Category Archives: Research News (General)

For the first time, researchers have found higher levels of Gram-negative bacteria antigens in brain samples from late-onset Alzheimer’s disease patients. Compared to controls, patients with Alzheimer’s had much higher levels of lipopolysaccharide (LPS) and E coli K99 pili protein. In addition, the researchers also found LPS molecules congregated with amyloid plaques, which have been linked to Alzheimer’s pathology and progression. The research was published in Neurology.

Researchers have not yet determined if the bacteria are causing Alzheimer’s disease or a consequence of it.

Many Gram-negative bacteria are pathogenic, including E. coli, Helicobacter pylori, salmonella, Chlamydophila pneumoniae and Shigella. Researchers have known for some time that infections can increase the risk of Alzheimer’s; however, this is the first time anyone has found increased levels of Gram-negative bacteria antigens in Alzheimer’s disease brains and bacterial molecules associated with the disease pathology. This research follows previous animal studies that showed bacterial LPS plus ischemia/hypoxia can increase amyloid β and produce amyloid plaque-like aggregates.

The study compared 24 gray and white matter samples from patients with the disease – using Consortium to Establish a Registry for Alzheimer’s disease criteria – with 18 samples from people who had shown no evidence of cognitive decline. While LPS and K99 were found in both groups, the prevalence was much higher in the Alzheimer’s patients. K99 was found in nine of 13 Alzheimer’s gray-matter samples compared to one of 10 controls by Western blot analysis. Increased K99 levels were also found in Alzheimer’s disease white matter samples. The story was similar with LPS, which was found in all six samples (three gray and three white matter) but not in the controls by Western blot analysis.

The researchers spent four years validating these results before publishing. In particular, they were concerned about contaminated samples, as LPS is commonly found in many reagents. However, the differentials between the Alzheimer’s disease samples and controls and the unique localizations of the molecules in Alzheimer’s brains seem to indicate the team avoided this pitfall.

These findings highlight the need to further investigate how infectious agents impact Alzheimer’s. While discovering LPS and K99 in Alzheimer’s disease brain samples is a good start, researchers must study the role bacteria may play in the disease pathology. A proven link between bacterial infections and Alzheimer’s could offer new opportunities to prevent and treat the disease.

Paper: “Gram-negative bacterial molecules associate with Alzheimer disease pathology”
Reprinted from materials provided by the UC Davis MIND Institute.

Although the hallmark symptoms of Parkinson’s disease (PD) – such as involuntary shaking, slowness of movement and muscle rigidity – are related to movement, recent evidence has suggested that memory impairment plays an outsized role in diminished quality of life and the burden placed on caregivers.

A new study finds that mutations in the gene for glucocerebrosidase (GBA), known to be a risk factor for PD, also have a powerful influence on the development of cognitive decline. The study was published in Annals of Neurology, the journal of the American Neurological Association.

Two defective copies of the GBA gene are known to cause Gaucher’s disease, a childhood disorder that causes death by age two or severe neurologic complications. One defective copy of the gene was once thought to be of little consequence, but has recently emerged as a common risk factor for Parkinson’s disease.

The new report examined 2,304 patients from the US, Canada and Europe, finding that 10 percent carried one (or more) defects in copies of the GBA gene. Patients carrying one defective GBA gene copy had an increased risk of memory troubles. This effect was most troublesome for patients carrying a GBA copy with the most severe type of defect — known as a neuropathic GBA mutation — whose risk of developing cognitive decline over time was increased by 217 percent. Approximately half of the carriers of a neuropathic GBA mutation developed global cognitive impairment within ten years of being diagnosed with Parkinson’s. Among the PD patients without a mutation, only about 20 percent developed this decline in cognitive function.

Therapies for Gaucher disease have been available since 1994. The researchers hope that their findings will open the door for a completely new type of clinical trials in Parkinson’s — GBA-directed trials designed to proactively prevent memory troubles in patients with movement-related symptoms.

Paper: “Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s”
Reprinted from materials provided by Brigham and Women’s Hospital.

Using LED lights flickering at a specific frequency, researchers have shown that they can substantially reduce the beta amyloid plaques seen in Alzheimer’s disease, in the visual cortex of mice.

This treatment appears to work by inducing brain waves known as gamma oscillations, which the researchers discovered help the brain suppress beta amyloid production and invigorate cells responsible for destroying the plaques.

Further research will be needed to determine if a similar approach could help Alzheimer’s patients, the researchers say. The study was published in Nature.

In a study of mice that were genetically programmed to develop Alzheimer’s but did not yet show any plaque accumulation or behavioral symptoms, the researchers found impaired gamma oscillations during patterns of activity that are essential for learning and memory while running a maze.

Next, the researchers stimulated gamma oscillations at 40 hertz in a brain region called the hippocampus, which is critical in memory formation and retrieval. These initial studies relied on a technique known as optogenetics, co-pioneered by Boyden, which allows scientists to control the activity of genetically modified neurons by shining light on them. Using this approach, the researchers stimulated certain brain cells known as interneurons, which then synchronize the gamma activity of excitatory neurons.

The researchers then began to wonder if less-invasive techniques might achieve the same effect. They came up with the idea of using an external stimulus — in this case, light — to drive gamma oscillations in the brain. The researchers built a simple device consisting of a strip of LEDs that can be programmed to flicker at different frequencies.

Using this device, the researchers found that an hour of exposure to light flickering at 40 hertz enhanced gamma oscillations and reduced beta amyloid levels by half in the visual cortex of mice in the very early stages of Alzheimer’s. However, the proteins returned to their original levels within 24 hours.

The researchers then investigated whether a longer course of treatment could reduce amyloid plaques in mice with more advanced accumulation of amyloid plaques. After treating the mice for an hour a day for seven days, both plaques and free-floating amyloid were markedly reduced. The researchers are now trying to determine how long these effects last.

Furthermore, the researchers found that gamma rhythms also reduced another hallmark of Alzheimer’s disease: the abnormally modified Tau protein, which can form tangles in the brain.

The researchers are now studying whether light can drive gamma oscillations in brain regions beyond the visual cortex, and preliminary data suggest that this is possible. They are also investigating whether the reduction in amyloid plaques has any effects on the behavioral symptoms of their Alzheimer’s mouse models, and whether this technique could affect other neurological disorders that involve impaired gamma oscillations.

Paper: “Gamma frequency entrainment attenuates amyloid load and modifies microglia”
Reprinted from materials provided by MIT.

A fault with the natural waste disposal system that helps to keep our brain cell ‘batteries’ healthy may contribute to neurodegenerative disease, a new study has found.

The research, published in the journal Cell Death and Disease, centres on problems with mitochondria — the powerhouses that produce energy within a cell.

The results support previous evidence that patients with Parkinson’s disease have faults with brain mitochondria, contributing to dysfunction and death within their neurons.

Faults in this system may play an important role in neurodegenerative diseases such as Parkinson’s and Alzheimer’s because they are caused by the death of neurons — the network through which we transfer information in our brain.

Using gene targeting in mice, the researchers have discovered that a faulty UPS in neurons leads to damaged mitochondria that produce less energy. Damaged mitochondria are also known to produce harmful molecules that injure the cell — oxidative stress — so it is vital that the brain is able to keep mending, removing and replacing them.

The study also found that when the UPS was faulty, the damaged mitochondria were not removed from neurons in the normal way by the process of autophagy, the disposal system that breaks down larger parts in the cell like mitochondria.

Paper: “Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway”
Reprinted from materials provided by the University of Nottingham.

Little is known about the role of the brain’s immune system in Alzheimer’s disease. But researchers have now found an early immune response in individuals with a genetic predisposition to Alzheimer’s: their brains showed abnormal immune reactions as early as about seven years before the expected onset of dementia.

These results demonstrate that in cases of Alzheimer’s, inflammatory processes in the brain evolve dynamically and are precursors of dementia. These immune responses can be detected by means of a protein in the cerebrospinal fluid, offering physicians the possibility to trace the progression of the disease. The study results are published in the journal Science Translational Medicine.

The researchers were able to detect increasing immune activity of the brain by measuring levels of the protein “TREM2” in the cerebrospinal fluid. TREM2 is segregated by certain immune cells of the brain – called microglia – and thus reflects their activity. In cases of the inherited form of Alzheimer’s disease, the timing for the onset of dementia can be precisely predicted. The researchers were therefore able to monitor the rise of TREM2 levels years before the expected occurrence of dementia symptoms.

In total, 127 individuals with a genetic predisposition to Alzheimer’s participated in the study. They were on average 40 years old. The vast majority showed no symptoms of dementia or had only minor cognitive impairments. The study was conducted as part of the so-called DIAN project (Dominantly Inherited Alzheimer Network), a worldwide network for research into the inherited form of Alzheimer’s disease.

Paper: “Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury”
Reprinted from materials provided by DZNE.

People with Parkinson’s disease and cognitive impairment have disruptions in their brain networks that can be seen on a type of MRI, according to a study appearing online in the journal Radiology.

Parkinson’s disease (PD) is a progressive disorder of the central nervous system characterized by tremors or trembling and stiffness in the limbs, impaired balance and coordination. It affects about 10 million people worldwide. As PD progresses, many patients develop mild cognitive impairment (MCI), a decline in cognitive abilities, including thinking, memory and language. MCI can be identified in approximately 25 percent of newly diagnosed PD patients, and patients with MCI progress to dementia more frequently than those with normal cognitive performance.

For the new study, researchers used an MRI technique called diffusion tractography to look for differences in the neural networks of PD patients with and without MCI.

Increasingly, the human brain is understood as an integrated network, or connectome, that has both a structural and functional component. By applying an analytical tool called graph analysis to the imaging results, researchers can measure the relationships among highly connected and complex data like the network of connections in the human brain.

The study group was made up of 170 PD patients, including 54 with MCI and 116 without, and 41 healthy controls. Analysis of imaging results showed that only PD patients with MCI had significant alterations at the brain network level. Measurements of the movement and diffusion of water in the brain, an indicator of the condition of the brain’s signal-carrying white matter, differentiated PD patients with MCI from healthy controls and non-MCI PD patients with a good accuracy. Researchers said the results show that cognitive impairment in PD is likely the consequence of a disruption of complex structural brain networks rather than degeneration of individual white matter bundles.

The results may offer markers to differentiate PD patients with and without cognitive deficits, according to researchers.

Paper: “Structural Brain Connectome and Cognitive Impairment in Parkinson Disease”
Reprinted from materials provided by the Radiological Society of North America.

People who live close to high-traffic roadways face a higher risk of developing dementia than those who live further away, new research has found.

The study, published in The Lancet, found that people who lived within 50 metres of high-traffic roads had a seven per cent higher likelihood of developing dementia compared to those who lived more than 300 meters away from busy roads.

The researchers examined records of more than 6.5 million Ontario, Canada, residents aged 20-85 to investigate the correlation between living close to major roads and dementia, Parkinson’s disease and multiple sclerosis.

Scientists identified 243,611 cases of dementia, 31,577 cases of Parkinson’s disease, and 9,247 cases of multiple sclerosis in Ontario between 2001 and 2012. In addition, they mapped individuals’ proximity to major roadways using the postal code of their residence. The findings indicate that living close to major roads increased the risk of developing dementia, but not Parkinson’s disease or multiple sclerosis, two other major neurological disorders.

As urban centres become more densely populated and more congested with vehicles on major roads, the researchers suggest the findings of this paper could be used to help inform municipal land use decisions as well as building design to take into account air pollution factors and the impact on residents.

Paper: “Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study”
Source: Public Health Ontario
 

A new study suggests that a key to Parkinson’s disease may lie in the mitochondria, the powerhouses of the cell.

The results were published in Nature Communications.

Mitochondria, it seems, are not able to adapt to the effects of aging in people who get Parkinson’s disease. Mitochondria contain their own DNA, which tell them how to build their power generators. In this study, researchers compared brain cells from healthy aged persons to those of individuals with Parkinson’s disease.

The researchers discovered that brain cells of healthy persons are able to compensate for the age-induced damage by producing more DNA in their mitochondria. This protective mechanism is weakened in individuals with Parkinson’s disease, leading to a loss of the mitochondria’s healthy DNA population.

“I believe we have discovered an essential biological mechanism that normally preserves and protects the brain from aging related damage. Intriguingly, this mechanism appears to fail in persons with Parkinson’s disease, rendering their brain more vulnerable to the effects of aging,” said neurologist Dr Charalampos Tzoulis, who directed the study.

Paper: “Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease”
Reprinted from materials provided by the University of Bergen.

Patients who had a diagnosis of Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB) and had higher levels of Alzheimer’s disease (AD) pathology in their donated post-mortem brains also had more severe symptoms of these Lewy body diseases (LBD) during their lives, compared to those whose brains had less AD pathology, according to new research. In particular, the degree of abnormal tau protein aggregations, indicative of AD, most strongly matched the clinical course of the LBD patients who showed evidence of dementia prior to their deaths, according to the study, which was published in The Lancet Neurology.

The team used post-mortem brain tissue donated by 213 patients with LBD and associated dementia, which was confirmed during autopsies to have alpha-synuclein pathology. They paired the tissue analysis with the patients’ detailed medical records. This unique study combined data from eight academic memory or movement disorder centers.

LBD is a family of related brain disorders made up of the clinical syndromes of PD, without or with dementia or DLB. LBD is associated with clumps of misshapened alpha-synuclein proteins. On the other hand, AD pathology is made up of clusters of the protein beta-amyloid called plaques and twisted strands of the protein tau, called tangles. Patients with LBD may have varying amounts of AD pathology, in addition to alpha-synuclein pathology.

Treatments directed at tau and amyloid-beta proteins are currently being tested in patients with Alzheimer’s disease. This study could help in selecting appropriate patients for trials of emerging therapies targeting these proteins singly or in combination with emerging therapies targeting alpha-synuclein protein in LBD.

The study suggests that Lewy body pathology may be the primary driver of disease seen in the patients; whereas, AD pathology has an impact on the overall course of disease.

None of the LBD patients had a clinical diagnosis of AD, but their post-mortem brain tissue revealed varying amounts of AD neuropathology. Post-mortem analysis of five brain regions per patient showed that they fell into one of four categories of AD pathology: 23 percent negligible or no AD, 26 percent had low-level, 21 percent intermediate, and 30 percent had high-level.

Increasing severity of AD pathology correlated with a shortened time from motor symptoms to the onset of dementia and death, with the most significant trends seen in the intermediate- and high-level AD groups compared to the low-level and no AD groups. Tau pathology, in particular, was the strongest predictor of a shorter time to dementia and death. AD pathology was also higher in patients who were older at the time of onset of motor symptoms and dementia.

The team also found that two relevant genetic variants in sequences of the patients’ DNA samples correlated with the amount of AD pathology. The frequency of a genetic variant in a gene coding for a protein involved in cholesterol metabolism (APOE, the most common risk factor for AD) was more frequent in patients who were in the intermediate or high AD pathology group compared to those in the low-level or no AD group. Interestingly, a variation in the gene for the protein GBA (a risk factor for LBD) was more frequent in patients without significant AD pathology. This gene is associated with LBD overall but not the subgroup with AD pathology.

In the brain, the enzyme GBA normally aids in the breakdown of worn out and misshapened proteins, such as alpha-synuclein. Together these findings suggest that genetic risk factors could influence the amount of AD pathology in LBD. Further understanding of the relationships between genetic risk factors and AD and alpha-synuclein pathology will help improve treatments for these disorders.

Paper: “Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis”
Reprinted from materials provided by the Perelman School of Medicine at the University of Pennsylvania.
 

Researchers have identified a naturally occurring molecule that has the potential for preserving sites of communication between nerves and muscles in amyotrophic lateral sclerosis (ALS) and over the course of aging — as well as a molecule that interferes with this helpful process.

The discovery in mice has implications for patients with ALS, also known as Lou Gehrig’s disease.

Published in The Journal of Neuroscience, the research team describes a growth factor called FGFBP1, which is secreted by muscle fibers and maintains neuromuscular junctions — a critical type of synapse that allows the spinal cord to communicate with muscles, sending signals from the central nervous system to create movements.

In mouse models of ALS, a growth factor associated with the immune system, called TGF-beta, emerges and prevents muscles from secreting factors needed to maintain their connections with neurons.

“TGF-beta is upregulated in ALS and in turn blocks expression of FGFBP1, which is released by muscle fibers to preserve the integrity of the neuromuscular junction,” said Gregorio Valdez, who led the study. “The body is trying to help itself by generating more TGF-beta. Unfortunately, TGF-beta accumulates at the synapse where it blocks expression of FGFBP1, accelerating degeneration of the neuromuscular junction.”

FGFBP1 also gradually decreases during aging, but more precipitously in ALS, because TGF-beta accumulates at the synapse, according to the researchers.

Paper: “Muscle fibers secrete FGFBP1 to slow degeneration of neuromuscular synapses during aging and progression of ALS”
Reprinted from materials provided by Virginia Tech.