Is dopamine transporter invariably impaired at the time of diagnosis in dementia with Lewy bodies?

Abstract

Assessment of the integrity of the nigrostriatal dopaminergic pathway with 123 I-ioflupane SPECT has been approved by the Food and Drug Administration and the European Medicines Agency for the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). This has fulfilled a previously unmet need, i.e. to support the clinical diagnosis of DLB that is usually difficult because of overlapping symptoms with AD and also with frontotemporal lobe degeneration and vascular cognitive impairment. Indeed, by pooling the results from nine clinicopathological studies including 135 DLB patients and 350 non-DLB patients, the average sensitivity of clinical diagnosis was 49 % (range 0 -83 %) and the average specificity (proportion of non-DLB patients correctly diagnosed clinically) was 92 % (range 79 -100 %) [1]. This specificity was considered good but the sensitivity was considered unacceptably low.The availability of 123 I-ioflupane SPECT for dopamine transporter (DAT) assessment in the early 2000s prompted a large European multicentre study published in 2007 whose conclusion was that 123 I-ioflupane SPECT has a good accuracy in detecting dopaminergic impairment both in probable and in possible DLB (with clinical diagnosis as the gold standard), achieving about 90 % specificity, similar to clinical diagnosis in previous studies, but a definitely higher sensitivity (77.7 %) thus pointing to this tool as a valuable support for the clinical diagnosis of DLB [2]. The demonstration of nigrostriatal dopaminergic impairment by SPECT or PET was included in the diagnostic criteria published in 2005 merely as a supportive feature [3]. Still a head-to-head comparison between 123 Iioflupane SPECT and neuropathology was needed. This was performed by Walker et al. [4] who found a specificity of 100 % and a sensitivity of 88 % with semiquantitative analysis of the posterior putamen. In early 2015 a Cochrane review of DAT SPECT concluded that DAT SPECT is more accurate than clinical diagnosis in DLB and that clinical diagnosis is unsuitable as a reference standard for assessing the accuracy of DAT imaging [5].However, the 88 % sensitivity found by Walker et al. suggests that one in eight DLB patients with confirmed DLB pathology at autopsy might have a normal 123 I-ioflupane SPECT scan. The patient with a normal scan actually had an asymmetric presentation with right-sided parkinsonism resembling a corticobasal syndrome, with abnormal posterior left putamen uptake on visual analysis but normal average counts between the two putamina (the index considered in the paper). On autopsy only mild neuronal loss with mild α-synuclein pathology were found in the substantia nigra (SN) of that patient, together with widespread tau tangle/neuritic pathology in both the putamen and caudate. Also, the patient was affected by diffuse DLB pathology in the neocortex, and the likelihood of clinical DLB was retrospectively estimate to be 'intermediate' according to the DLB criteria. After publication of that study, the opinion i...

EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes 1.0

“…In particular, given its high specificity (20% higher with respect to clinical diagnosis), the revised criteria for the diagnosis of DLB further reinforced the role of DAT SPECT considering it as a diagnostic biomarker [20]. It should be noted, however, that approximately 10% of patients who met pathologic criteria for DLB can show a normal DAT SPECT at the time of the clinical diagnosis (possibly becoming abnormal after 1.5-2 years) [67,68]. In a recent autopsy study, this finding was related to topographical heterogeneity of α-synuclein deposition [19].…”

Metabolic patterns across core features in dementia with lewy bodies

“…1 Clinically, distinguishing DLB from other neurodegenerative diseases, in particular Alzheimer disease (AD), represents a diagnostic challenge. [10][11][12] Accordingly, a complete picture of brain metabolism in DLB patients is needed to provide a reference for further studies. In particular, 3 indicative biomarkers have been identified: reduced dopamine transporter (DAT) uptake in basal ganglia as demonstrated by single photon emission computed tomography (SPECT) or positron emission tomography (PET), reduced uptake on 123 I-metaiodobenzylguanidine myocardial scintigraphy (mIBG), and polysomnographic confirmation of REM sleep without atonia.…”

“…A more comprehensive and robust approach to FDG PET in DLB is presently needed, especially to support clinical diagnosis in countries where DAT SPECT, mIBG, and/or polysomnogram have limited availability and, more in general, in the subgroup of DLB patients with negative DAT SPECT (at the time of symptoms onset) due to later involvement of the nigrostriatal pathway. [10][11][12] Accordingly, a complete picture of brain metabolism in DLB patients is needed to provide a reference for further studies. We aimed to identify by means of FDG PET those brain regions whose metabolic impairment has specific contributions to the expression of clinical core features in DLB patients and to evaluate the influence of disease severity on the expression of the general DLB hypometabolic pattern.…”

“…Although preliminary PET studies have investigated the impact of brain amyloidosis on neurodegeneration in DLB, tracers for α‐synuclein deposition are not yet available, and a comprehensive in vivo clinical/pathological correlation is not yet possible. A more comprehensive and robust approach to FDG PET in DLB is presently needed, especially to support clinical diagnosis in countries where DAT SPECT, mIBG, and/or polysomnogram have limited availability and, more in general, in the subgroup of DLB patients with negative DAT SPECT (at the time of symptoms onset) due to later involvement of the nigrostriatal pathway . Accordingly, a complete picture of brain metabolism in DLB patients is needed to provide a reference for further studies.…”

Associations among education, age, and the dementia with Lewy bodies (DLB) metabolic pattern: A European‐DLB consortium project

“…In this framework, further investigation of demographic variables, possibly affecting the DLB‐related metabolic pattern, is of great interest. A more precise characterization and clinical correlation of the FDG‐PET pattern is relevant for the following reasons: to raise the clinical suspicion of DLB in patients with a challenging clinical presentation; 14 for the subgroup of patients with a clinical diagnosis of DLB being negative at DAT‐SPECT imaging at the time of clinical onset (i.e., around 10%); 15 to support the differential diagnosis in countries where the indicative biomarkers, that is, DAT‐SPECT, 123 I‐MIBG scintigraphy, and/or polysomnogram have limited availability 15–19 . Moreover, before properly measuring the analytical and clinical validity of imaging biomarkers, it is crucial to identify potential relevant covariates that might impact the diagnostic performance of the test 20 .…”