Abstract
Background: Huntington’s disease (HD) is generally considered a hyperkinetic disorder, although hypokinetic features are part of the motor syndrome. Moreover, the striatum is considered to play a key role in initiating and executing motor programs and achieving optimal scheduling in response generation. Controversial results regarding the association between clinical features and markers of progression of the disease might be the result of inadequate restriction of clinical signs to the choreatic syndrome.
Objective: To determine the relationship of neurologic motor and cognitive indices in patients with HD with intrinsic neuronal loss in the striatum, as measured using raclopride C11 and PET.
Patients and Methods: A cross-sectional study was performed on 11 patients with mild HD (stages 0–2). Motor (Unified Huntington’s Disease Rating Scale [UHDRS], saccadic and tapping speed) and cognitive (verbal fluency, Trail Making Test, Stroop Test, Symbol Digit Modalities Test, Conditioned Associative Learning Test, and silhouette identification and object decision of the Visual Object and Space Perception battery) scores were correlated with raclopride C11 binding.
Results: Bradykinesia (a summation of five items of the UHDRS motor scale) was the best predictor for stage, that is, functional capacity, and showed a highly significant relationship with putaminous D2 binding (r = −0.94) and with CAG expansion length × years of age (r = 0.96). The exclusion of two patients with a rigid-akinetic HD variant did not alter these coefficients. Chorea was less well correlated than bradykinesia with D2 binding in all striatal regions. Performance on different cognitive tests, especially in timed tasks, was highly correlated with raclopride C11 binding in caudate nucleus and ventral striatum.
Conclusion: Loss of D2 binding in the striatum is highly correlated with the deficit in fast motor and cognitive processing in patients with early Huntington’s Disease. Thus, impairment of rapid execution of adequate responses to environmental changes seems to be a common manifestation of striatal disorders.
Huntington’s disease (HD) is a neurodegenerative disorder most severely affecting the striatum and some cortical areas. HD is caused by an unstable expansion of a CAG triplet in the gene encoding huntingtin (IT15).1 The CAG repeat is translated into an abnormal polyglutamine stretch in huntingtin. The biochemical basis for the specific neuronal loss of HD remains unclear, but it is apparently related to a particular vulnerability of striatal spiny neurons for the effect of the expanded polyglutamine tract in huntingtin.2 The length of the CAG expansion is correlated with the severity of the clinical picture3 and with the severity of neuropathologic features—including striatal cell loss4,5 and density of cortical neuronal intranuclear inclusions.6
The striatum is considered to modulate fast motor and cognitive processing.7-9 Although chorea is the most conspicuous feature of HD, it is only part of a generalized motor disturbance including bradykinesia, dystonia, and rigidity, which are most significant in functional terms.10 Cognitive performance is characterized by slowness and shifting difficulty8,11-13 but the extent to which cortical dysfunction is responsible for these problems is unclear. Within the striatum is considerable segregation of function.9 The putamen is mostly involved in sensorimotor processing; the caudate nucleus, in cognition and visual processing (tail); and the ventral striatum, in motivation and cognitive processing. Several studies using neuroimaging—from CT to PET—have addressed the relationship between clinical severity and striatal damage in patients with HD.13-19 In agreement with the earlier-mentioned segregation of striatal function, motor symptoms have been found to correlate with different measures of putaminous damage (e.g., cerebral blood flow and volume and glucose metabolism),15,17 but differences between hypokinetic and hyperkinetic symptoms were not explored. Using PET tracers for dopaminergic (D1 and D2) receptors, Turjanski et al.18 found no correlation of bradykinesia with loss of either type of receptor binding. Dopaminergic receptors and dopamine transporter tracers have also been used to evaluate the role of striatal dysfunction in patients with cognitive impairment caused by HD.13,19
In this study we used PET and raclopride C11, a selective D2 antagonist, with the goal of establishing the relationship of different motor—in particular bradykinesia and chorea—and cognitive indices to intrinsic striatal neuronal loss.
Patients and methods.
Patients.
Eleven patients were included in this study. Age and CAG length are listed in table 1. Disease severity was staged according to ratings on the Shoulson and Fahn’s Functional Capacity Scale.21 Three individuals were asymptomatic gene carriers (stage 0). Four symptomatic individuals were in stage 1 (minimal impairment), and four were in stage 2 (mild impairment). Two patients (9 and 10) had a predominantly akinetic variant. Patients regularly attended the Movement Disorders Unit of Fundación Jiménez Díaz (University Autónoma, Madrid), and they agreed to participate in this study. None of them had ever received neuroleptic treatment. The three presymptomatic individuals had a genetic predictive test done 1 to 3 years before this study, following recommended guidelines of the World Federation of Neurology, and have regular psychological support and neurologic follow-up.
Characteristics of the sample
Molecular analysis of the CAG expansion was performed, as previously described.22 For correlation with other indices, the number of triplets in excess (CAGn, −35.5) was multiplied by the age of the patient.5 This index was taken as an expression of genetic disease load normalized to each individual.
The study was approved by the ethics committees of the University Hospital in Zurich, Switzerland, and the Fundación Jiménez Díaz in Madrid, Spain.
Neurologic assessment.
Motor impairment was rated according to the Unified Huntington’s Disease Rating Scale (UHDRS) motor score.23 Global score and partial scores for chorea, dystonia, motor impersistence, gait, rigidity, body bradykinesia, finger tapping, and ocular movements (pursuit + saccade speed + saccade initiation) were considered. Bradykinesia was defined as the sum of scores for body bradykinesia, finger tapping, and ocular movements. These items were selected because the rating depends directly on the speed of movement and is not significantly affected by superimposed involuntary movements in the early stages of the disease. In addition, we measured horizontal saccadic speed and latency (with fixed predictable stimulus) with video nystagmus oculography24 and tapping speed on a computer keyboard (calculated for each hand as the time needed to make 40 pulsations).
The cognitive battery was administered by an experienced neuropsychologist (ABA). The following tests were chosen from the full battery proposed in the Core Assessment Program for Intracerebral Transplantation in Huntington’s Disease (CAPIT-HD) protocol:25 verbal fluency,26 Trail Making Test parts A and B,27 Stroop Test,28 Symbol Digit Modalities Test (SDMT),29 Conditioned Associative Learning Test (CALT, CAPIT-HD 2.0) and silhouette identification and object decision of the Visual Object and Space Perception (VOSP) battery.30 Mini Mental Status31 was included as a global indicator of cognitive function. Six unrelated healthy individuals, matched for age and educational level, were used as controls.
Scanning procedure and data analysis.
PET scans were performed for all patients within 2 months of neurologic and cognitive examination. The tomograph used was a CTI/Siemens scanner (type 933/04-16 Computer Technology and Imaging; Knoxville, TN; seven planes; transaxial resolution after reconstruction 8 mm full-width half-maximum). The patients were positioned with the head parallel to the orbitomeatal line (OM). The gantry field of view was chosen to cover the region from OM +2 cm to OM +7.6 cm, containing the complete striatum and the upper half of the cerebellum. With patients in the correct position, 10-minute transmission scans were performed using an external 68Ge ring source.
Thereafter, raclopride C11, a selective dopamine D2 antagonist of the class of benzamides,32 was administered over a period of 3 minutes using a continuous IV infusion pump. The injected dose ranged from 70 to 220 MBq. At the beginning of the tracer application, a dynamic scan sequence was started, consisting of 20 time frames, beginning with a 1-minute duration and gradually increasing to a 5-minute duration. Total scanning time after tracer application was 58 minutes. Regions of interest (ROIs) were placed over the putamen (elliptical region, 250 mm2) and the head of the caudate nucleus (circular region, 62.5 mm2) on the transverse planes with maximum raclopride C11 uptake. The ventral striatum was defined in the plane below, using an elliptic ROI (198 mm2). Cerebellar ROIs (one circular region of 780 mm2 over the cerebellar lobe of each hemisphere) were defined in a lower plane. Because the concentration of D2 receptors in the cerebellum has been shown to be negligible in the case of raclopride C11, the cerebellum was used as a reference tissue region. The regional binding potential was then calculated from a simplified reference tissue model with cerebellar input.33 Averaged measurements for both hemispheres were used.
Because raclopride C11 binding in human striatum has been shown to decrease with age,34 the individual patient data were expressed as percentages of the mean values of age-matched controls. Two groups of controls were used: 1) younger patients (mean age, 30 ± 4 y, n = 6) and 2) older patients (mean age, 40 ± 3 y, n = 5). No specific correction for striatal atrophy was attempted because raclopride C11 binding was used as a measure of striatal projecting neuron loss.
Statistical analysis was performed with the aid of the Statistical Package for Social Sciences version 7.5 for Windows (SPSS, Inc., Chicago, IL, 1996). Comparisons among groups were made using analysis of variance followed by Bonferroni multiple comparison post hoc test. Excluding controls, bivariate correlations were calculated between metabolic data and clinical scores of the patients.
Results.
The results of raclopride C11 uptake for each stage are shown in table 2, and comparative analyses of neurologic scores are summarized in table 3. Figure 1 shows the relationship between the length of the CAG expansion ([CAG − 35.5] × y) and the raclopride C11 binding potential in the three striatal ROIs. The decrease of raclopride C11 binding in presymptomatic patients, whenever present (table 2, fig. 1), was less than two SDs below the mean of age-matched controls, and these individuals had normal results on neurologic examination (table 3). Putaminous raclopride C11 binding was significantly different between the three stages (F2,8 = 29.98, p < 0.001; stage 0 versus 1, p < 0.005; stage 0 versus 2, p < 0.001; stage 1 versus 2, p < 0.05). In caudate nucleus and ventral striatum, significant differences were observed between presymptomatic (0) and symptomatic (1 or 2) binding potential but not between stages 1 and 2. The two akinetic patients showed the lowest binding potential in the putamen—the decrease being equal to or more than that in the caudate nucleus—and in the ventral striatum (p = 0.001). These two patients scored higher for rigidity than did other symptomatic patients.
[11C]-raclopride binding potential to striatal D2 receptors*
Statistics of neurologic motor and cognitive scores*
Figure 1. Relationship between raclopride C11 binding potential (BP) index (percentage of the mean uptake of age-matched controls) in the three striatal ROIs and the product of excess CAG triplet by age. Correlation coefficients are shown in the upper right corner. Squares = stage 0; triangles = stage 1; circles = stage 2.
Bradykinesia was the best predictor of stage, that is, functional capacity score (Wilks’ lambda = 0.061, F2,8 = 62; p < 0.001). It showed the highest correlation with CAG × age (r = 0.956; p < 0.001) and D2 binding potential loss. It was especially well correlated with putaminous binding potential (r = −0.94; p < 0.001; figure 2A). Exclusion of the two akinetic patients (9 and 10) did not modify these coefficients (r = 0.95 and r = −0.934; p < 0.001). Chorea, on the other hand, was less well correlated with other indices and slightly better with caudate nucleus binding potential (r = −0.63; p < 0.05) than with putamen binding potential (r= −0.60; figure 2B). The global motor score of the UHDRS showed good correlation with both molecular (CAG × age) index (r = 0.79; p < 0.01) and putamen binding potential (r = −0.75; p < 0.01). Computed tapping speed was correlated with binding potential in the putamen and ventral striatum (r = 0.73). Computed measure of horizontal saccadic speed was correlated with ventral striatum binding potential (r = 0.74) and other motor scores, whereas saccadic latency showed no correlation with other indices (only with UHDRS score for motor impersistence did the coefficient approach significance r = 0.6; p = 0.06).
Figure 2. Relationship between raclopride C11 binding potential index and A, bradykinesia; B, chorea; and C, Symbol Digit Modalities Test score (SDMT). Correlation with binding potential in caudate nucleus (open symbols) and putamen (closed symbols) are compared in A and B. Correlation coefficients are shown in the upper right corner. Symbol types represent stages as in figure 1.
Of the cognitive battery, the best predictor was SDMT, which showed high correlation coefficients with binding potential in all three regions, especially with the ventral striatum (r = 0.84; p < 0.01; figure 2C) and also with CAG by age (r = −0.91; p < 0.001). Stroop word reading (but not color naming or interference) and the Trail Making tests also showed significant correlation with PET and molecular indices (r \F 0.7–0.9). At a low level of significance, CALT correlated with caudate binding potential and silhouette identification of the VOSP and Mini Mental Status with ventral striatum (r = 0.72; p = 0.012). No significant associations were observed for verbal fluency.
Discussion.
Bradykinesia was defined as the additive score of five items of the UHDRS that depend basically on a slow motor performance, being hardly altered by involuntary movements among patient in early stages of HD. Bradykinesia was the best predictor for stage, that is, functional capacity, and it showed the highest correlation with CAG × age and with putaminous raclopride C11 binding potential (figure 2A). Exclusion of the two akinetic patients did not alter the relationship with either metabolic or molecular indices. The motor score of the UHDRS showed good correlation coefficients, but they were not quite as strong as those found for bradykinesia (most probably related to the weight of the chorea in the global score). Hence, bradykinesia is the common manifestation of neostriatal dysfunction in patients with HD as in patients with other striatal disorders.35 Even in patients in the early stages of disease, and even in classic choreatic patients,36 hypokinetic features can be easily identified and, in contrast to chorea, worsen as the disease progresses37 so that HD tends to evolve toward an akinetic, rigid syndrome.38-39
Two patients (9 and 10) had a juvenile rigid-akinetic form (Westphal variant). Interestingly, they both showed striking PET involvement of the ventral striatum (in addition to more than 70% reduction in putamen raclopride C11 binding potential) significantly more severe than the rest of the symptomatic patients. This loss of the typical dorsoventral pathologic gradient of striatal degeneration40-42 in the juvenile akinetic form underscores the notion that the longer the expansion is, the less selective (more widespread and less distinctive) the neuropathology becomes,2 as has been observed also in patients with other triplet expansion diseases.43 Also, experimental observations in primates indicate that chorea does not appear with lesions causing massive striatal damage,44 so although bradykinesia seems to be a direct expression of putaminous neuronal loss, worsening as the disease progresses, chorea seems the result of a transient imbalance in motor regulation.39 Preferential involvement, early in the course of the disease, of certain striatal neurons37-38,45 has been proposed to explain this symptom.
The relationship between computed measurements (tapping speed and saccadic movements) and raclopride C11 binding potential was not as high as that observed for their UHDRS counterparts (finger tapping and ocular movements). This is explained by the fact that these computerized measures take into account a single component of the movement, so although they offer an objective measure—most convenient for follow-up and comparative studies—they seem to be less sensitive in the early stages of the disease. Because a considerable reduction in raclopride C11 uptake can occur without noticeable motor impairment,20 the correlation coefficients to putaminous binding potential increased slightly when presymptomatic individuals were excluded.
Concerning neuropsychological performance, the best correlations were observed for timed tasks. These tests, which measure processing speed, were correlated with molecular (CAG × age) and motor indices and with raclopride C11 binding potential, especially SDMT (figure 2C). The latter has been reported to be one of the Wechsler Adult Intelligence Scale subtests affected first in patients with HD46 and to correlate with bicaudate ratio14 and putaminous dopamine transporter density.19 The Trail Making Test and CALT were better correlated with caudate nucleus binding potential, whereas the VOSP silhouette identification was only significantly correlated with binding potential in the ventral striatum, which might be implicated in visual discrimination.47 In one study, Lawrence et al.13 found a good correlation between striatal D2 receptors and performance for tasks requiring optimal timing and generation of motor responses. Nevertheless, the specific striatal contribution to cognitive impairment in patients with HD remains difficult to define because cortical damage and disruption of striatal projections to and from prefrontal cortex (which were not evaluated) may cause similar dysfunction.
The available information from clinical, pathologic, and experimental studies support a major role of the CAG expansion in the progression of the disease.2-6,46-48 Also, in our study, most clinical scores were significantly correlated with the length of expansion corrected for years of age. Such a relationship with respect to raclopride C11 uptake among another group of patients was reported by us.48 In the group presented here, putaminous binding potential of raclopride C11 showed the best correlation coefficient (figure 1). Striatal degeneration, as measured with raclopride C11, might progress nonlinearly, declining steeply in the first years (figure 1), but we cannot rule out a floor effect because the reduction observed in patients with stage 2 disease (i.e., moderate clinical impairment) was considerable (table 2).
With raclopride C11 binding studies, early impairment of striatal function is possible to detect, and the progression of the disease is possible to evaluate. These studies might prove helpful in the evaluation of therapeutic intervention. Moreover, the close relationship between clinical and metabolic striatal indices reported herein stresses the role of PET in unravelling the functional basis of neurologic disturbances in patients with HD. As in other striatal disorders, the major consequence of striatal dysfunction in patients with HD is shown to be a progressive deficit in fast motor and cognitive processing. Finally, bradykinesia is not only part of the motor disorder in patients with HD but also largely responsible for the progressive incapacity associated with this condition.10,39,49
Acknowledgments
Acknowledgment
The authors thank all of the patients and their families for collaborating in this project and all the people who made it possible, especially Mrs. Asunción Martínez-Descals, president of the Spanish Huntington’s Disease Association, Mrs. Eveline Signer, and Mrs. Nurten Simsek.
Footnotes
-
This work was supported by a grant of the European network for transplantation in Huntington’s disease (NEST-HD). R.S.P. was a fellow of the Fundación Conchita Rábago.
- Received February 15, 1999.
- Accepted July 29, 1999.
References
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