Periventricular and Deep White Matter Hyperintensity Thresholds in Aging: Exponential Progression, Cognitive Decline, and Neuroanatomic Atrophy

White matter hyperintensities (WMH), which are brain lesions associated with cerebral small vessel disease and aging, signify fiber loss and pruning. Analysis of T2-FLAIR MRI data from the NACC cohort, including cognitively normal (CN), cognitively impaired (CI), and Alzheimers disease (CI-AD) subjects, revealed that a significant subset of participants, even those classified as CN, harbor substantial periventricular (PVWMH) and deep white matter hyperintensity (DWMH) loads, while others displayed minimal or no PVWMH and DWMH, across ages 50-94 years. In this study, we quantified the thresholds and progression kinetics of PVWMH and DWMH and their impact on cognitive performance and neuroanatomic changes in the aging cohort (NCN = 521, NCI = 146, NCI-AD = 319). Our findings explore the impact of PVWMH and DWMH loads on global and specific cognitive domains to determine whether cognitive impairments are directly induced by PVWMH and DWMH loads, or mediated through distinct neuroanatomic structures. PV and DWMH loads are higher in CI and CI-AD subjects compared to CN but the PVWMH and DWMH loads are not discriminative of CI and CI-AD. The progression kinetics of PVWMH and DWMH volume with age indicate an exponential rate of increase, with PVWMH escalating approximately twice as fast as DWMH particularly around an inflection point at 61 years of age. PVWMH load presents with increased probability of occurrence in frontal horn compared to occipital horn while DWMH is diffused and accumulates significantly at later age than that observed for PVWMH. Multivariate global regression suggested significant effect (p<0.01) of PVWMH on Trail making tests (TMTs)-A and B (executive function), animal naming tests (semantic memory), with no significant effects observed for DWMH load. Indeed, beyond a threshold of PVWMH volume >2.3 mL, significant deficits in TMTs were observed compared to the subjects without PVWMH load. A PVWMH volume >2.3 mL and DWMH >2.75 mL is significantly associated with impairments in attention & working memory (Digit Span Tests), and semantic memory. Noticeably, significant neuroanatomic atrophy in the cerebral cortex, nucleus accumbens, RMFG, precentral, and paracentral gyrus is observed for PVWMH load >2.3 mL, while DWMH load was not significantly associated with neuroanatomic loss. Furthermore, a mediation model employing neuroanatomic volumes as mediator, PVWMH load as predictor and cognitive tests as outcome suggested that PVWMH volume contributes significantly to deficits in TMT-B mediated through atrophy in precentral gyrus (64%), accumbens (39%), paracentral gyrus (32%), rostral middle frontal gyrus (31%), and lingual gyrus (30%), each contributing distinct proportions, alongside the direct effect. DWMH load did not emerge as a significant predictor (direct or indirect) for the cognitive deficits. Further, no significant neuroanatomic mediations from PVWMH load were observed for other cognitive tests indicative of direct involvement of PVWMH load. Global cognition like MMSE was affected only at a higher PVWMH accumulation (>6 ml). HighlightsO_LIPVWMH escalates exponentially twice as fast as DWMH with age. C_LIO_LIPVWMH >2.3 mL is linked to cognitive deficits in executive function, semantic memory and neuroanatomic atrophy; DWMH less impactful. C_LIO_LIPVWMH, not DWMH, significantly affects cognitive decline via a unique set of brain structural loss. C_LIO_LIPVWMH and DWMH loads are not discriminative of CI and AD subjects. C_LI Overview O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/610993v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ff66b2org.highwire.dtl.DTLVardef@af3852org.highwire.dtl.DTLVardef@19ab4c5org.highwire.dtl.DTLVardef@1d226a6_HPS_FORMAT_FIGEXP M_FIG C_FIG