Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

Abstract

Patients who have dementia with Lewy bodies (DLB) show both clinical and histopathologic overlap with Alzheimer disease patients and Parkinson disease patients. In this study, we correlated the core features of DLB (dementia, parkinsonism, hallucinations, and fluctuations) with striatal dopamine transporter (DAT) availability as assessed with SPECT and 123 I-N-(3-iodoprop-2E-enyl)-2-b-carbomethoxy-3b-(4-methylphenyl) nortropane ( 123 I-PE2I) in patients with newly diagnosed DLB. Methods: Two hundred eighty-eight patients were consecutively included in the study as they were referred for diagnostic SPECT scanning of DAT with 123 I-PE2I. Of those patients, 51 had, on the basis of clinical guideline criteria, a probable-DLB diagnosis at follow-up 16 6 11.6 mo later. Before or on the day of the SPECT scan, DLB patients had a routine neurologic examination including Hoehn and Yahr grading and were cognitively evaluated with the Mini Mental State Examination. The central feature in dementia with Lewy bodies (DLB) is progressive dementia, but compared with other forms of dementia it has several additional frequent core features, namely fluctuations, hallucinations, and parkinsonism. Parkinson disease (PD), DLB, and PD dementia are seen as a spectrum of the same condition, "Lewy body diseases" (1). In the clinic, DLB and PD dementia are nosologically differentiated only by the time span between the development of parkinsonism and dementia. In DLB, cognitive problems occur less than a year after the onset of parkinsonism (2). The dopamine system is deeply involved in all Lewy body diseases, and dopamine is reduced in the basal ganglia as a consequence of the aggregation of Lewy bodies in this area of the brain (3,4).Imaging of the dopamine transporter (DAT) with SPECT serves as a surrogate marker of the nerve connection between axons from the substantia nigra and neurons in the striatum (5,6). An in vitro study of brains from monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, meant as a model of human DLB, suggested that the loss of DAT and the loss of striatal dopamine content are linearly correlated (7).In PD, many studies have shown a clear correlation between DAT binding and core features of parkinsonism (8). We identified only one DAT SPECT imaging study including 15 DLB patients correlating DAT binding (in which 123 I-2-b-carbomethoxy-3b-(4-iodophenyl)-N-(3-fluoropropyl)nortropane [ 123 I-FP-CIT] was used as the radioligand) with parkinsonism. The authors suggested that there might be a difference in the predilection for DAT uptake in PD versus DLB, since the caudate-to-putamen ratio was less reduced in DLB than in PD and, further, no correlation between severity of parkinsonism and DAT binding was found in DLB patients (9).SPECT imaging of cerebral blood flow has demonstrated frontoparietooccipital hypoperfusion patterns in DLB patients (10). The frontal hypoperfusion is interesting, since the dorsolateral circuit involved in planning and attention connects the frontal cortex with the striatum and ...

Loss of Dopamine Transporter Binding and Clinical Symptoms in Dementia With Lewy Bodies

“…These discrepancies could be owing to differences in study design or applied tests. For example, Ziebell et al found no association with severity of parkinsonism or cognition using only global scales such as the H & Y and MMSE scales, and Walker et al found also no association between striatal DAT binding and total UPDRS motor score or H & Y stage in DLB, compared to early PD showing an association . In contrast, we found associations using more‐detailed motor subscores and specific neuropsychological tests.…”

“…An inverse association was found between striatal DAT binding and visual hallucinations and between caudate nucleus DAT binding and delusions, depression, and apathy . In contrast, in another study, striatal DAT binding did not correlate with motor severity, global cognition, cognitive fluctuations, or hallucinations . These discrepancies could be owing to differences in study design or applied tests.…”

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

“…This is providing a useful diagnostic tool for differentiation between AD and DLB, while research is ongoing to identify the cognitive deficits associated with that deficit and potential targeted therapeutic interventions [457]. …”

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

“…Unlike several mGlu 1 or mGlu 5 -targeting PET radiotracers in human use, 40–45 there is an unmet need for probing mGlu 2 in clinical research and drug development towards this important receptor subtype in the glutamatergic pathway. As shown in Figure 1, there are continuous research efforts in the development of mGlu 2 PET tracers, 40–43 including [ 11 C]CMGDE ( 1 ), 46,47 [ 11 C]JNJ-42491293 ( 2 ), 48,49 [ 18 F]FE-JNJ42491293 ( 3 ), 50 [ 11 C]CMDC ( 4 ) 51 and two tracers ( 18 F-compound 5 and 11 C-compound 6 ) in the patent literature. 52,53 Among these studies [ 11 C]CMGDE ( 1 ), the first mGlu 2 radiotracer based on a prodrug of an antagonist LY341495, provided a foundation for the further development of a specific mGlu 2 tracer.…”