Tuesday, February 20, 2007

Changes In The Brain - Focusing on brain of a baby with DS

On the Einstein-Syndrome listserv there was a discussion regarding the brains of children with DS and how they are when they are born and in pregnancy. These are the recent posts I did on it and I thought this would be good information for others as well:


Back in November of '06 there was some discussion regarding the brains of children with DS starting out normal and then start going downhill at 6 months of age. Regina sent me 4 articles that she was able to get from a doctor who had said that the brains of children with DS start out normal and then go awry at 6 mths old. I finally had a chance to look at the 4 studies she emailed to me. I read in-depth one of the studies (see below) and skim read the others. I also did a bit of research on PubMed too. All 4 of these studies talk about the Dendritic cells (regards neurons & the brain). To look to these 4 studies and say that the brain of children with DS starts out normal is incorrect. These 4 studies were done in the 70's & 80's, so there obviously has been much advance in the research since then and particularly in regards to the brain. I wouldn't go just on these 4 studies to try to show that the brains in DS are normal. These studies do show some good things in regards to dendritic cells and such. In the study that I will quote below, they have already seen changes at 4 months of age! But, you can look this stuff up on PubMed and find that there are changes in the dendritic area in brains of children with DS as early as 19 wks gestation. So, there is newer research and evidence that shows that there are abnormalities in the DS brain in this particular area before birth. Plus, you cannot just look at one particular area and say that the brain is normal up until a certain age. There are many other problems present in the DS brain when they are born (as I posted back in November some studies & I'll repost those again).

Dendritic Atrophy in Children with Down's Syndrome. Becker, 1986

"The results suggest that the dendritic tree atrophies in early childhood in DS."

This study is speaking of the dendritic tree atrophying. This does not mean that the brain of children with DS is normal at birth. This shows that the dendritic tree has not yet atrophied at birth, but appears to start atrophy at a later age. There are many, many complex systems in the Down syndrome body which do not function correctly. When all of these systems start to cause problems it is not completely known. There are certain things that are present at birth (such as oxidative stress and many other things). The gene overexpressions are all present at birth (present when the child is created with the 21st chromosome mutation), but when each one's influence starts, it is not completely known.

In the beginning of this study, it cites several different studies which have been done that are examining the basis for mental retardation in DS. They mention throughout some changes which have been seen in children over 4 months of age. Things are changing at a young age.

An interesting thing in this study is that there are changes in a child with down syndrome even as an infant. One paragraph of the study states, "Our analysis of dendritic branching development in brains of patients with Down's syndrome reveals that the pattern of branching is different from that of control brains."

So, in this study they acknowledge that the brains of children with DS are different from normal brains. They go onto say that there are changes even in the infants, "In the infantile period, the total number of intersections was greater in subjects with Down's syndrome than in controls. By the juvenile period, the number of intersections was significantly decreased. . ."

Another spot in the study says, "With early growth and development, the normal dendritic tree expands. This expansion is not seen in Down's syndrome. On each of the measures ( . . .), the Down's syndrome neurons showed decreased numbers with increasing age."

As I stated above, the brains of children with DS are different at birth, but they do not start to see atrophy until the child gets older.

Another statement in the study states that they see another interesting difference in DS, at a young age of only 4 months. They write, "The Down's syndrome neurons showed one other striking difference from controls -- a relatively expanded dendritic tree at 4 months of age. There are several plausible explanations for the excessive early outgrowth of dendritic branches followed by subsequent atrophy. The excessive dendrite branching may be an abortive attempt by the neuron to compensate for the decreased numbers of spines and synapses on its receptive surfaces."

They speculate why this may happen and say, "The extra chromosome 21 may produce excess RNA and protein that cannot be permanently incorporated into the dendritic membrane or cytoskeleton, so membrane turnover is decreased. This would prevent the dendritic tree from being maintained, which would cause the neurons to become "atrophic" relative to the control dendritic pattern."

They note at the end of the article, "Like other investigators, we have found quantitative differences between controls and patients. . . a quantitative change should be expected." This is something I wish some of those people who are not for TNI would realize. A change should be expected in DS compared to normal individuals. They don't seem to realize that all too often!

Looking up some information on PubMed regarding the dendritic cells and DS brings up this current information:

---- This below abstract states that they see abnormalities in the fetus with Down Syndrome. Thus, showing that dendritic abnormalities are present in the brain of a baby with DS. I'll paste another abstract below which says that dendritic abnormalities are known to be one of the reasons for MR in Down Syndrome.

J Neuropathol Exp Neurol. 2004 Jul;
Trisomy 21 and the brain.
Mrak RE, Griffin WS.
In fetuses with Down syndrome, neurons fail to show normal dendritic development, yielding a "tree in winter" appearance. This developmental failure is thought to result in mental retardation. In adults with Down syndrome, neuronal loss is dramatic and neurofibrillary and neuritic Abeta plaque pathologies are consistent with Alzheimer disease. These pathological changes are thought to underlie the neuropsychological and physiological changes in older individuals with Down syndrome. Two chromosome 21-based gene products, beta-amyloid precursor protein (betaAPP) and S100B, have been implicated in these neuronal and interstitial changes. Although not necessary for mental retardation and other features, betaAPP gene triplication is necessary, although perhaps not sufficient, for development of Alzheimer pathology. S100B is overexpressed throughout life in Down patients, and mice with extra copies of the S100B gene have dendritic abnormalities. S100B overexpression correlates with Alzheimer pathology in post-adolescent Down syndrome patients and has been implicated in Abeta plaque pathogenesis. Interleukin-1 (IL-1) is a non-chromosome-21-based cytokine that is also overexpressed throughout life in Down syndrome. IL-1 upregulates betaAPP and S100B expression and drives numerous neurodegenerative and self-amplifying cascades that support a neuroinflammatory component in the pathogenesis of sporadic and Down syndrome-related Alzheimer disease.
PMID: 15290893 [PubMed - indexed for MEDLINE]

Prog Neurobiol. 2004 Oct
On dendrites in Down syndrome and DS murine models: a spiny way to learn.
Benavides-Piccione R,
Ballesteros-Yanez I,
de Lagran MM,
Elston G,
Estivill X,
Fillat C,
Defelipe J,
Dierssen M.
Cajal Institute, 28002 Madrid, Spain.
Since the discovery in the 1970s that dendritic abnormalities in cortical pyramidal neurons are the most consistent pathologic correlate of mental retardation, research has focused on how dendritic alterations are related to reduced intellectual ability. Due in part to obvious ethical problems and in part to the lack of fruitful methods to study neuronal circuitry in the human cortex, there is little data about the microanatomical contribution to mental retardation. The recent identification of the genetic bases of some mental retardation associated alterations, coupled with the technology to create transgenic animal models and the introduction of powerful sophisticated tools in the field of microanatomy, has led to a growth in the studies of the alterations of pyramidal cell morphology in these disorders. Studies of individuals with Down syndrome, the most frequent genetic disorder leading to mental retardation, allow the analysis of the relationships between cognition, genotype and brain microanatomy. In Down syndrome the crucial question is to define the mechanisms by which an excess of normal gene products, in interaction with the environment, directs and constrains neural maturation, and how this abnormal development translates into cognition and behaviour. In the present article we discuss mainly Down syndrome-associated dendritic abnormalities and plasticity and the role of animal models in these studies. We believe that through the further development of such approaches, the study of the microanatomical substrates of mental retardation will contribute significantly to our understanding of the mechanisms underlying human brain disorders associated with mental retardation.
PMID: 15518956 [PubMed - indexed for MEDLINE]

--- Another interesting study below done by Lubec states that there are significant abnormalities in babies with DS before birth. The babies they did these studies on were 19wks gestation.
J Neural Transm Suppl. 2001;
Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure.
Weitzdoerfer R,
Dierssen M,
Fountoulakis M,
Lubec G.
Department of Pediatrics, University of Vienna, Austria.
Information on fetal brain in Down Syndrome (DS) is limited and there are only few histological, mainly anecdotal reports and no systematic study on the wiring of the brain in early prenatal life exists. Histological methods are also hampered by inherent problems of morphometry of neuronal structures. It was therefore the aim of the study to evaluate neuronal loss, synaptic structures and dendritic spines in the fetus with Down Syndrome as compared to controls by biochemical measurements. 2 dimensional electrophoresis with subsequent mass spectroscopical identification of spots and their quantification with specific software was selected. This technique identifies proteins unambiguously and concomitantly on the same gel. Fetal cortex samples were taken at autopsy with low post-mortem time, homogenized and neuron specific enolase (NSE) determined as a marker for neuronal density, the synaptosomal associated proteins alpha SNAP [soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein], beta SNAP, SNAP 25 and the channel associated protein of synapse 110 (chapsyn 110) as markers for synaptosomal structures and drebrin (DRB) as marker for dendritic spines. NSE, chapsyn 110 and beta SNAP were comparable in the control fetus panel and in Down Syndrome fetuses. Drebrin was significantly and remarkably reduced and not even detectable in several Down Syndrome brain samples. Quantification of SNAP 25 revealed significantly reduced values in DS cortex and alpha SNAP was only present in half of the DS individuals. We conclude that at the time point of about 19 weeks of gestation (early second trimester) no neuronal loss can be detected but drebrin, a marker for dendritic spines and synaptosomal associated proteins alpha SNAP and SNAP 25 were significantly reduced indicating impaired synaptogenesis. Early dendritic deterioration maybe leading to the degeneration of the dendritic tree and arborization, which is a hallmark of Down Syndrome from infancy.
PMID: 11771761 [PubMed - indexed for MEDLINE]

Here's the earlier post that has the abstracts regarding the differences in the DS brain:

Here's a really good abstract I found that talks about oxidative stress in DS. This abstract below is saying that there is oxidative stress in DS, but it is not due to the overexpression of SOD1, at this point. But, rather due to the low levels of antioxidant and reducing agents, which cannot deal with getting rid of hydrogen peroxide. This makes lots of sense, since so many with DS are born with congenital heart defects, which have been associated with low antioxidant levels and increased oxidative stress.

Antioxidant proteins in fetal brain: superoxide dismutase-1 (SOD-1) protein is not overexpressed in fetal Down syndrome.
Gulesserian T, Engidawork E, Fountoulakis M, Lubec G.
Department of Pediatrics, University of Vienna, Austria.
Exposure of living organisms to reactive oxygen species (ROS), notably oxygen free radicals and hydrogen peroxide is closely linked to the very fact of aerobic life. Oxidants, however, are not always detrimental for cell survival, indeed moderate concentrations of ROS serve as signaling molecules. To maintain this level, cells have evolved an antioxidant defense system. Disruption of this balance leads either to oxidative or reductive stress. Down syndrome (DS) is a genetic disorder associated with oxidative stress. Overexpression of superoxide dismutase-1 (SOD-1) as a result of gene loading is suggested to be responsible for this phenomenon. To examine this view, we investigated the expression of thirteen different proteins involved in the cellular antioxidant defense system in brains of control and DS fetuses by two-dimensional electrophoresis (2-DE) coupled with matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS). No detectable change was found in expression of SOD-1, catalase, phospholipid hydroperoxide glutathione peroxidase, glutathione reductase, antioxidant enzyme AOE372, thioredoxin-like protein and selenium binding protein between control and DS fetuses. By contrast, a significant reduction was observed in levels of glutathione synthetase (P < color="#990000" size="4">Molecular changes in fetal Down syndrome brain
Ephrem Engidawork and Gert Lubec
Trisomy of human chromosome 21 is a major cause of mental retardation and other phenotypic abnormalities collectively known as Down syndrome. Down syndrome is associated with developmental failure followed by processes of neurodegeneration that are known to supervene later in life. Despite a widespread interest in Down syndrome, the cause of developmental failure is unclear. The brain of a child with Down syndrome develops differently from that of a normal one, although characteristic morphological differences have not been noted in prenatal life. On the other hand, a review of the existing literature indicates that there are a series of biochemical alterations occurring in fetal Down syndrome brain that could serve as substrate for morphological changes. We propose that these biochemical alterations represent and/or precede morphological changes. This review attempts to dissect these molecular changes and to explain how they may lead to mental retardation.
Full text @

Another follow-up post regarding this subject. I read through the study mentioned above by Gert Lubec and these are some notes from it:

I was reading through the study by Gert Lubec - Molecular changes in fetal Down syndrome brain - and thought I would note some points he makes regarding the differences that have been seen.

From the study:

"Stereological cell counting techniques, however, revealed that the second phase of cortical development and the emergence of lamination are both delayed and disorganized in fetal DS brain (Golden and Hyman 1994)"

" In addition, although the emergence and morphology of microglial cells appear not to differ from those in normal fetuses, microglial cells outnumber astroglial cells in fetal DS brain (
Wierzba-Bobrowicz et al. 1999)."

"In addition, other studies have revealed relatively delayed myelination, fewer neurones, lower neuronal density and distribution, and abnormal synaptic density and length, caused probably by prenatal abnormal neuronal migration and retarded synaptogenesis (
Wisniewski and Schmidt-Sidor 1989; Wisniewski 1990)."

"Consistent with the gene dosage effect, gene products that are over-expressed in fetal DS brain include Down syndrome critical region-1 (DSCR-1) (mRNA), intersectin (mRNA), S100β (mRNA and protein) and synaptojanin (protein) (
Table 1). DSCR-1 is a developmentally regulated gene involved in neurogenesis and its over-expression may contribute to brain abnormalities through inhibition of calcineurin-dependent gene transcription (Fuentes et al. 2000). The intersectin gene is widely expressed in fetal as well as adult tissues, and codes for two isoforms, short and long, by alternative splicing. The long isoform is brain specific; it takes part in synaptic vesicle recycling activities and is over-expressed in brain of DS fetuses compared with controls (Pucharcós et al. 1999). S100β protein exhibits a lifelong over-expression in DS brain (Griffin et al. 1998). Its mRNA is also documented to be increased in fetal DS brain (Epstein 2001). S100β is synthesized and released by astrocytes in response to serotonin (5-HT)-mediated stimulation of 5-HT1A receptors and appears to be an important neurotrophic agent during normal fetal brain development, with effects on neuroblasts and glia (Azmitia et al. 1992). Early over-expression of S100β may therefore indicate a potential role of this protein in dendritic abnormalities and mental retardation. More importantly, it can provide an important clue to the link between 5-HT and DS (Whitaker-Azmitia 2001). Synaptojanin is a highly abundant polyphosphoinositide phosphatase over-expressed in fetal DS brain (Arai et al. 2002). It modulates synaptic transmission and plays a role in clathrin-mediated synaptic vesicle endocytosis and signalling. Over-expression may form the neurochemical basis for impaired synaptic functions in DS brain."

"In stark contrast to the products mentioned above, collagen (VI) α1 chain precursor protein is decreased in fetal DS brain (
Engidawork et al. 2001a). "

"Reduced expression of collagen type (VI) α1 chain precursor complements the finding of deteriorated expression of axonal guidance proteins, including dihydropyrimidinase-related proteins in fetal DS brain (
Weitzdoerfer et al. 2001b)."

"Human Ets-2 is a proto-oncogene and transcription factor that defines the distal limit of the Down syndrome critical region. It is coded by the ets-2 gene, which is a member of the ets-2 gene family identified on the basis of homology to the v-ets oncogene isolated from the E26 erythroblastosis virus (
Raouf and Seth 2000). The ubiquitous distribution of Ets-2, including the brain (Bhat et al. 1987; Baffico et al. 1989), and its role in leukaemia and organogenesis together with the fact that its encoding gene is located on chromosome 21, would make Ets-2 a logical protein to provide evidence for the gene dosage hypothesis and its consequences. In this regard, the development of skeletal abnormalities resembling those of DS in transgenic mice over-expressing Ets-2 (Sumarsono et al. 1996) strengthened this view. However, neither Ets-2 message (Baffico et al. 1989) nor Ets-2 protein levels (Engidawork et al. 2001a) are significantly different between control and DS fetal brain, in contrast to what would be expected from a gene dosage effect. This discrepancy emphasizes that extra gene load is not always associated with gain of function."

"Indeed, although levels of β-amyloid precursor protein (APP) (
Epstein 2001) and superoxide dismutase [Cu–Zn] (SOD)-1 (de Haan et al. 1997) mRNA are increased in fetal DS brain, levels of the corresponding proteins are comparable to those in controls (Arai et al. 1996; Griffin et al. 1998; Engidawork et al. 2001a; Gulesserian et al. 2001)."

"In keeping with the lack of an adaptive response in DS, expression of catalase is unaltered in fetal DS brain (
Gulesserian et al. 2001), but it is SOD-1 activity (Brooksbank and Balazs 1984) rather than expression (Gulesserian et al. 2001) that was increased. "

"Accordingly, increased SOD-1 activity might be a consequence rather than an antecedent of oxidative stress. However, SOD-1 activity can later have a positive reinforcing effect. This line of thinking hints that there are other possible primary causes of oxidative stress in fetal DS. The possible candidates are peroxiredoxins and Aβ. Peroxiredoxins, a family of enzymes that detoxify hydrogen peroxide, are decreased in fetal DS brain (
Gulesserian et al. 2001) and Aβ can cause increased production of hydrogen peroxide and lipid peroxides (Behl et al. 1994). Although the exact mechanism by which Aβ causes accumulation of hydrogen peroxide is not known, three possible sources can be envisaged. The first is iron release from aconitase (Longo et al. 2000), shown to be increased in fetal DS brain (Bajo et al. 2002). The second is binding to advanced glycation end products receptor (Yan et al. 1997), which is also increased in fetal DS brain (Odetti et al. 1998). The third mechanism involves Aβ-mediated generation of hydrogen peroxide through its interaction with copper (Huang et al. 1999)."

"Among these molecular switches, synaptic proteins appear to sustain major alterations in prenatal DS brain. Synaptic proteins involved in activities ranging from neurotransmitter release to synaptic maturation during cortical development, including Aβ precursor-like protein-1, synaptosome-associated protein (SNAP)-25, αSNAP and septins, are significantly reduced (
Cheon et al. 2001; Weitzdoerfer et al. 2001a; Lubec G. unpublished data). Altered expression of these synaptic markers can provide at least a partial explanation for retarded synaptogenesis. Cholinergic and catecholaminergic markers are unaffected, whereas glutamatergic and serotonergic markers have been reported to be increased by some, if not all, authors (Brooksbank et al. 1989; Bar-Peled et al. 1991; Arai et al. 1996; Oka and Takashima 1999; Lubec et al. 2001b)."

"A host of proteins involved in signalling processes downstream of chemical transmission or other signal transduction pathways is also decreased in fetal DS brain (
Fig. 2). This includes 14-3-3 protein γ isoform, nucleoside diphosphate kinase (NDK)-B, Rab GDP-dissociation inhibitor (GDI)-β, signalling adapter proteins, such as receptor for activated C kinase (RACK)-1, Crk, Crk-like protein and Nck adapter protein 2 (Freidl et al. 2001; Weitzdoerfer et al. 2001c; Peyril et al. 2002; Lubec G. unpublished data). "

"Thus, transcription factors play a pivotal role in modelling and wiring the brain. Altered expression of several transcription factors has been reported in fetal DS brain, which tentatively explains the abnormal neurogenesis (
Table 2). At the mRNA level, repressor element-silencing transcription factor (REST) (also called neurone restrictive silencer factor), a transcription factor that plays an important role in brain development, neuronal plasticity and synapse formation, is down-regulated in neurospheres derived from fetal DS (Bahn et al. 2002). "

" Not unlike REST, the junD component of the AP-1 transcription factors implicated in neurogenesis and nuclear factor-kappa B, a transcriptional regulator of a multitude of genes involved in immune and inflammatory responses, is decreased in fetal DS brain (
Labudova et al. 1999). On the other hand, scleraxis, a basic helix–loop–helix type transcription factor that regulates growth and differentiation of numerous cells, is up-regulated (Labudova et al. 1999)."

"Aberrant expression of splicing, RNA stabilizing and translation factors has been noted in fetal DS brain (
Freidl et al. 2001; Engidawork E. et al., unpublished data) (Table 2). Collectively, these findings suggest that failure of the transcription and translation machinery early in life may be responsible for, or may reflect, impaired brain development and deficient wiring of the brain in DS."

"An increasing body of evidence indicates that cytoskeletal abnormalities are apparent in prenatal life and may be largely responsible for the cortical dysgenesis in DS"

"Components of the dynactin complex, such as centractin α and F-actin capping protein subunits, are significantly reduced in fetal DS brain (
Gulesserian et al. 2002), indicating disruption of a supply line that provides structural and functional materials required for normal growth to intraneuronal sites. "

"A number of actin-binding proteins have been shown to be decreased in fetal DS brain, underpinning that loss of actin function indeed accounts for dendritic and migration abnormalities. Drebrin, an actin-binding and -bundling protein that forms dendritic spines, has been noted to be missing (
Weitzdoerfer et al. 2001a). "

"Because cytoskeletal regulation is important for synapse development, its deregulation seems to be a major determinant for migration and synaptic abnormalities associated with DS (
Fig. 3)."

"Conspicuous morphological abnormalities start to be apparent in brains of newborns and older infants with DS. They have shortened basilar dendrites, a decreased number of spines with altered morphology and defective cortical layering (
Marin-Padilla 1976; Takashima et al. 1981; Becker et al. 1986; Schmidt-Sidor et al. 1990)."

Back to me:
There are SO many different abnormalities in the DS brain before birth or at birth and later on. It is amazing! It is so complex, they do not understand it all. All this seems like so much evidence for the use of TNI. And people try to say that they don't need anything different for their child than they do a regular child - do they not realize there are so many different abnormalities????? No, I don't think they do sometimes!

Lubec closes with this conclusion:

"It should be borne in mind that DS is a complex disorder because it is caused by an extra copy of a whole set of genes. The impact of gene over-dosage on the transcription level may vary because some genes are highly regulated. Thus, the presence of three copies of many genes may result either in over-expression or repression of transcripts. The effects of three copies of a gene may be even more complex at the protein level, as additional regulatory points are introduced, for example post-translational modifications that can alter the function or stability of the protein. The cumulative observations presented in this article suggest that the presence of an extra gene does not necessarily lead to a gain of function. Instead, the mere presence of a chromosomal imbalance appears to affect the coordinated regulation of expression and interaction of genes/proteins that have relevance to normal brain development and functions. Misexpression of genes/proteins that play crucial roles in neuromorphogenesis and neurogenic cascades appears to be the biological mechanism responsible for the pathogenesis of mental retardation in DS. Such aberration results in developmental abnormalities in neural patterning and signal transduction pathways, eventually leading to formation of suboptimal functioning neuronal circuitry (Fig. 4)."

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