Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults with a Fontan Circulation

Background: Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well-defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry and post-natal clinical factors. Methods: In a bi-national study, participants with a Fontan circulation without a pre-existing major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed using Cogstate software in 107 Fontan-participants and compared with control groups with transposition of the great arteries (TGA; n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the Fontan-participants and compared with healthy control data from the ABIDE I and II and PING data repositories. Clinical data were retrospectively collected. Results: Of the Fontan-participants with neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Fontan-participants performed worse in several areas of neurocognitive function compared with those with TGA and healthy controls (p<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan and longer time since Fontan procedure (p<0.05). Fontan-adults had more marked neurocognitive dysfunction than Fontan-adolescents in two domains (psychomotor function, p=0.01 and working memory, p=0.02). Structural brain injury was present in the entire Fontan cohort; presence of white matter injury was associated with worse paired associate learning (p<0.001), but neither the presence or severity of infarct, subcortical grey matter injury and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (p<0.001 in all regions) and smaller regional brain volumes in the majority of cerebral cortical regions (p<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (p<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (p≤0.04). Conclusions: Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller grey and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

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Insufficient Sleep Following Pediatric Mild Traumatic Brain Injury Correlates With Neurocognitive Dysfunction

Neurology ◽

10.1212/wnl.0000000000013046 ◽

2021 ◽

Vol 98 (1 Supplement 1) ◽

pp. S1.1-S1

Author(s):

Bailey Hull ◽

Patrick Karabon ◽

Neal Alpiner

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Sleep Disturbance ◽

Mild Traumatic Brain Injury ◽

Daytime Sleepiness ◽

Epworth Sleepiness Scale ◽

Neurocognitive Function ◽

Neurocognitive Dysfunction ◽

Neurocognitive Test ◽

Test Outcomes

ObjectiveAnalyze the impact of sleep disturbance on neurocognitive function in children recovering from mild traumatic brain injury (mTBI).BackgroundSleep disturbance of any nature is reported in more than half of all mTBI patients. The pathophysiology of sleep disturbance following mTBI is associated with structural and functional disruptions of sleep circuitry and circadian rhythm. Specifically in the pediatric population, untreated sleep disturbance has been shown to delay mTBI recovery and compound other morbidities including neurocognitive dysfunction.Design/MethodsA retrospective chart review of 118 pediatric patients (mean age = 14.56 ± 2.03 years) recovering from mTBI was performed. Epworth Sleepiness Scale (SF-8) results were analyzed in relation to CNS Vital Signs (CNSVS) neurocognitive test outcomes. SF-8 is a subjective estimation of a patient's daytime sleepiness. CNSVS uses a multitude of domains to objectively evaluate the overall neurocognitive status of a patient. Pearson correlations were calculated using a type I error of p < 0.05 between variables.ResultsEpworth Sleepiness Scale (SF-8) results showed 28.82% of participants experienced excessive daytime sleepiness sufficient enough to recommend medical attention. Upon further analysis, there was a significant negative correlation between SF-8 and CNSVS neurocognitive test outcomes including complex attention (r = −0.37; p = 0.0004), cognitive flexibility (r = −0.24; p = 0.0151), executive function (r = −0.21; p = 0.0350), and simple attention (r = −0.36; p = 0.0003) scores. This means as SF-8 scores increased (participants defined as excessively sleepy), neurocognitive function scores in these domains decreased. There was not enough evidence to conclude a significant correlation between other CNSVS domains and SF-8 (all p > 0.05).ConclusionsOur findings support the concern of neurocognitive dysfunction among pediatric mTBI patients with sleep disturbance. Further analysis is needed to determine if mTBI is the primary source or an exacerbating factor of sleep disturbance within this population. Nonetheless, these findings suggest a need for thorough evaluation when treating sleep concerns, irrespective of a history of childhood mTBI.

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ADOLESCENTS AND ADULTS WITH A FONTAN CIRCULATION HAVE IMPAIRED NEUROCOGNITIVE FUNCTION THAT IS ASSOCIATED WITH REDUCED BRAIN VOLUME

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(20)31175-x ◽

2020 ◽

Vol 75 (11) ◽

pp. 548

Author(s):

Charlotte Verrall ◽

Adrian Schembri ◽

Yves d'Udekem ◽

Diana Zannino ◽

Karin Du Plessis ◽

...

Keyword(s):

Brain Volume ◽

Neurocognitive Function ◽

Fontan Circulation ◽

Adolescents And Adults

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Adolescents and adults with Fontan circulation: insights from the PREpArE-Fontan registry

Cardiology in the Young ◽

10.1017/s1047951121002791 ◽

2021 ◽

pp. 1-9

Author(s):

Lars Søndergaard ◽

Jamil Aboulhosn ◽

Yves d’Udekem ◽

Céline Faure ◽

Wayne J Franklin ◽

...

Keyword(s):

Creatinine Clearance ◽

Receptor Antagonist ◽

Functional Class ◽

Fontan Circulation ◽

Endothelin Receptor Antagonist ◽

Endothelin Receptor ◽

Converting Enzyme Inhibitors ◽

Nyha Functional Class ◽

Lateral Tunnel ◽

Adolescents And Adults

Abstract The Patient Registry for Adolescents and Adults with Stable Fontan Circulation aims to describe a contemporary cohort of Fontan patients who could be eligible for a clinical trial investigating macitentan, an endothelin receptor antagonist. This international, non-interventional, multicentre, cross-sectional, observational registry enrolled patients with “stable” Fontan circulation ≥10 years following extra-cardiac conduit or lateral tunnel procedure. Main exclusion criteria were NYHA functional class IV, reoperation of Fontan circulation, or signs of disease worsening. Patient characteristics at enrolment are described; available data were collected during a single registration visit. Of the 266 screened patients, 254 were included in this analysis. At enrolment, median (interquartile range) age was 24 (20;30) years, 37%/63% of patients were from the USA/Europe, 54% were male, 54%/47% had undergone extra-cardiac conduit/lateral tunnel procedures, and 95% were in NYHA functional class I or II. History of arrhythmia was more common in older patients and patients with lateral tunnel; overall prevalence was 19%. Most laboratory values were within the normal range but mean creatinine clearance was abnormally low (87.7 ml/min). Angiotensin-converting enzyme inhibitors were used by 48% of patients and their use was associated with creatinine clearance <90 ml/min (p = 0.007), as was Fontan completion at an older age (p = 0.007). 53.4% of patients had clinical characteristics that could potentially meet an endothelin receptor antagonist trial’s eligibility criteria. The PREpArE-Fontan registry describes a cohort of patients who could potentially participate in an endothelin receptor antagonist trial and identified early subtle signs of Fontan failure, even in “stable” patients.

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Developing an adolescent and adult Fontan Management Programme

Cardiology in the Young ◽

10.1017/s104795112100175x ◽

2021 ◽

pp. 1-6

Author(s):

Adam M. Lubert ◽

Tarek Alsaied ◽

Andrew T. Trout ◽

Jonathan R. Dillman ◽

Joseph J. Palermo ◽

...

Keyword(s):

Single Ventricle ◽

Fontan Procedure ◽

Multiple Organ ◽

Fontan Circulation ◽

Management Programme ◽

Adverse Outcomes ◽

Cardiac Complications ◽

Organ Systems ◽

Adolescents And Adults ◽

Care Models

Abstract Patients with single-ventricle CHD undergo a series of palliative surgeries that culminate in the Fontan procedure. While the Fontan procedure allows most patients to survive to adulthood, the Fontan circulation can eventually lead to multiple cardiac complications and multi-organ dysfunction. Care for adolescents and adults with a Fontan circulation has begun to transition from a primarily cardiac-focused model to care models, which are designed to monitor multiple organ systems, and using clues from this screening, identify patients who are at risk for adverse outcomes. The complexity of care required for these patients led our centre to develop a multidisciplinary Fontan Management Programme with the primary goals of earlier detection and treatment of complications through the development of a cohesive network of diverse medical subspecialists with Fontan expertise.

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Abstract 36: Association of Parental Stroke with Cognitive and Brain MRI Measures in Offspring - The Framingham Heart Study

Stroke ◽

10.1161/str.43.suppl_1.a36 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

GALIT WEINSTEIN ◽

Alexa Beiser ◽

Rhoda Au ◽

Charles DeCarli ◽

Philip A Wolf ◽

...

Keyword(s):

Executive Function ◽

Brain Injury ◽

Verbal Learning ◽

Brain Mri ◽

Abstract Reasoning ◽

Parental History ◽

Brain Volumes ◽

Regional Brain ◽

Increased Risk ◽

History Of

Objectives- Parental stroke is related to an increased risk of stroke among the offspring. Vascular related brain changes, however, often occur before clinical stroke and the association of parental history of stroke and structural brain measures and cognition has not been fully explored. We hypothesized that prospectively verified parental stroke will be associated with increased vascular brain injury and poorer cognitive performance. Methods- A total of 1,297 Framingham offspring (mean age: 61 ± 9 years, 54% women) were studied. Of these, 9.9% had prospectively identified stroke in one or both parents before age 65. Volumetric brain MRI measures of total cerebral brain volume (TCBV), regional brain volumes, white matter hyperintensity volume (WMHV), and covert brain infarcts (CBI) and performance on tests of verbal memory, abstract reasoning, verbal learning and visuospatial memory (VRd) were compared for offspring with and without parental history of stroke. All measures were assessed cross-sectionally and longitudinally (mean duration of follow-up was 6.1±1.2 years). We used models adjusted only for age, sex, education and also additionally adjusted for vascular risk factors and for WMHV as an index of subclinical vascular brain injury. GEE models were used to adjust for sibling relationships among offspring. Results- Higher WMHV (β±SE=0.17±0.08;p=0.027) and lower VRd scores (β±SE=-0.80±0.34; p=0.017) at baseline were found in offspring with parental history of stroke. In addition, participants with parental stroke by age 65 years were more likely to be in the highest quintile of increase in WMHV (OR=1.87;p=0.04) as well as worsening executive function (Trails B-A) (OR:1.81;p=0.03). Parental stroke was not associated with total and regional brain volumes or with memory, abstract reasoning and verbal learning. Conclusions- In our community-based sample of middle-aged asymptomatic subjects, the occurrence of parental stroke by age 65 years is associated with higher baseline WMHV and with a more rapid increase in WMHV. Further, parental stroke is also associated with poorer performance on VRd and a decline in executive function. The effects on baseline WMH and VRd were substantial equivalent to 2.8 and 7 years of brain aging, respectively.

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Impact of baseline neurocognitive functioning on outcomes following rehabilitation of executive function training for veterans with history of traumatic brain injury

Applied Neuropsychology Adult ◽

10.1080/23279095.2018.1490738 ◽

2018 ◽

Vol 27 (2) ◽

pp. 108-120 ◽

Cited By ~ 1

Author(s):

Erica Kornblith ◽

Gary Abrams ◽

Anthony J.-W. Chen ◽

Joaquin Burciaga ◽

Mark D’Esposito ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Executive Function ◽

Brain Injury ◽

Neurocognitive Functioning ◽

History Of ◽

Executive Function Training

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Relation of Liver Volume to Adverse Cardiovascular Events in Adolescents and Adults With Fontan Circulation

The American Journal of Cardiology ◽

10.1016/j.amjcard.2021.10.045 ◽

2021 ◽

Author(s):

Adam M. Lubert ◽

Alexander R. Opotowsky ◽

Joseph J. Palermo ◽

Tarek Alsaied ◽

Cassandra Szugye ◽

...

Keyword(s):

Cardiovascular Events ◽

Liver Volume ◽

Fontan Circulation ◽

Adolescents And Adults

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Technological Innovations to Enhance Neurocognitive Rehabilitation

The Role of Technology in Clinical Neuropsychology ◽

10.1093/oso/9780190234737.003.0019 ◽

2017 ◽

Author(s):

Anthony J.-W. Chen ◽

Fred Loya

Keyword(s):

Brain Injury ◽

Real Life ◽

Intervention Development ◽

Neurocognitive Functioning ◽

Cognitive Changes ◽

Rehabilitation Care ◽

Neuroscience Research ◽

Neurocognitive Rehabilitation ◽

Neurocognitive Dysfunctions ◽

The Many

In an instant, a brain injury can cause changes that affect a person for a lifetime. Although traumatic brain injury (TBI) can result in almost any neurological deficit, the most common and persistent deficits tend to affect neurocognitive functioning. Functional issues may produce a tremendous chronic burden on individuals, families, and healthcare systems (Thurman, Alverson, Dunn, Guerrero, & Sniezek, 1999; Yu et al., 2003). The far-reaching impact of these seemingly “invisible” deficits is often not recognized. Individuals who have suffered a TBI may also be at increased risk for developing cognitive changes later in life (Mauri et al., 2006; Schwartz, 2009; Van Den Heuvel, Thornton, & Vink, 2007). Military veterans report even higher rates of persistent issues, especially in the context of posttraumatic stress (PTS) (Polusny et al., 2011). Despite their importance, chronic neurocognitive dysfunctions are often poorly addressed. A long-term view on care-oriented research and development is needed (Chen & D’Esposito, 2010). Even as we get deeper into the 21st century, there continue to be many gaps in the rehabilitation of neurocognitive functioning after brain injury. There is a need for increased effort to advance rehabilitation care and delivery. There are two major gaps in care that could benefit from neuroscience research and technology-assisted intervention development. First, there remains a major need for theory-driven approaches to cognitive training, accompanied by the development of innovative tools to support learning of useful skills and their generalization to help achieve real-life goals. Second, major gaps in the delivery and coordination of rehabilitation must be addressed in order to provide care to the many people with brain injury who lack access to services due to barriers imposed by distance, financial constraints, and disability. This chapter introduces and illustrates some technology-assisted innovations that may help to advance neurocognitive rehabilitation care. Examples of using technology to reach into the community via tele-rehabilitation, as well as examples of reaching students in a manner aligned with their scholastic goals, are discussed.

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Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury

Nanobiomedicine ◽

10.1177/1849543520970819 ◽

2020 ◽

Vol 7 ◽

pp. 184954352097081

Author(s):

Rick Liao ◽

Thomas R Wood ◽

Elizabeth Nance

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Calcium Influx ◽

Perinatal Asphyxia ◽

Pathological Process ◽

Global Brain Ischemia ◽

Excitatory Neurotransmitters ◽

Disease Site ◽

The Right ◽

Global Brain

Excitotoxicity is a primary pathological process that occurs during stroke, traumatic brain injury (TBI), and global brain ischemia such as perinatal asphyxia. Excitotoxicity is triggered by an overabundance of excitatory neurotransmitters within the synapse, causing a detrimental cascade of excessive sodium and calcium influx, generation of reactive oxygen species, mitochondrial damage, and ultimately cell death. There are multiple potential points of intervention to combat excitotoxicity and downstream oxidative stress, yet there are currently no therapeutics clinically approved for this specific purpose. For a therapeutic to be effective against excitotoxicity, the therapeutic must accumulate at the disease site at the appropriate concentration at the right time. Nanotechnology can provide benefits for therapeutic delivery, including overcoming physiological obstacles such as the blood–brain barrier, protect cargo from degradation, and provide controlled release of a drug. This review evaluates the use of nano-based therapeutics to combat excitotoxicity in stroke, TBI, and hypoxia–ischemia with an emphasis on mitigating oxidative stress, and consideration of the path forward toward clinical translation.

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