New study links brain cell structure to memory loss in aging and dementia

In a recently published study, Scientific advancesThe researchers assessed whether dendritic spine diameter in the temporal cortex was a better predictor of episodic memory performance in older adults than synaptic volume, taking into account beta-amyloid (Aβ) plaques (clumps of protein fragments in the brain), neurofibrillary tangles (NFTs) (twisted protein fibers in brain cells), and gender.

background

Episodic memory, essential for recalling personal experiences, declines with age and with neurodegenerative diseases, especially damage to the temporal cortex. Dendritic spines, a key postsynaptic compartment in the brain, affect synaptic strength and are important for memory. Spine loss occurs naturally with age, especially in areas essential for memory, and is more strongly associated with memory impairment in Alzheimer's disease (AD) (a progressive brain disorder that causes memory loss) than Aβ plaques or NFTs.

Further studies are required to clarify how specific features of dendritic spines contribute to memory function with age, beyond the effects of natural spine loss and general neurodegenerative pathologies.

About the Research

Postmortem samples from Brodmann brain areas (BA) 6 and BA 37 were taken from participants in the Religious Organizations Study and the Rush Memory and Aging Project (ROSMAP), which includes individuals without known dementia who enrolled and consented to annual clinical evaluations and brain donation at death.

This study was approved by the Institutional Review Board at Rush University Medical Center. All participants provided informed consent, including brain donation and resource sharing. Samples analyzed in this study encompassed a range of brain pathologies and cognitive scores, and adequately sized frozen tissue samples were available for the experiments.

Cognitive testing of ROSMAP participants included assessments of episodic memory, perceptual speed, visuospatial ability, semantic memory, and working memory, with composite scores calculated for each domain. In addition, the Mini-Mental State Examination (MMSE) was administered and a clinical diagnosis of major depressive disorder was made based on established criteria.

Brain samples from BA6 and BA37 were Golgi-Cox stained to visualize dendritic spines and synaptic markers. Dendrite imaging was performed by a blinded experimenter using a high-magnification bright-field microscope. Dendritic segments fulfilling certain criteria were selected for analysis, and 3D digital reconstruction of dendrites and spines was performed using dedicated software. Spine morphology was classified into different categories, and quantitative measurements were collected and analyzed. In total, 45,763 μm of dendritic length from 2,157 neurons was analyzed, yielding data for 55,521 individual spines.

Statistical analysis included a multi-stage approach to verify the generalizability of the results. Dendritic spine features were analyzed using Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify features that contribute most significantly to episodic memory performance in older adults. Cross-validation techniques ensured model accuracy, and results were replicated in independent samples. Spearman correlation was used to explore the relationship between dendritic spine features, pathology, and memory scores, and multiple comparisons were controlled to use an appropriate false discovery rate.

Research findings

Dendritic spines were harvested and analyzed from the frontal and temporal lobes of 128 individuals from ROSMAP. These postmortem samples were taken from BA6 within the premotor cortex and BA37 within the temporal lobe. Participants, with a mean age of 90.53 ± 6.06 years, presented with a range of cognitive performance scores and levels of AD-related neuropathology. Using brightfield microscopy, dendritic spine density and morphology in BA37 and BA6 tissue sections were imaged at 60x magnification and reconstructed in three dimensions. The data were then analyzed to determine the relationship between dendritic spine characteristics and episodic memory performance.

The BA37 and BA6 datasets were subjected to a supervised learning algorithm to identify specific dendritic spine features that may predict episodic memory performance beyond the influence of other variables such as AD-related neuropathology. Samples were split into a discovery set (n = 63) and a validation set (n = 62), with three cases excluded due to missing data. LASSO regression was performed on the discovery set to identify dendritic spine features most strongly associated with episodic memory function. Analysis revealed that BA37 spine head diameter was the most significant predictor of episodic memory performance.

Results were validated using nested model cross-validation on the replication set, confirming that a model including spine head diameter, NFTs, neurite Aβ plaques, and gender provided the best prediction of episodic memory. Removing spine length, density, and volume from the model further improved accuracy, highlighting the importance of temporal cortical spine head diameter in memory function.

Conversely, LASSO regression on the BA6 dataset identified spine length as the strongest predictor of episodic memory performance, although the association was weaker compared to BA37 spine head diameter. Models incorporating BA6 spine features did not perform as well, indicating that the contribution of spine head diameter to memory performance is specific to BA37 temporal cortex.

Further analyses revealed a significant positive correlation between BA37 spine head diameter and episodic memory scores, even after controlling for multiple comparisons. In contrast, BA37 spine density was not significantly correlated with cognitive scores or AD-related pathology, and no significant correlations were found between BA6 spine features and measures of cognition or pathology.

Conclusion

In summary, analyses using tissue samples from 128 ROSMAP participants revealed that larger dendritic spine head diameter in the temporal cortex was associated with improved episodic memory performance, while spine density had no significant effect. These findings suggest that synaptic strength, rather than synapse number, is important for memory maintenance in older adults, with implications for targeted therapeutic strategies in preclinical AD.