24 Dec 2015

At the International Dementia with Lewy Body Conference, held December 1-4 in Fort Lauderdale, Florida, brain imaging emerged as a promising adjunct to figuring out exactly what is going on in a patient’s brain during life. Given that the clinical diagnosis often misses DLB (see Part 1 of this series), and the pathological confirmation comes too late to help the patient, researchers are exploring imaging techniques to bridge this gap. This has created an increasingly varied research field.

MRI has been around the longest, but appears to be the least powerful in DLB. Showing MRIs from autopsy-confirmed cases, John O’Brien of Newcastle University, U.K., confirmed the general finding that the hippocampus in DLB does not shrink much. This finding has become part of the consensus diagnostic criteria. Because it is visible even on CT scans, which are widely available in routine clinical care, this finding is often used to support a diagnosis. And yet, it is not true in all cases, for example those with abundant tau pathology in the hippocampus (see Part 3 of this series). In addition, O’Brien noted more recent research findings that some cases of clinical DLB do have measurable atrophy elsewhere in the brain. This takes the form of subtle thinning in the insula area of the cortex, as well as in basal ganglia and other subcortical regions. Serial imaging in research studies suggests that this ongoing atrophy is related to concurrent Alzheimer’s pathology, O’Brien said.

Beyond structural MRI, functional imaging of the brain has generated a handful of measures—from FDG PET for glucose metabolism and rCBF PET or SPECT for blood flow to diffusion tensor imaging—that offer some consistent signals in DLB. Alas, although FDG PET is a robust technique for differential diagnosis of dementia, it is less powerful in early stages of disease, said Nicolaas Bohnen of the University of Michigan in Ann Arbor. By comparison, dopamine transporter imaging in the substantia nigra, done by ¹²³-Iodine ioflupane SPECT (aka FP-CIT or DaTscan) is highly sensitive, i.e., it does not miss cases as easily. A DaTscan greatly improves the diagnosis of DLB, though by itself it is also not always specific; dopaminergic nerve terminals sometimes degenerate in other diseases that can masquerade as DLB, Bohnen said. Thomas Beach of Banner Sun Health Research Institute in Sun City, Arizona, agreed, “An unknown fraction of people with positive DaTscans have PSP, CBD, or MSA rather than PD or DLB. We see this at our center and elsewhere.”

Amyloid PET, which picks up the plaques that accompany many cases of DLB (see Part 3 of this series), has further stocked up the neurologist’s toolbox. Several groups at the conference reported positive amyloid scans in a majority of DLB patients. Their amyloid burden tends to be in between that of controls and people with AD, similar to the burden seen in MCI. This jibes with the neuropathological finding of variable amounts of amyloid plaques accompanying Lewy pathology in DLB.

But it is the combination of the two that, at least in specialized research settings, outperforms even astute clinicians. For example, Bohnen described an ongoing study at UMichigan of 75 patients with diagnoses of mild dementia, agreed upon by a consensus of clinicians. Nuclear medicine neurologists made their own call based on PET scans for both dopamine terminals in striatum, and amyloid. In 2011, this study’s first paper reported that the neuroimaging diagnosis disagreed with the clinical one in 17 percent of AD cases, 29 percent of DLB, and a whopping 64 percent of FTD cases. Who was right? In Fort Lauderdale, Bohnen followed up with the news that 36 of the 75 patients had since come to autopsy, and neuropathology had validated the neuroimaging diagnosis in 33 of them (Burke et al., 2011; Albin et al., 2015). “The imaging-pathological correlation is much more accurate than the clinical-pathological correlation,” Bohnen said.

As more imaging tests come online, clinicians will be able to serve their patients better by incorporating scans into their diagnoses. Then they will be able to focus their clinical expertise on managing the manifold symptomatic challenges of DLB patients, who cannot tolerate some of the medications that might be used if the patient had AD, scientists agreed. At this point, dual scans are not approved by most insurance, though Bohnen told Alzforum that at the Veteran’s Affairs hospital where he works, both DAT and amyloid PET are done quite frequently and can be very helpful in selected patients.

Looking farther out to the research horizon, Bohnen mentioned two new imaging tracers worth watching. One is ¹⁸F-FEOBV, a PET tracer for vesicular acetylcholine transporters. In DLB, FEOBV PET generates a big signal reduction in the cortex, hippocampus, caudate nuclei, and the thalamus. “FEOBV shows marked cholinergic losses not only in cognitive but also motor-control regions in DLB, as previously shown by neuropathology,” Bohnen said (Petrou et al., 2014). At the conference, Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, reminded the audience that DLB causes degeneration in many transmitter systems across the nervous system.

The second emerging method may open a window to prodromal DLB, Bohnen said. Neuropathologists believe that some cases of Lewy body pathology reach the brain by way of the enteric nervous system, possibly as a consequence of exposure to toxins in food. Some scientists believe that α-synuclein pathology in intestinal neurons can damage cholinergic terminals there and lead to symptoms such as constipation, which is common in PD and DLB years before the better-known movement and cognitive symptoms. Scientists led by Per Borghammer at Aarhus University Hospital, Denmark, have begun to visualize this process.

Like MIBG scintigraphy of the heart, a diagnostic imaging test that picks up DLB in the peripheral nervous system (see Part 2 of this series), the new Danish approach also captures peripheral neurodegeneration via reduction of an affected neurotransmitter, in this case acetylcholine. But unlike MIBG, the Danish approach uses a radiolabeled version of the therapeutic drug donepezil as a PET tracer. Donepezil binds acetylcholinesterase in intestinal nerves and is, after all, highly active in this part of the body, as legions of nauseous donepezil-treated AD and DLB patients can attest. The scientists recently described how injected ¹¹C-donepezil flows and binds throughout the human body in healthy controls, as well as in 12 people with Parkinson’s disease. In them, 35 percent less of this tracer bound in the small intestine than in controls (Gjerloff et al., 2014; Gjerloff et al., 2015). “This is a very early, prominent signal. Imaging neurotransmitter changes or α-synuclein deposits in autonomous organs may become a game-changer in the field,” Bohnen said.—Gabrielle Strobel

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References

News Citations

1. Dementia with Lewy Bodies: Is the Research Ready For Clinical Trials 22 Dec 2015
2. Dementia with Lewy Bodies: Sharper Image for a Formerly Blurry Disease 23 Dec 2015
3. Through the Heart? Cardiology Tracer to Nail DLB Diagnosis 23 Dec 2015

Paper Citations

1. Burke JF, Albin RL, Koeppe RA, Giordani B, Kilbourn MR, Gilman S, Frey KA. Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography. Brain. 2011 Jun;134(Pt 6):1647-57. PubMed.
2. Albin RL, Fisher-Hubbard A, Shanmugasundaram K, Koeppe RA, Burke JF, Camelo-Piragua S, Lieberman AP, Giordani B, Frey KA. Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications. Ann Neurol. 2015 Nov;78(5):824-30. Epub 2015 Aug 25 PubMed.
5. Gjerløff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S, Danielsen EH, Terkelsen AJ, Hansen J, Pavese N, Brooks DJ, Borghammer P. Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET. Brain. 2015 Mar;138(Pt 3):653-63. Epub 2014 Dec 23 PubMed.

Further Reading

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