Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying ß-amyloid pathology.

ß-Amyloid pathology is elevated in ~30% of cognitively normal people over 65, and is associated with accelerated neurodegeneration in the pre-clinical stages of Alzheimer's disease. Recent findings reveal that brain iron might also act to propel neurodegeneration in people with underlying amyloid pathology. Here, repeated PET scans of fluorodeoxyglucose (FDG) were used as a biomarker for brain hypometabolism and a downstream biomarker of neurodegeneration to investigate whether levels of ferritin in the cerebrospinal fluid (CSF; a reporter of brain iron load) are associated with prodromal disease progression of people with high ß-amyloid pathology determined by established cut-off values in CSF t-tau/Aß42 ratio. Nineteen cognitively normal participants with low t-tau/Aß42, and 71 participants with high t-tau/Aß42 who were cognitively normal or had mild cognitive impairment were included as participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. These subjects had repeated FDG-PET scans at 6-month intervals for 2 years, and yearly intervals for up to a further 3 years. In mixed-effects linear models of FDG signal, baseline CSF ferritin was associated with an accelerated decline in FDG PET in high t-tau/Aß42 participants (ß[SE] = -0.066 [0.017]; P = .0002), but not in people with low t-tau/Aß42 (-0.029 [0.049]; P = .554). These data implicate iron as a contributing factor to neurodegeneration associated with ß-amyloid pathology, and highlight CSF ferritin as a complementary prognostic biomarker to the t-tau/Aß42 ratio that predicts near-term risk for disease progression.

Cerebral quantitative susceptibility mapping predicts amyloid-ß-related cognitive decline.

See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-ß by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-ß to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-ß load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-ß positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [ß(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [ß(standard error) = -0.139 (0.048), P = 0.004), and attention [ß(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [ß(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [ß(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-ß to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-ß positron emission tomography to stratify individuals at risk of decline.