White matter free water mediates the associations between placental growth factor, white matter hyperintensities, and cognitive status

Kyle C Kern; Manu Vohra; Marissa L Thirion; Danny J J Wang; Donna M Wilcock; Jeffrey F Thompson; Gary A Rosenberg; Abhay Sagare; Abhay Moghekar; Hanzhang Lu; Tiffany Lee; Fanny M Elahi; Claudia L Satizabal; Russell Tracy; Sudha Seshadri; Kristin Schwab; Karl Helmer; Herpreet Singh; Pia Kivisäkk; Steven M Greenberg; Keith Vossel; Joel H Kramer; Pauline Maillard; Charles S DeCarli; Jason D Hinman

doi:10.1002/alz.14408

White matter free water mediates the associations between placental growth factor, white matter hyperintensities, and cognitive status

Alzheimers Dement. 2024 Dec 18. doi: 10.1002/alz.14408. Online ahead of print.

Authors

Kyle C Kern^{1

2}, Manu Vohra¹, Marissa L Thirion¹, Danny J J Wang³, Donna M Wilcock⁴, Jeffrey F Thompson⁵, Gary A Rosenberg⁵, Abhay Sagare⁶, Abhay Moghekar⁷, Hanzhang Lu⁷, Tiffany Lee⁴, Fanny M Elahi⁸, Claudia L Satizabal⁹, Russell Tracy¹⁰, Sudha Seshadri⁹, Kristin Schwab¹¹, Karl Helmer¹¹, Herpreet Singh¹¹, Pia Kivisäkk¹¹, Steven M Greenberg¹¹, Keith Vossel¹, Joel H Kramer¹², Pauline Maillard¹³, Charles S DeCarli¹³, Jason D Hinman^{1

2}

Affiliations

¹ Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
² Department of Neurology, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California, USA.
³ Departments of Neurology and Radiology, University of Southern California, SHN, Los Angeles, California, USA.
⁴ Sanders-Brown Center on Aging, Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
⁵ Center for Memory and Aging, Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
⁶ Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷ Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA.
⁸ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁹ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, Department of Population Health Sciences, UT Health San Antonio, San Antonio, Texas, USA.
¹⁰ Departments of Biochemistry and Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.
¹¹ Department of Neurology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA.
¹² Memory and Aging Center, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, California, USA.
¹³ Department of Neurology, University of California Davis, Davis, California, USA.

PMID: 39692213
DOI: 10.1002/alz.14408

Abstract

Introduction: Placental growth factor (PlGF) may regulate cerebrovascular permeability. We hypothesized that white matter interstitial fluid accumulation, estimated via magnetic resonance imaging (MRI) free water (FW), would explain the associations between elevated PlGF, white matter hyperintensities (WMH), and cognitive impairment.

Methods: MarkVCID consortium participants ≥55 years old with plasma PlGF and brain MRI were included. We tested cross-sectionally whether FW mediated the associations between PlGF and WMH, or PlGF and cognition, measured using the Clinical Dementia Rating (CDR) scale and an executive function (EF) composite (Uniform Data Set version 3 [UDS3]-EF).

Results: For 370 participants (mean age 72), a higher PlGF was associated with higher FW, higher WMH, and higher CDR, but not UDS3-EF. Higher FW was associated with higher WMH, higher CDR, and lower UDS3-EF. FW explained 26% of the association between PlGF and CDR and 73% of the association between PlGF and WMH.

Discussion: Elevated PlGF may contribute to WMH and cognitive impairment through white matter FW accumulation.

Clinical trial registration: NCT06284213 HIGHLIGHTS: PlGF is a promising blood-based biomarker for vascular cognitive impairment. In MarkVCID, higher PlGF was associated with accumulated white matter FW on MRI. FW mediated the association between higher PlGF and MRI-visible white matter injury. FW mediated the association between PlGF and worse CDR scale. PlGF may contribute to cognitive dysfunction via accumulated interstitial fluid.

Keywords: dementia; diffusion tensor imaging; magnetic resonance imaging; placental growth factor; vascular cognitive impairment; white matter hyperintensities.

Associated data

ClinicalTrials.gov/NCT06284213

Abstract

Associated data

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