Enduring differential patterns of neuronal loss and myelination along 6-month pulsatile gonadotropin-releasing hormone therapy in individuals with Down syndrome

Abstract

Despite major progress in understanding the impact of the triplicated chromosome 21 on the brain and behaviour in Down syndrome, our knowledge of the underlying neurobiology in humans is still limited. We sought to address some of the pertinent questions about the drivers of brain structure differences and their associations with cognitive function in Down syndrome. To this aim, in a pilot magnetic resonance imaging (MRI) study, we monitored brain anatomy in individuals with Down syndrome receiving pulsatile gonadotropin-releasing hormone (GnRH) therapy over 6 months in comparison with typically developed age- and sex-matched healthy controls. We analysed cross-sectional (Down syndrome/healthy controls n = 11/27; Down syndrome-2 females/9 males, age 26.7 ± 5.0 years old; healthy controls-8 females/19 males, age 24.1 ± 2.5 years old) and longitudinal (Down syndrome/healthy controls n = 8/13; Down syndrome-1 female/7 males, age 26.4 ± 5.3 years old; healthy controls-4 females/9 males, 24.7 ± 2.2 years old) relaxometry and diffusion-weighted MRI data alongside standard cognitive assessment. The statistical tests looked for cross-sectional baseline differences and for differential changes over time between Down syndrome and healthy controls. The post hoc analysis confined to the Down syndrome group, tested for potential time-dependent interactions between individuals' overall cognitive performance and associated brain anatomy changes. The brain MRI statistical analyses covered both grey and white matter regions across the whole brain allowing for investigation of regional volume, macromolecular/myelin and iron content, additionally to diffusion tensor and neurite orientation and dispersion density characterization across major white matter tracts. The cross-sectional analysis showed reduced frontal, temporal and cerebellar volumes in Down syndrome with only the cerebellar differences remaining significant after adjustment for the presence of microcephaly (P _{family-wise-corrected} < 0.05). The volume reductions were paralleled by decreased cortical and subcortical macromolecular/myelin content confined to the cortical motor system, thalamus and basal ganglia (P _{family-wise-corrected} < 0.05). All major white matter tracts showed a ubiquitous mean diffusivity and intracellular volume fraction reduction contrasted with no differences in magnetization transfer saturation metrics (P _{family-wise-corrected} < 0.05). Compared with healthy controls over the same period, Down syndrome individuals under GnRH therapy showed cognitive improvement (Montreal Cognitive Assessment from 11.4 ± 5.5 to 15.1 ± 5.6; P < 0.01) on the background of stability of the observed differential neuroanatomical patterns. Despite the lack of adequate Down syndrome control group, we interpret the obtained cross-sectional and longitudinal findings in young adults as evidence for predominant neurodevelopmental neuronal loss due to dysfunctional neurogenesis without signs for short-term myelin loss.

Keywords: brain tissue properties; magnetic resonance imaging; morphometry; multi-parameter mapping; trisomy 21.

Graphical Abstract

Figure 1

Global brain metrics in Down syndrome (n  = 11, DS) compared with neurotypically developed healthy controlss (n  = 27, HC). (A–C) Boxplots representing TIV, WM and GM volume. (D–F) Boxplots representing relative differences (in %) between DS and HC in cerebellum, WM and GM, after adjusting for TIV. Significance levels of the two-tailed t-tests denoted as ***P  < 0.001, ****P  < 0.0001 and ns, not significant. DS, Down syndrome; HC, healthy controls; GM, grey matter; TIV, total intracranial volume; WM, white matter.

Figure 2

Cross-sectional baseline comparison of regional GM volume between individuals with DS (n  = 11) and neurotypically developed controls (n  = 27). Cohen’s d effect size (y-axis, upper third: left hemisphere; middle third: right hemisphere; lower third: cerebellar regions). Left: regional GM volume differences without (volume). Right: with TIV adjustment (volume TIV corrected). Significance levels of the two-tailed t-tests denoted with asterisk (*) FWE-corrected P_FWE < 0.05 and plus sign (+) for uncorrected P_uncorr < 0.001. DS, Down syndrome; FWE, family-wise error; GM, grey matter; TIV, total intracranial volume.

Figure 3

Cross-sectional baseline comparison of regional tissue microstructure between individuals with DS (n  = 11) and neurotypically developed controls (n  = 27). Cohen’s d effect size (y-axis, upper third: left hemisphere; middle third: right hemisphere; lower third: cerebellar regions). Regional GM microstructural MTsat, R1 and R2* differences. Significance levels of the two-tailed t-tests denoted with asterisk (*) FWE-corrected P_FWE  < 0.05 and plus sign (+) for uncorrected P_uncorr < 0.001. DS, Down syndrome; FWE, family-wise error; MTsat, magnetization transfer saturation; R1, effective longitudinal relaxation rate; R2*, effective transverse relaxation rate.

Figure 4

Cross-sectional baseline comparison of tract-specific WM volume and tissue microstructure between individuals with DS (n  = 7) and neurotypically developed controls (n  = 12). Comparison of (A) diffusion indices MD and ICVF and (B) relaxometry indices MTsat, R1 and R2* across 51 tracts. Cohen’s d effects sizes of the two-tailed t-tests denoted with solid dots (•) for P_FWE < 0.05, triangles (Δ) for P_uncorr < 0.001 and crosses (x) for non-significant results P_uncorr ≥ 0.001. DS, Down syndrome; FWE, family-wise error; ICVF, intracellular volume fraction; MD, mean diffusivity; MTsat, magnetization transfer saturation; R1, effective longitudinal relaxation rate; R2*, effective transverse relaxation rate; WM, white matter.

Figure 5

Comparison of longitudinal changes in GM volume between individuals with DS undergoing pulsatile GnRH therapy (n  = 8) and neurotypically developed controls without intervention over 6 months (n  = 13). Cohen’s d effect size (y-axis, upper third: left hemisphere; middle third: right hemisphere; lower third: cerebellar regions). Representation of trends in the absence of statistically significant differences between groups. DS, Down syndrome; GnRH, gonadotropin-releasing hormone; GM, grey matter.

Figure 6

Comparison of longitudinal changes in GM tissue microstructure between individuals with DS undergoing pulsatile GnRH therapy (n  = 8) and neurotypically developed controls without intervention over 6 months (n  = 13). Cohen’s d effect size (y-axis, upper third: left hemisphere; middle third: right hemisphere; lower third: cerebellar regions). Regional GM microstructural MTsat, R1 and R2* differences. Significance levels of the regression analyses result on relative changes over time denoted with asterisk (*) for FWE-corrected P_FWE  < 0.05. DS, Down syndrome; FWE, family-wise error; GnRH, gonadotropin-releasing hormone; GM, grey matter; MTsat, magnetization transfer saturation; R1, effective longitudinal relaxation rate; R2*, effective transverse relaxation rate.

Figure 7

Comparison of longitudinal changes in tract-specific WM volume and tissue microstructure between individuals with DS (n  = 7) and neurotypically developed controls (n  = 12). (A) Diffusion indices MD and ICVF and (B) relaxometry indices MTsat, R1 and R2* across 51 tracts. Cohen’s d effects sizes of the regression analyses result on relative changes over time. Representation of trends in the absence of statistically significant differnces between groups, Crosses (x) denote trends at P_uncorr ≥ 0.001. DS, Down syndrome; ICVF, intracellular volume fraction; MD, mean diffusivity; MTsat, magnetization transfer saturation; R1, effective longitudinal relaxation rate; R2*, effective transverse relaxation rate; WM, white matter.