Down syndrome: Neurons grown from stem cells show signature problems - Oxidative Stress

Down syndrome, the most common genetic form of intellectual disability, results from an extra copy of one chromosome.

Although people with Down syndrome experience intellectual difficulties and other problems, scientists have had trouble identifying why that extra chromosome causes such widespread effects.

Anita Bhattacharyya

In new research published this week, Anita Bhattacharyya, a neuroscientist at the Waisman Center at the University of Wisconsin-Madison, reports on brain cells that were grown from skin cells of individuals with Down syndrome.

The research, published the week of May 27 in the Proceedings of the National Academy of Sciences (PNAS), was a basic exploration of the roots of Down syndrome.

"Even though Down syndrome is very common, it's surprising how little we know about what goes wrong in the brain," says Bhattacharyya. "These new cells provide a way to look at early brain development."

The study began when those skin cells were transformed into induced pluripotent stem cells, which can be grown into any type of specialized cell.

One significant finding was a reduction in connections among the neurons, Bhattacharyya says. "They communicate less, are quieter. This is new, but it fits with what little we know about the Down syndrome brain."

Brain cells communicate through connections called synapses, and the Down neurons had only about 60 percent of the usual number of synapses and synaptic activity.

"This is enough to make a difference," says Bhattacharyya. "Even if they recovered these synapses later on, you have missed this critical window of time during early development."

The researchers looked at genes that were affected in the Down syndrome stem cells and neurons, and found that genes on the extra chromosome were increased 150 percent, consistent with the contribution of the extra chromosome.

However, the output of about 1,500 genes elsewhere in the genome was strongly affected. "It's not surprising to see changes, but the genes that changed were surprising," says Bhattacharyya.

The predominant increase was seen in genes that respond to oxidative stress, which occurs when molecular fragments called free radicals damage a wide variety of tissues.

"We definitely found a high level of oxidative stress in the Down syndrome neurons," says Bhattacharyya.

"This has been suggested before from other studies, but we were pleased to find more evidence for that. We now have a system we can manipulate to study the effects of oxidative stress and possibly prevent them."

Down syndrome includes a range of symptoms that could result from oxidative stress, Bhattacharyya says, including accelerated aging.

"In their 40s, Down syndrome individuals age very quickly. They suddenly get gray hair; their skin wrinkles, there is rapid aging in many organs, and a quick appearance of Alzheimer's disease. Many of these processes may be due to increased oxidative stress, but it remains to be directly tested."

Oxidative stress could be especially significant, because it appears right from the start in the stem cells.

"This suggests that these cells go through their whole life with oxidative stress," Bhattacharyya adds, "and that might contribute to the death of neurons later on, or increase susceptibility to Alzheimer's."

More information: Deficits in human trisomy 21 iPSCs and neurons,www.pnas.org/cgi/d… s.1216575110

Human cognition depends upon slow-firing neurons

Good mental health and clear thinking depend upon our ability to store and manipulate thoughts on a sort of "mental sketch pad."

In a new study, Yale School of Medicine researchers describe the molecular basis of this ability -- the hallmark of human cognition -- and describe how a breakdown of the system contributes to diseases such as schizophrenia and Alzheimer's disease.

Prof Amy Arnsten

"Insults to these highly evolved cortical circuits impair the ability to create and maintain our mental representations of the world, which is the basis of higher cognition," said Amy Arnsten, professor of neurobiology and senior author of the paper published in the Feb. 20 issue of the journal Neuron.

High-order thinking depends upon our ability to generate mental representations in our brains without any sensory stimulation from the environment.

These cognitive abilities arise from highly evolved circuits in the prefrontal cortex.

Mathematical models by former Yale neurobiologist Xiao-Jing Wang, now of New York University, predicted that in order to maintain these visual representations the prefrontal cortex must rely on a family of receptors that allow for slow, steady firing of neurons.

The Yale scientists show that NMDA-NR2B receptors involved in glutamate signaling regulate this neuronal firing.

These receptors, studied at Yale for more than a decade, are responsible for activity of highly evolved brain circuits found especially in primates.

Earlier studies have shown these types of NMDA receptors are often altered in patients with schizophrenia.

The Neuron study suggests that those suffering from the disease may be unable to hold onto a stable view of the world.

Also, these receptors seem to be altered in Alzheimer's patients, which may contribute to the cognitive deficits of dementia.

The lab of Dr. John Krystal, chair of the department of psychiatry at Yale, has found that the anesthetic ketamine, abused as a street drug, blocks NMDA receptors and can mimic some of the symptoms of schizophrenia.

The current study in Neuron shows that ketamine may reduce the firing of the same higher-order neural circuits that are decimated in schizophrenia.

"Identifying the receptor needed for higher cognition may help us to understand why certain genetic insults lead to cognitive impairment and will help us to develop strategies for treating these debilitating disorders," Arnsten said.

The above story is reprinted from materials provided by Yale University.

Dementia and the Late Onset of Dyslexia

Searching for Utopia

This post examines the differences between  Semantic dementia (SD), a progressive neurodegenerative disorder characterized by loss of semantic memory in both the verbal and non-verbal domains AND Semantic Aphasia (AD), a progressive neurodegenerative disorder or aphasia, characterised by the loss of recognition of the meaning of words and phrases.

The NIH paper this is taken from is very 'technical' in its form and is primarily for cognitive scientists to review and discuss but, with some effort on our part, we can see through the jargon to determine that current research is able to distinguish between the onset of Dementia and its effect on our cognitive abilities.


Below is an extract from the paper:

"This NIH study examined the impact of semantic impairment on a variety of “pre-semantic tasks” – lexical decision, object decision, colour decision, reading aloud, spelling to dictation, past tense generation and delayed picture copying – in semantic dementia (SD) and semantic aphasia (SA).

Previous research indicates that all of these tasks are affected in a highly predictable way by the semantic degradation in Semantic Dementia (see Patterson et al., 2006).

SD patients have difficulty with transformations that are atypical and make “regularisation errors” in which irregular items are produced as if they were domain-typical.

In contrast, we found that comprehension impairment in Semantic Aphasia did not result in this pattern.

1. In all seven “pre-semantic” tasks that we examined, the SA patients were less sensitive to typicality than the SD patients (producing significant group by regularity interactions), even though the two groups were matched for performance on semantic tests. 
2. In several tasks, the aphasic group were also less sensitive to item frequency and/or showed a smaller frequency by typicality interaction than the patients with SD. 
3. In production tasks, the SA patients made fewer regularisation errors and many more implausible responses than the SD group – for example, unrelated, semantic and perseverative errors.

The predicted effects of semantic impairment on pre-semantic tasks have been demonstrated most frequently in patients with SD.

In contrast, patients who show a breakdown in this association – i.e., preserved reading of irregular words despite pronounced semantic memory problems – are typically individuals with AD and stroke aphasia (Gerhand, 2001; Lambon Ralph et al., 1995).

These cases are viewed as highly significant by some researchers because they suggest that semantic memory impairment and regularisation errors on “pre-semantic” tasks are dissociable.

However, our findings indicate that strong typicality effects in “pre-semantic” tasks follow degradation of ATL semantic representations and not poor executive control of semantic cognition.

As the semantic deficit in SA and to some extent AD is likely to be related to poor executive control, individuals with these conditions do not disconfirm the hypothesis that semantic representations play an important role in “pre-semantic” cognition.

Read the full paper here at NIH website

Autistic Wandering: New CDC Code Approved

A very large percentage of people with autism "wander" - meaning they simply get up and walk or run off, for no obvious reason and in no obvious direction. This behavior is by no means limited to people with autism: the Alzheimers community may be even more vulnerable.

Wanderers often seem compelled to wander, which means that locked doors and fences aren't always enough to curb the behavior and caregivers can't possibly be vigilant all day and night, nor should they be asked to lock their loved ones in escape-proof settings.

The result of "wandering" can be tragic, and most of us have read stories of autistic people drowned in pools or dying of exposure.

To address this issue, the CDC has created a somewhat controversial new medical code which can be added to certain diagnoses, including autism, Alzheimers, and dementia. According to a CDC press release:

The , effective October 1, 2011, is designed to promote better data collection for and understanding of wandering and to prompt important discussions about safety among healthcare providers, caregivers, and the person with a disability to the fullest extent possible.
Wandering places children and adults with autism spectrum disorders (ASDs) or other disorders in harmful and potentially life-threatening situations--making this an important safety issue for individuals affected and their families and caregivers. Children and adults with ASDs and other developmental disabilities are at higher risk of wandering off than are children and adults without these disorders or other cognitive disorders....


This code is intended to capture information about individuals, with any condition classified in the ICD, who wander. Wandering was deleted as a subcode under the Alzheimer's and dementia code and added as a condition to be noted in association with disorders classified elsewhere [V40.31]. The intention is to provide a way to document, understand, and improve the situation for individuals who are at risk of injury or death due to dangerous wandering. Wandering should be coded if documented in the medical record by the provider (i.e., physician).
The wandering code is not linked to a specific diagnosis, nor is it part of the diagnostic codes used for autism or intellectual disabilities. The ICD-9-CM classifies behaviors and risk factors in addition to diseases and syndromes; as such, the wandering code is used in conjunction with other diagnostic and symptom or procedure codes.

More on Wandering and Autism

• Safety and the Autistic Runaway
• A Medical Code for Autistic Wandering: What's Your Opinion?
• Half of All Children with Autism Wander or Bolt
• Help Support Project Lifesaver

New Diagnostic Code for Autistic Wandering Approved for October, 2011

New reactive eye test may detect learning disabilities, early Alzheimer's

New reactive eye test may detect learning disabilities, early Alzheimer's

Two-year-old Jakeson Bowlby has a bull's eye sticker on his forehead that helps a computer system track the movement of his eyes.

He sits in a high chair and watches a video, but instead of Toy Story or another favourite, researchers at Queen's University show him a high-definition video that is part of a new test to assess brain function in toddlers. It jumps quickly from one image to another -- kangaroos sitting under a tree, kids playing soccer, buses and cars zooming by.

How quickly children can zero in on the kangaroos and follow the ball or the vehicles is a measure of how well their brains are directing the movement of their eyes, says Queen's neuroscientist Doug Munoz. He has devoted nearly two decades to documenting how eye control is related to abnormal brain function, both in children and adults.

His work is part of a broad investigation involving labs around the world which, over the last two decades, has laid the groundwork for relatively simple tests that could soon be used to detect everything from learning disabilities to the early onset of Parkinson's or Alzheimer's disease.

Munoz's latest project is aimed at the high chair set, a way to screen youngsters for problems that may make it difficult for them to learn in school. He and his colleague, Laurent Itti at the University of Southern California, have preliminary evidence that shows their "free viewing" test can identify children with attention deficit hyperactivity disorder and fetal alcohol spectrum disorder.