Brain microvascular calcification is increased in human donors with dementia compared to elderly controls: A pilot study

Kelly Borges^*Isabelle LombardiMackenzie SivilliJoseph AabyeIsabella RomanoSaud NasruddinMugdha Vijay PadalkarDaniel MoussourosOlga V. Savinova^*

• New York Institute of Technology, Old Westbury, United States

Introduction: Intracranial vascular calcification has been observed in the setting of both Alzheimer's disease (AD) and vascular dementia. Increased calcification in intracranial and extracranial arteries is associated with an increased risk of dementia; however, less is known about the prevalence and implications of microvascular calcification in AD and related dementias. In this study, we compared microvascular calcification in AD-relevant brain regions between human donors with vs. without dementia and/or late-onset AD diagnoses.Methods: Brain tissue was sampled bilaterally from basal ganglia, hippocampus, posterior cingulate cortex, substantia nigra, and subventricular zone, along with bilateral carotid arteries in a cohort of human donor cadavers with and without dementia at death (n=23, 61% females, 86.4 +/-7.9 years of age). An additional cohort included postmortem posterior cingulate cortex samples from NIH NeuroBioBank donors with and without confirmed late-onset AD (n=10, 40% females, 78.3 +/-2.1 years of age). All samples were scanned by micro-computed tomography. Vascular calcification was quantified as the sum of voxels at an intensity of ≥130 Hounsfield units in a standardized tissue volume. Findings were confirmed by histology.Our findings indicate higher odds of dementia per one quartile increase in microvascular calcification volume in the hippocampus (OR 9.601 [CI 2.518, 86.803], p=0.0091), posterior cingulate cortex (OR 2.894 [CI 1.222,8.923], p=0.0302), and subventricular zone (OR 2.851 [CI 1.153,9.482], p=0.0427). Similarly, in posterior cingulate cortex samples from the NeuroBioBank, significantly higher microvascular calcification was observed in late-onset AD cases (median 0.0153 [IQR 0.0075, 0.0581], % by volume) compared to controls (median 0.0024 [IQR 0.0016, 0.0104], % by volume; p=0.0265). Internal carotid calcification was significantly associated with microvascular calcification in the basal ganglia (OR 1.699 [CI 1.156, 2.496], p=0.0093), hippocampus (OR 1.580 [CI 1.056, 2.366], p=0.0281), and posterior cingulate cortex (OR 1.524 [CI 1.009, 2.299], p=0.0452).Discussion: Our findings indicate that microvascular calcification impacts brain regions relevant to morphologic changes (hippocampus) and hypoperfusion (posterior cingulate cortex) in AD. Our study expands on a recent report of increased brain calcification in the setting of AD, suggesting that microvascular calcification carries pathophysiological significance in the development and/or progression of AD and related dementias.