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. 2023 Dec 1;6(12):e2348341.
doi: 10.1001/jamanetworkopen.2023.48341.

Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems

Dea Garic  1   2 , Robert C McKinstry  3 , Joshua Rutsohn  4 , Rebecca Slomowitz  5 , Jason Wolff  6 , Leigh C MacIntyre  7 , Leigh Anne H Weisenfeld  1 , Sun Hyung Kim  2 , Juhi Pandey  8 , Tanya St John  9   10 , Annette M Estes  9   10 , Robert T Schultz  10 , Heather C Hazlett  1   2 , Stephen R Dager  11 , Kelly N Botteron  12 , Martin Styner  2 , Joseph Piven  1   2 , Mark D Shen  1   2 ; Infant Brain Imaging Study (IBIS) Network
Collaborators, Affiliations

Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems

Dea Garic et al. JAMA Netw Open. .

Abstract

Importance: Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume.

Objective: To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood.

Design, setting, and participants: This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022.

Exposure: PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging).

Main outcomes and measures: Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years.

Results: A total of 311 infants (197 [63.3%] male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (β = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006).

Conclusions and relevance: These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McKinstry reported receiving personal fees from Siemens Healthcare, Phelps Healthcare, and Turing Medical outside the submitted work. Dr St. John reported serving as an Autism Diagnostic Observation Schedule trainer outside the submitted work. Dr Estes reported grants from University of Washington during the conduct of the study. Dr Schultz reported grants from Children's Hospital of Philadelphia during the conduct of the study. Dr Botteron reported grants from NIH during the conduct of the study. Dr Styner reported grants from NIH R01-HD055741, grants from NIH P50-HD103573, and grants from NIH R01-MH118362 during the conduct of the study. Dr Shen reported grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Presence of Enlarged Perivascular Spaces (PVS) at Ages 6 to 24 Months
HL-negative indicates high likelihood of autism (ie, an older sibling with autism diagnosis) and no autism diagnosis at age 24 months; HL-positive, high likelihood of autism and autism diagnosis at age 24 months; and LL-negative, low likelihood of autism (ie, no older sibling with autism diagnosis) and no autism diagnosis at age 24 months. aP < .05.
Figure 2.
Figure 2.. Association of Enlarged Perivascular Spaces (PVS) at 24 Months With Greater Extra-Axial Cerebrospinal Fluid (CSF) Volume at Ages 6 to 24 Months
Figure 3.
Figure 3.. Association of Enlarged Perivascular Spaces (PVS) at Age 24 Months With Sleep Problems at School-Age
Dots indicate individual data points; bar, mean; box, 95% CI. aP < .01.
See this image and copyright information in PMC

Comment in

References

    1. Iliff JJ, Wang M, Liao Y, et al. . A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111. doi:10.1126/scitranslmed.3003748 - DOI - PMC - PubMed
    1. Lehtinen MK, Walsh CA. Neurogenesis at the brain-cerebrospinal fluid interface. Annu Rev Cell Dev Biol. 2011;27:653-679. doi:10.1146/annurev-cellbio-092910-154026 - DOI - PMC - PubMed
    1. Lehtinen MK, Zappaterra MW, Chen X, et al. . The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 2011;69(5):893-905. doi:10.1016/j.neuron.2011.01.023 - DOI - PMC - PubMed
    1. Lehtinen MK, Bjornsson CS, Dymecki SM, Gilbertson RJ, Holtzman DM, Monuki ES. The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci. 2013;33(45):17553-17559. doi:10.1523/JNEUROSCI.3258-13.2013 - DOI - PMC - PubMed
    1. Mashayekhi F, Draper CE, Bannister CM, Pourghasem M, Owen-Lynch PJ, Miyan JA. Deficient cortical development in the hydrocephalic Texas (H-Tx) rat: a role for CSF. Brain. 2002;125(Pt 8):1859-1874. doi:10.1093/brain/awf182 - DOI - PubMed

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