Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: A cross-sectional study

Abstract

ImportancePosterior white matter hyperintensities (WMH) in subjects across the Alzheimer’s disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology —not just arterial hypertension— impacts WMH, adversely influencing cognition.ObjectiveTo characterise the effects of AD pathology, namely β-amyloid (Aβ) and hypertension on WMH and cognition.DesignCross-sectional and longitudinalSettingMulticentreParticipantsWe analysed data from subjects with normal cognition (NC), subjective cognitive decline (SCD), and mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study. We focused on participants with available magnetic resonance imaging (MRI), cerebrospinal fluid biomarkers, and cognitive and hypertension information. We conducted analyses between 02.2022 and 06.2022.Intervention(s) (for clinical trials) or Exposure(s) (for observational studies)NAMain Outcomes and MeasuresSpatial distribution and volume of MRI WMH in relation to Aß42/40 levels and arterial hypertension. Mediation of the relationship between Aβ positivity and hypertension on cognition by the regional WMH volume.ResultsWe included 355 participants (median age 70.3 [IQR 66.0-74.4] years; 168 female; 121 NC, 154 SCD, 80 MCI). Hypertension and Aβ positivity were positively associated (pFTR<0.05) with WMH volume, with large spatial overlap in the occipital lobes (regression coefficient ± standard error; hypertension: 0.49±0.14; Aβ: 0.41±0.15), parietal lobes (hypertension: 0.62±0.23; Aβ: 0.61±0.24), corona radiata (hypertension: 0.55±0.19; Aβ: 0.61±0.24), optic radiation (hypertension: 0.64±0.19; Aβ: 0.50±0.20) and splenium (hypertension: 0.38±0.13; Aβ: 0.39±0.13). Global and occipital WMH volumes were strongly associated cognitive changes over a three-year period, estimated with preclinical Alzheimer’s cognitive composite 5 (PACC5) (global: 2.18±0.61, pFDR<0.01; occipital: 3.31±0.75, pFDR<0.01), regardless of Aβ and hypertension status. The association between Aβ positivity and baseline cognitive performance (direct-memory: -0.42±0.08, pFDR<0.01; executive: - 0.28±0.28, pFDR<0.01) was partially mediated by WMH in the corona radiata (indirect-memory: -0.04±0.02, pFDR<0.05; executive: -0.04±0.02, pFDR<0.01) and splenium (indirect-memory: -0.02±0.02, pFDR<0.01; executive: -0.04±0.02, pFDR<0.01). Evidence supporting hypertension affected cognition was insufficient (direct-memory: 0.03±0.07, pFDR=0.683; executive: -0.05±0.07, pFDR=0.499; PACC5 change: 0.01±0.02, pFDR =0.588).Conclusions and RelevancePosterior white matter is susceptible to vascular disease and Aβ accumulation. Its deterioration is involved in the association between Aβ and cognitive dysfunction. Posterior WMH could be a promising target to tackle the downstream damage related to the interacting and potentiating effect of these two pathologies.Trial RegistrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015)Key PointsQuestionIs the spatial distribution and volume of cerebral white matter hyperintensities (WMH) related to arterial hypertension, amyloid pathology, and cognition?FindingsIn this cross-sectional and longitudinal cohort study, WMH increased with hypertension and amyloid, with a spatial overlap in occipital and parietal lobes. Amyloid is involved in the relationship between WMH in corona radiata and splenium on cognitive performance. Global, occipital, and frontal WMH were strongly associated cognitive performance and worsening, regardless of hypertension and amyloid status.MeaningPosterior white matter is susceptible to vascular disease and amyloid pathology; its damage plays a role in the effect of amyloid pathology on cognition.