Author Archives: jpnd

Analysis of health insurance data suggests preventive effect

Type 2 diabetes most commonly occurs in late adulthood, and it has long been known that it can affect the patient’s mental health: Patients have a greater risk of developing dementia than non-diabetics. However, how does antidiabetic medication influence this risk? Researchers have investigated this issue in a new study based on data from the years 2004 to 2010 provided by the German public health insurance company AOK. These data set comprises information about diseases and medication related to more than 145,000 men and women aged 60 and over.

The analysis confirmed previous findings that diabetics have an increased risk of developing dementia. However, it was also found that this risk can significantly be modified by pioglitazone. This drug is taken as tablets. It is applied in short-term as well as in long-term treatment of diabetes as long as the body is still capable of producing its own insulin.

„Treatment with pioglitazone showed a remarkable side benefit. It was able to significantly decrease the risk of dementia,” says co-author Gabriele Doblhammer. „The longer the treatment, the lower the risk.” Risk reduction was most noticeable when the drug was administered for at least two years. Diabetics given this treatment developed dementia less often than non-diabetics.  „The risk of developing dementia was around 47 percent lower than in non-diabetics, i.e. only about half as large.”, she said.

Protection against nerve cell damage

Pioglitazone improves the effect of the body’s own insulin. Moreover, laboratory tests have long indicated that it also protects the nerve cells. The current results are therefore no surprise to neuroscientist Michael Heneka. „Pioglitazone is an anti-inflammatory drug that also inhibits the deposition of harmful proteins in the brain,” he says.

However, Heneka emphasizes that the exact mechanisms are not yet understood: „Our study suggests that pioglitazone has a preventive effect. This happens when the drug is taken before symptoms of dementia manifest. Thus, it protects in particular against Alzheimer’s, the most common form of dementia. The causes for this, whether pioglitazone only has this protective effect in diabetics or if it would also work in non-diabetics – all these questions have yet to be answered. The next logical step would therefore be clinical studies. These studies would specifically investigate the effect of pioglitazone and other antidiabetics on dementia.

Source:  Eurekalert

Scientists have identified a single blood protein that may indicate the development of Mild Cognitive Impairment (MCI) years before symptoms appear, a disorder that has been associated with an increased risk of Alzheimer’s disease or other dementias.

The research, published in the journal “Translational Psychiatry”, used data from over 100 sets of twins from TwinsUK, the biggest adult twin cohort in the UK. The use of 55 identical twin-pairs in the study allowed researchers to show that the association between the blood protein and a ten year decline in cognitive ability was independent of age and genetics, both of which are already known to affect the risk of developing Alzheimer’s disease, the most common form of dementia.

The study, the largest of its kind to date, measured over 1,000 proteins in the blood of over 200 healthy individuals using a laboratory test called SOMAscan*, a protein biomarker discovery tool that simultaneously measures a wide range of different proteins. Using a computerised test, the researchers then assessed each individual’s cognitive ability, and compared the results with the measured levels of each different protein in the blood.

For the first time, they found that the blood level of a protein called MAPKAPK5 was, on average, lower in individuals whose cognitive ability declined over a ten year period.

Source:  Medical Research Council, UK

An international team of researchers has developed a method for fabricating nano-scale electronic scaffolds that can be injected via syringe. Once connected to electronic devices, the scaffolds can be used to monitor neural activity, stimulate tissues and even promote regenerations of neurons.

The study entitled “Syringe-injectable electronics” was recently published in the journal Nature.

Nanotechnology and revealed an innovative method to employ tiny electronic devices in the brain, or other parts of the body, as a potential therapy for a wide range of disorders, including neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The study was performed by researchers at the Harvard University in Cambridge, Massachusetts and the National Center for Nanoscience and Technology in China.

The team had previously shown that cardiac or nerve cells grown with embedded nano-scale electronic scaffolds could generate a so-called “cyborg” tissue. The electronic devices could then record the electrical signals generated by the tissues, and measure signal changes when cardio- or neuro-stimulating drugs were administered to the cells.

Minimally invasive targeted delivery of electronics into artificial or natural structures is however a challenge. “We were able to demonstrate that we could make this scaffold and culture cells within it, but we didn’t really have an idea how to insert that into pre-existing tissue,” explained the study’s senior author Dr. Charles Lieber in a news release. Now, Dr. Lieber and colleagues have developed a pioneering method where sub-micrometer-thick mesh electronics can be delivered to their target through injection via a syringe.

Though not the first attempts at implanting electronics into the brain – deep brain stimulation has been used to treat a variety of disorders for decades – the nano-fabricated scaffolds operate on a completely different scale.

„Existing techniques are crude relative to the way the brain is wired,” Lieber explained. „Whether it’s a silicon probe or flexible polymers…they cause inflammation in the tissue that requires periodically changing the position or the stimulation. But with our injectable electronics, it’s as if it’s not there at all. They are one million times more flexible than any state-of-the-art flexible electronics and have subcellular feature sizes. They’re what I call „neuro-philic” – they actually like to interact with neurons.

Source:  Science Daily

Two studies in the May 19 issue of JAMA analyze the prevalence of the plaque amyloid among adults of varying ages, with and without dementia, and its association with cognitive impairment.

The earliest recognizable pathological event in Alzheimer’s Disease (AD) is cerebral amyloid-beta aggregation (protein fragments that clump together to form plaque).This pathology may be present up to 20 years before the onset of dementia.

Therefore, estimates of the prevalence of amyloid pathology in persons without dementia are needed to better understand the development of AD and to facilitate the design of AD prevention studies. Initiation of treatment for AD in the pre-dementia phase, when neuronal damage is still limited, may be crucial to have clinical benefit.

Led by Pieter Jelle Visser at VU University Medical Center in Amsterdam and Maastricht University, The Netherlands, these two studies compiled amyloid PET and cerebrospinal fluid (CSF) biomarker data from thousands of participants, and represent the largest data sets to date on how commonly amyloid builds up in people’s brains.

One meta-analysis looked at the prevalence of amyloid in cognitively normal people, and concluded that amyloid creeps into the brain 20 to 30 years before dementia can be diagnosed. This was particularly true for people who carry an ApoE4 allele; indeed, they developed amyloid at a younger age.

In the second study, the researchers compared amyloid prevalence among people clinically diagnosed with AD or other dementias, including dementia with Lewy bodies, frontotemporal dementia, and corticobasal syndrome. They found that the prevalence of brain amyloid in people diagnosed with most non-AD dementias was higher with increasing age. They concluded that older people may be likelier to have multiple pathologies, or to have been misdiagnosed. The data may help researchers set inclusion criteria for clinical trials, or make better diagnoses.

“The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD,” the researchers wrote. “Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”

However, the authors point out that follow-up studies need to be conducted since not all people with amyloid pathology develop dementia in their lifetime, and not all people with a clinical diagnosis of Alzheimer’s dementia have amyloid pathology.

“Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state,” they wrote. “Our prevalence rates can be used as an inexpensive and noninvasive approach to select persons at risk for amyloid positivity.”

The Innovative Medicines Initiative 2 (IMI 2) indicative topic text for Call 5 is now available, with heavy emphasis on Alzheimer’s Disease. The following topics are under consideration for inclusion in the call:

  • Patient perspective elicitation on benefits and risks of medicinal products from development through the entire life cycle, for integration into benefit risk assessments by regulators and health technology assessment bodies
  • Diabetic kidney disease biomarkers (DKD-BM)
  • Inflammation and Alzheimer’s disease (AD): modulating microglia function – focussing on TREM2 and CD33
  • Understanding the role of amyloid biomarkers in the current and future diagnosis and management of patients across the spectrum of cognitive impairment (from pre-dementia to dementia)
  • Evolving models of patient engagement and access for earlier identification of Alzheimer’s disease: phased expansion study
  • Apolipoprotein E (ApoE) biology to validated Alzheimer’s disease targets

Note: All information regarding future IMI Call topics is indicative and subject to change. Final information about future IMI Calls will be communicated after approval by the IMI Governing Board.

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons and with mitochondrial dysfunction.

Autophagy is a powerful process for removing such proteins and for maintaining mitochondrial homeostasis. Over recent years, evidence has accumulated to demonstrate that upregulation of autophagy may protect against neurodegeneration.However, autophagy dysfunction has also been implicated in the pathogenesis of various diseases.

This Review summarizes the progress that has been made in our understanding of how perturbations in autophagy are linked with neurodegenerative diseases and the potential therapeutic strategies resulting from the modulation of this process.

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.