From a recent study published in Scientific progressa group of researchers assessed whether the head diameter of the dendritic spine in the temporal cortex is a better predictor of episodic memory performance in older adults than the amount of synapses, responsible for β-amyloid (Aβ) plaques (clusters of protein fragments in the brain), neurofibrillary tangles (NFTs) (twisted protein fibers in brain cells) and sex.
Background
Episodic memory, essential for remembering personal experiences, declines with age and with neurodegenerative diseases, especially due to injury to the temporal cortex. Dendritic spines, important postsynaptic compartments in the brain, influence synapse strength and are crucial for memory. Spinal loss occurs naturally with aging, especially in areas vital to 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 research is needed to clarify how specific features of dendritic spines contribute to memory function in aging, beyond the effects of natural spine loss and common neurodegenerative pathologies.
About the study
Postmortem samples of the brain areas Brodmann area (BA) 6 and BA37 were obtained from participants in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), which includes individuals who enroll without known dementia and who agree to annual clinical evaluations and brain donation upon death.
The study was approved by an institutional review board at Rush University Medical Center. All participants gave informed consent, including consent for brain donation and sharing of their resources. The samples analyzed in this study included a range of brain pathologies and cognitive scores, with appropriately sized frozen tissue samples available for experimentation.
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 clinical diagnoses of major depressive disorder were made based on established criteria.
Dendritic spines and synaptic markers were visualized using Golgi-Cox staining of brain samples from BA6 and BA37. Imaging of dendrites was performed by a blinded investigator using bright-field microscopy at high magnification. Dendritic segments that met specific criteria were selected for analysis, and 3D digital reconstructions of dendrites and spines were performed using specialized software. Spinal morphology was classified into different categories and quantitative measurements were collected for analysis. A total of 45,763 μm of dendrite length from 2,157 neurons was analyzed, yielding data on 55,521 individual spines.
Statistical analyzes included a multi-stage approach to validate the generalizability of the results. Dendritic spine features were analyzed using Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify which features contributed most significantly to episodic memory performance in older adults. Cross-validation techniques ensured model accuracy and results were replicated in an independent sample. Spearman correlations were used to examine relationships between dendritic spine features, pathology, and memory scores, with multiple comparisons checked for use of an appropriate false discovery rate.
Study results
Dendritic spines were sampled and analyzed from the frontal and temporal cortex of 128 individuals from the ROSMAP. These postmortem samples were taken from BA6 in the premotor cortex and BA37 in the temporal cortex. The participants, who had a mean age of 90.53 ± 6.06 years, showed varying cognitive performance scores and levels of AD-related neuropathology. Using bright-field 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 could predict episodic memory performance above and beyond the effects of other variables, such as AD-related neuropathology. The samples were divided 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 the dendritic spine features most strongly associated with episodic memory function. The analysis found that spinal head diameter in BA37 was the most important predictor of episodic memory performance.
Results were validated using nested cross-validation of models in the replication set, which confirmed that models including spinal head diameter, together with NFTs, neuritic Aβ plaques, and sex, provided the best prediction of episodic memory. Removing spinal length, density and volume from the model further improved its accuracy, highlighting the importance of spinal head diameter in the temporal cortex for memory function.
Conversely, LASSO regression on the BA6 dataset identified spinal length as the strongest predictor of episodic memory performance, although the association was weaker compared to BA37 spinal head diameter. Models that included features of the BA6 spine did not perform as well, indicating that the contribution of spine diameter to memory performance is specific to the BA37 temporal cortex.
Further analysis showed a significant positive correlation between BA37 spinal head diameter and episodic memory score, even after controlling for multiple comparisons. In contrast, BA37 spine density did not significantly correlate with cognitive scores or AD-related pathology, and no significant correlations were found between BA6 spine features and cognition or pathology measures.
Conclusions
In summary, using tissue samples from 128 ROSMAP participants, the analysis revealed that larger dendritic spine head diameters in the temporal cortex were associated with better episodic memory performance, while spine density showed no significant effect. These findings suggest that synaptic strength, and not the number of synapses, is critical for memory maintenance in older adults, with implications for targeted therapeutic strategies in preclinical AD.