Longitudinal Intraindividual Cognitive Variability Is Associated With Reduction in Regional Cerebral Blood Flow Among Alzheimer’s Disease Biomarker-Positive Older Adults

Abstract

Intraindividual variability (IIV) across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer’s disease (AD). We have previously shown that greater IIV is cross-sectionally associated with reduced cerebral blood flow (CBF), but not with cortical thickness or brain volume, in older adults without dementia who were amyloid beta (Aβ) positive. However, there is little known about the association between change in IIV and CBF over time. Therefore, we examined 12-month longitudinal change in IIV and interactions of IIV and AD biomarker status on changes in regional CBF. Fifty-three non-demented Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants underwent lumbar puncture to obtain cerebrospinal fluid (CSF) at baseline and neuropsychological testing and magnetic resonance imaging (MRI) exams at baseline and 12-month follow-up evaluation. IIV was calculated as the intraindividual standard deviation across 6 demographically-corrected neuropsychological measures. Pulsed arterial spin labeling (ASL) MRI was acquired to quantify CBF and FreeSurfer-derived a priori CBF regions of interest (ROIs) were examined. AD biomarker positivity was determined using a published CSF p-tau/Aβ ratio cut-score. Change scores were calculated for IIV, CBF, and mean neuropsychological performance from baseline to 12 months. Hierarchical linear regression models showed that after adjusting for age and gender, there was a significant interaction between IIV change and biomarker-positivity (p-tau/Aβ+) for change in entorhinal and hippocampal CBF but not for the other ROIs. Specifically, increases in IIV were associated with reductions in entorhinal and hippocampal CBF among individuals who were biomarker-positive (n = 21). In contrast, there were no significant associations between change in IIV and CBF among those who were biomarker-negative (n = 32). Findings remained similar when analyses were performed adjusting for change in mean level of neuropsychological performance. Changes in IIV may be sensitive to changes in regional hypoperfusion in AD-vulnerable regions among AD biomarker-positive individuals, above and beyond demographics and mean neuropsychological performance. These findings provide further evidence supporting IIV as a potential marker of cerebrovascular brain changes in individuals at risk for dementia.

Cognitive dispersion is related to subtle objective daily functioning changes in older adults with and without cognitive impairment

“…Consistent with prior studies, individuals classified as having MCI exhibited greater levels of cognitive dispersion compared to CN older adults 6–11 . This further supports the idea that dispersion may increase with disease progression and serve as a prodromal indicator of cognitive change 10,11–12 . Additionally, our findings were generally consistent with prior work that found group differences between CN older adults and those with MCI on six of the nine passively assessed IADLs 16–21 .…”

“…Consistent with prior studies, individuals classified as having MCI exhibited greater levels of cognitive dispersion compared to CN older adults 6–11 . This further supports the idea that dispersion may increase with disease progression and serve as a prodromal indicator of cognitive change 10,11–12 .…”

“…[6][7][8][9][10][11] This further supports the idea that dispersion may increase with disease progression and serve as a prodromal indicator of cognitive change. 10,[11][12] Additionally, our findings were generally consistent with prior work that found group differences between CN older adults and those with MCI on six of the nine passively assessed IADLs. [16][17][18][19][20][21] A lack of group differences seen in prior work for pillbox use variables and day-to-day variability in distance driven may be related to various factors, including cohort differences, different driving sensors being used, and a change in daily activity patterns due to the COVID-19 pandemic, which led to older adults spending more time at home, having more structured daily routines, and traveling less during lockdown periods.…”

“…Bangen and colleagues also found that greater dispersion was linked to medial temporal lobe atrophy in individuals with mild cognitive impairment (MCI) 7 . Increases in dispersion over 12 months have also been associated with hypoperfusion in hippocampal and entorhinal cortex among individuals who were biomarker positive (ie, elevated CSF phosphorylated tau 181/Aβ 42 ratio) 10 . Cognitive dispersion has been shown to predict diagnostic conversion comparably to well‐established cerebrospinal fluid (CSF) biomarkers, suggesting it may be a promising non‐invasive alternative for early detection 11 …”

“…7 Increases in dispersion over 12 months have also been associated with hypoperfusion in hippocampal and entorhinal cortex among individuals who were biomarker positive (ie, elevated CSF phosphorylated tau 181/Aβ 42 ratio). 10 Cognitive dispersion has been shown to predict diagnostic conversion comparably to well-established cerebrospinal fluid (CSF) biomarkers, suggesting it may be a promising non-invasive alternative for early detection. 11 Cognitive dispersion has also been shown to be associated with clinical outcomes, including cognitive status and improving prediction of longitudinal disease progression.…”