Kaga, H. | Search bioRxiv

bioRxiv2026

Differential associations of insulin resistance with anterior hippocampal volume in mild cognitive impairment and Alzheimer's disease

Insulin resistance is increasingly recognized as a metabolic factor associated with Alzheimers disease (AD); however, its relevance to hippocampal structural changes--a key pathological feature of AD--across disease stages is not fully understood. To address this issue, we investigated the relationship between insulin resistance, hippocampal gray matter volume, and cognitive performance using data from the Alzheimers Disease Neuroimaging Initiative (ADNI), a large-scale neuroimaging dataset. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and its relationship with brain structure and cognitive performance was evaluated across diagnostic groups. In the mild cognitive impairment (MCI) group, higher insulin resistance was associated with larger anterior hippocampal gray matter volume, whereas in the AD group this association was reversed in direction. Furthermore, in the MCI group, anterior hippocampal gray matter volume was also positively associated with higher Mini-Mental State Examination (MMSE) scores, and an exploratory mediation analysis suggested a significant indirect association linking HOMA-IR, anterior hippocampal volume, and cognitive performance through anterior hippocampal volume. These findings suggest that the relationship between insulin resistance and AD-related brain changes differs across diagnostic groups, highlighting the importance of considering metabolic alterations in relation to disease status.

neuroscience↗

bioRxiv2026

Distinct cognitive and structural correlates of pain extent and central sensitization symptoms in older women and men with chronic pain

Chronic pain in later life may be accompanied by alterations in brain structure and cognition, but whether pain extent and central sensitization symptoms identify distinct brain-behavior patterns remains unclear. We examined associations of pain extent and central sensitization symptoms, assessed using the 9-item Central Sensitization Inventory (CSI-9), with regional gray matter volume and cognitive function in community-dwelling older adults. This cross-sectional study included 272 participants with chronic pain from the Bunkyo Health Study. Participants were classified as having single-site or multisite pain and by CSI-9 score as having lower or higher scores, with 12 or higher defining the higher group. Regional gray matter volume was quantified using 0.3-Tesla magnetic resonance imaging, and cognition was assessed using the Trail Making Test Part B (TMT-B), processing speed, and global and domain-specific measures. Pain extent and CSI-9 group interacted for TMT-B performance, with the longest completion time in participants with single-site pain and a higher CSI-9 score. No other cognitive outcome remained significant after correction for multiple testing. In categorical analyses, the higher CSI-9 group had smaller volumes in the right middle frontal gyrus, bilateral anterior cingulate cortex, right insula, right hippocampus, and bilateral amygdala, whereas pain extent and the interaction were not associated with regional volume. In a contextual comparison, only the single-site/higher CSI-9 group showed slower TMT-B performance than participants with no pain. Pain extent and central sensitization symptoms may represent partly distinct dimensions of chronic pain, although the small single-site/higher CSI-9 group and attenuation in several sensitivity analyses warrant caution. Significance StatementChronic pain is often described by where it hurts, but location alone may miss important differences between patients. In older adults, pain extent and symptoms measured by the 9-item Central Sensitization Inventory captured partly different aspects of chronic pain. Participants with pain at one site and a higher CSI-9 score performed most slowly on a task requiring attention and mental flexibility, whereas differences in regional brain structure were related mainly to CSI-9 score rather than pain extent. These findings support a multidimensional approach to chronic pain and may inform future research on cognitive vulnerability and brain health across pain conditions. Graphical Abstract Text O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/742487v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@8f6b84org.highwire.dtl.DTLVardef@1dbe805org.highwire.dtl.DTLVardef@5ddec3org.highwire.dtl.DTLVardef@cbff7a_HPS_FORMAT_FIGEXP M_FIG C_FIG Among older adults with chronic pain, pain extent and CSI-9 score captured different aspects of vulnerability. Slower performance on a task requiring attention and cognitive flexibility was concentrated in those with single-site pain and higher CSI-9 scores, whereas regional brain-volume differences tracked CSI-9 category more broadly.

neuroscience↗