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Brain arteriolosclerosis

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Abstract

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

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Abbreviations

AD:

Alzheimer’s disease

B-ASC:

Brain arteriolosclerosis

CAA:

Cerebral amyloid angiopathy

CADASIL:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

cAVU:

Cerebral arteriolar vascular unit

cSVD:

Cerebral small vessel disease

EPV:

Enlarged perivascular space

FLAIR:

Fluid-attenuated inversion recovery

FTLD-TDP:

Frontotemporal lobar degeneration with TDP-43 proteinopathy

H&E:

Hematoxylin and eosin

HS:

Hippocampal sclerosis

LATE:

Limbic-predominant age-related TDP-43 encephalopathy

MetS:

Metabolic syndrome

NACC NP:

National Alzheimer’s coordinating center neuropathology

NVU:

Neurovascular unit

pCASL:

Pseudo-continuous arterial spin labeling

SI:

Sclerotic index

SNP:

Single-nucleotide polymorphism

SWI:

Susceptibility weighted imaging

T2DM:

Type II diabetes mellitus

VCING:

Vascular cognitive impairment neuropathology guidelines

WMH:

White matter hyperintensity

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Acknowledgements

We are very grateful to the research volunteers, their families, and clinicians, as well as the other researchers who made this work possible. This study was also supported by California Dept of Public Health Grant A20-2947-5001 and NIH Grants P30 AG028383, R01 AG057187, R01 AG039621, R01 AG055449, K24 AG053435, R56 AG057191, R01 HD064993, U54 NS100717, U01 AG016976, RF1 NS118584, and S10 OD023573. Additional support came from Medical Research Council (MRC, G0500247) and previous Newcastle Centre for Brain Ageing and Vitality (BBSRC, EPSRC, ESRC and MRC, LLHW), and Alzheimer’s Research (ARUK). The Newcastle Brain Tissue Resource is funded in part by a grant from the UK MRC (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimer’s Society and ARUK as part of the Brains for Dementia Research Project. See Supplemental Acknowledgement for additional acknowledgments.

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Authors and Affiliations

  1. Department of Neuroscience, University Kentucky, Lexington, KY, 40536, USA

    Brittney L. Blevins

  2. Department of Pathology and Laboratory Medicine, David Geffen SOM at UCLA and Ronald Reagan UCLA Medical Center, Los Angeles, CA, 90095-1732, USA

    Harry V. Vinters & Shino D. Magaki

  3. University of Bristol and Southmead Hospital, Bristol, BS10 5NB, UK

    Seth Love

  4. Sanders-Brown Center on Aging, Department of Neuroscience, University Kentucky, Lexington, KY, 40536, USA

    Donna M. Wilcock, Brian T. Gold & Linda J. Van Eldik

  5. Department of Neurology and Pathology, UCSF, San Francisco, CA, USA

    Lea T. Grinberg

  6. Departments of Neurology and Pathology, Rush University Medical Center, Chicago, IL, 60612, USA

    Julie A. Schneider

  7. Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK

    Rajesh N. Kalaria

  8. Sanders-Brown Center on Aging, Department of Biostatistics, University Kentucky, Lexington, KY, 40536, USA

    Yuriko Katsumata, Lincoln M. P. Shade & David W. Fardo

  9. Laboratory of FMRI Technology (LOFT), USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, USA

    Danny J. J. Wang & Samantha J. Ma

  10. Sanders-Brown Center on Aging, Department of Pharmacology and Nutritional Sciences, University Kentucky, Lexington, KY, 40536, USA

    Anika M. S. Hartz

  11. Sanders-Brown Center on Aging, Department of Neurology, University Kentucky, Lexington, KY, 40536, USA

    Gregory A. Jicha & Frederick A. Schmitt

  12. National Institutes of Health, Bethesda, MD, USA

    Karin B. Nelson

  13. Department of Epidemiology, University Washington, Seattle, WA, 98105, USA

    Merilee A. Teylan

  14. Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA

    Eseosa T. Ighodaro

  15. Sanders-Brown Center on Aging, University Kentucky, Lexington, KY, 40536, USA

    Panhavuth Phe

  16. Sanders-Brown Center on Aging, Department of Epidemiology, University Kentucky, Lexington, KY, 40536, USA

    Erin L. Abner

  17. Departments of Pathology and Genomic Medicine and Neurology, Houston Methodist Hospital, Houston, TX, 77030, USA

    Matthew D. Cykowski

  18. Sanders-Brown Center on Aging, Department of Pathology, University of Kentucky, Lexington, KY, 40536, USA

    Peter T. Nelson

  19. Global Brain Health Institute, UCSF, San Francisco, CA, USA

    Lea T. Grinberg

  20. LIM-22, Department of Pathology, University of Sao Paulo Medical School, São Paulo, Brazil

    Lea T. Grinberg

  21. Rm 311 Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone Avenue, Lexington, KY, 40536, USA

    Peter T. Nelson

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  1. Brittney L. Blevins
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Blevins, B.L., Vinters, H.V., Love, S. et al. Brain arteriolosclerosis. Acta Neuropathol 141, 1–24 (2021). https://doi.org/10.1007/s00401-020-02235-6

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