Clinical Correlates in LRRK2-Related Parkinson disease

By Shyama Ghosh, PhD, ThomsonReuters Incidence & Prevalence Database Writer. Click here to visit her online

In a case report published in JAMA Neurology in January this year, Kalia et al. investigated the correlation of clinical features with Lewy body pathology in LRRK2-related Parkinson disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of genetic Parkinson disease, accounting for at least 4% of autosomal dominant forms of familial Parkinson disease and 1% of sporadic Parkinson disease worldwide. Disease-causing mutations are concentrated within the central region of the protein. At least 8 mutations are considered to be pathogenic with p.G2019S emerging as the most frequent mutation.

The literature review showed that Lewy body pathology was not present in all patients with LRRK2-related Parkinson disease. The mutation p.G2019S was more frequently associated with Lewy body pathology compared with other LRRK2 mutations.

Tremor was the most common presenting symptom for LRRK2 patients regardless of the presence of Lewy bodies (65%). The expression of certain nonmotor features, particularly cognitive impairment, anxiety, and orthostatic hypotension, was related to the presence of Lewy bodies. The association between cognitive impairment/dementia and the presence of Lewy bodies was maintained after adjustment for the degree of Alzheimer disease-related pathology (odds ratios 8.14 for all LRRK2 cases, and 76.03 for only p.G2019S cases). Thus, Lewy body pathology in LRRK2-related Parkinson disease may be a marker for a broader parkinsonian symptom complex.

Tremor and Parkinson Disease in the years 2030 and 2050

A recent study predicted greatly increased numbers of patients with movement disorders, particularly Lewy body dementia and Parkinson's disease, in the future. By 2050, the number of patients with Lewy body dementia and Parkinson's disease was projected to increase by 131% and 92%, respectively. This is assuming that prevalence of the diseases remains constant. In the study, data were analyzed for Canada, the United States, and Europe, but not Asia or Africa, as limited data on the prevalence of movement disorders existed. However, the proportional rise in people predicted to survive to older age by 2050 is even greater in Asia and Africa than in Europe and North America. By 2050 there are predicted to be 139 million people aged 60 years and older living in sub-Saharan Africa.

Projections: In the present study the projected number of sub-Saharan Africans (Tanzanians) with movement disorders (essential tremor and Parkinson's disease) in the years 2030 and 2050 was assessed. Using 2005 as a baseline, the prevalence of Parkinson's disease and essential tremor will increase by 184% and 178%, respectively, by 2025, if the population structure follows current projections and the prevalence rates remain stable. This rise is even greater than that projected for North America and Europe.

The authors believe that such trends are also applicable to other developing nations and other neurological disorders. This change in the prevalence of movement disorders is one example of the increasing burden of noncommunicable diseases following the epidemiological transition and population aging which is occurring in developing nations (see Article Review: "Projected Numbers of People with Movement Disorders in the Years 2030 and 2050: Implications for Sub-Saharan Africa, Using Essential Tremor and Parkinson's Disease in Tanzania as an Example" as cited in the Incidence and Prevalence Database).

Researchers discover how body's
good fat tissue communicates with brain

Brown fat tissue, the body's "good fat," communicates with the brain through sensory nerves, possibly sharing information that is important for fighting human obesity, such as how much fat we have and how much fat we've lost, according to researchers at Georgia State University (Atlanta).

The findings, published in The Journal of Neuroscience, help to describe the conversation that takes place between the brain and brown fat tissue while brown fat is generating heat.

Brown fat is considered "good fat" or "healthy fat" because it burns calories to help generate heat for our bodies and expend energy, while white fat stores energy for later and can increase the risk for health issues, such as diabetes and heart disease. A person with a healthy metabolism has less white fat and an active supply of brown fat.

Studies show that brown fat plays a big role in someone having the capability to burn more energy, becoming a tool to stay trim and fight obesity. Pharmaceutical companies are trying to target brown fat and activate it more, said Johnny Garretson, study author and doctoral student in the Neuroscience Institute and Center for Obesity Reversal at Georgia State.

The study found that when brown fat tissue was activated with a drug that mimics the sympathetic nervous system messages that normally come from the brain, the fat talked back to the brain by activating sensory nerves. The sensory nerves from brown fat increased their activity in response to direct chemical activation and heat generation.

"This is the first time that the function of sensory nerves from brown fat has been examined," Garretson said. "Brown fat is an active organ that's relatively important for metabolism, and we found a new pathway of its communication.

"The study informs us more about the communication between fat and the brain, which is really beneficial for treating human obesity. There is evidence that people with more brown fat have a better metabolism, lower instances of type II diabetes and are trimmer. Knowing how to increase the amount of brown fat activity or increase the brown fat, that's the future of trying to figure out yet another way to try and lose weight effectively and quickly."

The researchers speculate that brown fat is telling the brain many things, such as how much heat is being generated, how much and what types of free energy are being used or stored, how much fat we have and how much fat we've lost.

It was already known the brain communicates with fat tissue by telling it to break down and either release or use free energy for our bodies to function. This study shows a feedback loop between brown fat tissue and the brain.

The research team has studied the communication from fat to the brain and the brain to fat for years, but they're one of only a few labs in the world to examine communication from fat to the brain through the nervous system, Garretson said.

After learning new words, brain sees them as pictures

When we look at a known word, our brain sees it like a picture, not a group of letters needing to be processed. That's the finding from a Georgetown University Medical Center (GUMC) study published in the Journal of Neuroscience, which shows the brain learns words quickly by tuning neurons to respond to a complete word, not parts of it.

Neurons respond differently to real words, such as turf, than to nonsense words, such as turt, showing that a small area of the brain is "holistically tuned" to recognize complete words, says the study's senior author, Maximilian Riesenhuber, PhD, who leads the GUMC Laboratory for Computational Cognitive Neuroscience.

"We are not recognizing words by quickly spelling them out or identifying parts of words, as some researchers have suggested. Instead, neurons in a small brain area remember how the whole word looks—using what could be called a visual dictionary," he says.

This small area in the brain, called the visual word form area, is found in the left side of the visual cortex, opposite from the fusiform face area on the right side, which remembers how faces look. "One area is selective for a whole face, allowing us to quickly recognize people, and the other is selective for a whole word, which helps us read quickly," Riesenhuber says.

The study asked 25 adult participants to learn a set of 150 nonsense words. The brain plasticity associated with learning was investigated with functional magnetic resonance imaging (fMRI), both before and after training.

Using a specific fMRI technique know as fMRI-rapid adaptation, the investigators found that the visual word form area changed as the participants learned the nonsense words. Before training the neurons responded like the training words were nonsense words, but after training the neurons responded to the learned words like they were real words. "This study is the first of its kind to show how neurons change their tuning with learning words, demonstrating the brain's plasticity," said the study's lead author, Laurie Glezer.

The findings not only help reveal how the brain processes words, but also provides insights into how to help people with reading disabilities, says Riesenhuber. "For people who cannot learn words by phonetically spelling them out—which is the usual method for teaching reading—learning the whole word as a visual object may be a good strategy."

In fact, after the team's first groundbreaking study on the visual dictionary was published in Neuron in 2009, Riesenhuber says they were contacted by a number of people who had experienced reading difficulties and teachers helping people with reading difficulties, reporting that learning word as visual objects helped a great deal. That study revealed the existence of a neural representation for whole written real words—also known as an orthographic lexicon —the current study now shows how novel words can become incorporated after learning in this lexicon.

Crossing fingers can reduce feelings of pain

How you feel pain is affected by where sources of pain are in relation to each other, and so crossing your fingers can change what you feel on a single finger, finds new UCL research.

The research, published in Current Biology, used a variation on an established pain experiment, known as the "thermal grill illusion". In the thermal grill illusion, a pattern of warm-cold-warm temperatures applied to the index, middle and ring finger respectively causes a paradoxical, sometimes painful, sensation of burning heat on the middle finger – even though this finger is actually presented with a cold stimulus.

"The thermal grill is a useful component in our scientific understanding of pain," says Angela Marotta (UCL Institute of Cognitive Neuroscience), co-lead author in the research, "It uses a precisely-controlled stimulus to activate the brain's pain systems. This can certainly feel painful, but doesn't actually involve any tissue damage."

The thermal grill produces burning heat sensations because of a three-way interaction between the nerve pathways that tell the brain about warmth, cold and pain. The warm temperature on the ring and index fingers blocks the brain activity that would normally be driven by the cold temperature on the middle finger.

The researchers showed that this interaction was based on the spatial arrangement of the fingers. When the middle finger was crossed over the index finger, the paradoxical sensation of burning heat on the middle finger was reduced.

However, if the index finger was cooled and the middle and ring fingers were warmed, the burning heat sensation was now increased when the middle finger was crossed over the index finger.