Abstract
Article abstract Using 18F-fluorodopa PET and a constant 0.0062 influx rate in the putamen, dementia with Lewy bodies (n = 7) was distinguished from AD (n = 10) with a sensitivity of 86% and a specificity of 100%. A constant 0.0071 influx rate in the caudate yielded a sensitivity of 71% and a specificity of 100% for distinction of the two disorders. Despite a limited sample size, these findings suggest that assessing nigrostriatal dopaminergic function with 18F-fluorodopa PET may be a useful diagnostic aid in cases of dementia with Lewy bodies while patients are alive.–1576
Although dementia with Lewy bodies (DLB) and AD occasionally coexist in the same subject, and a definitive diagnosis of these two neurodegenerative disorders can only be made by postmortem pathologic examination of affected brains, early and reliable antemortem detection of DLB as well as distinguishing DLB from AD are critically important for several reasons. First, the extrapyramidal features of DLB can be successfully treated with l-dopa in most cases.1 Patients with DLB seem more likely to respond to cholinesterase inhibitors than patients with AD.2 Second, it is well documented that there is a great need to pay particular attention to life-threatening neuroleptic adverse effects in DLB.3 Finally, DLB may have a different rate of disease progression from AD.4
In 1996, the Consortium on Dementia with Lewy Bodies (CDLB) proposed clinical diagnostic criteria for DLB.5 Although adequate sensitivity and specificity of current CDLB criteria were achieved in a recent prospective validation study, it is likely that the diagnosis of DLB can be confounded by the absence of parkinsonian features, the presence of comorbid cerebrovascular disease, or both.6 This highlights the need to develop another clinical or laboratory diagnostic tool to provide greater precision in the antemortem diagnosis of DLB. Because PET using 18F-fluorodopa (Fdopa) provides a direct method of assessing presynaptic nigrostriatal dopaminergic function in living patients,7 we analyzed Fdopa uptake with PET in the caudate nucleus and putamen. Here, we report a significant difference in striatal Fdopa uptake between patients with DLB and AD, and that PET measures of Fdopa uptake are a useful aid in the diagnosis of DLB.
Patients and methods.
Patients.
The study population consisted of six patients with probable DLB and one with autopsy-confirmed DLB plus AD (mean age, 66.9 ± 10.0 years; range, 51 to 79), as well as 10 patients with probable AD (70.5 ± 8.4 years; range, 58 to 86) and eight age-matched normal control subjects (67.5 ± 10.2 years; range, 52 to 85). There was no significant difference in age between the three groups. Age-matched normal subjects were community-dwelling healthy volunteers without any confirmed neuropsychiatric disorders. The diagnosis of probable and definite DLB was established based on CDLB criteria.5 Patients with probable AD were diagnosed using National Institute of Neurologic and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.8 Comprehensive medical and neurologic examinations were performed, including brain MRI, to exclude other causes of dementia. The severity of dementia as assessed by the Mini-Mental State Examination was not significantly different between patients with DLB (15.7 ± 6.7 points) and those with AD (16.3 ± 5.0 points). Among three core CDLB criteria, parkinsonism was noted in all the patients with DLB in addition to fluctuating cognition or visual hallucination, or both. Six patients with DLB variably responded to l-dopa therapy. Supportive features for the diagnosis of DLB were occasionally noted.
Fluorodopa PET imaging.
The Committee on Clinical Investigation at Tohoku University School of Medicine and the Advisory Committee on Radioactive Substances at Tohoku University approved the protocol of our PET study. Written informed consent was obtained from the patients or family members prior to this study. All subjects underwent PET scans using a PT931 scanner (CTI, Knoxville, TN) with 7-mm axial and transaxial resolution. Following an IV bolus injection of 2.5 to 8.3 mCi of Fdopa, a series of 5-minute emission scans was carried out for 60 minutes and emission data were simultaneously collected from seven contiguous axial sections. Tissue Fdopa concentration was measured by defining regions of interest (ROI) on three image planes that included the caudate nucleus and putamen. ROI in the caudate nucleus and putamen were defined on a summed image of data collected during the PET scan. An influx rate constant (Ki) of Fdopa into the selected regions was then calculated by the method described by Patlak and Blasberg,9 with radioactivity of the cerebellar hemisphere as an input function as described previously.7
Results.
Regional uptake of Fdopa is shown in figure. In the DLB group, Ki values were reduced in the caudate nucleus (0.0064 ± 0.0017; p < 0.001) and in the putamen (0.0051 ± 0.0019; p < 0.005) compared with the AD group (caudate nucleus: 0.0119 ± 0.0021; putamen: 0.0092 ± 0.0014). However, there was no significant difference in Ki values between the AD and the normal groups, either in the caudate nucleus or the putamen. Using a cut-off value of 0.0062 (mean − 2 SD of the normal group) in the putamen, DLB could be distinguished from AD with a sensitivity of 86% and a specificity of 100%; a cut-off value of 0.0071 (mean − 2 SD of the normal group) in the caudate nucleus yielded a sensitivity of 71% and a specificity of 100%. FIGURE
Figure. Individual influx rate constant (Ki) value of 18F-fluorodopa (Fdopa Ki) in the caudate nucleus (left) and the putamen (right) in patients with AD and dementia with Lewy bodies (DLB) as well as age-matched normal control subjects and are shown. Each bar represents the mean Ki value averaged for the left and right caudate nucleus and putamen. In the caudate nucleus, Ki values were 0.0129 ± 0.0029 in normal subjects, 0.0119 ± 0.0021 in patients with AD, and 0.0064 ± 0.0017 in patients with DLB. In the putamen, Ki values were 0.0114 ± 0.0026 in normal subjects, 0.0092 ± 0.0014 in patients with AD, and 0.0051 ± 0.0019 in patients with DLB. Arrows indicate the Ki value of an autopsy-confirmed case. Statistical analysis was performed by one-way analysis of variance (ANOVA). NS = not significant
Discussion.
This PET study is the first to describe a pronounced reduction of striatal dopamine uptake in patients with DLB. There was only a small overlap in the Fdopa Ki values between the DLB and the AD groups, suggesting that a nigrostriatal dopaminergic function using PET and Fdopa may be an informative diagnostic adjunct for distinguishing DLB from AD while patients are alive. Our observations are in agreement with pathologic findings of a consistent loss of substantia nigra neurons and depletion of striatal dopamine content in DLB.10 However, because all patients with DLB examined here presented with parkinsonian features and most were responsive to l-dopa, we cannot exclude the possibility that a marked reduction of striatal dopamine uptake in the DLB group may have resulted from a chance sampling bias. Therefore, further studies on a different patient population with a different combination of the core CDLB criteria are needed to confirm our findings.
Acknowledgments
Acknowledgment
The authors thank Drs. Nagasawa, Hisanaga, Takeda, Tanji, and other members of the Miyagi Parkinson’s Disease Study Group for referral of patients, as well as the patients and their families who made this research possible.
- Received March 20, 2000.
- Accepted July 19, 2000.
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