Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis

Abstract

While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's disease (AD) pathology. Tau and Aβ pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Aβ pathology in limbic and most cortical regions. Tau and Aβ pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE.

Fig. 1

Semiquantitative staging of pathology in ALS. The figure illustrates the semiquantitative staging used to grade the extent of microglial activation (CD68, Ibal, images taken with ×40 objective, scale bar 100 μm), neuronal loss (NL, images taken with ×10, and TDP-43 pathology (images taken with ×40 objective)

Fig. 2

Subtypes of pathology in ALS. Anatomical heal map shows extern of TDP-43 pathology (a), neuronal loss (b), tau pathology (c). and Aβ pathology (d) in different regions of the central nervous system in ALS

Fig. 3

Microglial pathology in ALS. Bar plot shows microglial activation in the cortex and White matter Of different regions of the central nervous system of ALS as delected by staining for CD68 (a) and Ibal (b). Whiskers in bar plot indicate 95% confidence interval of mean. Amyg amygdala, CSC cervical spinal cord. Hipp hippocampus (CA1, subiculum), MF middle frontal gyrus, Mot motor conex, NL neuronal loss. SMT superior or middle temporal gyrus

Fig. 4

Pathology in ALS with and without dementia. Bar plots show extent of microglial activation (a, b), TDP-43 pathology (c), and neuronal loss (d) in ALS patients with (ALS-D) and without dementia (ALS-nD). Whiskers in bar plot indicate 95% confidence interval of the mean

Fig. 5

Pathology in ALS with and without impaired executive function. Bar plots shows extent of micgroglial activation (a, b), TDP-43 pathology (c), and neuronal loss (d) in ALS patients with and without impairment of executive function. Whiskers in bar plot indicate 95% confidence interval of the mean. Impairment of executive function was defined by scores below the median in both F-words test and Oral Trail Making Test

Fig. 6

Microglial activation in ALS with impairment of executive function. Images illustrate microglial aclivalion as seen by staining for CD68 and Iba I in the middle frontal gyrus of exemplary cases of ALS with (b, c, e, f) and without (a, d) impairment of executive function. Images a, b, d, and e taken wilh ×20 objective, scale bar 200μm. Images c and f show higher resolution (×60) of activated microglial cells

Fig. 7

Pathology in ALS related to MMSB. Bar plots Shaw extern of tau (a) and Aβ putholugy (b), as well as ncuronal loss (c), microglial activation (d, e) and TDP-43 patholopy (f) in ALS patients with MMSE above or equal to the median (MMSE high) and MMSE below the median (MMSE low). Whiskers in bar plot indicate 95% confidence Interval of the mean