Search

BackgroundCentral nervous system levels of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, regulate the neuroinflammatory response and may play a role in age-related neurodegenerative diseases. The longitudinal relation between peripheral levels of TNF-α and typical brain aging is understudied. We hypothesized that within-person increases in systemic TNF-α would track with poorer brain health outcomes in functionally normal adults.MethodsPlasma-based TNF-α concentrations (pg/mL; fasting morning draws) and magnetic resonance imaging were acquired in 424 functionally intact adults (mean age = 71) followed annually for up to 8.4 years (mean follow-up = 2.2 years). Brain outcomes included total gray matter volume and white matter hyperintensities. Cognitive outcomes included composites of memory, executive functioning, and processing speed, as well as Mini-Mental State Examination total scores. Longitudinal mixed-effects models were used, controlling for age, sex, education, and total intracranial volume, as appropriate.ResultsTNF-α concentrations significantly increased over time (p < .001). Linear increases in within-person TNF-α were longitudinally associated with declines in gray matter volume (p < .001) and increases in white matter hyperintensities (p = .003). Exploratory analyses suggested that the relation between TNF-α and gray matter volume was curvilinear (TNF-α 2p = .002), such that initial increases in inflammation were associated with more precipitous atrophy. There was a negative linear relationship of within-person changes in TNF-α to Mini-Mental State Examination scores over time (p = .036) but not the cognitive composites (all ps >.05).ConclusionSystemic inflammation, as indexed by plasma TNF-α, holds potential as a biomarker for age-related declines in brain health.

Cerebral perfusion declines across the lifespan and is altered in the early stages of several age-related neuropathologies. Little is known, however, about the longitudinal evolution of perfusion in healthy older adults, particularly when perfusion is quantified using magnetic resonance imaging with arterial spin labeling (ASL). The objective was to characterize longitudinal perfusion in typically aging adults and elucidate associations with cognition and brain structure. Adults who were functionally intact at baseline (n = 161, ages 47-89) underwent ASL imaging to quantify whole-brain gray matter perfusion; a subset (n = 136) had repeated imaging (average follow-up: 2.3 years). Neuropsychological testing at each visit was summarized into executive function, memory, and processing speed composites. Global gray matter volume, white matter microstructure (mean diffusivity), and white matter hyperintensities were also quantified. We assessed baseline associations among perfusion, cognition, and brain structure using linear regression, and longitudinal relationships using linear mixed effects models. Greater baseline perfusion, particularly in the left dorsolateral prefrontal cortex and right thalamus, was associated with better executive functions. Greater whole-brain perfusion loss was associated with worsening brain structure and declining processing speed. This study helps validate noninvasive MRI-based perfusion imaging and underscores the importance of cerebral blood flow in cognitive aging.

Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. Sixty-nine functionally normal older adults (mean age = 71.7) were assessed at 2 time points (mean interval = 2.9 years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD (b = -0.01, p = 0.06), but no other cross-sectional associations were significant (ps > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss (b = 27.09, p < 0.001), even after controlling for global volume loss (b = 10.83, p = 0.002). Greater telomere attrition was also associated with larger increases in fornix MD (b = -0.01, p = 0.012) and decreases in fornix fractional anisotropy (b = 0.004, p = 0.002). TL was not associated with changes in episodic memory (ps > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation.

Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. Sixty-nine functionally normal older adults (mean age = 71.7) were assessed at 2 time points (mean interval = 2.9 years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD ( b = −0.01, p = 0.06), but no other cross-sectional associations were significant ( p s > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss ( b = 27.09, p < 0.001), even after controlling for global volume loss ( b = 10.83, p = 0.002). Greater telomere attrition was also associated with larger increases in fornix MD ( b = −0.01, p = 0.012) and decreases in fornix fractional anisotropy ( b = 0.004, p = 0.002). TL was not associated with changes in episodic memory ( p s > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation. [ABSTRACT FROM AUTHOR]