Findings of MIBG Cardiac Scintigraphy: Dementia with Lewy Bodies and Related Dementia

Fig. 16.1

Representative cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy findings in patients with dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Delayed cardiac MIBG scintigraphy showed significant decreased accumulation of MIBG in DLB patient but not in AD

On the contrary, most of AD patients show normal cardiac MIBG uptake, consistent with normal autonomic function test result and lack of pathological cardiac sympathetic nerve involvements. Patients with frontotemporal dementia (FTD), CBD, PSP, and vascular dementia (VaD) also show normal cardiac MIBG uptake. Thus, it has been reported that cardiac MIBG scintigraphy can be a useful tool for differentiating DLB from AD, FTD, CBD, PSP, and VaD [5, 6, 12].

Slaets et al. investigated the potential diagnostic value of MIBG cardiac scintigraphy in 20 patients to determine whether the diagnosis of DLB or AD was ambiguous at baseline [15]. The authors classified the patients into two groups with a cutoff of heart-to-mediastinum (H/M) ratio at 1.68 and followed them for more than 6 months (n = 19) or confirmed the classification with an autopsy (n = 1). The mean follow-up time was 17 ± 14 months (range: 6–57 months). Ninety-five percent (19/20) of the patients were correctly classified as compared with clinical or definite diagnosis at follow-up, with sensitivity and specificity values for diagnosing DLB of 100 % (16/16) and 75 % (3/4), respectively. This study suggested that MIBG cardiac scintigraphy could be valuable for earlier differential diagnosis of DLB and AD.

Although several promising results have been published that suggest the usefulness of MIBG cardiac scintigraphy for differentiation of DLB and AD, most of these studies were conducted under very strict exclusion criteria because abnormal cardiac MIBG uptake has been reported in patients with diabetes mellitus, thyroid diseases, heart failure, and ischemic heart disease. In clinical practices, older dementia patients could present with these highly confounding factors. Thus, if only applied to selected patients without any disease conditions, MIBG would not be an effective tool for estimation of dementia. Interestingly, Sayagues and colleagues demonstrated that prior cardiac or vascular involvement did not influence the results of MIBG cardiac scintigraphy in a cohort of patients with reduced MIBG cardiac uptake and DLB diagnosis [16]. More recently, Slaets et al. described no significant difference of H/M ratio among DLB patients with diabetes mellitus, arterial hypertension, hyperlipidemia, ischemic heart disease, heart failure, or pharmacological treatments and in those without in clinically observable conditions [15]. Further prospective cohort studies are needed to validate the application of MIBG for differentiation of DLB and AD even including not only dementia patients without heart and vascular conditions but also those patients without these conditions.

16.2.1.1 MIBG in DLB: Results from a Meta-Analysis

Treglia et al. performed a comprehensive computer literature search in PubMed/MEDLINE and in the Embase databases of studies published through May 2010 regarding MIBG cardiac scintigraphy performed for differential diagnosis between DLB and other dementias [17]. According to eight studies comprising a total of 346 patients with dementia (152 patients with DLB and 194 patients with other dementias), the pooled sensitivity of MIBG cardiac scintigraphy for detection of DLB was 98 % [95 % confidence interval (CI), 94–100 %] and the pooled specificity of MIBG cardiac scintigraphy for differential diagnosis between DLB and other dementias was 94 % (95 % CI, 90–97 %). The area under the receiver operating characteristic (ROC) curve was 99. The authors concluded that MIBG cardiac scintigraphy was an accurate test for differential diagnosis between DLB and other dementias.

16.2.1.2 MIBG in DLB: Results from Multicenter Study

According to a multicenter study achieved at ten Japanese sites, the heart-to-mediastinum ratio calculated with the automated system showed that the sensitivity was 68.9 % and the specificity was 89.1 % for differentiating probable DLB from probable AD using both early and delayed images [18, 19]. By visual assessment, the sensitivity and specificity were similar. Even in patients with mild dementia [mini-mental state examination (MMSE) ≥22], the delayed heart-to-mediastinum ratio showed has a sensitivity of 77.4 % and a specificity of 93.8 %. The reasons for the differences in the sensitivity and specificity between mild and moderate to severe dementia groups are unknown. They showed that AD patients with extrapyramidal signs and hallucinations in the DLB group and patients with comorbidity of DLB and AD pathology in the AD group may have affected the accuracy of diagnosis in moderate to severe dementia cases. Moreover, comparing to the results of previous reports, both sensitivity and specificity were relatively low, even in mild dementia cases. This result indicates that patterns of disease evolution are more variable than previously suggested in DLB.

16.3 MIBG in DLB: Comparison with FP-CIT

Dopamine transporter imaging using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging has enabled the diagnosis of DLB and is included as suggestive features in the Consensus Criteria. According to a recent systematic review of clinical trials using ¹²³I-fluoropropyl (FP) carbomethoxy-3 beta-(4-iodophenyltropane) (CIT), ¹²³I-FP-CIT, the sensitivity was 78.5 % and specificity was 90.1 % for differentiating probable DLB from probable AD [19]. However, the sensitivity decreased to 38.2 % in possible DLB [20]. Figure 16.2 demonstrated the ¹²³I-FP-CIT findings in patients with DLB and AD.

Fig. 16.2

Representative ¹²³I-fluoropropyl (FP) carbomethoxy-3 beta-(4-iodophenyltropane) (CIT) findings in patients with dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). FP-CIT SPECT showed significant decreased accumulation of the putamen in patients DLB patient but not in AD

More recently, the usefulness of ¹²³I-FP-CIT for differentiating possible DLB from AD was reported. In this study, with 49 of 114 (43 %) individuals had an abnormal scans [21]. When comparing the diagnostic accuracy of both ¹²³I-MIBG cardiac scintigraphy and ¹²³I-FP-CIT SPECT in 20 patients with DLB and 11 with other dementias (6 AD, 3 FTD, and 1 VaD), the sensitivity (90 %), specificity (91 %), positive predictive value (95 %), and negative predictive value (83 %) were not exactly the same but were close in values [22].

Camacho et al. reported that 23 of 28 DLB patients who had reduced cardiac MIBG uptake also showed reduced ¹²³I-FP-CIT binding in basal ganglia with a positive correlation between the H/M ratio and the specific binding ratio of the striatum (P < 0.01) [23].

16.4 MIBG in DLB: Comparison with Brain Perfusion Imaging

Both occipital hypoperfusion and reduced cardiac MIBG uptake are supportive features in the diagnostic criteria for DLB. Comparisons between technetium-99 methyl cysteinate (99mTc-ethyl cysteinate) dimer brain perfusion SPECT and MIBG in 25 DLB patients showed that occipital hypoperfusion was observed in 68 %, and reduced cardiac MIBG uptake was observed in 96 % of the patients’ ethylcysteinate dimer brain perfusion SPECT and MIBG in 25 DLB patients; occipital hypoperfusion was observed in 68 % and reduced cardiac MIBG uptake was in 96 % [24].

Inui et al. investigated N-isopropyl-p-¹²³I-iodoamphetamine (¹²³I-IMP) brain perfusion SPECT and MIBG cardiac scintigraphy findings in 12 patients with probable DLB and 9 patients with possible DLB [9]. This study showed that 83.3 % of patients with probable DLB and 11.1 % with possible DLB had severe reductions in the bilateral occipital lobe in ¹²³I-IMP and also showed low ¹²³I-MIBG uptake. In 1 of 12 patients with probable DLB and 2 of 9 patients with possible DLB, no occipital hypoperfusion was observed but reduced cardiac MIBG uptake was noted. In this same study, 8.3 % with probable DLB and 66.7 % with possible DLB did not show any occipital hypoperfusion and reduced cardiac MIBG uptake.

MIBG cardiac scintigraphy is superior to brain perfusion imaging for differentiating DLB from AD. In particular, cardiac MIBG may provide a powerful differential diagnostic tool when it is difficult to distinguish cases of DLB from AD using brain perfusion SPECT [4, 25].

Oda et al. compared the reliability of brain perfusion SPECT and MIBG in predicting the conversion of possible DLB to probable DLB [26]. In this study, 33 of 94 patients met the criteria for probable DLB after 1 year of follow-up. The areas under the ROC curves for SPECT for predicting the conversion to probable DLB from possible DLB based on the occipital/cerebellum and occipital/striatum cortex ratios of blood flow counts were 0.591 and 0.585, respectively. In contrast, the areas under the ROC curves for ¹²³I-MIBG based on the early H/M ratio, delayed H/M ratios, and washout rate were 0.935, 0.936, and 0.884, respectively. These results indicate that ¹²³I-MIBG cardiac scintigraphy is a good predictor of the future conversion of possible DLB to probable DLB.

16.5 Prodromal DLB

The term “prodrome” is derived from the Greek word prodromos, meaning the forerunner of an event [27]. In clinical medicine, a prodrome refers to the early symptoms and signs of an illness that precede the characteristic manifestations of the fully developed illness [28].

It is becoming increasingly apparent that a prodromal stage exists prior to the time when DLB can be diagnosed by current diagnostic criteria. The identification of prodromal DLB is therefore clinically important, because this can promote understanding of the initiation and progression mechanisms during the pathological changes to DLB. Knowledge of these mechanisms may provide further information as to the etiology and pathophysiology of DLB, including the mechanisms of cell vulnerability and pathological selectivity. Furthermore, this information will aid in selecting earlier and more appropriate supplementary treatments, may provide for better rehabilitation and patient education, and will provide additional time for the patient to plan for inheritance and other estate issues. Lastly, prodromal DLB patients are an important group for future clinical trials to develop disease-modifying therapies. The initiation of a disease-modifying therapy in the prodromal stage may be associated with better improvement of the progression and prognosis for patients with DLB.

Figure 16.3 showed a patient with prodromal DLB patients. He complained visual hallucination, but parkinsonism and cognitive decline were not observed. Brain SPECT imaging showed occipital hypoperfusion. Accumulation of cardiac MIBG scintigraphy was significantly decreased. However, FP-CIT finding was normal. After 2 years, he showed cognitive decline and fulfilled diagnostic criteria of probable DLB.

Fig. 16.3

Figure 16.3 showed 80 patients with prodromal DLB patient. He complained visual hallucination, but parkinsonism and cognitive decline were not observed. Brain SPECT imaging showed occipital hypoperfusion. Accumulation of cardiac MIBG scintigraphy was significantly decreased. However, FP-CIT finding was normal. After 2 years, he showed cognitive decline and fulfilled diagnostic criteria of probable DLB

Fujishiro et al. retrospectively investigated the clinical courses of 90 patients with probable DLB, including olfactory dysfunction, dysautonomia, depression, and rapid eye movement sleep behavioral disorder (RBD), and reported that these DLB-related symptoms were observed in 87.8 % of the patients, preceding the onset of memory loss by between 1.2 and 9.3 years [29]. Particularly, recent studies demonstrated that RBD is frequently the first indication of forthcoming α-synuclein-associated disorders, including DLB, PD, or MSA. Approximately 82 % of RBD patients develop a neurodegenerative disorder and 32 % convert to DLB during long follow-up period [30].

As for the initiation of parkinsonism in RBD patients, it was estimated that a prodromal interval was ∼4.5 years on the Unified Parkinson’s Disease Rating Scale [31]. The estimated onset of autonomic dysfunction ranged from 11 to 20 years; systolic blood pressure drop (prior to 20.4 years) and constipation (15.3 years) had the earliest estimates. Systolic blood pressure drop, erectile dysfunction, and constipation have a potential to discern disease up to 5 years before diagnosis of α-synuclein-associated disorders with sensitivity ranging from 50 % to 90 % [32]. Interestingly, pathological findings of RBD patient who did not present parkinsonism when still alive showed widespread peripheral autonomic nervous system pathology including cardiac plexus [33].

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