Yearly Archives: 2015

A genetic study of over 173,000 individuals has confirmed that the TREM2 amino-acid-substitution mutation R47H increases the risk of Alzheimer disease in people of European descent.

Several studies have reported the TREM2 R47H mutation to be a risk factor for Alzheimer’s disease (AD), but the magnitude of this mutation’s role in AD and other neurodegenerative diseases has been far from clear.

“The effect size estimates varied widely across datasets,” says lead author of this study, Christina Lill University of Lübeck, Germany.

The results, published in the journal Alzheimer’s & Dementia, suggest the mutation contributes through tau dysfunction.

Two recent studies have investigated the direct links and associations between depression and Parkinson’s Disease

A longitudinal study from Sweden investigated the long-term risk of Parkinson disease (PD) after depression and evaluated potential confounding by shared susceptibility to the two diagnoses.

Published in the journal Neurology, this study demonstrated a time-dependent effect, dose-response pattern for recurrent depression, and lack of evidence for co-aggregation among siblings which together indicate a direct association between depression and subsequent PD. Given that the association was significant for a follow-up period of more than two decades, depression may be a very early pro-dromal symptom of PD, or a causal risk factor.

The effects of anti-depressive treatments for Parkinson’s Disease were also recently reviewed in the journal Parkinsonism & Related Disorders. The associated meta-analysis in the study demonstrates that pharmacologic treatment with antidepressant medications, specifically the selective serotonin reuptake inhibitors (SSRIs), and behavioral interventions (CBT) significantly improved depression among Parkinson’s disease patients.

The authors examined trials assessing treatment for depression in Parkinson’s disease (dPD) and found that:

SSRIs demonstrate significant improvement in depressive symptoms.
Cognitive behavioral therapy (CBT) shows a substantial effect in dPD treatment.
Evidence of efficacy of both SSRIs and CBT is provided, at least on the short term.

Cohort Study: Depression and subsequent risk of Parkinson disease – A nationwide cohort study. Gustaffssonn et al., Neurology. Published online before print May 20, 2015, doi: 10.1212/WNL.0000000000001684

Antidepressive treatments for Parkinson’s disease: A systematic review and meta-analysis
Emily Bomasang-Layno, et al., Parkinsonism & Related Disorders, Available online 16 May 2015

Three former top researchers at Genentech (now part of Roche Holding), have raised $217 million in venture capital to start a new company, Denali Therapeutics, focused on treating and curing neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s.

The news is sign of a financial turnaround for research efforts against these brain diseases that have been tough to beat.

NeuroPerspective, a newsletter that tracks neurological treatments, says in the past five years the number of drugs being developed by large drug makers for brain and nervous system disorders fell 50% to 129 – but that last year, investors poured $3.3 billion into the field, more than in any of the last ten years.

The raise for Denali is a series A, the very first round of getting funding for a new company. It is the largest such round in biotech history.

Researchers at the Luxembourg Centre for Systems Biomedicine (LCSB), of the University of Luxembourg, have successfully measured metabolic profiles, or the metabolomes, of different brain regions, and their findings could help better understand neurodegenerative diseases.

The metabolome represents all or at least a large part of the metabolites in a given tissue, and thus, it gives a snapshot of its physiology.

“Our results, obtained in the mouse, are promising”, says Manuel Buttini: ”They open up new opportunities to better understand neurodegenerative diseases, such as Parkinson’s, and could offer new ways to intervene therapeutically. In addition, with the help of metabolic profiles, such as those we have measured, the efficacy of novel therapeutic interventions could be tested more efficiently than with more common approaches.” The researchers have just published their results in the American Journal of Pathology.

Neurodegenerative processes, such as those occurring in Parkinson’s disease, are characterized by pathological alterations of the brain cells: these cells lose their structure and function, a process that is accompanied by changes in their metabolism. Until now, most scientists have always focused on just one or a few aspects of the disease to better describe and understand the underlying mechanisms. By analysing the whole metabolome however, LCSB researchers have realized a more global approach: they now can analyse hundreds of biomolecules, produced by nerve cells in upper, middle, and lower brain regions of the mouse. In the process, they not only look at healthy brains, but also at brains in which neurodegeneration occurs.

Study demonstrates that free-water provides a potential non-invasive progression marker of the substantia nigra region in the brain.

Parkinson’s disease is a CNS disorder that results from the loss of cells in various parts of the brain, including a region called the substantia nigra. The substantia nigra cells produce dopamine, a chemical messenger responsible for transmitting signals within the brain that allow for coordination of movement.

With no objective test or biomarker for Parkinson’s, there is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson’s disease. This study’s authors had previously found elevated free-water levels in the substantia nigra for patients with Parkinson’s disease compared with controls in single-site and multi-site cohorts.

In this study, published in the journal “Brain”, they tested the hypotheses that free-water levels in the substantia nigra of Parkinson’s disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year.
The researchers conducted a longitudinal study in controls (n = 19) and patients with Parkinson’s disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra.

The results found that free water levels increases with progression of Parkinson’s disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year, thus demonstrating that free-water provides a potential non-invasive progression marker of the substantia nigra.

Longitudinal changes in free-water within the substantia nigra of Parkinson’s disease
Edward Ofori ,et al., DOI: http://dx.doi.org/10.1093/brain/awv136

Over the past few years, the OECD has conducted work in a number of areas related to innovation in biomedical research and health innovation for healthy ageing.

Entitled “Enhancing Translational Research and Clinical Development for Alzheimer’s Disease and other Dementias”, this report is the main output from a Nov 2014 OECD workshop aimed to provide an international forum for all stakeholders to drive forward a change in the global paradigm in biomedical research and health innovation for Alzheimer’s disease and other dementias.

Discussions at the workshop have shown that progress on key issues is being made, thanks to a willingness of stakeholders to join forces and work together towards a future cure.

In line with recommendations of the G8 Dementia Summit Declaration to strengthen collaboration for innovation and cross-sector partnerships this report considers the challenges and options to promote and accelerate research in dementia and its transformation into innovative therapies and diagnostics.

Scientists at Mayo Clinic, Jacksonville, Florida, USA have created a novel mouse that exhibits the symptoms and neurodegeneration associated with the most common genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both of which are caused by a mutation in the a gene called C9ORF72. The study was published in the journal Science.

ALS destroys nerves that control essential movements, including speaking, walking, breathing and swallowing. After Alzheimer’s disease, FTD is the most common form of early onset dementia. It is characterized by changes in personality, behavior and language due to loss of neurons in the brain’s frontal and temporal lobes. Patients with mutations in the chromosome 9 open reading frame 72 (C9ORF72) gene have all or some symptoms associated with both disorders.

“Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with theC9ORF72 mutation,” said the study’s lead author, Leonard Petrucelli, Ph.D., chair and Ralph and Ruth Abrams Professor of the Department of Neuroscience at Mayo Clinic, and a senior author of the study. “These mice could greatly improve our understanding of ALS and FTD and hasten the development of effective treatments.”

To create the model, Ms. Jeannie Chew, a Mayo Graduate School student and member of Dr. Petrucelli’s team, injected the brains of newborn mice with a disease-causing version of the C9ORF72 gene. As the mice aged, they became hyperactive, anxious, and antisocial, in addition to having problems with movement that mirrored patient symptoms. The brains of the mice were smaller than normal and had fewer neurons in areas that controlled the affected behaviors. The scientists also found that the mouse brains had key hallmarks of the disorders, including toxic clusters of ribonucleic acids (RNA) and TDP-43, a protein that has long been known to go awry in the majority of ALS and FTD cases.

“Finding TDP-43 in these mice was unexpected” Dr. Petrucelli said. “We don’t yet know how foci and c9RAN proteins are linked to TDP-43 abnormalities, but with our new animal model, we now have a way to find out.” Dr. Petrucelli and his team think these results are an important step in the development of therapies for these forms of ALS and FTD and other neurodegenerative disorders.

Chew et al. “C9ORF72 Repeat Expansions in Mice Cause TDP-43 Pathology, Neuronal Loss and Behavioral Deficits,” Science, May 14, 2015. DOI: 10.1126/science.aaa9344

The National Institutes of Health, USA has released recommendations that provide a framework for a bold and transformative Alzheimer’s disease research agenda.

Developed at the February 2015 Alzheimer’s Disease Research Summit 2015: Path to Treatment and Prevention, the highly anticipated recommendations provide the wider Alzheimer’s research community with a strategy for speeding the development of effective interventions for Alzheimer’s and related dementias.

These recommendations call for a change in how the academic, biopharmaceutical and government sectors participating in Alzheimer’s research and therapy generate, share and use knowledge to propel the development of critically needed therapies.

Although past research has associated obesity with increased risk of dementia, a new study – deemed the largest ever to assess the link between body mass index and dementia risk – suggests obesity could actually be a protective factor against the condition, while people who are underweight may be at increased risk.

A large retrospective cohort study, published in The Lancet Diabetes and Endocrinology, has revealed a surprising association between being underweight in mid-life and late-life, and increased risk of dementia.

The study assessed the medical records of almost 2 million people in the UK in order to gain a better understanding of how obesity affects dementia risk. The researchers found that, compared with adults who had a healthy BMI (between 20-25 kg/m2), those who were underweight – defined in this study as a BMI less than 20 kg/m2 – during middle age were 34% more likely to be diagnosed with dementia. This increased risk remained for 15 years after adults’ underweight status was recorded.

The team notes that participants with a BMI of less than 18.5 kg/m2 are usually classed as underweight, but the threshold was raised in this study to allow comparisons with past studies, which have defined a BMI of less than 20 kg/m2 as underweight.

The researchers also found that middle-aged adults’ risk of dementia steadily reduced as their BMI increased. Compared with adults who had a healthy BMI, those who were severely obese (BMI greater than 40 kg/m2) were 29% less likely to develop dementia. The team says their results remained even after accounting for factors associated with increased dementia risk, including smoking and alcohol consumption. In addition, the results were not affected by adults’ age at dementia diagnosis or the decade in which they were born, according to the researchers.

Source: Medical News Today

New research highlights how nerves – whether harmed by disease or traumatic injury – start to die, a discovery that unveils novel targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Peripheral neuropathy damages nerves in the body’s extremities and can cause unrelenting pain, stinging, burning, itching and sensitivity to touch. The condition is commonly associated with diabetes or develops as a side effect of chemotherapy.

Nerve cells talk to each other by transmitting signals along communication cables called axons. Such signals underlie vital activities, such as thinking and memory, movement and language. As part of the study, the researchers showed they could prevent axons from dying, a finding that suggests therapies could be developed to counteract the withering away of nerve axons.

The research, by scientists at Washington University School of Medicine in St. Louis, is reported online April 23 in the journal Science.

”We have uncovered new details that let us piece together a major pathway involved in axon degeneration,” said senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. ”This is an important step forward and helps to identify new therapeutic targets. That we were able to block axon degeneration in the lab also gives us hope that drugs could be developed to treat patients suffering from a variety of neurological conditions.”

A common thread among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signaling and prevents nerves from communicating with one another. Axon degeneration is thought to be an initiating event in many of these disorders. In fact, an unhealthy axon is known to trigger its own death, and researchers are keenly interested in understanding how this happens.

Working in cell cultures, fruit flies and mice, Milbrandt and co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology, and their colleagues showed that a protein already known to be involved in axon degeneration, acts like a switch to trigger axon degeneration after an injury.

Moreover, they found that this protein, once unleashed, causes a rapid decline in the energy supply within axons. Within minutes after the protein – called SARM1 – is activated in neurons, a massive loss of nicotinamide adenine dinucleotide (NAD), a chemical central to a cell’s energy production, occurs within the axon.

Source: News-Medical.net