DIMENSIONS Spring 2011

Focus on Research: Confronting a Century of Lewy Body Confusion

by James Leverenz, MD and Andrew David

photo micrograph of Lewy body within a brain cell

In 1912, a young scientist working in the University of Munich Department of Psychiatry made a discovery that would simultaneously transform our understanding of dementia and lead to great confusion among patients, family members, and even medical professionals.

While working in the lab of Aloysius ("Alois") Alzheimer — the scientist who is immortalized in the lexicon of human disease for his manuscript describing the first recorded case of Alzheimer's disease — F. H. Lewy observed several unique abnormalities in the brain cells of people with Parkinson's disease.

Then, seven years later, Konstantin Trétiakoff, a Russian scientist working in Paris, bumped up against these brain abnormalities in his own research and referred to them as Lewy bodies in honor of Dr. Lewy's original discovery. However, even then there was confusion about how these Lewy bodies worked in the brain — Dr. Lewy thought the Lewy bodies congregated in a brain area known as the pallidum and that this was the site of parkinsonism in the brain, whereas Dr. Trétiakoff thought that the substantia nigra was the main brain area affected by parkinsonism.

It turns out that Dr. Trétiakoff was right, but there's still a lot of confusion around these brain abnormalities. So what do we know for sure about these Lewy bodies? For starters, Lewy bodies can only be observed in the brain cells of patients who have died and undergone brain autopsy. In terms of their appearance, Lewy bodies are too small to see with the naked eye, but through the lens of a microscope, they typically appear as round blotches of color surrounded by a halo of a lighter color (see photo). We also have learned that Lewy bodies are a buildup of a protein called alpha-synuclein, though the reason that these protein aggregations form in some brain cells and not others is still unclear and a matter of ongoing research.

photo of scientists in Alzheimer's lab

Today, the confusion about Lewy bodies is often associated with how exactly they relate to particular forms of dementia. Scientists bandy about all kinds of names for Lewy body dementias. They speak of "dementia with Lewy bodies," "diffuse Lewy body disease," "Lewy body variant Alzheimer's disease," and "Parkinson's disease dementia," to name a few. But even the clinicians who care for people with Lewy body dementias and the researchers who attempt to find new treatments for these disorders are sometimes a bit perplexed by the multitude of names and disorders.

Part of the reason for this confusion stems from the fact that Lewy bodies are found in the brain cells of multiple clinical disorders. When Dr. Lewy and his colleagues first studied these brain abnormalities, they only examined the associations between Lewy bodies and the movement disorder Parkinson's disease. However, in the 1960s, Japanese investigators discovered Lewy bodies in the brain cells of deceased patients with dementia but no Parkinson's disease. The Lewy bodies in these patients were found in multiple brain regions and hence their illnesses were referred to as "diffuse Lewy body disease." To complicate matters further, investigators in the 1980s noted that up to half of the patients with Alzheimer's disease also had Lewy bodies in their brain cells at autopsy; these patients came to be referred to as patients who had suffered from the "Lewy body variant of Alzheimer's disease." Finally, it is increasingly clear that the majority of patients with Parkinson's disease also develop dementia later in their disease, and thus we have the term "Parkinson's disease dementia." Unfortunately, it is still unclear whether all of these disorders that are associated with dementia and Lewy bodies are entirely separate diseases, an overlap of multiple diseases, or all the same disease.

photo of Dr. F.H. Lewy

During the last fifteen years, investigators have tried to clarify the terms used for the various Lewy body disorders as a way of making sure that everyone is talking about the same thing when we speak of specific Lewy body disorders. We have also attempted to use terms that more precisely connect the world of clinical care to the world of research, especially research that involves autopsy findings like Lewy bodies. To this end, terms like "diffuse Lewy body disease," which lack a clear catalog of clinical symptoms, are being used less frequently than terms like "dementia with Lewy bodies," which relate to a specific clinical profiles. For example, "dementia with Lewy bodies" is accepted as the way to describe patients whose earliest symptoms include a decline in thinking abilities (which is often accompanied by visual hallucinations and a sleep problem called REM sleep behavior disorder) and who later develop such Parkinson's disease symptoms as tremor, increased muscle tone, slowness of movements, and gait problems. When the brains of these patients are examined, they show clear signs of Lewy body brain cell changes and, over half the time, brain cell changes that are characteristic of Alzheimer's disease (or the "Lewy body variant of Alzheimer's disease"). Conversely, patients whose difficulties begin with the motor symptoms of Parkinson's disease and only develop dementia later in their illness are identified as having "Parkinson's disease dementia." Like the dementia with Lewy bodies patients, these patients also typically show evidence of Lewy bodies at autopsy, but only a small number of these individuals have significant changes that are associated with Alzheimer's disease.

Given that up to half of Alzheimer's disease patients have the "Lewy body variant" and that most Parkinson's disease patients develop dementia, we can estimate that 1 to 2 million Americans have one form or another of the Lewy body dementias. As our society ages, this number will only continue to increase. And so, F. H. Lewy's century-old discovery is an important one—one that we must do our best to understand and learn to prevent.

So where do we go from here? Researchers at both the UW ADRC and the recently funded Pacific Northwest Udall Center (PANUC) have begun a series of studies that examine the Lewy body dementias. Researchers at these centers are interested in learning about the effects of these diseases on how patients move and think. They are also interested in determining what changes occur in the brain when patients encounter particular problems or stresses. These studies of Lewy body dementias examine brain changes using advanced brain imaging techniques, cutting-edge methods of measuring brain chemicals in blood and cerebrospinal fluid, and sophisticated genetics practices. We anticipate that by applying these techniques we might further dispel the confusion surrounding Lewy bodies and arrive at a better understanding of how these Lewy body dementias affect the brain. From this knowledge, we hope to develop better treatments for the devastating symptoms of dementia and, one day, to develop a cure.


Top of Page | Next Story | Spring 2011 Index