STUDY PROJECTS ALZHEIMER'S DEMENTIA CASES WILL ALMOST TRIPLE BY 2050

A new study published online by the journal Neurology projects that, in the U.S. alone, there will be 13.8 million individuals living with Alzheimer’s disease dementia in 2050 – almost triple the estimated 4.7 million individuals suffering from Alzheimer’s in 2010.  The study, led by Liesi Hebert of Rush University Medical Center, also projects that, of the 13.8 million individuals with Alzheimer’s dementia in 2050, approximately 7 million will be age 85 or older. 

This sharp increase will be due primarily to the aging baby boom population, and is in line with projections that other researchers have previously made.  As stated by study co-author Jennifer Weuve:

“All of these projections anticipate a future with a dramatic increase in the number of people with Alzheimer's and should compel us to prepare for it. … Our study draws attention to an urgent need for more research, treatments and preventive strategies to reduce this epidemic.”

[ScienceDaily]

GUIDELINES ISSUED FOR AMYLOID POSITRON EMISSION TOMOGRAPHY (PET) IMAGING

The Alzheimer’s Association, together with the Society for Nuclear Medicine and Molecular Imaging (SNMMI), have jointly released the first-ever guidelines for the clinical use of amyloid PET imaging.  As background, PET is a type of nuclear imaging that provides three-dimensional images of specific regions of interest within the body.  In amyloid PET imaging, a radiopharmaceutical agent is injected into the body and binds specifically to amyloid protein, enabling the imaging of areas within the brain where amyloid has clumped into plaques.

There has recently been considerable interest in utilizing PET in the diagnosis of Alzheimer’s disease.  However, this is challenging as many healthy individuals, including elderly individuals with normal cognitive abilities, possess elevated levels of amyloid plaques; these plaques are also characteristic of other diseases in addition to Alzheimer’s.

In order to evaluate how PET could be used appropriately in conjunction with suspected cases of Alzheimer’s disease, the Alzheimer’s Association and SNMMI formed the Amyloid Imaging Taskforce, and charged it with formulating appropriate guidelines.  These newly-released guidelines specify what groups of individuals would be appropriate candidates for amyloid PET imaging, and also what groups would not be good candidates.  Also specified are various inappropriate uses of amyloid PET imaging, such as determining the severity of dementia, as a substitute for genetic testing, or for non-medical reasons.

The Taskforce indicates that PET could potentially be used to aid in the diagnosis of individuals exhibiting cognitive impairment, but stresses that this must be considered in conjunction with other clinical information, must be done only after a comprehensive examination by an appropriately skilled physician, and only if the presence or lack of amyloid would increase the certainty of a diagnosis, and would result in changes to the individual’s treatment plan.

It is hoped that amyloid PET imaging may represent an important tool in the appropriate diagnosis and treatment of Alzheimer’s and other forms of dementia.  As stated by SNMMI President, Frederic H. Fahey, D.Sc.,

“Working together, we hope that the information garnered from amyloid PET imaging will aid in diagnosis and play a pivotal role in the development of new treatments for Alzheimer's.”

[Alzheimer's Association]

SALIVARY GLAND BIOPSY MAY ENABLE DIAGNOSIS OF PARKINSON'S DISEASE

New findings announced by a team of researchers led by Charles Adler of the Mayo Clinic Arizona indicate that a biopsy of the salivary gland may represent a viable diagnostic test for Parkinson's disease.  Through autopsies of individuals who had suffered from Parkinson's, the researchers had previously found that the submandibular glands (one of the three pairs of major salivary glands in the human body) have one of the highest concentrations of the protein alpha-synuclein outside of the brain.  Within the brain of Parkinson's sufferers, this protein forms the abnormal clumps known as Lewy bodies that are characteristic of the disease.  

In the current study, core needle biopsies of the submandibular gland were taken from eleven living patients who had suffered from Parkinson's between six and fourteen years.  Alpha-synuclein was found to be present within the submandibular glands of nine of the eleven patients.  The researchers therefore surmise that such biopsies, which were well-tolerated by patients, could represent a viable test for diagnosing Parkinson's disease.

Next steps will include testing individuals who have more recently begun to exhibit Parkinson's symptoms, at which point it is difficult to make an accurate diagnosis.  At present, the accuracy of diagnosis ranges from approximately 50% at early stages, to 80-90% in individuals who have had the disease for 5-10 years.  There is no definitive diagnostic test for Parkinson's other than at autopsy, such that clinicians must attempt to initiate appropriate treatment even though the presence of Parkinson's is uncertain.  According to Adler:

"A lot of people who look like they have Parkinson's disease early on really don't have it, so we'd like to see if this biopsy test would be able to prove the presence of PD in earlier-onset, shorter-duration patients. Doing the biopsy and finding the abnormal protein would tell us that we are in fact treating Parkinson's disease because before, we wouldn't be quite sure." 

[Medscape]

PROTECTING ALDEHYDE DEHYDROGENASE ACTIVITY MAY REPRESENT PATHWAY FOR TREATING PARKINSON’S DISEASE

A team of researchers at UCLA has learned that exposure to the pesticide benomyl initiates a cascade of cellular events that may ultimately result in the development of Parkinson’s disease.  A link between the pesticides paraquat, maneb and ziram had previously been linked to an increased incidence of Parkinson’s; the current study focused on determining whether there is a similar link to Parkinson’s and exposure to benomyl – a pesticide whose use was banned by the EPA in 2001, but whose toxic effects are believed to linger in those exposed to its use.

Specifically, the researchers demonstrated that exposure to benomyl prevents the enzyme aldehyde dehydrogenase, or ALDH, from controlling the accumulation of the naturally-occurring toxin 3,4-dihydroxyphenylacetaldehyde, or DOPAL, within the brain.  If left unchecked by ALDH, DOPAL accumulates, resulting in damage to dopaminergic neurons and increasing an individual’s risk for developing Parkinson’s.

It is believed that only a small fraction of Parkinson’s disease cases are caused by genetic factors.  These new findings may provide insight into other factors leading to the development and progression of the disease and, ultimately, to how it may be effectively prevented or treated. According to investigator Arthur G. Fitzmaurice:

“Environmental factors almost certainly play an important role in this disorder.  Understanding the relevant mechanisms — particularly what causes the selective loss of dopaminergic neurons — may provide important clues to explain how the disease develops."

[UCLA Newsroom]

2012 SEES HIGHEST NUMBER OF FDA NEW DRUG APPROVALS SINCE 1996

A total of 39 new drugs were approved by the FDA in 2012 – an increase over the 30 new drug approvals made by the FDA in 2011, and almost double the 21 approved in 2010.  It is anticipated that this trend may continue into 2013; for example, the European Medicines Agency – which is responsible for the scientific evaluation of applications for marketing authorizations within the European Union – projects that 54 new drug applications will be received in 2013, as compared with 52 in 2012 and 48 in 2011.  This sentiment is echoed by FDA spokesperson Sandy Walsh, who indicates that the pipeline of new drugs in development is continuing to grow.

The new drug approvals are viewed as positive news for the pharmaceutical industry, which experienced significant losses to generic manufacturers in 2012 due to patent expirations.  Major U.S. drug manufacturers alone lost an approximate $21 billion in revenues, with European pharmaceutical companies losing approximately $10 billion.

However, it is difficult to project the overall impact that these new drugs will have on pharmaceutical revenues, or on the overall health of the industry.  While it is projected that some of the drugs approved in 2012 will prove to be blockbusters, others target rare diseases and are unlikely to pull in multibillion dollar revenues.

Investors will also be watching closely to see how the new drugs perform commercially once they reach the market, since securing payment for innovative medicines is an increasingly tough fight.

[Reuters]

NOVEL SPECTROSCOPIC TECHNIQUE MAY LEAD TO GREATER UNDERSTANDING OF NEURODEGENERATIVE DISEASES

Researchers led by Angel Marti and Laura Segatori of Rice University have developed a novel spectroscopic technique that will enable scientists to monitor protein aggregation within living cells.  This technique utilizes a novel molecular probe comprising a ruthenium dipyridophenazine derivative to visualize and monitor alpha-synuclein fibril formation in real time, and to quantify aggregates within living neuroglioma cells.  The probe binds to misfolded alpha-synuclein proteins that form fibril clumps, and lights up when triggered by a laser – but only when the probe is attached to a fibril.  Clumping and aggregation can then be tracked via photoluminescence spectroscopy.

As a proof of principle, the researchers created an in vitro cell model of Parkinson's disease and found their ruthenium complexes clearly labeled fibrillar alpha-synuclein proteins in cells.

This could represent a breakthrough in understanding the molecular mechanisms of neurodegenerative diseases characterized by the formation of insoluble fibrillar deposits, such as Parkinson’s and Huntington’s.  It is envisioned that the technique will be of value in the identification and screening of potential new drugs against these diseases, by enabling the monitoring of their activity against protein aggregation and fibril formation.

[Medical News Today]

NEW STUDY HIGHLIGHTS CHALLENGES OF BRINGING NEW DRUGS TO MARKET

According to a study released earlier this week by the UK’s Office of Health Economics, R&D costs have risen from $199 million (USD) per new drug in the 1970s to $1.9 billion in the 2000s.  This staggering increase is attributed to four key factors:

• an increase of almost 600% in out-of-pocket research expenses;
• lower success rates for clinical drug development, particularly in areas such as neurodegenerative diseases such as Alzheimer’s, cancer, and autoimmune diseases such as arthritis;
• the time required to take a drug through development to market – an average of 13.5 years in the 2000s as compared with 6 years in the 1970s; and
• an increase in the cost of capital from 8% in the 1970s to 11% in the 2000s. 

In response, pharmaceutical companies are pursuing various new models for collaboration and innovation, while attempting to streamline R&D efforts by being more selective - for example, by making decisions at earlier stages of development regarding the market potential of new drug candidates.  However, even should R&D costs be effectively lowered, another key challenge lies ahead in the form of obtaining reimbursements for innovative treatments.  As stated by Jorge Mestre-Ferrandiz, lead author of the OHE study: 

“Just as new approaches to R&D are crucial to the future, so are new approaches to facilitating market entry and use. These are essential both to encouraging R&D and ensuring that patients have the earliest access possible to life-changing therapies.”

[FierceBiotech]

NEW FINDINGS MAY ADVANCE UNDERSTANDING OF PARKINSON'S DISEASE

A team of researchers led by Bernardo Sabatini of Harvard Medical School has learned that dopamine neurons within a region of the brain known as the striatum, which is involved in movement and learning, release a neurotransmitter known as GABA in addition to dopamine.  It has previously been known that when these dopamine neurons die, as is the case in individuals with Parkinson’s disease, the brain’s ability to initiate movement is impaired.  This has led to the use of dopamine precursors for treating Parkinson’s; these precursors are converted to dopamine within the brain, and generally are effective in alleviating the symptoms of Parkinson’s for a time.  However, the effectiveness of these drugs wears off over time, though the reasons for this have not previously been understood. 

Sabatini and colleagues set out to study what happens when striatal dopamine neurons are activated.  Surprisingly, rather than observing the effects of dopamine release, the researchers observed the rapid inhibition of striatal neurons by GABA.  Further studies confirmed that GABA was being released directly by these neurons, even in the absence of vesicular GABA transporter – a protein that generally acts to package shuttle GABA within the brain.  Taking this a step further, the researchers found that another protein – vesicular monoamine transporter – shuttles GABA in addition to dopamine. 

These findings may impact not only our understanding of Parkinson’s disease, but may also shed light on why current dopamine precursors may only have limited efficacy – perhaps ultimately leading to new treatments:

“What makes this important now is that every manipulation that has targeted dopamine by targeting the vesicular monoamine transporter has altered GABA as well. And nobody’s paid any attention to it,” said Sabatini. “Every Parkinsonian model that we have in which we’ve lost dopamine has actually lost GABA, too. So we really have to go back now and think: Which of these effects are due to loss of GABA and which are due to loss of dopamine?”

[Harvard Medical School]

NEW FINDINGS REGARDING CAFFEINE'S POTENTIAL ROLE IN REDUCING ALZHEIMER'S RISK

Much has been made in recent months of scientific findings indicating that caffeine consumption appears to be linked to a reduced risk of developing Alzheimer’s and other neurodegenerative diseases.  However, while researchers observed that caffeine somehow suppressed the appearance of amyloid plaques within the brain, the mechanisms behind this were not clearly understood.

Now, a team of researchers led by Gregory Freund of the University of Illinois has found that caffeine appears to be capable of blocking inflammation within the brain.  The researchers observed that mice that had been given caffeine were capable of recovering memories and forming new ones far more rapidly following an acute hypoxic event (that is, temporarily halting breathing and blood flow) than those mice that had not been given caffeine prior to the induction of hypoxia. 

Upon exploring this further, the researchers learned that hypoxia initiates a cascade within the brain that ultimately results in cognitive decline.  Specifically, hypoxia triggers the release of adenosine within the brain, activating an enzyme known as caspase-1; this in turn stimulates the production of beta cytokine IL-1 – which plays a major role in the development of inflammation.  Taking this a step further, the researchers observed that caffeine is capable of blocking adenosine receptors and hence the activation of caspase-1.

While this news will certainly be of interest to coffee drinkers, the researchers are optimistic that these insights regarding how caffeine is capable of blocking inflammation within the brain may also lead to the development of novel drugs that could potentially be effective in the prevention and/or treatment of Alzheimer’s.

[io9]

P7C3 CLASS OF NEUROPROTECTIVE COMPOUNDS PROTECT IN MOUSE MODELS OF AMYOTROPHIC LATERAL SCLEROSIS AND PARKINSON'S DISEASE

As published online today in the Proceedings of the National Academy of Sciences, a team of researchers at the University of Texas Southwestern Medical Center has shown that the compound P7C3A20 blocks death of spinal cord motor neurons and improves motor function in a mouse model of amyotrophic lateral sclerosis (ALS).  These researchers, led by Andrew Pieper, Joseph Ready and Steve McKnight, have also shown in a companion paper that active members of the P7C3 series of compounds additionally block cell death of dopaminergic neurons in the MPTP toxin mouse model of Parkinson's disease (PD).  By contrast, the researchers demonstrate that the putative neuroprotective drug Latrepiridine (Dimebon) does not confer protection in the ALS or PD models.

P7C3A20 is a more highly active analog of P7C3, a proneurogenic, neuroprotective compound that has previously been shown to restore hippocampal structure and function in mice suffering from pathologically high levels of neuronal death within the dentate gyrus, and also to impede hippocampal cell death and preserve cognition in terminally aged rats.

The researchers also demonstrated that P7C3 and P7C3A20 protect against the death of dopaminergic neurons and preserve mobility in a C. elegans model of PD, indicating that the cell death mechanism blocked by the P7C3 series of molecules is conserved across a range of species.   It is anticipated that the chemical scaffold represented by P7C3 and P7C3A20 may represent the basis for developing new therapeutic agents against these, and potentially other, neurodegenerative diseases, for which there are currently no effective treatments.

Beyond what has been reported in mouse models of Parkinson’s disease and amyotrophic lateral sclerosis, the researchers are working collaboratively with others to test whether the P7C3 class of chemicals might be protective in animal models of traumatic brain injury and peripheral nerve injury.  It is recognized that there may be many other opportunities for the testing of a broadly neuroprotective chemical, including Alzheimer’s disease, stroke and other conditions associated with nerve cell death.  We openly welcome collaborative relationships with scientists skilled in other models of nerve cell death.

2M BioTech licenses the patent applications from the owner, the Board of Regents of the University of Texas System.  We have sought to obtain broad worldwide patent coverage on both composition of matter and the use of this class of chemicals and improved derivatives as pro-neurogenic, neuroprotective compounds. 

We are actively progressing toward a human clinical testing program with resources available through our team at UTSWMC and other relationships.  However, we are also exploring partnering and licensing opportunities with pharmaceutical and biotech companies where such opportunities present an opportunity to speed the development of these chemicals into useful drugs.

[PNAS - ALS article]  [PNAS - Parkinson's article]