High magnification photomicrographs of a tau tangle (left) and an alpha-synuclein Lewy body (right)
PHILADELPHIA – Patients who had a diagnosis of Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB) and had higher levels of Alzheimer’s disease (AD) pathology in their donated post-mortem brains also had more severe symptoms of these Lewy body diseases (LBD) during their lives, compared to those whose brains had less AD pathology, according to research from the Perelman School of Medicine at the University of Pennsylvania
. In particular, the degree of abnormal tau protein aggregations, indicative of AD, most strongly matched the clinical course of the LBD patients who showed evidence of dementia prior to their deaths, the team reports in The Lancet Neurology
First Online, ahead of the January print edition.
The team used post-mortem brain tissue donated by 213 patients with LBD and associated dementia, which was confirmed during autopsies to have alpha-synuclein pathology. They paired the tissue analysis with the patients’ detailed medical records. This unique study combined data from eight academic memory or movement disorder centers, including the Penn Alzheimer’s Disease Core Center (ADCC) and the Udall Center for Parkinson’s Disease Research.
LBD is a family of related brain disorders made up of the clinical syndromes of PD, without or with dementia or DLB. LBD is associated with clumps of misshapened alpha-synuclein proteins. On the other hand, AD pathology is made up of clusters of the protein beta-amyloid called plaques and twisted strands of the protein tau, called tangles. Patients with LBD may have varying amounts of AD pathology, in addition to alpha-synuclein pathology.
Treatments directed at tau and amyloid-beta proteins are currently being tested in patients with Alzheimer’s disease. This study could help in selecting appropriate patients for trials of emerging therapies targeting these proteins singly or in combination with emerging therapies targeting alpha-synuclein protein in LBD.
The study, led by David Irwin, MD, an assistant professor of Neurology at Penn and an attending cognitive neurologist in the Penn Frontotemporal Degeneration Center and the Center for Neurodegenerative Disease Research, suggests that Lewy body pathology is the primary driver of disease seen in the patients; whereas, AD pathology has an impact on the overall course of disease.
“We are excited with the results of this collaborative study that points to tau as a major correlate of dementia since therapies targeting tau in AD are advancing and they could be as relevant to AD as to LBD with co-occurring AD-like tau pathology.” Irwin said. “In addition, clinical trials for other synuclein-related brain disorders may be improved by taking into account biomarkers of AD pathology.”
“This study is important for many reasons, not the least of which it illustrates the power of research that harnesses the resources of all of these collaborating centers,” said senior author John Q. Trojanowski, MD, PhD, director of the Penn ADCC and Udall Center and a professor of Pathology and Laboratory Medicine.
None of the LBD patients had a clinical diagnosis of AD, but their post-mortem brain tissue revealed varying amounts of AD neuropathology. Post-mortem analysis of five brain regions per patient showed that they fell into one of four categories of AD pathology: 23 percent negligible or no AD, 26 percent had low-level, 21 percent intermediate, and 30 percent had high-level.
Increasing severity of AD pathology correlated with a shortened time from motor symptoms to the onset of dementia and death, with the most significant trends seen in the intermediate- and high-level AD groups compared to the low-level and no AD groups. Tau pathology, in particular, was the strongest predictor of a shorter time to dementia and death. AD pathology was also higher in patients who were older at the time of onset of motor symptoms and dementia.
“We found that patients with a higher burden of Alzheimer’s pathology also had a higher burden of alpha-synuclein pathology in their brain,” Irwin said. “From this, we inferred a potential synergism between the deleterious processes in AD and DLB.” Trojanowski added there is experimental evidence for synergies between these pathologies in animal models.
The team also found that two relevant genetic variants in sequences of the patients’ DNA samples correlated with the amount of AD pathology. The frequency of a genetic variant in a gene coding for a protein involved in cholesterol metabolism (APOE, the most common risk factor for AD) was more frequent in patients who were in the intermediate or high AD pathology group compared to those in the low-level or no AD group. Interestingly, a variation in the gene for the protein GBA (a risk factor for LBD) was more frequent in patients without significant AD pathology. This gene is associated with LBD overall but not the subgroup with AD pathology.
In the brain, the enzyme GBA normally aids in the breakdown of worn out and misshapened proteins, such as alpha-synuclein. Together these findings suggest that genetic risk factors could influence the amount of AD pathology in LBD. Further understanding of the relationships between genetic risk factors and AD and alpha-synuclein pathology will help improve treatments for these disorders.
In the near future, using both post-mortem brain tissue and imaging in living patients, researchers in the Udall Center and ADCC will study how declines in cognitive ability relate to AD pathology in LBD. They hope this collaborative approach will help improve the diagnosis of these co-occurring indicators as early as possible in living patients.
This study was funded by the National Institutes of Health (K23 NS088341, P50 NS053488, P30 AG010124, P50 AG005133, P30 AG028383,P30 AG008017, P50 NS062684, P50 AG005136, P50 NS062684, R01 NS48595, U01 AG006781, R01 NS065070), as well as the Veterans Affairs Geriatric Research Education and the Clinical Center at the VA Puget Sound Health Care System.
Other coauthors are Murray Grossman, Daniel Weintraub, Howard I. Hurtig, John E Duda, Sharon X. Xie, Edward B. Lee, Vivianna M. Van Deerlin, Oscar L. Lopez, Julia K. Kofler, Peter T. Nelson, Gregory A. Jicha, Randy Woltjer, Joseph F. Quinn, Jeffery Kaye, James B. Leverenz, Debby Tsuang, Katelan Longfellow, Dora Yearout, Walter Kukull, C. Dirk Keene, Thomas J. Montine, and Cyrus P. Zabetian.