23 Dec 2015

For all the brain-imaging research scientists in North America and Europe have been doing on dementia with Lewy bodies (DLB) over the past decade, could it be said they were a little slow to catch on to an option that plainly does the trick? At the International Dementia with Lewy Bodies conference December 1-4 in Fort Lauderdale, Florida, a little-known scintigraphy method wowed the audience. While international research slowly advanced on a panoply of MRI, CT, SPECT, PET, and even multimodal methods, Japanese researchers cleanly and methodically moved one method across the finish line. They performed clinical studies, standardized their method across centers, ran a multicenter trial. In 2012, bingo! The Japanese health authorities approved the test as a diagnostic aid for DLB, Parkinson’s dementia (PDD) and Parkinson’s disease, and national health insurance agreed to cover the procedure. The test in question is called ¹²³I-Metaiodobenzylguanidine Myocardial (aka MIBG) scintigraphy. MIBG, the tracer, is an analog of norepinephrine. It binds to adrenergic nerve terminals of the postganglionic sympathetic nerve that innervate the heart muscle. Its uptake is characteristically reduced in LBD, PDD, and DLB—essentially reflecting the α-synuclein-induced sympathetic denervation that underlies some of the autonomic symptoms of DLB.

Gamma-scintigraphy is widely available and routinely used in medicine, for example for bone scans to diagnose osteoporosis. The MIBG tracer has been available in both Europe and North America for years. In the United States it goes by the name of AdreView. It is indicated for the detection of tumors of the adrenal gland, but also as an adjunct to assess sympathetic innervation of the heart. Cardiologists use MIBG scintigraphy in the context of heart failure. Most neurologists do not, but in Fort Lauderdale, many said that they would like to start. James Leverenz at the Cleveland Clinic in Columbus, Ohio, echoed the stance of many colleagues at the conference when he said, “The cardiologists at my clinic use MIBG. I wish I could use it for the differential diagnosis of DLB.”

In the United States, one argument that has held back development of MIBG was a concern that it would erroneously indicate DLB in people with diabetes or other conditions common in the elderly. However, a multicenter study presented by Cristina Muscio of Fondazione Europea Ricerca Biomedica and Pietro Tiraboschi of Fondazione IRCCS Istituto Neurologico Carlo Besta in Milan showed that myocardial uptake of MIBG was normal in old people with concomitant diabetes or mild heart disease consistent with New York Heart Association classes I or II. This suggested to Tiraboschi and Muscio that the concern might be overstated. Likewise, a recent Belgian study reported that MIBG worked properly in patients in routine clinical care who were not handpicked to exclude diabetes, heart disease, and other conditions (Slaets et al., 2015). 

“The argument that MIBG gives a false positive read in diabetics is wrong. MIBG provides a robust, reliable measurement,” agreed Douglas Galasko of the University of California, San Diego. To better understand whether MIBG is useful in real-life clinical settings, Tiraboschi said, additional data are needed from larger samples of subjects with diabetes and/or heart disease. In response to audience questions about confounding conditions, Masahito Yamada of Kanazawa University Graduate School of Medicine in Japan clarified that only people with severe congestive heart failure and those who take certain antidepressants should not have the procedure.

“We have MIBG at MGH,” said Stephen Gomperts of Massachusetts General Hospital in Boston. “I’d like to look into what it takes to use it for DLB.” Kejal Kantarci of the Mayo Clinic in Rochester, Minnesota, welcomed MIBG as a complement to the imaging toolbox that specifically captures the autonomic degeneration of this multifaceted disease.

“The MIBG data presented here look stellar. Of all imaging modalities we have thus far, it looks to be the most sensitive and specific,” said Bradley Boeve, also at Mayo in Rochester. So what were the data?

First, a note on the existing literature. Over the past 15 years, researchers at different centers in Japan and Korea have published dozens of papers building a case that MIBG myocardial scintigraphy is helpful in distinguishing dementia with Lewy bodies from Alzheimer’s and other related conditions (e.g., Yoshita et al., 2001; Watanabe et al., 2001; Yoshita et al., 2006; Nakajima et al., 2008; Kobayashi et al., 2009; and many others). Research groups in Spain, Italy, and Germany weighed in, too (e.g., Estorch et al., 2006; Estorch et al., 2008; Novellino et al., 2010; Jost et al., 2010). Meta-analyses and calls for standardization started appearing (e.g., Fröhlich et al., 2010; Teglia and Cason, 2012), and before long, there was a body of evidence from well over 100 papers, almost exclusively from Asia and Europe. The year 2015 has seen 15 papers alone on MIBG in DLB. It is not a contradictory literature. Most reports confirm the clinical usefulness of MIBG for this purpose.

At the conference in Fort Lauderdale, three presentations focused on MIBG. Yamada, of Kanazawa University, picked up from numerous single-center studies that over the years have reported high sensitivity and specificity, for an overall accuracy of MIBG scintigraphy in the mid-to-high 90th percentile. To see how that held up in a broader trial, and to put MIBG on a national footing, Japanese scientists conducted a 10-center study of 133 people with a consensus clinical diagnosis of DLB or AD.

This trial followed on the heels of a previous effort to standardize the acquisition procedure across the different camera-collimators systems in place across the country. Much as was done in ADNI years ago, a traveling calibration phantom was used to work out how to harmonize the values generated across 84 Japanese institutions and convert them to a unified H/M ratio, the main output measure of MIBG scintigraphy for DLB (Nakajima et al., 2014). The H/M ratio is a standardized ratio of the tracer’s uptake in the heart versus the mediastinum, which is essentially the space in the chest that houses the lungs and other organs there. Previously, centers performed the procedures in their own way, taking the images at different times after the injection, calculating the H/M ratio based on different-shaped regions of interest, coming up with different cut-offs, etc. Standardization makes it much easier now to perform multicenter studies, said Yamada.

In the first major trial, three readers who were blinded to the clinical diagnosis classified each image as normal or abnormal. The trial also evaluated an automated calculation of the H/M ratio based on regions of interest. This calculation achieved a sensitivity of 68.9 and specificity of 89.1 to distinguish DLB from AD; the visual assessment came out at 68.9 and 87.0 percent, respectively. In a subgroup whose dementia was still mild, the numbers were 77.4 and 93.8 percent, respectively (see Yoshita et al., 2015). As expected, his multicenter accuracy is lower than in previous single-site studies, Yamada said, but still good enough for MIBG to be useful in routine clinical care. Other researchers at the conference strongly agreed. Ron Postuma of McGill University, Montreal, summed up a general sentiment when he said, “This is very impressive evidence, and good enough for use in diagnosis.”

Satoshi Orimo of Kanto Central Hospital in Tokyo tied low uptake of MIBG in the heart to degeneration of sympathetic nerve terminals. He conducted the kind of postmortem validation study that is generally seen to clinch the connection between an imaging signal and what it claims to represent. These studies require postmortem tissue from autopsy-confirmed patients who died not too long after having received the imaging method in question. More broadly across the field of neurodegeneration, these studies have been done for every FDA-approved amyloid PET tracer and are starting in tau PET tracers, as well.

Showing how this was done for MIBG myocardial scintigraphy in life, Orimo presented data from six Japanese sites, on heart muscle tissue from 23 people with Lewy body disease and two controls who had had Alzheimer’s or multiple-system atrophy (MSA). People with AD tend not to have orthostatic hypotension or cardiac sympathetic nerve degeneration; people with MSA do have the marked orthostatic hypotension of DLB, but theirs is due to degeneration in central and preganglionic neurons, not the postganglionic nerve that degenerates in DLB and is imaged by MIBG.

The scientists stained snippets of the heart’s left ventricle with antibodies against neurofilament and tyrosine hydroxylase, the catecholaminergic enzyme in peripheral sympathetic neurons, α-synuclein. They compared this immunohistochemistry with the MIBG H/M ratio. This measure is markedly reduced in DLB. Orimo reported a statistically significant correlation between the two measures. In essence, in cases where the H/M ratio had been down during life, the TH-immunoreactive nerve fibers were gone after death, confirming that MIBG most likely detects the loss of these axons in DLB. This study appeared in print last September (Takahashi et al., 2015). It follows previous studies linking the degeneration of these nerve endings to the presence of α-synuclein aggregates (Orimo et al., 2008). 

“This clinical-pathological correlation is compelling,” Boeve told Alzforum.

Several studies have compared MIBG to 123-I-FP-CIT, aka DaTscan, a SPECT method to quantify degeneration of dopaminergic nerve terminals in the striatum. FP-CIT SPECT is available in Europe, North America, and Japan. In Fort Lauderdale, Muscio and Tiraboschi directly compared the diagnostic value of DaTscan to MIBG in 32 people with a clinical diagnosis of DLB and 27 people with a non-DLB dementia. All were referred to five dementia centers in Italy in 2012. This is the first prospective longitudinal comparison study in the field, in that people received an independently verified clinical diagnosis, both striatal and heart imaging, and then were re-evaluated clinically a year later to see if the initial diagnosis was correct or needed to be changed. The clinicians and the image readers were respectively blinded to imaging data and to clinical information until the end of the study. At baseline, MIBG sensitivity and specificity to DLB were 87 and 100 percent, respectively, and 87 and 78 percent for FP-CIT SPECT. At follow-up, clinicians changed their mind about two patients, reclassifying them from possible DLB to AD. This upped the sensitivity and specificity of MIBG to 93 and 100 percent, and for FP-CIT SPECT to 90 and 76 percent.

FP-CIT SPECT performed worse because it also picked up low striatal uptake in some of the AD and FTD patients, many of whom had symptoms of parkinsonism. Their MIBG uptake in the heart’s sympathetic nerve was normal. “MIBG resulted to be more specific for excluding dementias other than DLB. The feeling that MIBG scintigraphy has a great diagnostic value in correctly identifying DLB has recently led many neurologists in Italy’s Lombardy region to use this technique off-label to differentiate DLB from other types of dementia, especially AD,” Muscio told Alzforum.

MIBG scintigraphy could come in handy for differential diagnosis. At a clinical neuroimaging-pathology symposium held at the conference, Yamada presented a case of overlapping pathology of DLB and PSP in a woman who had dementia, depression, parkinsonism, and autonomic symptoms. She could have had either underlying disease. Her MIBG scan showed clear denervation of the sympathetic nerve, clinching a diagnosis of Lewy body disease. Orimo presented a case of a woman who had autonomic symptoms and could have had PD or MSA. Her FP-CIT scan had shown reduced striatal dopamine transporters, but that is the case in both diseases, Orimo said. Her MIBG scan showed denervation of the sympathetic nerve, for a PD diagnosis. MIBG is a biomarker for the presence of neuronal Lewy pathology in the heart, which occurs in PD and DLB, but not in related diseases including AD, MSA, FTD, CBD, or PSP, Yamada told Alzforum.

MIBG in Differential Diagnosis. Sympathetic cardiac nerve degeneration reduces MIBG uptake in α-synucleinopathies such as Parkinson’s, Parkinson’s dementia, dementia with Lewy bodies, and pure autonomic failure (blue). This is not the case in controls or other diseases such as multiple-system atrophy, progressive supranuclear palsy, corticobasal degeneration, vascular parkinsonism, essential tremor, Alzheimer’s, and frontotemporal dementia. [Courtesy of Satoshi Orimo, Kanto Central Hospital.]

Last August, a study by researchers at the University of Tokyo reported that the accuracy of FP-CIT SPECT and MIBG scintigraphy overall was similar in 133 patients with either AD or DLB. This direct comparison found the combination of both tests to be best. Interestingly, patients with reduced MIBG uptake had more REM sleep behavior disorder while patients with reduced FP-CIT uptake had more parkinsonism (Shimizu et al., 2016). In October 2014, researchers at Fujita Health University School of Medicine near Nagoya, Japan, reported that MIBG heart scintigraphy was superior to brain perfusion SPECT and MRI in distinguishing DLB from AD (Inui et al., 2014). 

Finally, in Fort Lauderdale, scientists discussed how they could best capture prodromal DLB in their efforts to find early stage patients for future therapy trials. A recent paper by Japanese scientists had laid groundwork in reporting that cardiac MIBG uptake strongly predicted the progression from possible to probable DLB (Oda et al., 2013). Studies in Japan are offering MIBG imaging to cohorts of people who have symptoms thought to precede DLB, such as REM sleep disorder or certain psychiatric conditions. In his talk, Hiroshige Fujishiro of Nagoya University, Japan, emphasized the need to offer combined clinical and MIBG biomarker studies to middle-aged and older patients who present to psychiatrists, for example, with major depressive disorder (see also Kobayashi et al., 2015). Likewise, at the conference, John-Paul Taylor, Alan Thomas, and Paul Donaghy, all of Newcastle University, U.K., noted that MIBG imaging was a promising biomarker in prodromal DLB research (Donaghy et al., 2015).—Gabrielle Strobel

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References

Paper Citations

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External Citations

1. New York Heart Association classes

Further Reading

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