Can Researchers Detect Dementia With Lewy Bodies at the Prodromal Stage?

Series - International Lewy Body Dementia Conference:

For neurodegenerative disease, the mantra is “go early,” based on the theory that intervention at prodromal stages may be most effective. Early detection could also help patients and families plan for the future, and avoid drugs contraindicated for particular conditions. But defining early disease can be tricky (see Part 1 of this series). At the International Lewy Body Dementia conference, held June 24–26 in Las Vegas, researchers discussed how best to recognize the prodromal stage of dementia with Lewy bodies (DLB). Many symptoms are detectable years before dementia sets in, providing an opportunity for early diagnosis. However, most symptoms are not specific for DLB. To truly nail early diagnosis, biomarkers will be required, speakers agreed. They suggested some promising candidates, including electroencephalography and tests of color vision. Ultimately, early diagnosis will probably rely on some combination of biomarkers and clinical features, researchers concluded.

  • Clinical DLB symptoms are not specific and sensitive enough for diagnosis at the prodromal stage.
  • The most informative biomarker is brain imaging to assess dopaminergic function.
  • EEG and loss of color vision both show potential as prodromal biomarkers.

“We’re introducing the concept of prodromal DLB, but we need more research to fully define it,” Kejal Kantarci of the Mayo Clinic in Rochester, Minnesota, told Alzforum. At the moment, a diagnosis of prodromal DLB would be used only for research studies, not in clinical practice, she added.

The criteria for a diagnosis of DLB were recently updated. A diagnosis now requires either two of the four core clinical features—cognitive fluctuations, REM sleep disorder, visual hallucinations, and parkinsonism—or one of these features plus an indicative biomarker, such as loss of dopamine transporters or damage to cardiac nerves (Jun 2017 news). The updated diagnostic guidelines do not define prodromal disease, however, because it is not yet clear how best to identify it.

Color Vision Provides Clue. A color vision test that asks people to order 15 shades in a spectrum can distinguish prodromal DLB from AD.

A working group convened by Ian McKeith of Newcastle University, U.K., is tackling this problem. McKeith noted that DLB can first present as cognitive impairment, delirium, or a psychiatric problem such as psychosis or depression (Kosaka et al., 1990; McKeith et al., 1992; Vardy et al., 2013). Based on the existing literature, the working group believes DLB that starts as mild cognitive impairment (MCI) is most amenable to early diagnosis at this time, McKeith said.

Researchers in Las Vegas noted that DLB symptoms can be detected at the MCI stage, years before a diagnosis of dementia. Matthew Barrett of the University of Virginia identified 121 people in the National Alzheimer’s Coordinating Center database who started out cognitively normal but were later diagnosed with DLB. About half of them had sleep problems, depression, and apathy for as long as five years prior to their diagnosis. These symptoms can characterize other neurodegenerative diseases too, however.

Alan Thomas of Newcastle University pointed out the catch-22 for DLB clinical symptoms: Sensitivity and specificity trade off with each other. In a cohort of 65 people diagnosed with MCI and abnormal dopaminergic function who were followed for up to six years, 41 went on to develop Lewy body dementia, while 24 were diagnosed with Alzheimer’s disease. Unusual symptoms, such as delusions and visual hallucinations, were highly specific for DLB, but had a sensitivity of only 10 to 15 percent. In other words, these symptoms were not always present in prodromal disease. Common symptoms, such as depression, apathy, and anxiety, were much more sensitive, but not specific for DLB (Donaghy et al., 2018). 

Likewise, Bradley Boeve of the Rochester Mayo Clinic reported data from a cohort of 74 patients who were diagnosed first with MCI, followed until death, and later confirmed to have DLB at autopsy. At the prodromal stage, only half the cohort had REM sleep disorder, a third had parkinsonism, and a quarter had cognitive fluctuations or visual hallucinations. Even at the time of death, only 80 percent of this autopsy-confirmed cohort met diagnostic criteria for DLB, Boeve said. With clinical features this variable, biomarkers will be crucial for diagnosis at the MCI stage, he concluded.

But what biomarker? The best one would be a direct measure of α-synuclein pathology, but this does not yet exist, Kantarci noted. Efforts to find one are ongoing, with one study suggesting that α-synuclein deposits in skin nerves could distinguish DLB patients from other dementias such as Alzheimer’s and frontotemporal dementia (Donadio et al., 2017). A method for amplifying protein aggregates, called real-time quaking-induced conversion (rt-QuiC), has been used to detect cerebrospinal fluid α-synuclein aggregates in Parkinson’s disease and might have potential for DLB (Dec 2016 news; Apr 2019 news). Others are trying to develop an α-synuclein PET tracer (Apr 2018 news). “An α-synuclein biomarker would revolutionize the field,” Kantarci told Alzforum.

Lacking that, researchers need surrogate biomarkers. Among these, low uptake of the radiolabeled dopamine transporter ligand DaTscan by basal ganglia is most helpful, distinguishing MCI due to DLB from that due to AD with 54 percent sensitivity and 89 percent specificity, Kantarci said. The sensitivity goes up to 61 percent if two or more core clinical features of DLB are included in the analysis (Thomas et al., 2018). 

Other biomarkers are still exploratory, but researchers at the conference were excited by the potential of EEG, which is a low-cost, readily available technology. In one small study of 47 people with MCI followed for three years, all 20 who progressed to DLB had abnormal EEGs at baseline. By contrast, all but one of the 14 who progressed to AD had normal readings (Bonanni et al., 2015). Laura Bonanni of the Università degli Studi G. d’Annunzio of Chieti-Pescara, Italy, who led the study, noted that the European DLB Consortium measures EEG in its longitudinal cohort study and will provide more data on how readings change over time in these patients (see Part 2 of this series).

Jessica van der Zande of the Alzheimer Center, Amsterdam, also touted the potential utility of quantitative EEG as a marker of progression. She followed 38 people who had MCI, an abnormal DaTscan, and one core feature of DLB. Those with an abnormal EEG reading at baseline progressed to Lewy body dementia in an average of 2.8 years, compared with 6.9 years for those with a normal EEG. This equates to a hazard ratio of 8.8. Van der Zande noted that the presence of amyloid pathology did not affect EEG readings, suggesting that Lewy bodies drive this abnormality (van der Zande et al., 2018). 

Meanwhile, other talks suggested impaired color vision as a potential biomarker. Elie Matar of the University of Sydney noted that problems with color vision can start up to 12 years before a diagnosis of Lewy body disease (Fereshtehnejad et al., 2019). The reason is unclear; while blood flow and metabolism in the visual cortex are low in DLB, Lewy bodies are rare there (Khundakar et al., 2016). Nonetheless, one-quarter of people with DLB have normal color vision, so the symptom is not universal.

Robert Unger of the Cleveland Clinic in Ohio compared color vision among 62 people with DLB, 25 with MCI that was likely due to DLB based on core disease features, and 24 with AD. He used the Farnsworth D15 Color Vision Impairment Test, which asks people to arrange 15 colors in a spectrum (see image above). Two-thirds of DLB patients performed poorly on the test, compared with 44 percent of the prodromal group and 18 percent of AD patients. Overall, adult-onset poor color vision gave an odds ratio of 10:1 for distinguishing prodromal DLB over AD. Color vision problems correlated with low scores on the MOCA, as well as atrophy of the right transverse superior temporal lobe, but did not correlate with core DLB features in this study.

Researchers in Las Vegas thought the findings were worth further study. One clinician noted that he has seen about five AD patients who told him that colors looked brighter after they started taking cholinesterase inhibitors. Perhaps these patients had some Lewy body pathology, he speculated.—Madolyn Bowman Rogers

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References

News Citations

  1. New Tool Kit Helps Physicians Recognize and Manage Lewy Body Dementias
  2. DLB Guidelines Get a Makeover
  3. Methods to Detect Amyloid Seeds Improve, Extend to Blood and Parkinson’s
  4. Spitting, Sniffing: Is This How We Will Dx Parkinson’s?
  5. Will PET Tracer, Monkey Model, Finally Bulk Up Toolbox for Parkinson’s?
  6. Consortia Assemble Worldwide to Take on Lewy Body Dementia

Paper Citations

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  7. Bonanni L, Perfetti B, Bifolchetti S, Taylor JP, Franciotti R, Parnetti L, Thomas A, Onofrj M. Quantitative electroencephalogram utility in predicting conversion of mild cognitive impairment to dementia with Lewy bodies. Neurobiol Aging. 2015 Jan;36(1):434-45. Epub 2014 Jul 15 PubMed.
  8. van der Zande JJ, Gouw AA, van Steenoven I, Scheltens P, Stam CJ, Lemstra AW. EEG Characteristics of Dementia With Lewy Bodies, Alzheimer's Disease and Mixed Pathology. Front Aging Neurosci. 2018;10:190. Epub 2018 Jul 3 PubMed.
  9. Fereshtehnejad SM, Yao C, Pelletier A, Montplaisir JY, Gagnon JF, Postuma RB. Evolution of prodromal Parkinson's disease and dementia with Lewy bodies: a prospective study. Brain. 2019 Jul 1;142(7):2051-2067. PubMed.
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