Art preserves skills despite onset of vascular dementia in ‘remarkable’ case of a Canadian sculptor

The ability to draw spontaneously as well as from memory may be preserved in the brains of artists long after the deleterious effects of vascular dementia have diminished their capacity to complete simple, everyday tasks, according to a new study by physicians at St. Michael’s Hospital.

The finding, scheduled to be released today in the Canadian Journal of Neurological Sciences, looked at the last few years of the late Mary Hecht, an internationally renowned sculptor, who was able to draw spur-of-the moment and detailed sketches of faces and figures, including from memory, despite an advanced case of vascular dementia.

"Art opens the mind," said Dr. Luis Fornazzari, neurological consultant at St. Michael’s Hospital’s Memory Clinic and lead author of the paper. "Mary Hecht was a remarkable example of how artistic abilities are preserved in spite of the degeneration of the brain and a loss in the more mundane, day-to-day memory functions."

Hecht, who died in April 2013 at 81, had been diagnosed with vascular dementia and was wheelchair-bound due to previous strokes. Despite her vast knowledge of art and personal talent, she was unable to draw the correct time on a clock, name certain animals or remember any of the words she was asked to recall.

But she quickly sketched an accurate portrait of a research student from the Memory Clinic. And she was able to draw a free-hand sketch of a lying Buddha figurine and reproduce it from memory a few minutes later. To the great delight of St. Michael’s doctors, Hecht also drew an accurate sketch of famed cellist Mstislav Rostropovich after she learned of his death earlier that day on the radio.

While she was drawing and showing medical staff her own creations, Hecht spoke eloquently and without hesitation about art.

"This is the most exceptional example of the degree of preservation of artistic skills we’ve seen in our clinic," said Dr. Corinne Fischer, director at St. Michael’s Hospital’s Memory Clinic and another of the paper’s authors. "As well, most of the other studies that have been done in this area looked at other kinds of dementia such as Alzheimer’s disease or frontal temporal dementia, while this is a case of cognitive reserve in a patient with fairly advanced vascular dementia."

Dr. Fornazzari previously wrote a paper detailing a musician who, despite declining health because of Alzheimer’s disease, could still play the piano and learn new music. As well, in October 2011, Dr. Fischer and colleagues looked at bilingual patients with Alzheimer’s and discovered they had twice as much cognitive reserve as their unilingual counterparts.

Educators should take a page from these results and encourage schools to teach the arts – whether sculpture, painting or music – rather than cutting back on them, said Dr. Fornazzari. “Art should be taught to everyone. It’s better than many medications and is as important as mathematics or history.”

Both physicians want to lead a larger study of artists with neurological illnesses to further explore the importance of art and cognitive brain capacity.

New models advance the study of deadly human prion diseases

By directly manipulating a portion of the prion protein-coding gene, Whitehead Institute researchers have created mouse models of two neurodegenerative diseases that are fatal in humans. The highly accurate reproduction of disease pathology seen with these models should advance the study of these unusual but deadly diseases. 

“By altering single amino acid codons in the gene coding for the prion protein, in the natural context of the genome—no over expression or other artificial manipulations—we can produce completely different neurodegenerative diseases, each of which spontaneously generates an infectious prion agent,” says Whitehead Member Susan Lindquist. “The work irrefutably establishes the prion hypothesis.”

According to the prion hypothesis, prion proteins infect by passing along their misfolded shape in templated fashion, unlike viruses or bacteria, which depend on DNA or RNA to transmit their information. Certain changes to the prion protein (PrP) create a misshapen structure, which is replicated by contact. The misfolded proteins accumulate, creating clumps that are toxic to surrounding tissue. 

PrP is expressed at high levels in the brain, and prion diseases, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or “mad cow disease”) in cows, and scrapie in sheep, wreak havoc on the brain and other neural tissues. Some prion diseases, like BSE, can be transmitted from feed animals to humans.

The study of these highly unusual but devastating prion diseases has to date been thwarted by a lack of animal models that faithfully mimic the disease processes in humans. However, Walker Jackson, a former postdoctoral researcher in Lindquist’s lab is changing that, creating novel mouse models of human fatal familial insomnia (FFI) and CJD. His research is reported online this week in the Proceedings of the National Academy of Sciences (PNAS).

To generate the models, Jackson created two mutated versions of the PrP-coding gene by changing a single codon—one of the three-nucleotide “words” in genes that code for the various amino acids in proteins. One mutation is known to cause FFI, while the other induces CJD. Unlike previous models that randomly inserted the mutations into the genome, occasionally increasing PrP expression, Jackson’s models faithfully mimic the human disease—from as to disease onset, to PrP production, to infectiousness. In the brain, his FFI mice develop neuronal loss in the thalamus and his CJD mice experience spongiosis in the hippocampus and the cerebellum, reflecting the damage seen in the brains of human patients.

“Walker (Jackson)’s work provides two extraordinary models of neurodegeneration,” says Lindquist, who is also a professor of biology at MIT. “Most mouse models produce pathology that only distantly resembles human diseases. These nail it, for two of the most enigmatic human diseases in the world.”

With the FFI and CJD models in hand, Jackson says he’s excited to investigate how the pathology of these diseases develops.

“Now we have two interesting models that are selectively targeting specific parts of the brain: the thalamus in FFI and the hippocampus in CJD,” says Jackson, who is now a Group Leader at the German Center for Neurodegenerative Disease. “But instead of focusing on areas that are heavily affected by the disease, we’ll be looking at the areas that seem to be resisting the disease to see what they’re doing. The protein is there, but for some reason, it’s not toxic.”

Initial characterization of one of the models (for FFI) was reporter earlier in Neuron.

How Neurons Get Wired

Two different versions of the same signaling protein tell a nerve cell which end is which, UA researchers have discovered. The findings could help improve therapies for spinal injuries and neurodegenerative diseases.

University of Arizona scientists have discovered an unknown mechanism that establishes polarity in developing nerve cells. Understanding how nerve cells make connections is an important step in developing cures for nerve damage resulting from spinal cord injuries or neurodegenerative diseases such as Alzheimer’s.

In a study published on Aug. 12 in the journal Proceedings of the National Academy of Sciences, UA doctoral student Sara Parker and her adviser, assistant professor of cellular and molecular medicine Sourav Ghosh, report that the decision which will be the “plus” and the “minus” end in a newborn nerve cell is made by a long and a short version of the same signaling molecule.

Nerve cells – or neurons – differ from many other cells by their highly asymmetric shape: Vaguely resembling a tree, a neuron has one long, trunk-like extension ending in a tuft of root-like bristles. This is called the axon. From the opposite end of the cell body sprout branch-like structures known as dendrites. By connecting the “branches” of their dendrites to the “root tips” of other neurons’ axons, nerve cells form networks, which can be as simple as the few connections involved in the knee-jerk reflex or as complex as those in the human brain.

Parker and her team found that embryonic nerve cells manufacture a well-known signaling enzyme called Atypical Protein Kinase C (aPKC) in two varieties: a full-length one and a truncated one. Both varieties compete to bind the same molecular partner, a protein called Par3. If the short form of aPKC pairs up with Par3, it tells the cell to grow a dendrite, and if the long one pairs up with Par3, it will make an axon instead.

When the researchers blocked the production of the short form, the nerve cell grew multiple axons and no dendrites. When they created an artificial abundance of the short form, dendrites formed at the expense of axons. UA undergraduate student Sophie Hapak performed many of the experiments revealing how the two isoforms compete for Par3.

"We show that wiring a neuronal circuit is much more complex than previously thought," said Ghosh. "The process has a built-in robustness that explicitly defines which part of the cell is ‘positive’ and which is ‘negative.’"

"In order to have a functioning neuronal circuit, you have to have receiving and sending ends," Parker said. "Initially, when a neuron is formed, it lacks the polarity it needs once it develops into a part of a circuit. The mechanism we discovered establishes that polarity."

"How the various brain regions are wired is the basis of emotion, memory and all cognitive functions," said Ghosh, who is a member of the UA’s BIO5 Institute. "Establishing neuronal polarity in single neurons is absolutely essential for neuronal circuits to form."

"If we understand this mechanism, we could think about methods to spur new axons after the original ones were severed in a traumatic spinal cord injury, for example," Ghosh said.

The findings defy conventional wisdom, which maintains that a developing neuron will make dendrites by default unless instructed by the long form of aPKC to make an axon instead. By cultivating and studying neurons just after they formed, Parker and her group found that both forms of aPKC, long and short, are initially distributed equally throughout the cell. These forms subsequently segregate into different parts of the cell as the neuron matures and establishes polarity.

Because the cells were isolated from rat brains and kept in culture, the researchers could demonstrate that no external clues from other cells are needed to instruct a developing neuron. Whether the establishment of polarity is a random process or whether other signals yet to be identified play a role in regulating the abundance of the two aPKC varieties is not known.

A possible blood test for Alzheimer’s disease?

A new blood test can be used to discriminate between people with Alzheimer’s disease and healthy controls. It’s hoped the test, described in the open access journal Genome Biology, could one day be used to help diagnose the disease and other degenerative disorders.

Alzheimer’s disease, the most common form of dementia, can only be diagnosed with certainty at autopsy, so the hunt is on to find reliable, non-invasive biomarkers for diagnosis in the living. Andreas Keller and colleagues focused on microRNAs (miRNAs), small non-coding RNA molecules known to influence the way genes are expressed, and which can be found circulating in bodily fluids including blood.

The team, from Saarland University and Siemens Healthcare highlighted and tested a panel of 12 miRNAs, levels of which were found to be different amongst a small sample of Alzheimer’s patients and healthy controls. In a much bigger sample, the test reliably distinguished between the two groups.

Decent biomarkers need to be accurate, sensitive (able to correctly identify people with the disease) and specific (able to correctly pinpoint people without the disease). The new test scores over 90% on all three measures. But whilst the test shows obvious promise, it still needs to be validated for clinical use, and may eventually work best when combined with other standard diagnostic tools, such as imaging, the authors say.

As people with other brain disorders can sometimes show Alzheimer’s-like symptoms, the team also looked for the miRNA signature in other patient groups. The test distinguished controls from people with various psychological disorders, such as schizophrenia and depression, with over 95% accuracy, and from patients with other neurodegenerative disorders, such as mild cognitive impairment and Parkinson’s disease, with lower accuracy. It also discriminated between  Alzheimer’s patients and patients with other neurodegenerative disorders, with an accuracy of around 75%. But by tweaking the miRNAs used in the test, accuracy could be improved.

The work builds on previous studies highlighting the potential of miRNAs as blood-based biomarkers for many diseases, including numerous cancers, and suggests that miRNAs could yield useful biomarkers for various brain disorders. But it also sheds light on the mechanisms underpinning Alzheimer’s disease. Two of the miRNAs are known involved in amyloid precursor protein processing, which itself is involved in the formation of plaques, a classic hallmark of Alzheimer’s disease.  And many of the miRNAs are believed to influence the growth and shape of neurons in the developing brain.

(Image: Reuters)

Scientists ID compounds that target amyloid fibrils in Alzheimer’s, other brain diseases

UCLA chemists and molecular biologists have for the first time used a “structure-based” approach to drug design to identify compounds with the potential to delay or treat Alzheimer’s disease, and possibly Parkinson’s, Lou Gehrig’s disease and other degenerative disorders.

All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.

Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.

The UCLA researchers, led by David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer’s and other degenerative diseases.

In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg’s laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.

The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

A number of non-structure-based screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils. Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils. In addition, several dyes have been found to reduce amyloid’s toxic effects, although significant side effects prevent them from being used as drugs.

Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, Jiang, Eisenberg and colleagues conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.

Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein’s toxic effects, which in the past has proved very difficult. Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect.

While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein’s toxicity and to increase the stability of amyloid fibrils — a finding that lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer’s symptoms.

The researchers hypothesize that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.

An estimated 5 million patients in the U.S. suffer from Alzheimer’s disease, the most common form of dementia. Alzheimer’s health care costs in have been estimated at $178 billion per year, including the value of unpaid care for patients provided by nearly 10 million family members and friends.

In addition to uncovering compounds with therapeutic potential for Alzheimer’s disease, this research presents a new approach for identifying proteins that bind to amyloid fibrils — an approach that could have broad applications for treating many diseases.

Key Molecular Pathways Leading to Alzheimer’s Identified

Key molecular pathways that ultimately lead to late-onset Alzheimer’s disease, the most common form of the disorder, have been identified by researchers at Columbia University Medical Center (CUMC). The study, which used a combination of systems biology and cell biology tools, presents a new approach to Alzheimer’s disease research and highlights several new potential drug targets. The paper was published today in the journal Nature.

Much of what is known about Alzheimer’s comes from laboratory studies of rare, early-onset, familial (inherited) forms of the disease. “Such studies have provided important clues as to the underlying disease process, but it’s unclear how these rare familial forms of Alzheimer’s relate to the common form of the disease,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC. “Most important, dozens of drugs that ‘work’ in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer’s. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease.”

Non-familial Alzheimer’s is complex; it is thought to be caused by a combination of genetic and environmental risk factors, each having a modest effect individually. Using so-called genome-wide association studies (GWAS), prior reports have identified a handful of common genetic variants that increase the likelihood of Alzheimer’s. A key goal has been to understand how such common genetic variants function to impact the likelihood of Alzheimer’s.

In the current study, the CUMC researchers identified key molecular pathways that link such genetic risk factors to Alzheimer’s disease. The work combined cell biology studies with systems biology tools, which are based on computational analysis of the complex network of changes in the expression of genes in the at-risk human brain.

More specifically, the researchers first focused on the single most significant genetic factor that puts people at high risk for Alzheimer’s, called APOE4 (found in about a third of all individuals). People with one copy of this genetic variant have a three-fold increased risk of developing late-onset Alzheimer’s, while those with two copies have a ten-fold increased risk. “In this study,” said Dr. Abeliovich, “we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer’s, is there a consistent pattern?”

Surprisingly, even in the absence of Alzheimer’s disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer’s disease,” said Dr. Abeliovich. “We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on ‘transcriptomics’—a broad molecular survey of the expression levels of the thousands of genes expressed in brain.”

Using the network analysis tools mentioned above, the researchers then identified a dozen candidate “master regulator” factors that link APOE4 to the cascade of destructive events that culminates in Alzheimer’s dementia. Subsequent cell biology studies revealed that a number of these master regulators are involved in the processing and trafficking of amyloid precursor protein (APP) within brain neurons. APP gives rise to amyloid beta, the protein that accumulates in the brain cells of patients with Alzheimer’s. In sum, the work ultimately connected the dots between a common genetic factor that puts individuals at high risk for Alzheimer’s, APOE4, and the disease pathology.

Among the candidate “master regulators” identified, the team further analyzed two genes, SV2A and RFN219. “We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer’s disease.”

The researchers evaluated the role of SV2A, using human-induced neurons that carry the APOE4 genetic variant. (The neurons were generated by directed conversion of skin fibroblasts from individuals at high risk for Alzheimer’s, using a technology developed in the Abeliovich laboratory.) Treating neurons that harbor the APOE4 at-risk genetic variant with levetiracetam (which inhibits SV2A) led to reduced production of amyloid beta. The study also showed that RFN219 appears to play a role in APP-processing in cells with the APOE4 variant.