Inside Africa. ALS/MND may occur earlier in Africa and be more common in men. Image: Fêtes des Masques à Kiri, Bobo Dioulasso, Burkina Faso, Guillaume Colin & Pauline Penot, Flickr.

Nearly 20% of people with ALS in the US live at least 5 years after being diagnosed. But in Africa, according to a recent analysis, people show the first signs of ALS earlier, are diagnosed later and die more quickly from the disease.

A group of neurologists and epidemiologists led by Université de Limoges’ Philippe Couratier MD hopes to change that by identifying people with ALS/MND throughout Africa and studying their disease.  The multinational, longitudinal study, called TROPALS, aims in part, to identify key prognostic factors that enable physicians to better manage the disease.

The collaboration is one of a growing number of partnerships that hopes to better understand, recognize and treat complex genetic diseases in Africa.

ALS Today’s Michelle Pflumm PhD caught up with participating neurologist Athanase Millogo MD of Burkina Faso at a networking meeting at the NIH’s Fogarty International Center in Maryland to learn more about TROPALS and its potential impact on people with ALS/MND in Africa going forward.

To find out more about the challenges of treating ALS/MND in Africa, read ALS, Circle in the Sand. To learn about efforts to identify the genetic and environmental contributors of complex genetic diseases in Africa, check out NIH and Wellcome Trust’s H3Africa.

 

Postcard from Quito.  Miriam Bucheli PhD talks about ELA-Ecuador and how she hopes the project will help the nation.

Physicians knew children in the 1920s lived in a “lead world”.  Mild cases of colic and muscle spasms were commonplace due to the ingestion of paint chips.  And, children were sickened by drinking water delivered by lead pipes.

Lead became tightly regulated.  By 1978, only lead-free paints could be found at the local hardware store. Cars could run on unleaded gasoline. Copper pipes delivered drinking water. And, lead-free earthenware could be found on dinner tables throughout the US.

But high in the Andean mountains, the indigenous peoples of Ecuador cling to the old ways.  Huddling around bubbling cauldrons of molten lead now salvaged from old car batteries, potters continue to create shiny ceramic lead-glazed roof tiles that Ecuadorian homeowners crave.

The lead levels, estimated to be more than 10 times higher than the limit recommended by the US' Centers for Disease Control and Prevention, have been linked to learning deficits.  And, scientists suspect, may even predispose people later in life to develop ALS.

Now, researchers from the San Francisco University of Quito in Ecuador led by neuroscientist Miriam Bucheli PhD hope to determine whether chronic lead exposure contributes to ALS and results in increased cases of the disease. 

“A link to ALS could create awareness [and] encourage people to change their lifestyles because the disease is so debilitating” says Bucheli.

 

Team ELA-Ecuador. Project coordinator Ivan Sisa MD and epidemiologist Marco Fornasini MD PhD.  Also pictured left to right, USFQ medical students Priscila Villalba, Alejandra Mendoza, Diana Chicaiza, Carolina Franco, Barbara Mantilla and Amelia Calderon. Image courtesy of Miriam Bucheli PhD. Reproduced with permission.

The study is part of a growing effort, called ELA-Ecuador, to unravel the genetics and environmental influences that contribute to the disease.

Nearly 20 genes by some estimates are linked to ALS. But mutations in these genes alone, scientists suspect, may not result in ALS. Other factors such as chemical exposures, lifestyle choices and viral infections are also speculated to contribute to the onset of the disease.

Scientists hope to identify these risk factors in part, by interviewing people at high risk for developing the disease.

In the US, researchers at the University of Miami led by neurologist Michael Benatar MD PhD hope to pinpoint what triggers ALS in people harboring familial ALS-associated mutations.  And, a multi-institutional US team led by Duke University School of Medicine epidemiologist Silke Schmidt DSc MS hopes to discover why US veterans appear to be about twice as likely to develop the disease.

Now, the ELA-Ecuador team is turning to the same epidemiologist, Stanford University School of Medicine's Lorene Nelson PhD, to conduct the same kinds of interviews, in hopes to identify risk factors including lead exposure in people from the Andean region.

“We are using the same questionnaires,” explains Bucheli, “so that we can eventually compare the data from other countries.”

Southern Exposure

Lead exposure has been suspected for decades to be a possible risk factor for ALS because the toxic substance can damage the central nervous system.  

Some studies suggest that higher lead levels could increase the risk of developing ALS. But other studies have been inconclusive. 

A big part of the problem is that these studies are extremely difficult to do. Circulating lead levels can increase during the disease course due to bone breakdown making total levels tricky to estimate. And the difference in lead levels can be difficult to determine because the levels in circulation are relatively small.

By studying a large population of people exposed daily to high levels of lead, Bucheli hopes to be able to finally determine whether or not lead exposure contributes to ALS. And at the same time, help people reduce their risk of developing the disease.

“If you know you have a higher risk for ALS, you may choose to change rather than continue old practices,” says Bucheli.

References

Counter, S.A., Buchanan, L.H. and Ortega F. (2005) Neurocognitive impairment in lead-exposed children of Andean lead-glazing workers. Journal of Occupational and Environmental Medicine 47(3), 306-312. Abstract | Full Text (Subscription Required)

Counter, S.A. et al. (2000). Environmental lead contamination and pediatric lead intoxication in an Andean Ecuadorian village.  International Journal of Occupational and Environmental Health 6(3), 169-176. Abstract | Full Text (Subscription Required)

Counter, S.A., Buchanan, L. H., Ortega, F., and Rifai, N. (2000). Blood lead and hemoglobin levels in Andean children with chronic lead intoxication. Neurotoxicology 21(3), 301-308. Abstract | Full Text (Not Online)

Counter, S.A., Buchanan, L.H., Rosas, H.D. and Ortega F. (1998) Neurocognitive effects of chronic lead intoxication in Andean children. Journal of Neurological Sciences 160(1), 47-53.  Abstract | Full Text (Subscription Required)

Fang, F. et al. (2010) Association between blood lead and the risk of amyotrophic lateral sclerosis. American Journal of Epidemiology 171(10), 1126-1133. Abstract | Full Text 

Haley, R.W. (2003) Excess incidence of ALS in young Gulf War veterans. Neurology 61(6), 750-756. Abstract | Full Text 

Horner, R.D. et al. (2003) Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology 61(6), 742-749. Abstract | Full Text 

Ruddock, J.C. (1924) Lead poisoning in children. Journal of the American Medical Association 82(21), 1682-1684.  Full Text

Schmidt, S. et al. (2008) Genes and environmental factors in veterans with amyotrophic lateral sclerosis: the GENEVA study. Neuroepidemiology 30(3), 191-204. Abstract | Full Text 

Further reading

Ahmed, A. and Wicklund, M.P. (2011) Amyotrophic lateral sclerosis: what role does environment play? Neurologics Clinics 29(3), 689-711. Abstract | Full Text (Subscription Required)

Callaghan B., Feldman D., Gruis K. and Feldman, E. (2011) The association of exposure to lead, mercury, and selenium and the development of amyotrophic lateral sclerosis and the epigenetic implications. Neurodegenerative Diseases 8(1-2), 1-8.  Abstract | Full Text (Subscription Required) 

Patient Resources

ELA-Ecuador.  Contact | ALS TDI | Website

The Pre-Familial Amyotrophic Lateral Sclerosis (Pre-fALS) Study. Contact | ALS TDI |  Website

 

Postcard from Burkina Faso. There are only 5 neurologists in Burkina Faso.  But that doesn’t stop Athanase Millogo MD from making a difference for people with ALS beyond his nation’s borders. Photo courtesy of Athanase Millogo MD.  All rights reserved.

With the opening of dozens of specialized ALS clinics and the establishment of multipractice care programs, nearly 1 out of every 5 people with ALS in the US now lives at least 5 years after being diagnosed with the disease.  And, nearly 1 out of 10 survives more than a decade.

But in Africa, ALS is instead a neglected non-communicable disease.  Few general practitioners recognize motor neuron disorders.  And, most people cling to traditional healing practices resulting in treatments being prescribed according to a recent analysis as much as 4.5 years after the first signs of the disease.

A group of neurologists, called TROPALS, however is determined to turn things around for people with ALS in Africa.  The team has launched an unprecedented multicenter longitudinal study to describe ALS in Africa.  And, at the same time identify key challenges facing these populations in hopes to ultimately to develop interventions to improve their quality of life.

“We are working for the patients,” explains Athanase Millogo MD, head of the Department of Medicine, Bobo-Dialousso Teaching Hospital in Burkina Faso. “We are not sitting in our offices making computations.  We hope to improve the outcome of people with the disease.”

Reference

Marin, B. et al. (2012) Juvenile and adult-onset ALS/MND among Africans: incidence, phenotype, survival: a review. Amyotrophic Lateral Sclerosis 13(3), 276-283.  Abstract |  Full Text  (Subscription Required)

Researcher Resources

Etude Epidémiologique de la Sclérose Latérale Amyotrophique sous les Tropiques (TROPALS) Email | Website

Study of Amyotrophic Lateral Sclerosis Under the Tropics (TROPALS) Email | Website

 

Postcard from Chandigarh.  Akshay Anand PhD talks about how he hopes to discover the secret behind the longevity of certain people with ALS/MND.

Inspired by physicist Stephen Hawking, Post Graduate Institute of Medical Education and Research (PGIMER) neuroscientist Akshay Anand PhD is determined to find out why certain people with ALS live longer with the disease.  Turning his attention to his hometown of Chandigarh, he hopes to discover why people with ALS in India live nearly ten years longer with the disease.

He suspected that higher levels of the blood vessel-forming substance VEGF could be a possible reason people from India live longer with ALS.  Lower levels of VEGF appear to increase the risk of getting ALS.  And, reduced VEGF according to preclinical studies results in neurodegenerative disease.

“All neurons would be happy to have more supply of nutrients coming from blood vessels,” explains Anand.  “Any disruption in the supply of blood [however] could lead to neurodegeneration.”

 

Soakin' Up the VEGF.  Blood vessels are formed at the right place and at the right time in part by restricting the levels of VEGF (yellow) available through the VEGF scavanger receptor VEGF-R1/FLT1 (green). Image: Journal of Biological Chemistry.

To put his theory to the test, he teamed up with PGIMER neurologist Sudesh Pradhakar MD to take a look at levels of VEGF circulating in people with ALS.  The researchers focused on 100 people from Northern India – including 50 people with ALS. The team found that the levels of VEGF appeared to be more than three-times higher in the spinal cord of people with definite ALS compared to people without the disease.

These results suggested that increased nourishment, delivered by additional blood vessels via astrocytes, may help ALS-ravaged motor neurons stay alive longer, slowing down the disease.

The team subsequently found, in a study that included 36 people with ALS from Northern India, that the boost in VEGF might be explained by reduced levels of the VEGF “sponge” VEGF-R1/FLT1.

Now, the PGIMER team hopes to look at more people with ALS to determine whether or not circulating levels of VEGF or VEGF-R1/FLT1 correlate with the stage and severity of the disease.  And, at the same time, evaluate whether VEGF-R1/FLT1 could be used as a biomarker to identify people who live longer with the disease.

“Who knows?  This could be the molecule,” says Anand.  “The suppression, reduction or inhibition [of VEGF-R1/FLT1] could actually if not curb the fatality of the disease, at least extend the survival time.”

References

Anand, A., Gupta, P.K., Sharma, N.K. and Prabhakar, S. (2012) Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients. European Journal of Neurology 19(5), 788-792. Abstract | Full Text

Gupta, P.K., Prabhakar, S., Sharma, S. and Anand A. (2011) Vascular endothelial growth factor-A (VEGF-A) and chemokine ligand-2 (CCL2) in amyotrophic lateral sclerosis (ALS) patients. Journal of Neuroinflammation 8, 47. Abstract | Full Text

Gupta, P.K., Prabhakar, S., Abburi, C., Sharma, N.K. and Anand A. (2011) Vascular endothelial growth factor-A and chemokine ligand (CCL2) genes are upregulated in peripheral blood mononuclear cells in Indian amyotrophic lateral sclerosis patients. Journal of Neuroinflammation 8, 114.  Abstract | Full Text

Lambrechts, D. et al. (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genetics 34(4), 383-394.  Abstract | Full Text (Subscription Required)

Oosthuyse, B. et al. (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genetics 28(2): 131-138.  Abstract | Full Text (Subscription Required)

 

Postcard from Reykjavik.   ALS/MND International Alliance Chairman Guðjón Sigurðsson talks about how he hopes to make life better for people with ALS. He has been the head of MND Iceland since 2005.

Many people find extra energy going to the gym.  ALS/MND International Alliance Chairman Guðjón Sigurðsson, however, finds his second wind helping to improve the quality of life for people with ALS and to rid the world of this "damned" disease.

"Helping people with ALS every way I can,” says Sigurðsson. "That’s what keeps me going.”

Guðjón Sigurðsson was diagnosed with ALS in 2004. But despite an uncertain future, he had no doubt he could make a difference for people with the disease.

Now the head of MND Iceland,  Sigurðsson has worked with health professionals, government officials and other patient advocacy groups around the world to raise awareness about ALS and provide better care for the people with the disease.  He has helped put in place a patient registry in Iceland.  He has helped deliver wheelchairs to people with ALS in Mongolia. And, most recently, he has teamed up with ALS health professionals in China to encourage acceptance of people with the disease.

“We have to work together,” says Sigurðsson, “we cannot afford to go solo.”