Table 1. Summary of studies examining the associations between chronic health conditions and cognitive performance in individuals with DS.

Author(s), Year; CHC Category	Study Type (location)	Age range (years): n Population	Neurocognitive measure(s)	Neurocognitive Scoring/Domains	Neurocognitive Results
Andreou et al., 2002 Sleep disorder	Prospective cohort (Greece)	17–25: 12 DS+SDB	Raven Progressive Matrices (RPM)	Raw: Visual-Spatial, Reasoning  1) Sum of correct items	SDB negatively correlated with visual-spatial scores, particularly in adults with DS+ untreated SDB.
Chen et al., 2013 Sleep disorder	Prospective cohort (U.S.)	14–31: 29 DS+parent- rated OSA	1) Choice Reaction Time test 2) Verbal Fluency test 3) Knock-Tap Test	Raw: Executive Function  1) mean reaction time  2) sum of words generated  3) sum of correct responses	The severity of parent-rated OSA in DS moderately correlated with executive function performance. More severe symptoms predicted poorer performance.
Breslin et al., 2014 Sleep disorder	Prospective cohort (U.S.)	7–12: 38 DS±OSA	Cambridge Neuropsych. Test Automated Battery (CANTAB): 1) Intra-Extra Dimensional Set Shifting 2) Paired-Associative Learning Task 3) Simple Reaction Time Task Kaufman Brief Intelligence Test (KBIT-II)	Raw: Executive Function  1) Stages completed  2) Mean errors  3) Median reaction time SS: Full, Verbal, Non-verbal IQ	DS+OSA completed fewer stages for the set shifting task of cognitive flexibility. Reaction time and mean errors did not differ between groups. DS+OSA had lower verbal IQ. No differences in full-scale or non-verbal IQ.
Brooks et al., 2015 Sleep disorder	Prospective cohort (U.S.)	6–14: 25 DS±OSA	Stanford-Binet Intelligence Scales, 4th Edition (SB-4) Beery-Buktenica Developmental Test of Visual-Motor Integration (Berry VMI) Conners Hyperactivity Index *Parent rept	SS: Full IQ, Bead Memory, Vocabulary, Quantitative Pattern Analysis, Memory for Sentences, Comprehension SS: Visual, Motor, and Visual-Motor Integration SS: Attention	No differences in cognitive performance between DS children with and without OSA. Total sleep time and latency contributed to cognitive performance. Of 10 DS+OSA, the 5 treated with adenotonsillectomy and/or CPAP showed improvements in parent-reported attention.
Joyce et al., 2017 Sleep disorder	Case control (U.K.)	2–5: 44 DS+SDB: 22 TD+SDB: 22	Mullen Scales of Early Learning (MSEL)	Sc: Gross motor, fine motor, visual reception, receptive language, expressive language Raw: sum of total score	SDB in preschoolers with DS not associated with cognitive outcomes involving motor skills and language.
Joyce et al., 2019 Sleep disorder	Prospective cohort (U.K.)	3–6: 80 DS±OSA	Behavior Rating Inventory of Executive Function–Preschool Version (BRIEF-P) *Parent rept	T score: Inhibit, shift, emotional control, working memory, inhibitory self-control index, flexibility index, emergent metacognition index, global executive composite, plan/organize	OSA associated with poorer working memory, emotional control, and shifting (aspects of executive function).
Lee et al., 2019 Sleep disorder	Prospective cohort (Taiwan)	6–18: 30 DS±OSA	Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) Wechsler Intelligence Scale for Children (WISC-IV) Wechsler Adult Intelligence Scale (WAIS-III) Developmental Neuropsychological Assessment (NEPSY) visuomotor precision	Sc: Vocabulary (this was the only subtest reported in the results) SS: FSIQ Sc: Fine motor skills	After adjustment for age and FSIQ, DS+OSA not associated with deficits in vocabulary or visuomotor precision. In a subgroup of ages 6–12 years, OSA associated with lower WPPSI-R vocabulary. No associations with visuomotor precision.
Rihtman et al., 2010 Cardiovascular disorder	Cross-sectional (Israel)	6–17: 60 DS±other congenital anomalies (36 CHD)	Stanford-Binet Intelligence Scales (SB-4) Beery-Buktenica Developmental Test of Visual-Motor Integration (Berry VMI)	SS: Full IQ, Verbal, Abstract/Visual, Qualitative Reasoning, Short-Term Memory SS: Visual, Motor, and Visual-Motor Integration	Presence or severity of congenital anomaly (i.e. CHD) not associated with cognitive performance.
Visootsak et al., 2011 Cardiovascular disorder	Case control (U.S.)	0.5–2: 29 DS+CHD: 12 DS-CHD: 17	Bayley Scales of Infant and Toddler Development (Bayley-III)	SS: Cognitive, Language, and Motor.	Infants with DS+CHD had lower motor composite scores, but no differences in cognitive or language composite scores.
Visootsak et al., 2013 Cardiovascular disorder	Case control (U.S.)	2–3.5: 29 DS+CHD: 12 DS-CHD: 17	Mullen Scales of Early Learning (MSEL)	Sc: Expressive Language, Receptive Language, Visual Reception, Fine Motor	No differences in expressive, receptive language, or visual and fine motor.
Alsaied et al., 2016 Cardiovascular disorder	Cross-sectional (U.S.)	0–2: 36 DS+CHD: 12 DS-CHD: 24 3–5: 38 DS+CHD: 7 DS-CHD: 31 6–18: 104 DS+CHD: 26 DS-CHD: 78	Bayley Scales of Infant and Toddler Development (Bayley-III) Peabody Developmental Motor Scales (PDMS-II) Brief Rating Inventory of Executive Function (BRIEF) *Parent rept Differential Ability Scales (DAS-II) Stanford-Binet Intelligence Scales (SB-5)	SS: Language, Motor Sc:" Receptive Language, Expressive Language, Fine Motor, Gross Motor Raw: Visual Motor, Grasping SS: Fine Motor T score: Executive function, Initiate, Global executive composite, Behav. Regulation, Emotional control, Inhibit, Plan/Organize, Monitor, Working memory, Composite organization of materials SS: Nonverbal IQ SS: Full IQ, Knowledge, Qualitative Reasoning, Visual Spatial	Infants with DS+CHD had lower receptive, expressive, and language scores. No differences in fine/gross motor scores. Preschoolers with DS+CHD did not differ in auditory or expressive language, visual motor, grasping, or fine motor scores. Children with DS+CHD did not differ in executive function, nor in performance-based measures of nonverbal IQ, full IQ, knowledge, qualitative reasoning, and visual spatial skills.
Visootsak et al., 2016 Cardiovascular disorder	Case-control (U.S.)	0.5–2: 57 DS+CHD: 20 DS-CHD: 37	Bayley Scales of Infant and Toddler Development (Bayley-III)	Raw Composite: Cognitive, Expressive Language, Receptive Language, Gross Motor, Fine Motor	In adjusted analyses, DS+ASVD had lower gross motor and cognition/ expressive language scores.
Rosser et al., 2018 Cardiovascular disorder (among other CHC)	Cross-sectional (U.S.)	6–25: 226 DS+CHD:122 DS-CHD: 104	Arizona State Cognitive Battery: CANTAB, reaction time, paired-associate learning, spatial span, intra/extradimensional set-shifting Virtual computer-generated arena Modified dots task Finger sequencing task Developmental Neuropsychological Assessment (NEPSY) visuomotor precision Kaufman Brief Intelligence Test (KBIT-II) Scales of Independent Behavior-Revised (SIB-R)*Parent rept Behavior Rating Inventory of Executive Function-School Age (BRIEF)* Parent rept Nisonger Child Behavior Rating Form (NCBRF) *Parent rept	Z scores: Associative learning, reaction time, memory span, set-shifting Raw: Spatial learning Raw: Inhibitory control, working memory Raw: Sensorimotor function Sc: Fine motor skills SS: Full, Verbal, Non-verbal IQ Sc: Motor, social and communication, personal living, community living skills T score: Executive function, Initiate, Global executive composite, Behav. Regulation, Emotional control, Inhibit, Plan/Organize, Monitor, Working memory, Composite organization of materials Sc: Compliant/calm, adaptive social, conduct problems, insecure/anxious, hyperactive, self-injury/stereotypic, self-isolated/ritualistic, overly sensitive	CHD requiring surgery in the first years of life was not associated with poorer cognitive ability for both performance-based and proxy-reported assessments, after adjusting for gender, race/ethnicity, socioeconomic status.
Wasant et al., 2008 Cardiovascular & thyroid disorders (among other CHC)	Cross-sectional (Thailand)	3–6: 100	Capute Scales of Cognitive Adaptive Test/Clinical Linguistic and auditory Milestones Scales (CAT/CLAMS)	SS: Developmental Quotient (DQ)	CHD, but not thyroid disorders, was associated with lower DQ. Family income and age at the first speech-training program were the only independent predictors of DQ.
Tapp et al., 2005 Seizure disorder	Prospective cohort (U.S.)	1–3: 29 DS+IS: 8 DS-seizures: 21	Bayley Scales of Infant and Toddler Development (Bayley-III)	Sc: Receptive Language, Expressive Language, Fine Motor, Gross Motor SS: Cognitive	DS+IS scored lower across all cognition domains. IS treatment delays did not contribute to neurodevelopmental outcomes.

DS = Down syndrome, TD = typically developing without Down syndrome, SDB = sleep disordered breathing, WS = William’s syndrome, ID = Intellectual disability, CHC = Chronic health condition, CHD = Congenital heart disease, ASVD = Atrioventricular septal defect, ASD = Atrial septal defect, OSA = Obstructive sleep apnea, IS = infantile spasms, SQ = sleep quality, IQ = intelligence quotient, DQ = developmental quotient, MA = mental age, SS = standard composite score, SD = 15. Sc = Scaled scores based on age-normed T scores.