Author Archives: jpnd

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.