Dementia with Lewy bodies is a devastating disorder, combining some of the worst features of Alzheimer’s and Parkinson’s, but it is relatively rare and often goes unrecognized. DLB research has lagged far behind that for AD and PD, but is rapidly gaining ground. At a recent conference in Las Vegas, researchers discussed worldwide progress in building the infrastructure to support large longitudinal studies and clinical trials for DLB. Researchers presented guidelines for improving diagnosis and management of the disease, and scientists discussed how best to identify prodromal cases for research studies.
New Tool Kit Helps Physicians Recognize and Manage Lewy Body Dementias
Lewy body dementia, the second-most-common progressive dementia after Alzheimer’s disease, receives relatively little attention and few research dollars, and often goes undiagnosed. Comedian Robin Williams, perhaps the most famous person to have died from this disease, was diagnosed only after his death, when neuropathologists found the protein- and lipid-laden Lewy body deposits throughout his brain and brainstem. “I had never even heard of the disease,” his widow, Susan Schneider Williams, told the audience at the International Lewy Body Dementia conference, held June 24–26 in Las Vegas. For her husband, as for many patients with the disorder, the diagnostic uncertainty led doctors to prescribe medications that worsened his disease. The lack of a clear diagnosis also made it difficult to comprehend the multitude of distressing symptoms, including paranoia, delusions, and the unpredictable fluctuations of his cognitive skills throughout the day. “He thought he was going crazy,” Susan Williams said. “A diagnosis would have helped us cope.”
Could researchers improve the diagnosis and management of DLB by providing more information and clear guidelines to physicians? A U.K. program shows how this might work. In Las Vegas, John O’Brien of the University of Cambridge described the DIAMOND-Lewy research program, a collaboration between Cambridge and Newcastle University that is funded by the National Institute for Health Research. The acronym stands for “improving the DIagnosis And Management Of Neurodegenerative Dementia of Lewy body type.” DIAMOND-Lewy encompasses Parkinson’s disease dementia (PDD) as well as dementia with Lewy bodies (DLB). It provides a checklist to help physicians diagnose and manage DLB and PDD patients. The checklist is based on the current consensus criteria for these diseases (McKeith et al., 2017). In an initial study, use of the checklist improved recognition of Lewy body dementia at hospital clinics in England, and led to some benefits for patients and caregivers over a six-month period.
Researchers in Las Vegas called this an important advance, and one of the most exciting things they heard at the conference. “The DIAMOND-Lewy project is truly impressive in scope and detail. The recommendations are comprehensive, which will surely enable more optimal management of these complex patients,” Bradley Boeve of the Mayo Clinic in Rochester, Minnesota, told Alzforum.
As a first step to improving care, DIAMOND-Lewy researchers assessed what barriers hinder diagnosis. In two U.K. regions, the North East and East Anglia, it took patients more than a year on average and 20 clinical consults to be diagnosed with DLB, as compared with six months and 3.5 clinical consults for other dementias. Half of DLB patients initially received a different diagnosis. Why was diagnosis so difficult? O’Brien and colleagues found that, in part, physicians lacked knowledge about the disease. For example, many doctors did not ask their patients about sleep disturbances, a key early sign of DLB. Another issue, however, was that doctors believed nothing could be done to improve the lives of people with DLB, and were reluctant to make the diagnosis.
To combat the first problem, the DIAMOND Lewy team developed two different tool kits—one to standardize diagnosis of DLB, and the other for PDD (Thomas et al., 2016). They revised the DLB tool kit a year later to reflect newly updated criteria for diagnosing the disorder (Jun 2017 news; Thomas et al., 2018). The DLB and PDD tool kits are freely available, along with a video describing their use. The DLB tool kit provides specific screening questions to help assess whether a patient has any of the four core features of the disease: cognitive fluctuations, REM sleep disorder, visual hallucinations, and parkinsonism. The presence of two or more indicates probable DLB. The tool kit also queries the three indicative DLB biomarkers—abnormal dopaminergic imaging, damage to cardiac nerves, and confirmation of REM sleep problems by polysomnography. One of these plus a core feature likewise indicates probable DLB.
Did use of the DLB tool kit improve diagnosis? In Las Vegas, O’Brien presented unpublished data that suggests it does. In the 18 months prior to adopting the instrument, an average of 4.6 percent of the 4,504 dementia cases seen in the North East and East Anglia regions were labeled DLB. After the tool kit was introduced, DLB diagnoses jumped to 6.2 percent of 2,058 dementia cases seen, a 35 percent increase. By contrast, use of the PDD tool kit did not change diagnoses of this disease, which held steady at about 9 percent of dementia cases. Diagnoses were not confirmed by autopsy.
What about the second need identified by the study—better management of patient health? DLB patients typically fare worse than those with other dementias, such as Alzheimer’s, noted John Paul Taylor of Newcastle University in the U.K. They are admitted to the hospital more often, accumulate higher bills, report lower quality of life, and die sooner. Could standardizing the way physicians manage the disease improve outcomes?
For this, DIAMOND-Lewy researchers developed a separate tool kit aimed at defining the best clinical care. They reviewed the literature on physician care for people with Lewy body dementia, and summarized the treatment measures in 252 statements. These statements dealt with issues such as which medications to prescribe for people with DLB or PDD, which ones to avoid, what dosages to use, and what non-pharmacological interventions might be helpful. Then the researchers convened a panel of 26 experts to evaluate these measures. The panel discussed each statement and voted whether to accept or reject it as a best practice, ending up with 161 consensus care statements in the tool kit. A one-page overview lists the primary management strategies for each symptom, as well as practices to avoid. For example, antipsychotics can hasten disease progression for DLB patients, and dopamine replacement therapy needs to be carefully titrated, as high doses can worsen hallucinations. The evidence underpinning this management tool kit is in press at Lancet Neurology.
To evaluate this management tool kit, the researchers shared it with 11 memory or movement disorder health services in the North East and East Anglia, while 11 other services maintained the usual standard of care. Among the 22 clinics, 127 people newly diagnosed with DLB or PDD were assessed at baseline, three, and six months. Participants were mostly men, with an average age in the late 70s. Eighty-four percent completed the study. Sixty percent were diagnosed with DLB and 40 percent with PDD.
Did the tool kit improve health? Reporting unpublished data, the researchers found no difference on several measures of cognitive and motor function. However, 40 percent of the usual care group were rated as steeply declining on the clinical global impression (CGI) scale over the six months, versus 20 percent of the tool kit group. Caregivers reported a similar impression, with less decline in patients cared for under the new guidelines. In addition, caregivers in the tool kit group self-reported less depression, stress, and perceived emotional burden than those in the control group did. Economically, the tool kit group fared better as well. Medication costs rose, but this was offset by a large drop in healthcare and social care costs, resulting in an overall financial savings.
The findings are encouraging, especially because not every health service that received the tool kit used it effectively, Claire Bamford of Newcastle noted in Las Vegas. Her team interviewed 31 clinicians who took part in the study. Almost uniformly, doctors praised the design of the tool kit, saying they liked how information was highlighted, the different levels of detail available on how to manage each symptom, and guidelines on medication dosage. One doctor called it a “one-stop shop” for Lewy body dementia information. Clinicians expressed high confidence in the quality of the information, and said it made them think more about the whole patient and their health needs, rather than treating each symptom separately.
However, clinics varied widely in how they used the tool kit. Only some integrated it into their practices, while others simply held copies on file. When it was used successfully, it was often because one person at the health service championed the tool kit and took the lead in incorporating it into clinical practice, Bamford said. In ongoing work, the DIAMOND-Lewy team is looking for ways to support use of this tool by clinics and to roll it out more broadly to primary care clinics and inpatient wards. Audience members in Las Vegas suggested that a phone app, which could be easily updated as standards change, might be most effective and user-friendly.—Madolyn Bowman Rogers
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- Thomas AJ, Taylor JP, McKeith I, Bamford C, Burn D, Allan L, O'Brien J. Revision of assessment toolkits for improving the diagnosis of Lewy body dementia: The DIAMOND Lewy study. Int J Geriatr Psychiatry. 2018 Oct;33(10):1293-1304. Epub 2018 Aug 9 PubMed.
Consortia Assemble Worldwide to Take on Lewy Body Dementia
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.
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
- New Tool Kit Helps Physicians Recognize and Manage Lewy Body Dementias
- DLB Guidelines Get a Makeover
- Can Researchers Detect Dementia With Lewy Bodies at the Prodromal Stage?
- Study Finds Low Incidence of Dementia with Lewy Bodies
- Chuck Feeney Award to Bolster Dementia Prevention in Developing Countries
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Can Researchers Detect Dementia With Lewy Bodies at the Prodromal Stage?
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.
“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
- New Tool Kit Helps Physicians Recognize and Manage Lewy Body Dementias
- DLB Guidelines Get a Makeover
- Methods to Detect Amyloid Seeds Improve, Extend to Blood and Parkinson’s
- Spitting, Sniffing: Is This How We Will Dx Parkinson’s?
- Will PET Tracer, Monkey Model, Finally Bulk Up Toolbox for Parkinson’s?
- Consortia Assemble Worldwide to Take on Lewy Body Dementia
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