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Advanced Neurology Improving cognitive development in Down syndrome

performed on the four blastomeres as these earlier stem having been exposed to a drug placebo and the same
cells are totipotent, which means that each one is capable training program. A retest 16 months later showed partial
of generating a complete organism while eliminating the persistence of the effects. This experiment is inconclusive,
other three blastomeres. However, whether performed at however. Its design does not allow to quantify the respective
day 2 or 3 embryonic life, there would not be enough time influences of drug and training in the results. The design
available between syngamy and chromosome editing for should have included three groups of subjects matched for
rendering the therapeutic intervention practical. age and sex, that is, 1: EGCG alone; 2: Cognitive training
alone; and 3: EGCG + cognitive training.
3. Epigenetic reduction of gene
overexpression More genes located on Hsa21, but DYRK1A is
overexpressed in trisomy 21. They also need to be
Identifying genes on Hsa21 with a dosage imbalance downregulated. Alternatively, natural variation in gene
contributing to alterations in brain, behavior, and health expression may also modulate the outcome of gene
in persons with DS is a foremost task. Ait Yahya-Graison dosage imbalances. Prandini et al. have suggested that
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et al. counted 120 genes expressed in lymphoblastic cells overexpression of some gene sequences is compensated
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derived from individuals with DS. About 20% of these back post-transcriptionally toward typical dosage
genes were overexpressed in correspondence with the levels. However, Hunter et al. insist that gene dosage
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gene dosage effect (i.e., 1.5) or even amplified beyond compensation is not a common mechanism in DS.
that level, including genes DYRK1A, APP, and EURL that It depends on the aneuploid chromosome, the tissue
play important roles in cell functions and neurogenesis. analyzed, and the stage of development.
DYRK1A transgenic mice exhibit neurogenesis alterations,
brain, and behavioral abnormalities comparable to those A huge task awaits biomedical research in testing
of persons with DS. In humans, gene expression studies safe molecular products with the capacity to regulate the
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of amniotic fluid, placenta, and cardiac tissues during overexpressed genes in trisomy 21.
fetal development suggest that in DS at least 40 genes Complicating the matter is the outcome of an
are involved in craniofacial changes, nervous system investigation by Donovan et al. revealing an important
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development, intellectual disability, cardiac anomalies, and molecular heterogeneity in trisomy 21. These researchers
myeloproliferative disorders. 17 analyzed blood samples from 356 participants with DS
Epigenetics offers hope for improving the biological and 146 euploid controls matched for age and sex. They
development of individuals with DS by regulating gene identified several subtypes of trisomy based on differential
expression. overexpression patterns of genes on chromosome 21, both
among different Hsa21 genes and across DS individuals.
A natural product, epigallocatechin-3-gallate (EGCG),
has generated much interest in recent years. It is a Comparative analyses among these subtypes revealed
a strong heterogeneity in the dysregulation of key
polyphenol of green tea with antioxidant properties and pathophysiological processes across the molecular subtypes
the capacity to inhibit the expression of the kinase encoded of trisomy 21. Future research linking these molecular
by gene DYRK1A. Experiments with mouse models of DS
show that when administered early in development, EGCG differences with DS symptoms may force clinical strategies
rescues neurogenesis. 18,19 Controlling product dosage and into a more personalized approach to DS.
treatment duration is essential. Chronic administration 4. Brain pharmacotherapy
of doses of 100 mg EGCG/kg/daily from embryonic time
to early postnatal days in Ts64Dn mice has detrimental Neurogenesis impairment during the fetal stage in DS
effects on craniofacial development whereas doses of has three major causes: (1) abnormalities in the neural
30 mg/kg/day improve the facial skeleton. 20 differentiation of iPSCs into NSCs and cell cycle alterations
reducing proliferation of NSCs leading to brain hypotrophy
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De la Torre et al. tested the effect of a one-year (between 10 and 30% reduction in weight, size, and
treatment with EGCG green tea extracts, 9mg per kilo volume); (2) augmented differentiation of NSCs into glial
of weight daily, administered orally and coupled with elements (oligodendrocytes and astrocytes) at the expense
cognitive training, in a sample of 54 adolescents and adults of neural cells; and (3) abnormal neuron maturation
with DS, women, and men, aged between 16 and 34 years. with reduced dendritic areas, spine density, and reduced
Participants treated with green tea extracts containing neuronal connectivity. 25-27
EGCG and simultaneously enrolled in a cognitive training
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demonstrated a significant superiority in memory, visual Stagni and Bartesaghi have identified a series of genes
recognition, and daily routines abilities over the subjects responsible for neurogenesis impairment in DS, among

Volume 4 Issue 1 (2025) 3 doi: 10.36922/an.3785