Abstract
Objective: To study the nigrostriatal pathways in 21 patients with dementia with Lewy bodies (DLB), 19 drug naive Parkinson disease (PD) patients, and 16 controls using a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) and SPECT in order to assess similarities or differences between DLB and PD.
Methods: A SPECT scan was carried out 3 to 4 hours after administration of 185 MBq (IV) of FP-CIT. Using occipital cortex as a radioactivity uptake reference, ratios for the caudate nuclei and the anterior and posterior putamina of both hemispheres were calculated. From the FP-CIT binding measurements, asymmetry indices and caudate:putamen ratios were derived.
Results: The DLB and PD groups had lower FP-CIT binding in all striatal areas than controls (analysis of variance: p < 0.001 in all measures). DLB patients also had significantly lower binding in the caudate nucleus than the PD patients. There was greater asymmetry of uptake in the posterior putamina of PD patients than DLB patients (p < 0.04) and controls (p < 0.01). The mean caudate:putamen ratio for the DLB group was not significantly different from that of the controls, while the mean caudate:putamen ratio of the PD group was higher than that of the control group (p < 0.001) and the DLB group (p < 0.001).
Conclusion: This study showed differences between PD and DLB in the pattern of striatal dopaminergic dysfunction. DLB patients do not have the characteristic selective degeneration of ventrolateral nigral neurons seen in PD. This could explain some of the clinical differences between DLB and PD.
Clinically and pathologically, there is considerable overlap between dementia with Lewy bodies (DLB) and idiopathic Parkinson disease (PD). Whether they are parts of a spectrum of a single disorder—Lewy body disease—or whether they are separate nosologic entities remains debatable. Histopathologically, PD and DLB cannot always be distinguished,1 and the final decision as to whether the diagnosis is PD, PD with dementia (PDD), or DLB is made on purely clinical grounds. In particular, it depends on the presence and timing of onset of cognitive impairment.2
PD is caused by the degeneration of pigmented dopaminergic cells of the substantia nigra, which project via the nigrostriatal pathway to the striatum. The earliest and greatest loss is in the ventrolateral tier of the substantia nigra, which contrasts with relative sparing of the ventrolateral tier in the neuronal loss of normal aging. This regional selectivity is most marked in early onset PD. It corresponds to a more profound dopamine deficit in the posterior putamen than in the caudate nucleus.3 In PD there is a positive correlation between the severity of nigral cell loss and both the disease duration and the severity of parkinsonism.4,5⇓
SPECT using the ligand 123I-labeled N-delta-(fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophe-nyl)tropene (FP-CIT) can assess the presynaptic nigrostriatal dopaminergic system during life. FP-CIT striatal uptake on both sides is significantly reduced in early and in advanced PD. In keeping with autopsy studies, the uptake in the putamen is consistently lower than the uptake in the caudate nucleus.6,7⇓ FP-CIT striatal uptake is also reduced in DLB.8,9⇓ In this study we compared the patterns of dopaminergic disruption in DLB and PD patients and looked at the relationship between extrapyramidal signs and the severity of dopaminergic dysfunction in the two groups. We used the same cohorts of patients and controls as in our previously reported study.9
Methods.
Of the 21 DLB patients, 15 were diagnosed clinically with DLB according to the Consensus DLB criteria2 and the other six had their diagnosis of DLB confirmed at autopsy by established methods.10 Three DLB patients were taking levodopa medication at the time of their scans and medication was not discontinued for the scans. Three DLB patients were receiving neuroleptic medication for psychosis. Patients with PD were recruited from a neurology clinic at the time of first presentation to a neurologist (R.W.H.W.). The diagnosis of PD was made according to the UK PD Society Brain Bank criteria.11 None of the PD patients had been exposed to any antiparkinsonian medication at the time of scanning.
Patients with DLB.
For each patient a detailed history of memory impairment was obtained both from the patient and from an informant. This was followed by a full psychiatric history, a mental state examination, and a physical examination with an emphasis on neurologic examination. The following tests were also performed:
Mini-Mental State Examination (MMSE)12
Cambridge Cognitive Function Examination (CAMCOG), a neuropsychological test battery that forms part of a standardized psychiatric assessment schedule, the Cambridge Mental Disorders of the Elderly Examination (CAMDEX)13
Clinical Dementia Rating (CDR)14
Unified PD Rating Scale, motor part only (UPDRS)15
Hoehn and Yahr stage (H&Y stage)16
Patients with PD.
Tests performed were MMSE, CAMCOG, CDR, UPDRS, and H&Y stage.
Controls.
Information was gathered from controls regarding their medical and psychiatric history and any regular medication. Controls were not taking any drugs known to affect the dopaminergic system. A mental state examination and a limited physical examination were carried out. Tests performed were MMSE, CAMCOG, UPDRS, and H&Y stage.
FP-CIT SPECT scan.
SPECT studies were carried out at the Institute of Nuclear Medicine, University College London Medical School. Thyroid metabolism was blocked with potassium iodate, as recommended for reduction of possible irradiation of the gland.
All participants underwent scanning with a brain dedicated scanner, the Strichman Medical Equipment 810 linked to a Macintosh computer. The Strichman camera consists of 12 individual detectors, each equipped with a focusing collimator. The transaxial resolution of this camera is 7.6 mm full width half maximum and the axial resolution is 12.5 mm. The measured concentration of radioactivity was expressed as Strichman Medical Units (SMU; 1 SMU = 100 Bq/mL). Scanning took place between 3 and 4 hours after injection of FP-CIT (185 MBq). Usually 8 to 10 slices were acquired starting at the cerebellum level upwards to include basal ganglia. A few patients were difficult to scan, and in these a smaller number of slices (3 to 5) were acquired at the level of the basal ganglia to include the entire basal ganglion region. The overall scanning time for each patient was 30 to 45 minutes.
All scans were analyzed by D.C.C., who was unaware of the diagnostic status of the subjects. The images were automatically reconstructed. For the analysis of striatal binding, the ratio of specific to nonspecific binding was calculated by summing two to three adjacent transverse slices that showed the most intense striatal uptake. Regular circular regions of interest were employed to calculate the average striatal to nonspecific radioactivity ratios for both hemispheres (figure 1). We used occipital cortex to measure nonspecific uptake. The formula used was as follows: 
Figure 1. FP-CIT scan showing regions of interest in caudate nucleus, anterior and posterior putamen, and occipital cortex.
where STR is the mean radioactivity (in SMU) in the striatum (caudate, anterior, or posterior putamen) and OCC is the mean radioactivity in the occipital cortex. FP-CIT binding was calculated for caudate, anterior, and posterior putamen separately for each hemisphere.
From the posterior putamen FP-CIT binding measurements the asymmetry of binding between the two sides was expressed as an asymmetry index: 
The relationship between FP-CIT binding in the caudate nucleus and the putamen for each individual was expressed as follows: 
Ratios were calculated for the sum of the binding values of the caudate of each side divided by the sum of the binding values of the posterior putamen of each side for each individual.
Data analysis.
Data were analyzed using SPSS/PC+ version 10.0 (Statistical Package for Social Sciences). For PD patients “contralateral side” was defined as the side opposite to the clinically worse affected side. For DLB patients it was difficult clinically to decide which side should be taken as the more affected, as some patients did not have any extrapyramidal signs, and therefore contralateral was arbitrarily assigned to the left side and ipsilateral to the right side. The same applied for the controls. Analysis of variance (ANOVA) and Student t-test were used to assess differences among the different groups (DLB, PD, and controls) of the FP-CIT binding in the caudate nuclei and anterior and posterior putamen regions. The caudate:putamen ratios and the asymmetry indices were analyzed using the nonparametric Kruskal-Wallis and Mann-Whitney tests. Relationships between different clinical variables and binding measures were explored using Spearman’s rank correlations for ordinal data.
Results.
Results are presented for 21 patients with DLB, 19 patients with PD, and 16 controls. Cohort characteristics are presented in tables 1 and 2⇓.
Table 1 Cohort characteristics of patients with DLB, patients with PD, and controls
Table 2 Ratings of patients with DLB, patients with PD, and controls
Caudate and putamen FP-CIT binding.
The contralateral and the ipsilateral radioactivity binding in the caudate nucleus and in the anterior and the posterior putamen for all groups is shown in table 3. There was a difference between PD patients and controls and between DLB patients and controls in all binding measures (p < 0.001). When comparing the PD and the DLB groups, the DLB patients had lower binding in the caudate (ipsilateral p < 0.001; contralateral p < 0.01) than the PD patients.
Table 3 Semiquantitative FP-CIT binding measures, means (95% CI); % controls means
Of the 21 DLB patients, 14 were judged on clinical examination to have rigidity, and 7 were not rigid. Interestingly the caudate and putamen counts were as low in the non-rigid group as in the rigid group, with no overlap between the non-rigid group and the normal controls. Six of the non-rigid DLB patients have developed rigidity at follow-up. Two of the non-rigid group have had autopsy confirmation of the diagnosis of DLB.
Caudate:putamen ratio.
The caudate:putamen ratios for all three groups are shown in figure 2. The mean ratio for the DLB group was not significantly different from that of the controls, while the mean ratio for the PD group was different from the control group (p < 0.001) and from the DLB group (p < 0.001).
Figure 2. Caudate:putamen ratio for Parkinson disease (PD), dementia with Lewy bodies (DLB), and healthy controls (means and 95% CI of the means).
Asymmetry index.
Asymmetry indices for the posterior putamen for all three groups are shown in figure 3. There was a significant difference in the asymmetry indices for the posterior putamen among the three groups (p < 0.02, Kruskal-Wallis test). The difference in the asymmetry indices in the posterior putamen was due to more marked asymmetry of binding in patients with PD. There was no statistical difference in the posterior putamen asymmetry indices of the DLB and control groups. There were differences in the posterior putamen asymmetry indices of the PD and DLB patients (p < 0.04, Mann-Whitney test), and PD and control groups (p < 0.01, Mann-Whitney test).
Figure 3. Posterior putamen asymmetry index for Parkinson disease (PD), dementia with Lewy bodies (DLB), and healthy controls (means and 95% CI of the means).
Subgroup of DLB and PD patients matched for age and duration of illness.
To ensure that the significant differences between DLB and PD patients were not due to inappropriate age matching and different disease duration, the same analyses were repeated for a subgroup of DLB and PD patients matched for age and disease duration (12 cases in each group, the oldest DLB and the youngest PD patients having been excluded). There was no significant difference between the subgroup of DLB and PD patients in UPDRS score or H&Y staging. Whereas in the complete cohorts there was a difference (p < 0.02) in contralateral posterior putamen binding between PD and DLB (see table 3), in the matched cohorts this was no longer the case. Nevertheless DLB patients continued to have lower binding in the ipsilateral caudate (p < 0.001, t-test) and the contralateral caudate (p < 0.002) than the PD patients. There continued to be a difference in the asymmetry indices for the posterior putamen (p < 0.04, Mann-Whitney test) and the caudate:putamen ratios (p < 0.002, Mann-Whitney test) for the two groups.
Correlation of FP-CIT binding and UPDRS and H&Y scores.
There was a negative correlation in the PD group between the UPDRS scores and the ipsilateral and the contralateral posterior putamen binding (rho = −0.71, p < 0.02 and rho = −0.64, p < 0.04). There was also a negative correlation between the H&Y stage and the ipsilateral anterior putamen binding (rho = −0.66, p < 0.001) in the PD group. There were no correlations between either the UPDRS score or the H&Y stage and any striatal binding measures in either the DLB group or the controls.
Discussion.
This study demonstrates that there is a difference in striatal dopaminergic dysfunction between PD and DLB. DLB patients had a uniform decrease in the dopamine uptake sites compared to controls in both the caudate and the anterior and posterior putamen (in all sites ∼39%). In contrast, patients with PD had less severe loss of binding sites in the caudate (∼23%) but more pronounced loss in the putamen, in particular in the posterior putamen contralateral to the clinically worse affected side (∼52%). The different pattern of loss of dopamine transporter was further highlighted by the caudate:putamen ratios. These results suggest that DLB patients do not have the characteristic selective degeneration of ventrolateral nigral neurons that has been repeatedly shown in PD in both autopsy and imaging studies.3,6,17⇓⇓
The substantia nigra zona compacta can be divided into a ventrolateral tier, a dorsomedial tier, and a paranigral tier, each projecting respectively to the putamen, caudate nucleus, and the nucleus accumbens. The pathway from the ventrolateral tier is crucial for motor function and the other two pathways may be important for cognitive and emotional functions.3 The more severe loss of caudate binding in DLB, compared to early PD, might be one of the explanations for some of the cognitive and psychiatric symptoms in DLB.
The second difference between the PD and DLB groups was in the asymmetry index in the posterior putamen. Patients with PD had a more asymmetric loss of binding sites in the posterior putamen than DLB patients and controls. This accords with the observation that patients with DLB present with more symmetric motor signs than patients with PD18 and with the observation that symmetric extrapyramidal features are associated with dementia.19
In the PD group there was a significant correlation between the UPDRS scores and the posterior putamen binding. However there was no significant correlation between the UPDRS score and the striatal binding in the DLB group. The reason for the lack of correlation between parkinsonian symptoms in DLB and the loss of FP-CIT uptake (which is presynaptic) may be the extensive postsynaptic pathology in the striatum in the DLB cases20 that would not be demonstrated by FP-CIT binding. Three studies have examined the correlation of parkinsonian signs and FP-CIT binding measures in PD. In a study of 6 early and 12 advanced PD patients, both ipsilateral and contralateral binding measures correlated with H&Y stage but not with motor UPDRS score.6 Surprisingly, however, in a further study by the same group,7 no significant correlation was found between striatal FP-CIT binding and disease severity. By contrast, in a study of 41 PD patients of varying severity, the FP-CIT binding measures in the striatum correlated with disease severity assessed by UPDRS and with duration of illness.21 No other study has looked at the correlation of striatal dopamine transporter binding and UPDRS in DLB. An autopsy study revealed no correlation between substantia nigra degeneration and parkinsonian signs in DLB, although the parkinsonian signs were those recorded at presentation, a considerable time before the autopsies.22
An important limitation of this study is that some of the patients may turn out at autopsy to have an alternative diagnosis. Although the specificity of the DLB consensus criteria is fairly good, most studies suggest that about 15% of patients are misclassified. Likewise the clinical misdiagnosis rate in PD is at least 10%.23 The non-PD conditions that are most frequently clinically misdiagnosed as PD are progressive supranuclear palsy and multiple system atrophy,11,23⇓ and they generally cause a more symmetric rigid akinetic syndrome than PD. Thus the observations concerning the asymmetry index presented here might be even more striking if autopsy data were available for the PD patients. Similarly the lower caudate binding in DLB by comparison with PD might become more pronounced if autopsy data were available for all the DLB patients, since some of the clinically diagnosed DLB patients may in fact have AD.
There is a view that there is really no distinction between DLB and PDD. In this study we have not scanned PDD patients. We would expect that the development of dementia due to Lewy body disease in PD patients would be associated with loss of caudate binding. If marked asymmetry of posterior putamen binding persisted in PDD patients, then there would still be an identifiable difference between PDD and DLB.
The severity of the cortical pathology in DLB by comparison with PD is undoubtedly a major determinant of the differences in the clinical features of the two conditions. This study, however, shows that there are also significant differences in striatal dopamine uptake between DLB and PD, which could underlie some of their clinical differences.
Acknowledgments
Supported by grants from Amersham Health & Novartis.
Footnotes
Professor Costa has acted as a consultant for Amersham Health and has received compensation in excess of $10,000. Professor McKeith and Dr. Zuzana Walker have acted as consultants for Amersham Health.
- Received September 24, 2003.
- Accepted in final form January 8, 2004.
References
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