Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: A cross-sectional study
Authors: Bernal Jose , Schreiber Stefanie , Menze Inga , Ostendorf Anna , Pfister Malte , Geisendörfer Jonas , Nemali Aditya , Maass Anne , Yakupov Renat , Peters Oliver , Preis Lukas , Schneider Luisa , Herrera Ana Lucia , Priller Josef , Spruth Eike Jakob , Altenstein Slawek , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Schott Björn H. , Rostamzadeh Ayda , Glanz Wenzel , Buerger Katharina , Janowitz Daniel , Ewers Michael , Perneczky Robert , Rauchmann Boris-Stephan , Teipel Stefan , Kilimann Ingo , Laske Christoph , Munk Matthias H. , Spottke Annika , Roy Nina , Dobisch Laura , Dechent Peter , Scheffler Klaus , Hetzer Stefan , Wolfsgruber Steffen , Kleineidam Luca , Schmid Matthias , Berger Moritz , Jessen Frank , Wirth Miranka , Düzel Emrah , Ziegler Gabriel 
Published: October 2022

Background Posterior 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. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition. Methods We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.2 [IQR 66.0-74.4] years; 176 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function—derived from multiple neuropsychological tests using confirmatory factor analysis—, baseline preclinical Alzheimer’s cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over course of three years (ΔPACC5). Results Subjects with hypertension or Aβ positivity presented the largest WMH volumes (pFDR<0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aβ: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aβ: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aβ: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aβ: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aβ: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aβ: 0.28 ± 0.12). Hypertension, Aβ positivity, and WMH were connected to cognition. First, WMH coincided with worse cognitive performance and outcomes (pFDR<0.05), regardless of Aβ and hypertension. Accelerated cognitive decline was associated with WMH in the genu of the corpus callosum and segments of the forceps major and inferior fronto-occipital longitudinal fasciculus (pFDR<0.05). Second, hypertension was indirectly linked to cognitive performance at baseline and over time via splenial WMH (indirect-only effect; memory: -0.05 ± 0.02,pFDR=0.029; executive: -0.04 ± 0.02,pFDR=0.067; PACC5: -0.05 ± 0.02,pFDR=0.030; ΔPACC5: -0.09 ± 0.03,pFDR=0.043). Third, the relationship between Aβ positivity and baseline and longitudinal cognitive performance was independent of WMH burden. Conclusions Posterior white matter is susceptible to hypertension and Aβ accumulation and it mediates the association between hypertension and cognitive dysfunction. Posterior WMH could be a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies. Trial Registration German Clinical Trials Register (DRKS00007966, 04/05/2015)