage of disease. It is likely that other cognitive functions such as delayed recall memory and semantic knowledge are affected only when the disease progresses beyond this point with involvement of nonfrontal areas, especially the hippocampal complex and temporal lobes.

In terms of correlating cognitive deficits to disease duration, the rate of decline for the mean latency for pattern recognition memory was associated, suggesting that lower performance on this measure is associated with longer duration of HD symptoms. This lends some support to the notion that visuospatial measures are sensitive to the progression of cognitive impairment although it may not be a prominent feature of early HD.2,32⇓ The relevance of cognitive deficits to activities of daily living was evident in that a significant relationship was found between the Total Functional Assessment subsection of the UHDRS and executive function (i.e., the strategy score for the one-touch Tower of London task). This suggests that cognitive ability to direct attention and plan rather than motor performance was related to the ability to perform functional everyday activities successfully.38

Finally, our findings suggest that fractionation of executive processes may provide a clearer picture of cognitive change in HD. However, disentangling component executive processes and types of tests is not a straightforward matter, and it could be that timed measures may be even more sensitive to longitudinal change due to the finer scale of measurement.7 Nevertheless, we identified tests that are most sensitive at detecting longitudinal changes in early HD, which may be of value in better understanding the pathophysiologic changes at this stage of disease and in monitoring novel disease-modifying pharmacologic or surgical interventions.

Appendix

Members of the NEST-HD Consortium: A.E. Rosser, MRCP, PhD (University of Cardiff); S.B. Dunnett, DSc (University of Cardiff); J.D. Pickard, MChir, FMedSci (University of Cambridge); R.A.C. Roos, MD, PhD (Leiden University); D. Craufurd, FRCPsych (University of Manchester); P.J. Morrison, MD (Belfast City Hospital); S.A. Simpson, MD (University of Aberdeen); T. Benke, MD (University of Innsbruck); G. Berrios, MD, FRCPsych, FMedSci (University of Cambridge); N. Kennedy, MRCPsych (University of Cambridge); A.C. Wagle, MD, MRCPsych (University of Cambridge); N. Chada, MD (South Tyrone Hospital, Belfast); P. Harper, FRCP (University of Wales School of Medicine, Cardiff); R. Harper, MRCPsych (University of Wales School of Medicine, Cardiff); D.J. Brooks, MD (MRC Cyclotron Unit, Hammersmith Hospital, London); P. Piccini, MD (MRC Cyclotron Unit, Hammersmith Hospital, London); N. Pavese, MD (MRC Cyclotron Unit, Hammersmith Hospital, London).