SAN DIEGO—In patients with Lewy body disease, CSF biomarkers may predict the extent of Alzheimer’s disease pathology, according to a new postmortem analysis presented at the 142nd Annual Meeting of the American Neurological Association.
In the small, prospective study, David Irwin, MD, Assistant Professor of Neurology at the University of Pennsylvania in Philadelphia, and colleagues found that higher antemortem CSF levels of total tau protein and lower amyloid beta1–42 levels were associated with postmortem evidence of cerebral Alzheimer’s disease and synuclein pathology. The connection between CSF amyloid beta1–42 and tau protein had been shown in Alzheimer’s disease, but not in Lewy body disease.
David Irwin, MD
The findings could have prognostic implications, because about 40% of patients with Lewy body disease have enough amyloid beta1–42 and tau tangle pathology to have a secondary diagnosis of Alzheimer’s disease, and greater Alzheimer’s disease pathology has been linked to shorter survival. The results also could help individualize therapy, because patients with Lewy body disease and Alzheimer’s disease characteristics might respond better to antisynuclein and Alzheimer’s disease therapies, according to Dr. Irwin.
The CSF ratio of total tau to amyloid beta1–42 predicted the presence or absence of Alzheimer’s disease pathology with 90% sensitivity and 100% specificity.
If the results are confirmed, “we can identify who has Alzheimer’s copathology and who has a more aggressive form of Lewy body disease where it is reaching the cortex rather than being in the brainstem, and that correlates with memory loss, dementia, and other things that impair the patient’s functioning,” said Dr. Irwin.
The Udall Center for Parkinson’s Research at the University of Pennsylvania has an active autopsy program, and a significant number of patients with Parkinson’s disease donated their brains for research. “It is rare to have autopsy-confirmed samples where we can validate what we are measuring in the spinal fluid to what is actually accumulating in the brain,” Dr. Irwin said.
The study included 24 patients with autopsy-confirmed Lewy body disease who had undergone CSF testing during life. The researchers calculated ordinal pathology scores of tau tangles, amyloid beta1–42 plaques, and alpha-synuclein pathology in seven regions of the brain, producing a global pathology score for each variable. The subjects were then categorized into a group of participants with Lewy body synuclein stages and medium to high Alzheimer’s copathology (SYN+AD, n = 10) and a group with little or no Alzheimer’s copathology (SYN−AD, n = 14).
The researchers analyzed potential associations involving total tau, phosphorylated tau, and amyloid beta1–42. They found that amyloid beta1–42 levels were significantly different between SYN+AD and SYN−AD patients (147.2 pg/mL vs 231.1 pg/mL, respectively), as were CSF total tau levels (63.9 pg/mL vs 36.9 pg/mL). Phosphorylated tau was not significantly different between groups (20.2 pg/mL vs 15.5 pg/mL), which surprised the researchers, since it “is usually the strongest correlate of tangles in the brain,” said Dr. Irwin.
A ratio of CSF total tau to amyloid beta1–42 higher than 0.30 distinguished between SYN+AD and SYN−AD (area under the curve [AUC], 0.92; 90% sensitivity; 100% specificity), while CSF amyloid beta1–42 less than 185 pg/mL identified the neocortical synuclein stage (AUC, 0.92; 77% sensitivity; 82% specificity).
—Jim Kling