Abstract
BackgroundPlasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects.MethodsTwenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics.ResultsStatistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping.ConclusionWe conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases—possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.
Highlights
Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD)
The subjects had a mean age of 73.6 years (± 6.1), mean Mini-Mental State Examination (MMSE) score of 25.9 (± 3.0), and a mean plasma NfL level of 27.9 pg/mL (± 10.7)
No correlations were detected between MMSE ratings and plasma NfL levels (ρ = − 0.057, P = 0.78) or cortical PK11195 binding, or between CDRSOB scores and plasma NfL levels (ρ = 0.257, P = 0.20) or PK11195 binding
Summary
Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects. Methods: Twenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Patients with amyotrophic lateral sclerosis where pyramidal tract involvement is present show greatly raised CSF NfL levels, while those with only peripheral motor neuron disease (progressive muscular atrophy) show smaller elevations [2, 3]. No relationship was found between cognitive status and CSF NfL levels in AD patients, though disability of Huntington’s disease cases, when rated with the UHDRS, correlated with CSF NfL levels [6]
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