Effects of age on the hippocampus and verbal memory in adults with autism spectrum disorder: Longitudinal versus cross‐sectional findings

Abstract

Research studying aging in adults with autism spectrum disorder (ASD) is growing, but longitudinal work is needed. Autistic adults have increased risk of dementia, altered hippocampal volumes and fornix integrity, and verbal memory difficulties compared with neurotypical (NT) adults. This study examined longitudinal aging in middle-age adults with ASD versus a matched NT group, and compared findings with cross-sectional age effects across a broad adult age range. Participants were 194 adults with (n = 106; 74 male) and without (n = 88; 52 male) ASD, ages 18-71. Participants (n = 45; 40-70 age range) with two visits (2-3 years apart) were included in a longitudinal analysis. Hippocampal volume, fornix fractional anisotropy (FA), and verbal memory were measured via T1-weighted MRI, diffusion tensor imaging, and the Rey Auditory Verbal Learning Test, respectively. Longitudinal mixed models were used for hippocampal system variables and reliable change index categories were used for Auditory Verbal Learning Test analyses. Multivariate regression was used for cross-sectional analyses. Middle-age adults with ASD had greater longitudinal hippocampal volume loss and were more likely to show clinically meaningful decline in short-term memory, compared with NT. In contrast, cross-sectional associations between increasing age and worsening short-term memory were identified in NT, but not autistic adults. Reduced fornix FA and long-term memory in ASD were found across the broad cross-sectional age range. These preliminary longitudinal findings suggest accelerated hippocampal volume loss in ASD and slightly higher rates of clinically-meaningful decline in verbal short-term memory. Contradictory cross-sectional and longitudinal results underscore the importance of longitudinal aging research in autistic adults. Lay SummaryAutistic adults have increased risk of dementia, differences in brain memory structures, and difficulty with memory compared with neurotypical (NT) adults. However, there are no publications that follow the same middle-age autistic adults over time to see how their brain and memory change. Our preliminary findings in a small middle-age autism sample suggest a key memory brain structure, the hippocampus, may shrink faster over 2-3 years compared with NT, and short-term memory may become more challenging for some. Across a broad adult range, autistic adults also had reduced integrity of connections to the hippocampus and greater challenges with long-term memory. In our larger sample across a broad Broc A. Pagni and Melissa J. M. Walsh contributed equally to this work.

Preliminary findings of accelerated visual memory decline and baseline brain correlates in middle-age and older adults with autism: The case for hippocampal free-water

“…These findings are supported by hypotheses that neurogenetic alterations associated with ASD may increase risk for age-related neurodegenerative conditions (Hickman et al, 2022). Further, we recently published preliminary longitudinal findings in middle-age and older adults with ASD suggesting accelerated hippocampal volume loss and short-term verbal memory decline (Pagni et al, 2022). Otherwise, characterizations of cognitive and brain aging trajectories for adults with ASD are primarily limited to cross-sectional studies, with inconsistent findings of safeguarded, parallel, or exacerbated brain and cognitive aging patterns (Geurts et al, 2016;Koolschijn et al, 2017;Braden and Riecken, 2019;Walsh et al, 2019;Bathelt et al, 2020;Tse et al, 2021).…”

“…Baseline group means and standard deviations for hippocampal system metrics can be found in Supplementary Table 3. As we have published previously on this cohort, the ASD group had smaller hippocampal volume and reduced fornix FA than the NT group (Pagni et al, 2022). Group differences in free-water did not reach statistical significance.…”

“…Furthermore, a cross-sectional study of cortical thickness suggests that temporal regions associated with memory function may be vulnerable to accelerated atrophy in ASD (Braden and Riecken, 2019). Recent longitudinal evidence from our group showed accelerated hippocampal volume loss in middle age and older adults with ASD versus matched NT adults (Pagni et al, 2022). Thus, preliminary evidence indicates that hippocampal structural features (e.g., volume) may serve as promising candidate biomarkers for predicting cognitive aging risk in ASD.…”

“…We used longitudinal mixed models to estimate diagnosis-differential trajectories of short-term and long-term visual memory change (WMS VR I and II) over time using SAS 9.4. Given literature suggesting between-subject variability in cognitive aging trajectories (Pagni et al, 2022), models included random intercepts and slopes. For these models, age was split into two separate variables per recommendations from Guillaume et al (2014): between-subject (BS) age variability and within-subject (WS) age variability.…”

“…For example, in investigations of (Koolschijn et al, 2017). Furthermore, we have previously shown reduced fornix FA in adults with ASD compared to NT participants (Pagni et al, 2022). Given the sensitivity of the fornix as a biomarker of cognitive aging risk in typical aging and dementia, as well as alterations to fornix integrity observed in adults with ASD, fornix microstructural features like FA may also serve as a promising biomarker for predicting memory aging trajectories in ASD.…”