Carla Startin

The importance of understanding individual differences in Down syndrome

In this article, we first present a summary of the general assumptions about Down syndrome (DS) still to be found in the literature. We go on to show how new research has modified these assumptions, pointing to a wide range of individual differences at every level of description. We argue that, in the context of significant increases in DS life expectancy, a focus on individual differences in trisomy 21 at all levels—genetic, cellular, neural, cognitive, behavioral, and environmental—constitutes one of the best approaches for understanding genotype/phenotype relations in DS and for exploring risk and protective factors for Alzheimer’s disease in this high-risk population.

The LonDownS adult cognitive assessment to study cognitive abilities and decline in Down syndrome.

Background: Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with an ultra-high risk of developing Alzheimer’s disease. However, there is individual variability in the onset of clinical dementia and in baseline cognitive abilities prior to decline, particularly in memory, executive functioning, and motor coordination. The LonDownS Consortium aims to determine risk and protective factors for the development of dementia and factors relating to cognitive abilities in people with DS. Here we describe our cognitive test battery and related informant measures along with reporting data from our baseline cognitive and informant assessments. Methods: We developed a cognitive test battery to assess general abilities, memory, executive function, and motor coordination abilities in adults with DS, with informant ratings of similar domains also collected, designed to allow for data on a broad range of participants. Participants (n=305) had a range of ages and abilities, and included adults with and without a clinical diagnosis of dementia. Results: Results suggest the battery is suitable for the majority of adults with DS, although approximately half the adults with dementia were unable to undertake any cognitive task. Many test outcomes showed a range of scores with low floor and ceiling effects. Non-verbal age-adjusted IQ scores had lower floor effects than verbal IQ scores. Before the onset of any cognitive decline, females aged 16-35 showed better verbal abilities compared to males. We also identified clusters of cognitive test scores within our battery related to visuospatial memory, motor coordination, language abilities, and processing speed / sustained attention. Conclusions: Our further studies will use baseline and longitudinal assessments to explore factors influencing cognitive abilities and cognitive decline related to ageing and onset of dementia in adults with DS.

Variation in the X-Linked EFHC2 Gene Is Associated with Social Cognitive Abilities in Males

Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males.

Developing an Informant Questionnaire for Cognitive Abilities in Down Syndrome: The Cognitive Scale for Down Syndrome (CS-DS).

Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). Abilities relating to executive function, memory and language are particularly affected in DS, although there is a large variability across individuals. People with DS also show an increased risk of developing dementia. While assessment batteries have been developed for adults with DS to assess cognitive abilities, these batteries may not be suitable for those with more severe IDs, dementia, or visual / hearing difficulties. Here we report the development of an informant rated questionnaire, the Cognitive Scale for Down Syndrome (CS-DS), which focuses on everyday abilities relating to executive function, memory and language, and is suitable for assessing these abilities in all adults with DS regardless of cognitive ability. Complete questionnaires were collected about 128 individuals with DS. After final question selection we found high internal consistency scores across the total questionnaire and within the executive function, memory and language domains. CS-DS scores showed a wide range, with minimal floor and ceiling effects. We found high interrater (n = 55) and test retest (n = 36) intraclass correlations. CS-DS scores were significantly lower in those aged 41+ with significant cognitive decline compared to those without decline. Across all adults without cognitive decline, CS-DS scores correlated significantly to measures of general abilities. Exploratory factor analysis suggested five factors within the scale, relating to memory, self-regulation / inhibition, self-direction / initiation, communication, and focussing attention. The CS-DS therefore shows good interrater and test retest reliability, and appears to be a valid and suitable informant rating tool for assessing everyday cognitive abilities in a wide range of individuals with DS. Such a questionnaire may be a useful outcome measure for intervention studies to assess improvements to cognition, in addition to detecting dementia-related cognitive decline. The CS-DS may also be a useful tool for other populations with ID.

Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome

BackgroundDown syndrome (DS) may be considered a genetic form of Alzheimer’s disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions.MethodsWe measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis.ResultsNF-L concentrations increased with age (Spearman’s rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status.ConclusionsNF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia.

Aging related cognitive changes associated with Alzheimer's disease in Down syndrome

Individuals with Down syndrome (DS) have an extremely high genetic risk for Alzheimers disease (AD), however, the course of cognitive decline associated with progression to dementia is ill‐defined. Data‐driven methods can estimate long‐term trends from cross‐sectional data while adjusting for variability in baseline ability, which complicates dementia assessment in those with DS.

Sequence of cognitive changes associated with development of Alzheimer's disease in Down syndrome - data driven analysis

Objective Individuals with Down syndrome (DS) have an extremely high genetic risk for Alzheimer’s disease (AD) however the course of cognitive decline associated with progression to dementia is ill-defined. Data-driven methods can estimate long-term trends from cross-sectional data while adjusting for variability in baseline ability, which complicates dementia assessment in those with DS. Methods We applied an event-based model to cognitive test data and informant-rated questionnaire data from 283 adults with DS (the largest study of cognitive functioning in DS to date) to estimate the sequence of cognitive decline and individuals’ disease stage. Results Decline in tests of memory, sustained attention / motor coordination, and verbal fluency occurred early, demonstrating that AD in DS follows a similar pattern of change to other forms of AD. Later decline was found for informant measures. Using the resulting staging model, we showed that adults with a clinical diagnosis of dementia and those with APOE 3:4 or 4:4 genotype were significantly more likely to be staged later, suggesting the model is valid. Interpretation Our results identify tests of memory and sustained attention may be particularly useful measures to track decline in the preclinical/prodromal stages of AD in DS whereas informant-measures may be useful in later stages (i.e. during conversion to dementia, or post-diagnosis). These results have implications for the selection of outcome measures of treatment trials to delay or prevent cognitive decline due to AD in DS. As clinical diagnoses are generally made late into AD progression, early assessment is essential.

The Relationship Between Sound–Shape Matching and Cognitive Ability in Adults With Down Syndrome

Down syndrome (DS), the most common genetic cause of intellectual disability, is characterised by a pattern of cognitive deficits hypothesised as relating to later developing neural systems. Multisensory integration (MSI) has been shown to benefit cognitive performance on numerous tasks in the typically developing population and is implicated in the early development of various cognitive processes. Given these developmental links of both MSI and DS it is important to determine the relationship between MSI and DS. This study aimed to characterise sound-shape matching performance in young adults with DS as an indicator of MSI (correct response rate around 90% in typically developing individuals). We further investigated the relationship between task performance and estimated cognitive ability (verbal and non-verbal) in addition to everyday adaptive behavior skills. Those answering correctly (72.5%) scored significantly higher across cognitive and adaptive behavior measures compared to those answering incorrectly. Furthermore, 57.1% of individuals with estimated cognitive ability scores below the median value answered correctly compared to 89.5% of individuals scoring above the median, with similar values found for adaptive behavior skills (57.9% vs 94.4%). This preliminary finding suggests sound-shape matching deficits are relatively common in DS but may be restricted to individuals of lower ability as opposed to being a general characteristic of DS. Further studies investigating aspects of MSI across a range of modalities are necessary to fully characterise the nature of MSI in DS and to explore underlying neural correlates and mechanisms.

GENETIC DISSECTION OF SEVERITY AND ONSET MODULATORS FOR ALZHEIMER’S PATHOLOGY IN DOWN SYNDROME USING CELLULAR SYSTEMS

Madhav Thambisetty, Cristina Legido-Quigley, King’s College London, London, United Kingdom; Kings College London, London, United Kingdom; Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom; Johns Hopkins University School of Medicine, Baltimore, MD, USA; Duke University, Durham, NC, USA; National Institute on Aging, Baltimore, MD, USA. Contact e-mail: stuart.snowden@kcl.ac.uk

USING FUNCTIONAL NEAR INFRARED SPECTROSCOPY (FNIRS) TO MEASURE FRONTAL CORTICAL ACTIVITY IN ADULTS WITH DOWN SYNDROME

ADNI1 to 2 transition, ADNI3 updates the study with recent MRI advances. ADNI2 included DTI, but only for GE scanners. ADNI3 includes diffusion for all manufacturers involved (GE, Philips, and Siemens), and emphasizes consistency across scanners. The resolution has been improved from 2.7 to 2.0mm (isotropic), and, where simultaneous multislice (SMS) acceleration is available, acquires three diffusion shells, supporting advanced diffusion analyses such as NODDI and DKI. Methods: To serve the general dementia research community, the diffusion protocol was designed to support three different analyses: DTI, with an emphasis on cross-sectional and longitudinal consistency; tractography, calling for more directions at higher diffusion weighting (b); and multi-compartment analyses such as NODDI and DKI, which require > 2 b values. Each depends on spatial resolution and SNR, but the time available for diffusion in ADNI3 is limited to around 8 minutes, and most scanners will not have SMS capability until partway through ADNI3. This strongly favors a HARDI-type acquisition with two protocols, a basic b1⁄41000 s/mm shell, and for SMScapable scanners, the addition of shells at b 1⁄4 500 and 2000s/mm. The directions were evenly spaced using an electrostatic repulsion algorithm. Results: Figure 1 shows the ADNI3 diffusion parameters. Conclusions:All ADNI3 sessions will acquire diffusion scans, with sites switching from Basic to Advanced protocol as SMS becomes available. The Advanced protocol includes the Basic one as a subset for consistency. References: 1. Zhang, H., Schneider, T., Wheeler-Kingshott, C. A. & Alexander, D. C. NODDI: Practical in vivo neurite orientation dispersion and density imaging of the human brain. NeuroImage 61,1000–1016 (2012). 2. Jensen, J. H., Helpern, J. A., Ramani, A., Lu, H. & Kaczynski, K. Diffusional kurtosis imaging: The quantification of non-gaussian water diffusion by means of magnetic resonance imaging. Magn. Reson. Med. 53,1432–1440 (2005). 3. Caruyer, E., Lenglet, C., Sapiro, G. & Deriche, R. Design of multishell sampling schemes with uniform coverage in diffusion MRI. Magn. Reson. Med. 69, 1534–1540 (2013). P3-328 USING FUNCTIONAL NEAR INFRARED