Temporal course of neurodegenerative effects on cognition in old age

Abstract

Objective: To test the hypothesis that different forms of neurodegeneration are differentially related to longitudinal cognitive trajectories in old age.

Methods: Participants are 420 older persons from 2 clinical-pathologic studies without cognitive impairment at study onset. They completed a battery of 17 cognitive tests annually for a minimum of 5 years, died, and underwent a neuropathologic examination to quantify neuronal neurofibrillary tangles and transactive response DNA-binding protein 43 (TDP-43) pathology and to identify Lewy bodies and hippocampal sclerosis. The authors used sigmoid mixed models based on the 4-parameter logistic distribution to decompose nonlinear global cognitive trajectories into components and assess the relation of each neuropathologic marker to each trajectory component.

Results: Cognitive function was assessed for a mean of 10.5 years before death. In the absence of pathology, global cognition was relatively stable before declining moderately in the last 3 to 4 years of life. Tangles were related to all trajectory components except initial level. TDP-43 pathology was the only marker related to initial level of function. It was also associated with an earlier midpoint of decline but not to slope of decline. Hippocampal sclerosis was related to an earlier midpoint of decline and more rapid slope of decline. Lewy bodies were associated with faster slope of decline and lower level of function proximate to death.

Conclusion: Neurodegenerative processes are differentially related to cognitive trajectories, with TDP-43 pathology most potently impacting incipient cognitive decline, AD pathology and hippocampal sclerosis affecting the progression of cognitive decline, and Lewy bodies impacting terminal decline. (PsycINFO Database Record

Figure 1

Illustration of how a shift in one parameter impacts the trajectory of change in the standardized composite measure of global cognition estimated in the sigmoid mixed model: initial level (upper left, θ₁=−1, θ₂=2.5, θ₃=1, θ₄= 0.6, 0.7 and 0.9), midpoint of decline (upper right, θ₁=−1, θ₂=2, 3 and 4, θ₃=3, θ₄= 0.7), slope (lower left, θ₁=−1, θ₂=1, θ₃=1, 2 and 3, θ₄= 0.7), final level (lower right, θ₁=−0.3, 0, 0.3, θ₂=2.5, θ₃=1, θ₄=1).

Figure 2

Trajectories of change in the standardized composite measure of global cognition associated with no pathology (blue line), tangles only (orange line), TDP-43 pathology only (green line), hippocampal sclerosis only (gray line), or Lewy bodies only (black line), from a sigmoid mixed model adjusted for age at death, sex, and education.

Figure 3

Trajectories of change in the standardized composite measure of global cognition associated with different levels of tangles (upper panel) and TDP-43 pathology (lower panel) from sigmoid mixed models adjusted for age at death, sex, and education.

Figure 4

Trajectories of change in the standardized composite measure of global cognition associated with no pathology (blue solid line), TDP-43 pathology only (green solid line), TDP-43 pathology and tangles (purple dashed line), TDP-43 pathology and hippocampal sclerosis (black dashed line), and TDP-43 pathology and Lewy bodies (gray dashed line), from a sigmoid mixed model adjusted for age at death, sex, and education.

Figure 5

Trajectories of change in the standardized composite measure of global cognition associated with no pathology (blue solid line); TDP-43 pathology, tangles, and hippocampal sclerosis (pink dotted line); TDP-43 pathology, tangles, and Lewy bodies (red dotted line); and TDP-43 pathology, tangles, hippocampal sclerosis, and Lewy bodies (yellow dashed line), from a sigmoid mixed model adjusted for age at death, sex, and education.