Rate of memory decline is associated with neuronal nuclear protein (NeuN) positive cells count in middle temporal gyrus in the Adult Changes in Thought (ACT) autopsy cohort

Abstract

AbstractBackgroundThe trace of memory has not been well studied in middle temporal gyrus (MTG). Although neuronal loss is minimal in most cortical regions of the aging brain, changes in synaptic physiology of ageing neurons may contribute to altered connectivity. In the Adult Changes in Thought (ACT) autopsy cohort, we explored if memory decline is associated with NeuN (neuronal nuclear protein), a biomarker for mature neurons, in MTG.MethodACT study participants were 5,763 older adults randomly sampled from an integrated healthcare delivery system in King County, Washington. We standardized composite memory scores to N(0,1) at baseline. We calculated slopes of memory decline over time using mixed‐effects models, where time was parameterized as years before death.Among 69 individuals who underwent brain autopsy, we measured NeuN positive cell count from whole slide image analysis using HALO in five tissue layers (molecular, external granular, external pyramidal, internal granular, internal pyramidal + multiform) from brain tissue in MTG. In each layer, we normalized NeuN positive cell count over the tissue area. We derived an average NeuN positive cell count (ANPCC) by averaging the values across the layers (Figure 1).We regressed ANPCC on memory slope, adjusting for age at death and sex. In secondary models, we added disease severity (Braak staging) and presence of APOE ε4 alleles separately. We also analyzed layer‐specific ANPCC.Result64 individuals were included for analysis (Table 1).Memory decline in this sample was 0.10 units per year, similar to the entire cohort. Slower decline in memory (β = 0.10; p‐value = 0.002) was significantly associated with increased average ANPCC (Table 2). Adjusting for Braak staging and APOE ε4 gave similar results. Findings were statistically significant across all but the molecular layer.ConclusionANPCC is associated with slower memory decline in multiple neocortical layers in MTG, irrespective of disease staging or APOE genotype. Since Alzheimer’s disease afflicts adult neuronal populations, survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Further analyses are needed to understand the functional range of NeuN and processes that lead to loss of NeuN immunoreactivity in cells.