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
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
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
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
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.