Greater hippocampal volume is not always a reliable predictor of learning and memory ability in older adults


When it comes to certain parts of the brain, bigger doesn’t necessarily equate to better memory.

According to a new study led by Michigan State University, a larger hippocampus, a curved, seahorse-shaped structure embedded deep in the brain, does not always reliably predict learning and memory abilities in older adults.

It’s normal for the hippocampus to shrink as we age, but it’s much more pronounced in people with mild cognitive impairment or Alzheimer’s disease. Scientists long believed that a bigger hippocampus meant a better memory until a 2004 study showed that its size does not always matter for memory in older adults. But scientists are only now starting to understand why.

This latest study published online in the journal Cerebral Cortex shows the size or volume of the hippocampus is only a meaningful marker of learning for older people with more intact limbic white matter – the neural circuitry that connects the hippocampus to the rest of the brain.

“Our findings highlight the need to measure not just the size of the hippocampus but also how well it’s connected to the rest of the brain when we look for physical markers of memory decline in older adults,” said Andrew Bender, lead author on the study and assistant professor of epidemiology and biostatistics, and neurology and ophthalmology at MSU’s College of Human Medicine.

The study has potential implications for earlier diagnosis of aging-related memory disorders such as Alzheimer’s disease. Some older adults whose brain scans show a larger hippocampus – perhaps due to high levels of education, physical activity, or social and cognitive engagement – could have their cognitive decline overlooked or mischaracterized if physicians do not also consider their white matter connectivity.

Bender, and colleagues at Harvard University, the Hungarian Academy of Sciences and the Max Planck Institute for Human Development, analyzed two different types of MRI brain scans: one that evaluated hippocampal size and another that evaluated the white matter circuitry that connects the hippocampus with other brain regions involved in learning. The scans came from more than 330 older adults who are part of the Berlin Aging Study-II, or BASE-II, a large, population-based investigation of aging in Germany.

The BASE-II participants also took learning and memory tests in which they heard a list of 15 words and then had to record as many words as they could remember. Each participant repeated the exact same test five times to gauge how they learn through repetition.

This shows a pink brain on top of a pile of white brains

The study has potential implications for earlier diagnosis of aging-related memory disorders such as Alzheimer’s disease. Image is in the public domain.

Bender and colleagues then analyzed the relationships between how quickly the participants learned and the size of their hippocampus and white matter structure. They reported that faster learning was found only in older adults who had both a larger hippocampus and more uniform white matter circuitry connecting it to other parts of the brain.

“Our findings reinforce a growing perspective that studying age-related changes in learning and memory from a systems perspective appears far more informative in understanding different patterns of brain and cognitive declines than focusing on any single brain region,” Bender said.

Next, he and his colleagues plan to analyze new data from BASE-II participants who returned for a second round of brain scans and memory recall tests two to three years after their first visits.

“By following people over time,” Bender said, “we can see if there is actually change in older adults’ brain structure and whether that is linked with observable declines in learning and memory.”

Hippocampus is among the most important brain structures involved in memory13, and is a critical site of pathogenesis in dementing illnesses such as Alzheimer’s Disease47. Decades of ex vivo human studies and in vivo animal studies have revealed anatomical and functional heterogeneity of the hippocampal subfields812. Yet, until recently, very few in vivo studies in humans had shown dissociable relationships between performance in different memory domains and hippocampal subfield anatomy or function1315.

The role of the hippocampal subfields with respect to select domains of memory thus remains under explored. Recent work has shown that errors during real-world spatial navigation are negatively associated with hippocampal tail volume in mild cognitive impairment (MCI), but with Cornu Ammonis (CA) 3 volume in healthy controls16.

Yet, despite this, there remains a limited understanding of the role of hippocampal subfields in other memory domains relied on in daily life, such as verbal episodic memory (e.g., recalling a grocery list) or semantic memory (e.g., retrieving familiar nouns) [but see17].

Verbal episodic and semantic memory have been shown to dissociate to hippocampal versus anterior temporal regions respectively1822. However, much of our understanding of these dissociations is based on small and heterogeneous patient cohorts1921.

Little is known about these relationships in the context of healthy ageing; less still is known about the effects of age with respect to relationships between hippocampal subfields and specific memory domains, despite evidence of age-related variation in subfield anatomy2325.

Recent advances in computational methods and atlases available for anatomical MRI have improved the reliability and efficiency with which histologically-validated hippocampal parcellations may be applied to in vivo datasets9,2629. Spatially refined subfield parcellations have now been used in studies of clinical disorders30,31, and in one study of MCI and educational attainment32.

Nevertheless, a pressing concern is the quantification of relationships between hippocampal subfields, memory domains, and age, particularly given projected worldwide growth in dementia prevalence in older adults33, and the key role of hippocampus in modulating memory34.

Here, we explored the role of hippocampal subfield anatomy with respect to two domains of memory, in healthy ageing. In a large, non-demented sample of community-dwelling older adults, we aimed to dissociate memory domains based on their expected patterning with hippocampal subfield volumes. We predicted relationships would emerge between verbal episodic memory (list learning and retrieval) and volumes of subfields CA1, CA2/3, CA4, and granule cell layer of dentate gyrus (GC-DG) – regions heavily implicated in encoding and retrieval processes12,35.

In contrast, we expected that fluency in semantic memory (retrieval of familiar category names) would show little if any relationship with subfield volumes19. We appraised these relationships in tandem with age-related differences in subfield volumes, by assessing the robustness of effects related to memory alongside fits for cross-sectional age.

Michigan State University


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