Research into dementia with Lewy bodies has lagged behind that for Alzheimer’s and Parkinson’s diseases, in part because DLB is difficult to identify, and less common. Many DLB trials fold because enrollment goals cannot be met. To enable larger studies, researchers in Europe, Asia, and North and South America are establishing consortia that will pool resources. At the International Lewy Body Dementia conference, held June 24–26 in Las Vegas, speakers described how these efforts are building the infrastructure for longitudinal observational studies, for biomarker discovery, and for clinical trials.

  • Prospective cohort studies of DLB are enrolling in Europe, Australia, and the U.S.
  • Japan has led in running DLB trials and supporting patients’ families.
  • South America is setting up the infrastructure for dementia trials.

DLB has been a hard disease to pin down because of its multitude of symptoms (see Part 1 of this series). Lewy body deposits can appear throughout the brainstem, limbic system, and cortex, and affect multiple body systems including movement, sleep, cognition, and autonomic functions. In Las Vegas, Susan Schneider Williams, widow of the comedian Robin Williams, who died with the disorder in 2014, described it as “a sea monster with 40 tentacles.” However, recent consensus diagnostic criteria defined four core symptoms and three indicative biomarkers (Jun 2017 news). This has enabled physicians to better recognize the disease (see Part 1). Criteria for prodromal disease are still unclear, and under development (see Part 3). In addition to difficulties with diagnosis, DLB is relatively rare, making up about 4 percent of dementia cases worldwide (Oct 2013 news). This has held back studies, but researchers now hope to get around the problem by launching large collaborative efforts.

In Europe, the European DLB Consortium represents a “one-stop shop” for researchers, said Dag Aarsland of King’s College London. Established in 2015, the consortium comprises 40 centers in 13 countries. Its first project was to consolidate into a single database the retrospective data on 1,208 Lewy body patients seen at the centers. This allowed researchers to better estimate the annual rate of cognitive decline in DLB, compare patterns of atrophy in DLB and AD, and correlate hypometabolism patterns with specific clinical symptoms (Kramberger et al., 2017; Oppedal et al., 2019; Morbelli et al., 2019). 

What researchers really yearn for, however, are prospective cohorts that will allow them to investigate the natural history of the disease, and tap participants for clinical trials. The European DLB Consortium has established such a cohort, enrolling 623 patients from 12 countries to date. Participants were diagnosed according to the latest clinical criteria (Jun 2017 news). The largest centers are in Spain, France, Italy, and the Netherlands, which contribute about 100 participants each. The centers collect several types of imaging data, including MRI, FDG PET, and DaT scans, as well as EEG scans and fluid biomarkers. The consortium is setting up a biobank for access to samples, and finalizing a web-based database that will go live this fall, noted Elaine Tomkinson of King’s College, who coordinates the project. One goal of the consortium will be to explore the utility of biomarker combinations to improve diagnosis and prognosis, Aarsland said in Las Vegas.

In the U.S., efforts are less centralized, comprising several separate initiatives. James Leverenz of the Cleveland Clinic Lou Ruvo Center for Brain Health leads the largest—the Dementia with Lewy Bodies Consortium. Established by the National Institutes of Health in 2015 with a $6 million grant, this network of nine centers, coordinated by the Cleveland Clinic, plans to enroll 216 patients with probable or early stage Lewy body disease into a longitudinal study. They will be extensively characterized, with the goal of identifying better biomarkers. All participants agree to autopsy as well.

Clinical, cognitive, imaging, and biofluid data from the study will be entered into the Parkinson’s Disease Biomarker Program (PDBP) database, in a format compatible with other large databases such as the National Alzheimer’s Coordinating Center. PDBP was launched in 2013 by the National Institute of Neurological Disorders and Stroke, and started including DLB data in 2017. Fluid samples will be stored at BioSEND, the NINDS repository at Indiana University.

Other smaller U.S. studies complement this research. Columbia University has established an ethnically diverse cohort of 160 DLB patients who will be followed annually and autopsied after death. The Mayo Clinic in Jacksonville, Florida, will collect several types of longitudinal imaging data, including amyloid and tau, on a separate cohort of 90 DLB patients to find what markers best correlate with diagnosis and progression. A University of Michigan study will compare imaging to rates of cognitive decline in 100 Lewy body dementia patients. All of these studies are supported by PDBP, and data will be stored there in a standardized format.

In Japan, large-scale DLB research has been underway for more than a decade. The DLB Society Japan, established in 2007, brings together 393 researchers, neurologists, and psychiatrists, said Manabu Ikeda of Osaka University. The society’s goal is to stimulate research, facilitate clinical trials, and inform the public and government about the disease. Many members run their own longitudinal cohorts. For example, Osaka University follows 50 people with DLB and 50 with probable prodromal disease, collecting clinical, neuropsychological, imaging, and biofluid data, Ikeda told Alzforum. He did not say how these probable prodromal cases were diagnosed.

Japan has also led the way in involving patients and families in research. The DLB Family Association meets yearly with the DLB Society, and a DLB Support Network run by local volunteers helps patients and families. These organizations aid recruitment, enabling Japan to run large clinical trials, Ikeda noted. The country approved the first drug for DLB anywhere in the world in 2014, giving the nod to donepezil to treat cognitive impairment. In 2018, Japan approved the antiepileptic drug zonisamide as an adjunct to levodopa for parkinsonism in DLB. Currently, Japan participates in the international Phase 2 trial of Eisai’s phosphodiesterase 9 inhibitor, E2027, for cognitive decline in DLB. No other DLB trials are currently active in Japan, although another zonisamide study is planned for later this year, Ikeda told Alzforum.

Only a few DLB trials are active elsewhere, notably Phase 2 trials of the cancer drug bosutinib and the related tyrosine kinase inhibitors nilotinib and K0706. There is also a Phase 2 trial of the MAP kinase inhibitor neflamapimod, a Phase 2 of LY3154207, a dopamine receptor modulator, and a Phase 3 of the anti-psychotic pimavanserin. “There’s a huge need for more trials,” noted Marwan Sabbagh of the Cleveland Clinic Lou Ruvo Center for Brain Health.

DLB patients often accumulate amyloid plaques and neurofibrillary tangles, pathological hallmarks of Alzheimer’s disease, as well. In a neuropathology study of 417 DLB brains, about half had plaques and a third had tangles, Daniel Ferreira of the Karolinska Institute in Solna, Sweden, said in Las Vegas. It is unclear what the effects of this are. In Australia, researchers are recruiting 100 people with probable DLB to participate in a longitudinal study that will try to unravel the influence of amyloid and tau in the disease. Rosie Watson of The Florey Institute of Neuroscience and Mental Health in Parkville, Australia, said they have recruited 25 people so far. Their average age is 73 and their MMSE scores average 25 out of 30. At baseline, 70 percent of this group are positive for brain amyloid, but very few for tau. Participants will undergo clinical assessments every six months and imaging every 18 months. This study is currently expanding to other sites in Australia, and may provide a framework for developing a clinical research network there, Watson noted.

Researchers are gearing up to modernize Lewy body dementia research in other ways as well. Agustin Ibañez at the Global Brain Health Institute, San Francisco, and Mario Parra at the University of Strathclyde, Glasgow, Scotland, launched the Latin America and Caribbean Consortium on Dementia (LAC-CD) in 2018. It now comprises more than 160 members from 15 countries. Its goals are to increase awareness of these diseases, improve public policies around dementia, and help standardize procedures for dementia diagnosis and management, much like the Global Brain Health Institute (Nov 2015 news). Members are linking up their studies and databases to leverage the power of big data, Jennifer Yokoyama of the University of California, San Francisco, said in Las Vegas. They have not yet established a cohort study of DLB, although they hope to add that, Yokoyama said.

The eventual goal for DLB researchers is to create a global network that shares progress and challenges, Aarsland said. Already, researchers are trying to harmonize data collection worldwide and look for opportunities to collaborate. Conference attendees were impressed by the rate of progress. “None of this infrastructure existed five years ago,” Leverenz said. Simon Lewis of the University of Sydney, who co-chaired the consortia session, noted that the scale of this is “mind-blowing.”—Madolyn Bowman Rogers


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News Citations

  1. New Tool Kit Helps Physicians Recognize and Manage Lewy Body Dementias
  2. DLB Guidelines Get a Makeover
  3. Can Researchers Detect Dementia With Lewy Bodies at the Prodromal Stage?
  4. Study Finds Low Incidence of Dementia with Lewy Bodies
  5. Chuck Feeney Award to Bolster Dementia Prevention in Developing Countries

Paper Citations

  1. . Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. J Alzheimers Dis. 2017;57(3):787-795. PubMed.
  2. . A signature pattern of cortical atrophy in dementia with Lewy bodies: A study on 333 patients from the European DLB consortium. Alzheimers Dement. 2019 Mar;15(3):400-409. Epub 2018 Nov 12 PubMed.
  3. . Metabolic patterns across core features in dementia with lewy bodies. Ann Neurol. 2019 May;85(5):715-725. Epub 2019 Mar 22 PubMed.

External Citations

  1. Dementia with Lewy Bodies Consortium
  2. cohort
  3. longitudinal imaging data
  4. University of Michigan study
  5. PDBP
  6. Phase 2 trial
  7. Phase 2 trials of the cancer drug bosutinib
  8. nilotinib
  9. K0706
  10. neflamapimod
  11. LY3154207
  12. pimavanserin

Further Reading