The Pathogenesis of Down’s Syndrome Essay

Dzevdet Smajlovic, professor from the Department of Neurology at the University of Tuzla in Bosnia stated that

On November 26th 1901, Alois Alzheimer, an assistant physician at the psychiatric institution in Frankfurt met Auguste D, aged 51 (Berrios , 2004). After talking to her and carrying out the preliminary diagnostics, the physicist realized during talking to her that his patient was giving different answers to the same questions. She also often stopped mid-sentence as if she had forgotten what she was going to say. She seemed confused and anxious. When she died, Alzheimer received her brain for analysis. When he was inspecting the brain, he came to notice the neurons had thick, strongly staining fibrils. Moreover, the cortex was full of plaques of unknown composition. Auguste D’s brain

Down syndrome is a genetic disorder that numerous individuals around the world suffer from; it is an intellectual disability that is caused by having one too many chromosome 21 copies, trisomy 21. The average person has two copies of chromosome 21 in each cell, whereas, an individual with Down syndrome has an extra copy of chromosome 21. This happens when either the sperm or egg cell undergoes atypical cell division during development. In the United States, there are approximately 400,000 individuals who have been diagnosed with Down syndrome, according to the last census in 2012 (National Down Syndrome Society).

Much research has supported the fact that there is brain structure differences in individuals diagnosed with FASD (Nunez, el al 2011). Research into the brain of individuals has discovered abnormalities in the volume and thickness of the frontal lobes (Nunez, el al 2011). This results in impairments in attention, working memory, and executive functioning that can be traced back to the frontal lobes (Nunez, el al 2011). In addition researchers have also found smaller volumes of basal ganglia, which is a group of nuclei associated with motor control and learning (Nunez, el al 2011). Furthermore, caudate nucleus, which is inside the basal ganglia has also been found to be smaller in individuals was FASD (Nunez, el al 2011). Caudate nucleus is associated with mental flexibility and behaviour inhibition (Nunez, el al 2011). The hypothalamus, which is most responsible for its link with the nervous system was also found to be smaller in individuals was FASD (Nunez, el al 2011). Moreover, the thalamus was also found to be of smaller volume and is responsible for relaying motor and sensory signals to the cerebral cortex (Nunez, el al 2011). Luckily studies have also found that the hippocampus, which required for the formation of memories was left relatively normal (Nunez, el al 2011). The most affected area has been pinpointed as being the anterior vermis, located inside the

Individuals with APSD exhibit neuroanatomical differences compared with individuals without the diagnosis. Magnetic resonance imaging (MRI) studies have identified an 11.0% reduction in prefrontal gray matter in individuals diagnosed with ASPD (Raine, Lencz, Bihrle, LaCasse, &

The occipital lobe is in a posterior position and the function of the occipital lobe is vision including perception and colour and movement (Stannard Gromisch, 2012). Atrophy is described as a process of tissue wastage or cell death (Lippincott Williams & Wilkins, 2006). According to (Jones & Gaillard, 2005-2013) the pathology of PCA includes Neuritic plagues and neurofibrillary tangles which are found in the parieto-occipital and temporo-occipital areas, as well as occasionally in the primary visual cortex. It is thought that PCA is a version of AD, with very little difference in the pathology. “Neuritic plagues or senile plagues are extracellular and composed of a central core of beta-amyloid peptides aggregated together with fibrils of beta-amyloid, dystrophic neurites, reactive astrocytes, phagocytic cells, and other proteins and protein fragments derived from degenerating cells or liberated from neurons” (Weerakkody & Gaillard, 2005-2013).

Reduction in brain and neuronal sizes with an increase in cell density is consistently observed in several brain regions of patients with RTT (Calfa et al, 2015). These areas include the cerebral cortex, hypothalamus and the hippocampal formation (Belichenko et al, 2009). According to Belichenko (2009) dendritic morphology of neurons has been observed in a number of neurodevelopmental disorders, including RTT. An autoradiography done in the frontal cortex and basal ganglia of individuals affected by RTT have shown complex abnormalities in the density of glutamate receptors such as NMDA-(N-methyl-d-aspartate), AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate- and metabotropic receptors (Blue et al, 1999).The prefrontal cortex of girls who were 2-8-year-old had increased NMDA receptors as compared to 10 year old girls who had reduced NMDA receptors. Receptor density was dependent on age of the patient (Blue et al, 1999). Changes in the neurons, such as decreased dendrites and decreased dendritic spine numbers are observed; particularly, changes in the hippocampal CA1 pyramidal neurons are shown (Chapeau et al, 2012). When compared to an age-matched control, researchers noticed that RTT affected patients had lower dendritic spine density in their

As a medical practitioner, I was always fascinated by the complexities of the human nervous system. A few years later, during my neurology residency training, I developed special interests in the field of neurodegenerative disorders and dementias. These are largely non-curable disorders

Neurodevelopmental disorders are characterized by impairments of the growth and development of the central nervous system as they occur by origin, or during infancy and childhood, inhibiting functions that affect emotion, learning, self-control, motor skills, and memory. Specific disorders within this spectrum include but are not limited to, fetal alcohol syndrome, autism, Tourette syndrome, fragile-X syndrome, Down syndrome, ADHD, Mendelsohn’s syndrome, and schizophrenia. Neurodevelopmental disorders stem from many causes, ranging from chromosomal deficiency, genetic and metabolic diseases, immune disorders, infectious diseases, physical trauma, and nutritional, toxic, and environmental factors (Bale, et.al., 2010).

The first study was longitudinal in nature. Seventeen participants with FASD and twenty-seven controls aged five to fifteen years old were involved in the study. The FASD participants were recruited from a clinic specializing in FSD, and they had been diagnosed with an alcohol related disorder. FASD is a term that encompasses a few conditions of varying severity and participants of various conditions were included. The patients underwent a special type of MRI scan called diffuse tensor imaging (DTI). 92 scans were collected total in this study and each participant received either two or three scans. Specific details of the brain’s white matter can be visualized by using DTI. Both groups had some commonalities in some structural areas that are expected to change as an outcome of development. DTI showed that there were microstructural anomalies in the areas of the brain including by not limited to the corpus callosum and connective fibers (Treit et al., 2013). When the white matter tracts of the two groups were compared, the FASD group had many abnormal structural changes. The areas where large differences were noted were in the

In FD, neuronal atrophy impinges the anterior, frontal and temporal brain lobes. Language difficulty and varied behaviour are common

At least eight to ten layer V pyramidal neurons from the visual cortex monocular region were selected from each brain for analysis utilizing light microscopy. Each of these neurons had to have an apical dendrite of at least 80μm long and exhibited full Golgi impregnation represented by a lack of floating spine heads. Each neuron underwent analysis of the apical dendrite, and following regions if present: apical oblique (branch protruding from apical dendrite), first order basilar branch (branching directly from pyramidal cell), second order basilar branch (separated from first order branch), third order basilar branch (from second order branch) and forth order basilar branch (from third order branch). A segment of at least 10μm long and at least 2μm away from bifurcations, was selected from the structures mentioned above, and analyzed based on the number of dendritic spines and morphology of dendritic spines. Each dendritic spine was categorized based on similarity to 12 categories (Figure 1) modified from those described in Irwin et al., 2002 as seen in Figure 2. All final analyses were done under 100X magnification. Length of the each segment was recorded, as well as the thickness of the segment at the starting and end points. The segment thickness was recorded to ensure that any differences in dendritic spine density was not due to differences in dendritic branch thickness.

Pachygyria represents similar disorder with less severe pathology than in lissencephaly, as areas of normal laminar organization can be seen. However, these two conditions are not mutually exclusive and can occur together in the same brain, thus they are considered as different degrees of the same fundamental disorder in cell migration and cortical

However, unlike the healthy control participants, “D.F. did not show activation in the superior parieto-occipital sulcus, […which] has been shown to be activated during arm movement tasks” (James et al., 2006). MRI images revealed anatomical abnormalities outside of the ventral stream. Despite this finding, researchers James et al. (2006) concluded from the experiments that the affected structures remained functional. According to Pisella et al. (2006) “this may be partially explained by the reorganization of surrounding intact brain tissue” (Pisella, Binkofski, Lasek, Toni, & Rossetti, 2006). After sustaining damage, the brain could have shown plasticity; new neuronal connections from areas outside the damage site took over some of the function that was impaired from the lesion. Therefore, this would indicate why D.F., was able to perform the arm movement task, despite the marked

Down syndrome is a genetic disorder in which a person is born with an extra copy of chromosome 21. There are three genetic variations that cause Down syndrome: Trisomy 21, Mosaic Trisomy 21 or Translocation Trisomy 21. There are many ways in which theses disorders affect the body.  Trisomy 21 occurs when an egg or sperm comes in with an extra copy of chromosome 21, then, once an embryo is formed and starts to develop, the chromosome is replicated in every single cell of the embryo. Trisomy 21 is the most common type of Down syndrome. About 92% of Down syndrome patients have this type. People with Trisomy usually have physical problems.