Immune response kinetics to SARS-CoV-2 infection and COVID-19 vaccination among nursing home residents-Georgia, October 2020-July 2022.

BACKGROUND: Understanding the immune response kinetics to SARS-CoV-2 infection and COVID-19 vaccination is important in nursing home (NH) residents, a high-risk population. METHODS: An observational longitudinal evaluation of 37 consenting vaccinated NH residents with/without SARS-CoV-2 infection from October 2020 to July 2022 was conducted to characterize the immune response to spike protein due to infection and/or mRNA COVID-19 vaccine. Antibodies (IgG) to SARS-CoV-2 full-length spike, nucleocapsid, and receptor binding domain protein antigens were measured, and surrogate virus neutralization capacity was assessed using Meso Scale Discovery immunoassays. The participant's spike exposure status varied depending on the acquisition of infection or receipt of a vaccine dose. Longitudinal linear mixed effects modeling was used to describe trajectories based on the participant's last infection or vaccination; the primary series mRNA COVID-19 vaccine was considered two spike exposures. Mean antibody titer values from participants who developed an infection post receipt of mRNA COVID-19 vaccine were compared with those who did not. In a subset of participants (n = 15), memory B cell (MBC) S-specific IgG (%S IgG) responses were assessed using an ELISPOT assay. RESULTS: The median age of the 37 participants at enrollment was 70.5 years; 30 (81%) had prior SARS-CoV-2 infection, and 76% received Pfizer-BioNTech and 24% Moderna homologous vaccines. After an observed augmented effect with each spike exposure, a decline in the immune response, including %S IgG MBCs, was observed over time; the percent decline decreased with increasing spike exposures. Participants who developed an infection at least two weeks post-receipt of a vaccine were observed to have lower humoral antibody levels than those who did not develop an infection post-receipt. CONCLUSIONS: These findings suggest that understanding the durability of immune responses in this vulnerable NH population can help inform public health policy regarding the timing of booster vaccinations as new variants display immune escape.

A Longitudinal Study of Local Gyrification Index in Young Boys With Autism Spectrum Disorder.

Local gyrification index (LGI), a metric quantifying cortical folding, was evaluated in 105 boys with autism spectrum disorder (ASD) and 49 typically developing (TD) boys at 3 and 5 years-of-age. At 3 years-of-age, boys with ASD had reduced gyrification in the fusiform gyrus compared with TD boys. A longitudinal evaluation from 3 to 5 years revealed that while TD boys had stable/decreasing LGI, boys with ASD had increasing LGI in right inferior temporal gyrus, right inferior frontal gyrus, right inferior parietal lobule, and stable LGI in left lingual gyrus. LGI was also examined in a previously defined neurophenotype of boys with ASD and disproportionate megalencephaly. At 3 years-of-age, this subgroup exhibited increased LGI in right dorsomedial prefrontal cortex, cingulate cortex, and paracentral cortex, and left cingulate cortex and superior frontal gyrus relative to TD boys and increased LGI in right paracentral lobule and parahippocampal gyrus, and left precentral gyrus compared with boys with ASD and normal brain size. In summary, this study identified alterations in the pattern and development of LGI during early childhood in ASD. Distinct patterns of alterations in subgroups of boys with ASD suggests that multiple neurophenotypes exist and boys with ASD and disproportionate megalencephaly should be evaluated separately.

Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2-4 years: a case-control study.

BACKGROUND: We previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6-24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a later diagnosis of autism spectrum disorder. In this study, we aimed to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism. METHODS: In this case-control MRI study, children with autism spectrum disorder or with typical development aged 2-4 years were recruited from the community to the UC Davis MIND Institute Autism Phenome Project, based in Sacramento, CA, USA. The autism spectrum disorder group comprised children with autism spectrum disorder who were either normal risk (ie, from simplex families) or high risk (ie, from multiplex families). Measurements of extra-axial CSF volume, brain volume, head circumference, sleep problems, and familial risk status were derived from MRI and behavioural assessments. We applied a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex to the current dataset. FINDINGS: Between July 20, 2007, and Dec 13, 2012, 159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans. The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex (least-squares mean 116·74 cm3 [SE 3·33] in autism group vs 101·40 cm3 [3·93] in typical development group; p=0·007; Cohen's d = 0·39). Subgroups of normal-risk (n=132) and high-risk (n=27) children with autism spectrum disorder had nearly identical extra-axial CSF volumes (p=0·78), and both subgroups had significantly greater volumes than controls. Both extra-axial CSF volume (p=0·004) and brain volume (p<0·0001) uniquely contributed to enlarged head circumference in the autism spectrum disorder group (p=0·04). Increased extra-axial CSF volume was associated with greater sleep disturbances (p=0·03) and lower non-verbal ability (p=0·04). The machine learning algorithm correctly predicted autism spectrum disorder diagnosis with a positive predictive value of 83% (95% CI 76·2-88·3). INTERPRETATION: Increased extra-axial CSF volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder. Increased extra-axial CSF volume is detectable using conventional structural MRI scans from infancy through to age 3 years. These results suggest that increased extra-axial CSF volume could be an early stratification biomarker of a biologically based subtype of autism that might share a common underlying pathophysiology. FUNDING: US National Institutes of Health.

Functional Connectivity of the Amygdala Is Disrupted in Preschool-Aged Children With Autism Spectrum Disorder.

OBJECTIVE: The objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical relevance of observed alterations in amygdala connectivity. METHOD: A resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls). RESULTS: The ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05). CONCLUSION: These findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity.

Persistence of megalencephaly in a subgroup of young boys with autism spectrum disorder.

A recurring finding in autism spectrum disorder research is that head and brain growth is disproportionate to body growth in early childhood. Nordahl et al. (2011) demonstrated that this occurs in approximately 15% of boys with autism. While the literature suggests that brain growth normalizes at older ages, this has never been evaluated in a longitudinal study. The current study evaluated head circumference and total cerebral volume in 129 male children with autism and 49 age-matched, typically developing controls. We determined whether 3-year-old boys with brain size disproportionate to height (which we call disproportionate megalencephaly) demonstrated an abnormal trajectory of head growth from birth and whether they maintained an enlarged brain at 5 years of age. Findings were based on longitudinal, structural MRI data collected around 3, 4, and 5 years of age and head circumference data from medical records. At 3 years of age, 19 boys with autism had enlarged brains while 110 had brain sizes in the normal range. Boys with disproportionate megalencephaly had greater total cerebral, gray matter, and white matter volumes from 3-5 years compared to boys with autism and normal sized brains and typically developing boys, but no differences in body size. While head circumference did not differ between groups at birth, it was significantly greater in the disproportionate megalencephaly group by around 2 years. These data suggest that there is a subgroup of boys with autism who have brains disproportionate to body size and that this continues until at least 5 years of age. Autism Res 2016, 9: 1169-1182. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders.

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4-6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism.