Posterior hippocampal CA2/3 volume is associated with autobiographical memory recall ability in lower performing individuals

People vary substantially in their capacity to recall past experiences, known as autobiographical memories. Here we investigated whether the volumes of specific hippocampal subfields were associated with autobiographical memory retrieval ability. We manually segmented the full length of the two hippocampi in 201 healthy young adults into DG/CA4, CA2/3, CA1, subiculum, pre/parasubiculum and uncus, in the largest such manually segmented subfield sample yet reported. Across the group we found no evidence for an association between any subfield volume and autobiographical memory recall ability. However, when participants were assigned to lower and higher performing groups based on their memory recall scores, we found that bilateral CA2/3 volume was significantly and positively associated with autobiographical memory recall performance specifically in the lower performing group. We further observed that this effect was attributable to posterior CA2/3. By contrast, semantic details from autobiographical memories, and performance on a range of laboratory-based memory tests, did not correlate with CA2/3 volume. Overall, our findings highlight that posterior CA2/3 may be particularly pertinent for autobiographical memory recall. They also reveal that there may not be direct one-to-one mapping of posterior CA2/3 volume with autobiographical memory ability, with size mattering perhaps only in those with poorer memory recall

Lifestyle factors and neuroimaging metrics as predictors of cognitive performance in healthy aging

Despite all the advances made in health-related and psychological sciences, advancing age continues to be accompanied by cognitive decline. Aging is usually associated with major changes in the structure and functioning of the brain that lead to impairments in multiple cognitive functions. The trajectories of age-related effects on the brain and cognition exhibit considerable differences across cognitive domains and across individuals, and investigating approaches and factors that might prevent brain and cognitive decline during aging is considered a topic of great scientific and public health relevance. The overall goal of this thesis was to evaluate age-related differences in brain structure and functional connectivity to further our understanding of the neural mechanisms involved in age-related declines in cognition. This thesis also aimed to investigate the influence of lifestyle factors on age differences in cognition, and in that regard, I focused on the effects of sleep quality and physical activity on memory. In Study 1, I assessed the impact of aging on grey matter volume of the medial temporal lobe MTL and prefrontal cortex PFC and compared the relative contributions of MTL and PFC structures to age differences in associative memory. My findings emphasize the critical role of the frontal lobes, and the control processes they subserve, in determining the detrimental effects of age on memory. Additionally, I observed that the relationship between frontal grey matter volume and memory was not moderated by age or sex, suggesting that greater volume in PFC structures relates to better memory performance across the lifespan and in both sexes. In Study 2, I assessed the effects of age on functional brain networks. Given the essential role of the arousal system (ARAS) in cortical activation and previous findings of disrupted ARAS functioning with age, I investigated the hypothesis that age-related changes in ARAS-cortical functional connectivity may contribute to commonly observed age-related differences in cortical connectivity. The findings of this study showed that the arousal system is functionally connected to widespread cortical regions and suggest that age differences in functional connectivity within the cortex may be driven by age-related changes in the brainstem and these altered connectivity patterns have important implications for cognitive health. In Study 3, I investigated the relationship between sleep quality, physical activity, and memory in middle-age and older adults, in addition to assessing the impact of the COVID-19 pandemic on participants’ mood and sleep quality. Our results showed that people who were more active reported better sleep quality and showed better memory, and better sleep quality was associated with better memory. Moreover, our findings also showed that some of the beneficial effects of physical activity on cognition are partially mediated by improved sleep. Additionally, this study indicated that the COVID-19 pandemic had a deleterious effect on people’s sleep quality and overall well-being. Taken together, these studies suggest that aging is associated with disruptive effects on brain structure and function, and that these changes are associated with age-related cognitive decline. Additionally, our study supported the association between lifestyle factors, more specifically, sleep quality and physical activity, and cognitive performance during aging

Release of cognitive and multimodal MRI data including real-world tasks and hippocampal subfield segmentations

We share data from N = 217 healthy adults (mean age 29 years, range 20-41; 109 females, 108 males) who underwent extensive cognitive assessment and neuroimaging to examine the neural basis of individual differences, with a particular focus on a brain structure called the hippocampus. Cognitive data were collected using a wide array of questionnaires, naturalistic tests that examined imagination, autobiographical memory recall and spatial navigation, traditional laboratory-based tests such as recalling word pairs, and comprehensive characterisation of the strategies used to perform the cognitive tests. 3 Tesla MRI data were also acquired and include multi-parameter mapping to examine tissue microstructure, diffusion-weighted MRI, T2-weighted high-resolution partial volume structural MRI scans (with the masks of hippocampal subfields manually segmented from these scans), whole brain resting state functional MRI scans and partial volume high resolution resting state functional MRI scans. This rich dataset will be of value to cognitive and clinical neuroscientists researching individual differences, real-world cognition, brain-behaviour associations, hippocampal subfields and more. All data are freely available on Dryad

The function and structure of the entorhinal cortex in mild cognitive impairment

The function and structure of the entorhinal cortex in mild cognitive impairment Background: The entorhinal cortex (EC) is the first brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). As such, tests of EC function may help aid detection of the disease in its earliest stages. Animal and human studies indicate that the posteromedial (pmEC) and anterolateral (alEC) subdivisions of the EC are involved respectively in navigation and object-location memory. The advent of immersive VR (iVR) technology provides an opportunity to determine whether tests of pmEC and alEC function has value in the detection of AD prior to dementia onset. Aim: To test the hypotheses that measures of pmEC and alEC function and structure differentiate i) patients with mild cognitive impairment (MCI) from age-matched healthy controls and ii) MCI patients at high and low risk of developing AD dementia. Methodology: Participants underwent testing of EC function using novel iVR paradigms of path integration and object-location memory. Total EC, pm-EC and al-EC volumes were segmented from high resolution MRI. A proportion of MCI patients underwent CSF testing for AD biomarkers to separate into biomarker-positive and negative groups (MCI+ and MCI-). The ability of the VR tests to classify pre-dementia AD (i.e. MCI+ patients) was compared with that of a battery of comparator cognitive tests used in current clinical and research practice. 8 Results: Performance on the path integration task was not only impaired in MCI but importantly differentiated MCI+ from MCI- with greater classification accuracy than comparator cognitive tasks. Task performance correlated with pm-EC volume. For the object-location task MCI patients demonstrated larger distance errors than controls, with performance associated with both anterolateral EC volume and total hippocampal volume. However, no difference between MCI+ and MCI- was observed. Conclusion This work demonstrates that iVR-based testing of EC function may improve diagnosis of early AD above and beyond current cognitive tests. The basis of such tests on single cell physiology and their comparability with behavioural tasks used in animal models of disease, confers additional advantages for translational research aimed at understanding the mechanisms linking pathological spread, disruption of cell physiology and behavioural alterations in early AD.MRC Sackler fund

There is more to memory than recollection and familiarity.

Theoretical models of memory retrieval have focused on processes of recollection and familiarity. Research suggests that there are still other processes involved in memory reconstruction, leading to experiences of knowing and inferring the past. Understanding these experiences, and the cognitive processes that give rise to them, seems likely to further expand our understanding of the neural substrates of memory

Investigating the role of normal and abnormal beta-amyloid processing in cognition

Alzheimer’s Disease (AD) affects over 30 million people worldwide, however no disease modifying therapies have been approved to date. The majority of failed therapeutic intervention targeted the accumulation of beta-amyloid (Aβ) species. While these interventions were effective in preclinical mouse models of early stage amyloid pathology they failed to translate into the clinic. While several explanations may underlie this apparent lack of translation, one commonly held view is that first generation mouse models possess artefacts that contribute to brain and cognitive phenotypes. Another factor that has not received detailed consideration is the extent to which reduction of endogenous amyloid production influences cognition and synaptic processes in cognitively normal mice. This thesis aimed to elucidate the role of Aβ in cognitive function in both wild-type (WT) mice and a novel single knock-in mouse APP-NL-F mouse model of pre-symptomatic amyloid pathology. Selective inhibition of Aβ production was achieved by using the 2B3 antibody, which binds to the β-cleavage site of the amyloid precursor protein (APP), sterically inhibiting metabolism. 2B3 administration significantly reduced Aβ and altered glutamate receptor dynamics in the hippocampus of 5-month old WT mice following icv (intracerebroventricular) infusion. These mice failed to detect changes in object-in-place (OiP) associations, confirming that hippocampal Aβ was required for this cognitive task. APPNL-F knock-in mice express a humanised Aβ sequence with the Swedish (KM670/671NL) and Iberian (I716F) mutations within the endogenous murine APP gene. These mice underwent behavioural characterisation at 8 and 17 months of age and this revealed a pattern of selective memory deficits that were age-dependent. This included an age-dependent deficit in a foraging-based spatial working memory task and deficits in both associative OiP and temporal order recognition memory. 2B3 infusion in aged WT and APPNL-F mice reduced Aβ production but resulted in dissociable effects on memory. A deficit in OiP performance was rescued by 2B3 administration in APPNL-F mice but performance was impaired in healthy WT controls. These data provide novel evidence for the importance and dynamic role of Aβ in both normal and early stage AD pathology. One implication of these findings is that, should anti-amyloid therapies gain traction in the treatment of pre-symptomatic AD, the benefits must be weighed against the potential adverse effect of disrupting normal amyloid function