Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Neurology’ category

Healthcare innovation can take many forms. It can be a breakthrough in our understanding of the biology of cancer, or a disease that allows new drugs to target it in an effective way, for example. We also see it with advances in medical technology such as implants that can help restore vision or imaging techniques that may allow faster and more accurate diagnoses.

However, one area that I had not thought about until recently was how innovation in a building’s design can impact the delivery of healthcare.

We interact with design every day without thinking much about it. Advertisers use design in brand marketing all the time to create instantly recognizable logos that we automatically associate with a product.

Listeners to Roman Mars’ outstanding podcast, 99% Invisible, will already be familiar with the power of design in everyday life. This podcast is well worth a listen!

Currently, I’m in Liverpool in the North West of England for personal and professional reasons, and while here I’m looking at some of the innovative work being done in the area around dementia care.

Last week I visited Everton FC who, in partnership with Mersey Care NHS Trust, use their facilities to engage and provide support to local people in the community who have dementia.

Since then I have also been to Liverpool City Councils’ Sedgemoor Dementia Support Centre in Norris Green.  The Centre recently won a national design award at the health care equivalent of the Oscars (Best Care Complex at the Healthcare Design Awards).

My mother, Audrey, had Alzheimer’s disease – a form of dementia – and spent the last two years of her life in a nursing home.  While the carers were wonderful people, I always found it rather depressing to visit.  She spent everyday sitting in a standard care home chair in a lounge area that had little cognitive stimulation other than a TV blaring in the background, high up on the wall, just creating mindless noise.

While Audrey’s memory was a bit like a Swiss cheese, she was able to engage in a conversation and had moments of great lucidity. As Tommy Dunne (@TommyTommyTee18), who has early onset Alzheimer’s told me at Everton FC: he has dementia, but he’s not demented!

I was curious to know what was innovative about the Sedgemoor dementia support centre; can design really make such a difference in the delivery of health care to those with dementia?  You can judge for yourself after watching the audio slideshow from my visit.

Sedgemoor shows what can be done in the public sector. Like many examples of successful innovation it had a champion with a vision, willing to take risks, think outside the box and break from the norm of what might otherwise have been a utilitarian oblong box.

That champion with a vision is Liverpool City Council’s Joy McDonnell, a qualified architect who was the client lead. Joy spent two hours giving me a guided tour of Sedgemoor, explaining how each part of the building, even down to the fixtures and fittings, was designed to afford the maximum benefit to users with dementia. I was blown away.

Since it was going to be impossible for me to do justice to a two-hour visit as part of a 6-minute radio documentary I’m producing for a journalism course, I’ve taken some of the pictures from my visit and matched these with the sound I recorded to create an audio slideshow:

What I hope is that Sedgemoor is not just an isolated example, but sets a precedent for future buildings. This is how more dementia care facilities could be designed. If Liverpool City Council can create a publicly funded building like this for the same price as they would an oblong box, why can’t others repeat it around the country?

I would have loved the nursing home my Mother ended up in to have had many of the design features I saw at Sedgemoor.  I could see how this would have improved her quality of life, helped stimulate her memories and keep her more active and engaged.

For anyone who has a chronic long-term illness, such as cancer or dementia, it’s not just about how long you live, but having a good quality of life while you are alive. That is something we should all aspire to for our loved ones and ourselves.

I would like to thank Liverpool City Council, and in particular the press office and dementia support lead, Phil Wong, for making my visit happen. Thanks also to Sedgemoor Manager Mary Plumpton for a warm welcome. Joy McDonnell was not only generous with her time, but gave of herself to bring Sedgemoor to life for me. Thank you, Joy!

If you have come across some innovative programs in the dementia or Alzheimer’s area, do feel share them in the comments section below.

Update June 5, 2014: listen to Living well with dementia – a personal journey

My research into designing for dementia was undertaken while on a BJTC accredited diploma in radio journalism course based at Radio City in Liverpool. You can listen via SoundCloud to the documentary I produced on living well with dementia – a personal journey:

UPDATE November 20th, 2014: BJTC Awards by @maverickny

I’m delighted to announce that Pieter’s fantastic work on dementia won the BJTC 2014 Award for Best Radio Documentary!

Thank goodness for Twitter and being able to follow the live event in Birmingham, UK remotely…

BJTC Awrd 2014

Dementia care is a “quiet crisis” that already touches many families and will touch many more as we live longer in our old age and the huge baby boomer population reaches retirement age.

The Alzheimer’s Research Trust estimate that 1 in 3 over the age of 65 will have dementia by the time they die. Alzheimer’s disease is one type of dementia.

To cope with this explosion, more care will need to be provided in the community.

Mersey Care NHS Trust, who provide mental health care in Liverpool, Sefton and Kirby, have partnered with Everton FC, an English Premier League Club to support members of the local community with dementia.

Everton v Crystal Palace April 16 2014

Everton FC vs Crystal Palace at Goodison Park on April 16, 2014.

The innovative program called “Pass on the Memories” (Twitter: @efc_potm) helps more than 120 people with memory loss through activities that take place two days a week at Goodison Park. Support is offered via facilitators in the club and health professionals from Mersey Care.

The meetings help trigger sporting memories, but also engages participants in group social activities and visits, thereby keeping them mentally active and engaged.

When I visited, members of the group were about to head off for a visit to the Museum of Liverpool, which would no doubt stimulate powerful memories for many.

As some readers of the blog may know, my mother Audrey (who died recently at age 89) had Alzheimer’s disease.  It’s a progressive disease with no known cure.  I watched her memory slowly but surely deteriorate over several years.  A keen dancer, she reached a point where she couldn’t remember how to dance anymore.

What Everton FC is doing by lending their support to the Pass on the Memories scheme, is something that sporting clubs around the world should all consider in their communities.

Goodison Park home of Everton FC

Sporting clubs derive considerable support from local communities and have facilities that are vastly underused outside of games. Many of their fans will sadly develop dementia. Engaging the local community in this way is a tremendous way of giving back.

As social services continue to be cut back in Liverpool due to budget cuts, I’m impressed by the way Mersey Care and Everton FC are helping those with dementia have the best quality of life they can through this type of local partnership.

If it didn’t exist, I expect many people would end up just sitting at home all day with little mental stimulation or interaction.

Henry Mooney Everton FCDuring my visit to Goodison Park, I spoke with Everton FC Community Engagement Manager, Henry Mooney (@HMooney23) who plays a key role in running the Pass on the Memories program at the club. He told me you don’t have to be an Everton fan to participate. 🙂

Living with Alzheimer’s disease is not easy.  Unlike a physical disability, you can’t readily tell if someone has dementia, they look normal much like the rest of us.

Tommy Dunne

Tommy Dunne, 61, was diagnosed with early stage Alzheimer’s disease three years ago. He told me that just because he has dementia, does not mean he is demented. Raising awareness of dementia and getting rid of the stigma associated with it is something we all can help with.

As the number of people with dementia grows, those who provide services (shops, transport etc) will need to be educated on how they can help people with dementia maintain their independence and undertake the activities of daily living that we all take for granted.

I was pleasantly surprised and pleased to see that Tommy is active on Twitter (@TommyTommytee18). It’s a great way to share his experiences.

I’ve included excerpts of the interviews I did with Tommy and Henry Mooney in the radio documentary on dementia that I produced – you can listen via the embedded SoundCloud at the end of this post or using this link.

If you are in the Liverpool area and have a family member with dementia, I encourage you to find out more about this innovative program.

Taking a more strategic view, I’m still shocked by how little progress there has been in drug development to tackle dementia, and in particular Alzheimer’s disease.

In comparison to oncology where research is focused on multiple new targets for drugs, as well as novel biomarkers that can help predict who are more likely to respond, dementia research seems like a record stuck in the groove.

Focusing on one target has failed to yield an effective Alzheimer’s drug despite spending hundreds of millions on clinical research.

More needs to be done to understand the biology of Alzheimer’s disease and generate new insights into potential new targets that at the very least delay the progression of a disease that many of us will possibly end up with in the future.

Update April 30, 2014: Everton FC write up my visit on their Community news site

I was thrilled to hear that John Howard, (@JHowEFC08) Media Officer for Everton in the Community has written about my visit to the Pass on the Memories program. He’s published a really well written post on the Everton FC community website that goes into more detail about the program.

Pieter Droppert interviewing Tommy Dunne. Picture Credit: John Howard, Everton FC

Here’s the link to John’s piece if you are interested in more information: Pieter’s views on Pass on the Memories

Update May 19, 2014: Talking about Dementia on BBC Radio Merseyside Daybreak show

At the start of Dementia Awareness Week in the UK, I was very grateful for the opportunity to go on the May 18, 2014 edition of BBC Radio Merseyside’s Daybreak show, produced by Helen Jones.

I talked about my late mother, Audrey and some of the innovations in dementia care that I’ve written about on the blog. If you have the chance do listen to an excerpt from the show:

Update June 5, 2014: listen to living well with dementia – a personal journey

My research into Everton’s Pass on the Memories program was undertaken while on a BJTC accredited diploma in radio journalism course based at Radio City in Liverpool. You can listen via SoundCloud to the documentary I produced on living well with dementia – a personal journey:

Drug development for neurodegenerative brain diseases such as Parkinson’s or dementia, of which Alzheimer’s is the most common form, needs to focus on patients early in the disease, not those where brain damage has already occurred.

Diagnosing and treating patients more effectively earlier will, even if you aren’t able to instigate a cure, offer the ability to modify the disease progression and slow or delay when brain damage occurs.  In the case of Alzheimer’s, once the amyloid plaques (tangles of misshapen proteins) have accumulated in nervous tissue, it has so far been impossible to untangle or remove them.

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Several retired American Football stars have ended up with chronic traumatic encephalophy (CTE), previously known as dementia pugilistica. It’s similar to Alzheimer’s disease in that the brain ends up with neurofibrillary tangles.

Science Translational Medicine Cover May 16CTE has also been seen in soldiers who have experienced blast induced traumatic brain injury (bTBI) from improvised explosive devices (IEDs). I previously wrote on this blog about how nanotechnology may revolutionize the detection of TBI using a nanomaterial that changes color.

Research published in the May 16, 2012 issue of Science Translational Magazine by Lee Goldstein and colleagues from the Molecular Aging and Development Laboratory at Boston University & other institutions, compared CTE neuropathology in blast-exposed military veterans and athletes with repetitive concussion injury.

For the first time they have shown similarities in what happens to the brains of soldiers when they are blown up and to athletes in sports that have repeated head impacts.

The reseachers looked at 8 post-mortem brains, 4 military veterans aged 22 to 45 with a history of blast exposure were compared to 4 athletes aged 17 to 27 who were either American Football players or, in one case, a wrestler. Despite the small sample size, the results showed similar brain trauma in the two groups:

“the effects of blast exposure, concussive injury, and mixed trauma (blast exposure and concussive injury) were indistinguishable.”

It is worth noting that the brain neuropathysiology seen was different from that seen with Alzheimer’s disease (AD).

The researchers went on to develop a mouse model that could be used to investigate the link between blast exposure, brain neuropathology and behavior.  I encourage you to read the STM paper for full details on this.

Some of the key findings of their mouse experiments were:

  • Blast exposure induces traumatic head acceleration in a blast neurotrauma mouse model
  • Single-blast exposure persistently impairs axonal conduction and long-term potentiation of activity-dependent synaptic transmission in the hippocampus
  • Single-blast exposure induces long-term behavioural deficits that are prevented by head immobilization during blast exposure.

The authors conclude that their results “provide compelling evidence linking blast exposure to long-lasting brain injury.”

What this research suggests to me is:

  • An ongoing need to design safer head protection for athletes and soldiers
  • The need to monitor and detect traumatic brain injury (I wrote last year about how nanomaterials were being developed to monitor blast exposure)
  • Need to identify those genetic factors (e.g. carrying the APOE e4 allele leads to a high risk of developing Alzheimer’s disease) that may lead to a heightened risk of developing dementia or CTE.

The paper by Goldstein and colleagues in STM is well worth reading if you have an interest in this area and the debate about the safety of young people in high-contact sports.

Reference

ResearchBlogging.orgGoldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716

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Braingate array

Photo: braingate2.org

Research published online first today, and in the May 17 2012 issue of Nature describes promising results of a clinical trial with tetraplegics (all four limbs paralyzed) that allowed the control of an external robotic arm (DEKA arm) using an embedded microarray in the brain, the BrainGate neural interface system.

One of the two study participants who had the array implanted 5 years ago, was able to use her mind to control a robotic arm and serve herself coffee from a bottle, 15 years after she became completely paralyzed & unable to speak.

The results from a team of researchers from the Department of Veterans Affairs, Brown University, MGH, Harvard Medical School (BrainGate Research Team) and the German Aerospace Center, Institute of Robotics and Mechatronics are promising.

The BrainGate system is the size of a small pill, and consists of a grid of 96 electrodes that are implanted in the motor cortex of the brain. By placing the grid next to the part of the brain that controls movement, neuronal activity associated with a movement can be translated into a computer command that drives an external robotic device.

The results reported by Leigh Hochberg MD, PhD & colleagues in Nature, offers hope to those paralyzed or who have limbs amputed, that in the future, innovations in neurotechnology may allow thoughts to control prosthetics or external robots.

Courtesy of Nature Video, you can watch how a paralyzed woman controls a robotic arm with her thoughts – this is an amazing video that is well worth watching:

How does it work, according to clinical trial subject T2:

I just imagined moving my own arm and the [DEKA] arm moved where I wanted it to go.

Subject S3 commented:

I think about moving my hand and wrist. I’m right handed so, it’s very comfortable and feels natural to imagine my right hand moving in the direction I want the robotic arm to move.

The challenge with this type of medical news is the danger of hype over hope, so to better put the results in perspective, I am delighted to have some expert commentary in the form of a guest blog post from D. Kacy Cullen, Ph.D, Assistant Professor at the University of Pennsylvania, Department of Neurosurgery Center for Brain Injury and Repair.

The Cullen laboratory at Penn applies Neural Engineering principles and technologies to the area of Neurotrauma, and is actively researching how to use neural tissue engineering-treatments to promote regeneration and restore function.

Commentary by D. Kacy Cullen, PhD 

This work is a natural extension/combination of the group’s previous work (1) involving human patients and computer cursor movements, and (2) non-human primates and robotic arm control.  So, this “next step” was anticipated, and in fact larger trials (involving various groups) are being initiated to investigate brain-based neural interface systems to drive the DEKA arm in subjects with limb loss (i.e. absent CNS damage/deficits).

The most compelling features to me were the decoding/training algorithm and the fact that one of the patients had her micro-electrode array implanted 5 years earlier.

Decoding/training: The use of signal filtering/thresholding in combination with open-loop (imagining and watching movement) and closed-loop (controlling the arm with visual feedback) recording/training was innovative and relatively efficient (31 min). However, in each case, the subjects had worked controlling arms previously (over years for S3 and 3 trials for T2).

A major challenge with recording ensemble neuronal activity in the motor cortex (or anywhere in the cortex) is signal attenuation and drift over time; so, each day/session typically requires re-training and re-calibration.

I would be curious to see how the subjects did in other independent trials – perhaps visual feedback can allow the user to “correct” the cortical inputs and hence reduce movement errors more rapidly in subsequent trials.  Nonetheless, it is remarkable that the subjects were able to manipulate the arm and drive it in a controlled and useful manner in a relatively short amount of time.

5 years: using an electrode array implanted 5 years earlier to control the robotic limb is very impressive.  The finding bodes well for the potential of this brain-based approach to yield useful cortical data chronically.

A major challenge is that over time the brain gradually rejects these non-organic electrodes, causing a build up of micro-scar tissue around the electrodes and a decreased neuronal density in the vicinity of the electrodes.

This process is partly due to mechanical mismatch between the electrode the brain causing inflammatory “micro-motion”.  This is likely exacerbated by subject motion/walking, which would not be an issue with the patients in this study but will be for the amputee study.

Nonetheless, this study noted “lower spike amplitudes and fewer contributing (active) channels” compared to earlier years, which is consistent with micro-scar tissue and fewer neurons close to electrodes.

Although this work is a natural next step, I do not want to trivialize the supreme competence, technical savvy, and attention to detail necessary to pull this off.  This group is highly competent and has the experience and skill to execute this very complex and multi-faceted neural engineering project to assist chronically disabled patients.

Reference

ResearchBlogging.orgHochberg, L., Bacher, D., Jarosiewicz, B., Masse, N., Simeral, J., Vogel, J., Haddadin, S., Liu, J., Cash, S., van der Smagt, P., & Donoghue, J. (2012). Reach and grasp by people with tetraplegia using a neurally controlled robotic arm Nature, 485 (7398), 372-375 DOI: 10.1038/nature11076

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My mother has Alzheimer’s disease – I first suspected some form of dementia when her friends told me that she didn’t dance anymore.  Of course she insisted she did, but it was clear she had “forgotten” the steps in a way that was beyond the forgetfulness of getting older.

As a European snow bird she would travel to Malta each year to escape the damp, grey English winters.  One year when I visited her in Malta, I noticed when she went up to the hotel dinner buffet, she could not “remember” where to return to.

With a blank and vacant look she would gaze out hoping to find a clue that jarred her memory.  Friends gently directed her to the right table and diffused the embarrassment with humor.

Sadly during my visit I saw that she could no longer remember the names of people she had holidayed with for 10 years each winter, or what clothes she had worn the day before.  Her holiday companions and the hotel treated her with kindness, but it was the beginning of a decline, and her last winter in Malta.

At home, she has struggled to manage activities of daily living and the need for care has increased.   As a family, we’ve endeavored to support her independence for as long as possible, but a nursing home is now in the not too distant horizon.

Which is why I have a personal interest in Alzheimer’s disease.  It’s an area where innovation needs to catch up with demand for treatment and therapies, not to treat it when it’s happened – it’s too late to untangle the damage, but to delay it’s occurrence in those at risk.

This week in the New England Journal of Medicine (NEJM), research showed that continued treatment of moderate to severe Alzheimer’s disease with donepezil (Aricept) provides modest cognitive and functional benefits.

By the time moderate to severe disease has set in, the damage has already been done, and the train has left the station metaphorically speaking.  Those with this status require the support of caregivers.  This study was undertaken in community-dwellings i.e. some form of nursing home or care facility.

In their NEJM paper, Robert Howard of the Institute of Psychiatry & UK colleagues assessed changes in Standardized Mini-Mental State Examination (SMMSE) & Bristol Activity of Daily Living (BADLS) scores in moderate to severe Alzheimer’s patients who received donepezil or memantine in a double-blind, placebo controlled trial.

Patients continued to decline over the course of the study, so what the study showed was that by giving a cholinesterase inhibitor, the rate of decline was slowed.  The functional benefit was equivalent to 32% of the total deterioration seen over 12 months.

However, dramatic as this significant benefit sounds, the author’s rightly caution that the improvements in cognition and function were small relative to the overall decline in cognitive and functional status seen in all patients.

While this paper offers evidence-based medicine for the continuation of donepezil in those with moderate to severe disease, this treatment does not lead to a cure or restoration of function.

A study sample size of 430 was estimated to give a 95% power to detect a 1.0 point difference in SMMSE scores between donepezil and placebo groups, and 90% power to detect a 2.0 point difference.  In the end a total of 295 participants were enrolled.

The results showed that:

“Patients who were assigned to continue taking donepezil, as compared with those assigned to discontinue donepezil, had scores on the SMMSE that were higher (indicating better cognitive function) by an average of 1.9 points (95% CI, 1.3 to 2.5; P<0.001) and scores on the BADLS that were lower (indicating less functional impairment) by an average of 3.0 points (95% CI, 1.8 to 4.3; P<0.001).”

The researchers noted that:

“The severity of dementia at entry significantly influenced the effect of donepezil on SMMSE scores, with larger benefits observed in patients with moderate disease (SMMSE score, 10 to 13) than in those with severe disease (SMMSE score, 5 to 9).”

More information on the study design and detailed results can be found in the published NEJM paper.

My Mother takes donepezil and I’m pleased to see that there’s now some clinical data to support its continued use, as she will no doubt progress.

All those with loved ones who have Alzheimer’s will be pleased with any news that delays the progression of this debilitating disease.

Reference

ResearchBlogging.org
Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., Burns, A., Dening, T., Findlay, D., Holmes, C., Hughes, A., Jacoby, R., Jones, R., Jones, R., McKeith, I., Macharouthu, A., O’Brien, J., Passmore, P., Sheehan, B., Juszczak, E., Katona, C., Hills, R., Knapp, M., Ballard, C., Brown, R., Banerjee, S., Onions, C., Griffin, M., Adams, J., Gray, R., Johnson, T., Bentham, P., & Phillips, P. (2012). Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease New England Journal of Medicine, 366 (10), 893-903 DOI: 10.1056/NEJMoa1106668

Cancer Research UK issued a press release today about a phase 2 trial (GALA-5) in glioblastoma that caught my attention.

The trial, led by Colin Watts from the University of Cambridge, will treat patients with 5-Amino-Levulinic Acid (5-ALA), a metabolic marker of malignant glioma cells.  5-ALA is preferentially taken up by brain tumor cells and then converted into a strongly fluorescing porphyrin.

This conversion by the body of 5-ALA to a fluorescent chemical, shows the location of the glioblastoma when imaged under ultraviolet light.

Flourescent-5-ALA-Glioblastoma-Dr Colin Watts

The practical application of this is that it allows better identification of the tumor margins and avoids the removal of unnecessary brain tissue.

The use of fluorescent imaging to aid surgery is also being investigated in other tumors. Sally Church on Pharma Strategy Blog recently wrote about the use of folate receptor alpha fluorescence imaging in ovarian cancer.

It will be interesting to see how the GALA-5 phase 2 clinical trial in glioblastoma progresses.  The fluorescent imaging technology while promising is not without its pitfalls and potential risks.

As Jörg-Christian Tonn and Walter Stummer note in Vol 55 of “Clinical Neurosurgery (2008) some of the pitfalls with fluorescence-guided resection using ALA include:

  • Problem of overhanging margins i.e. inability to see all the tumor in the field of vision
  • Cysts leading to collapse of parts of the tumor with the result that areas are missed
  • Wrongly placed craniotomies preclude complete resection of contrast-enhancing tumor
  • Some cases of gliosarcoma show only modest fluorescence accumulation
  • Delay in drug administration may lead to less than optimal fluorescence
  • Exponential decrease in light with growing distance to fluorescent tissue, resulting in weak fluorescence intensity

No doubt many of the above issues will be controlled for in the GALA-5 trial. The challenge with imaging techniques is, however, in consistency and reproducibility outside of experienced clinical research investigation sites.

It will be interesting to see whether the potential pitfalls can be overcome such that this promising experimental imaging becomes routine in glioblastoma surgery.

Story Source: BBC Health

In a letter to the science journal Nature, published online on August 21, 2011, scientists from Northwestern University in Chicago report findings that could help develop drugs for patients with Amyotrophic Lateral Sclerosis (ALS), more commonly known as Lou Gehrig’s disease.

ALS is a progressive, fatal, degenerative motor neurone disease, which results in the inability to walk, get out of bed, move arms, hands, swallow or chew. Unlike Alzheimer’s disease, cognitive functions are not usually impaired, making it a particularly nasty disease when faced with awareness of disease progression.

According to Wikipedia, ALS is one of the most common neuromuscular diseases worldwide, with 1 or 2 people in every 100,000 developing ALS each year.

One of the characteristics of ALS and other neurodegenerative disease is the accumulation of protein aggregates or inclusions. Amyloid-ß plaques and intracellular tau neurofibrillary tangles are common in Alzheimer’s disease, for example.

By contrast, in ALS, a hallmark of the disease pathology is the presence of ubiquitin-positive, protein aggregates in spinal motor neurons.

The new research from Northwestern University shows how a mutation in UBQLN2, the gene that encodes ubiquilin 2, may be the cause of ALS in some patients.

The UBQLN2 mutation results in a failure to properly encode the protein, ubiquilin 2, a member of the ubiquitin-like protein family known as ubiquilins. The result is that normal protein degradation through the ubiquilin pathway is impaired, leading to cellular deposits and abnormal protein aggregation.

How did the team at Northwestern discover this insight?

Using DNA sequencing they looked at a five-generation family with 19 affected by ALS and sought to identify the causative gene in the transmission of this disease.  They found that a mutation in UBQLN2, the gene that encodes ubiquilin 2 was the key difference in those family members with or without ALS.

They subsequently tested the hypothesis that UBQLN2 mutations were causative of ALS using clinical data from 40 individuals in 5 families with UBQLN2 mutations. Interestingly in eight patients with the UBQLN2 mutation and ALS, dementia was also present suggesting a possible link between ubquilin 2 inclusions and dementia.

The team explored this correlation by examining brain autopsy samples of 15 cases without UBQLN2 mutations, of which 5 had experienced dementia as well as ALS. They found no ubiquilin 2 pathology in the hippocampus of the 10 ALS patients without dementia, but did find it in the 5 that had experienced both ALS and dementia. They noted:

The correlation of hippocampal ubiquilin 2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicates that ubiquilin 2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

They also observed that:

We did not observe obvious differences in the distributions of wild-type and mutant ubiquilin2.

The authors concluded:

These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well.

These interesting findings by the Northwestern group were reported in Nature, and while promising, must be treated with caution for several reasons:

  1. It is still early-stage preliminary research on a small group of subjects.
  2. The exact function of ubiquilin 2 is not well understood.
  3. Not all ALS patients have the UBQLN2 mutation
  4. If the UBQLN2 mutation is not present in all ALS patients, then this mutation is not the sole means by which ALS develops.
  5. UBQLN2 may not be the only mutation involved in the pathophysiology of ALS.

The data from Northwestern does, however, offer hope that in the future, gene therapy or new treatments could be developed that stop or slow disease progression. Targeting the ubquilin pathway and the UBQLN2 mutation may, for example, prevent the abnormal protein turnover and aggregation that leads to impaired signaling and loss of function seen in ALS.

Further research into pathogenic pathways could lead to new targets for drug development, not only for the treatment of ALS but also dementia, and other neurodegenerative disorders.

ResearchBlogging.orgDeng, H., Chen, W., Hong, S., Boycott, K., Gorrie, G., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G., Donkervoort, S., Bigio, E., Brooks, B., Ajroud, K., Sufit, R., Haines, J., Mugnaini, E., Pericak-Vance, M., & Siddique, T. (2011). Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature DOI: 10.1038/nature10353

Story source:  LA Times & Fierce Biotech

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