Press "Enter" to skip to content

A Brief History of More Time: PGIMER’s work in the context of existing knowledge in ALS

Chandigarh: A team of researchers led by Akshay Anand, associate professor, neuroscience research lab, department of neurology, Post Graduate Institute of Medical Education and Research (PGIMER), explores why most Western patients with ALS (amyotrophic lateral sclerosis) die within 3 to 5 years from the onset of symptoms, whereas Indian patients with ALS survive for 10 or more years.

Akshay Anand

Introduction

Amyotrophic lateral sclerosis (ALS) belongs to the group of devastating motor neuron diseases characterized by degeneration and death of motor neurons, being rapidly progressing disorder of the brain that selectively impairs the control of the neuromuscular junctions (read muscle control) thereby impacting mobility, voluntary muscles, breathing and eventually death.

Although the mutations in the gene coding for SOD (super oxide dismutase — an enzyme responsible for reducing harmful effects of oxidants) is known to be responsible for only 10 per cent of cases, majority of scientists believe this to result from unknown factors which are random.

Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. However, about 10 per cent of ALS patients survive for 10 or more years and majority of them live in India. Therefore, other unidentified genetic causes clearly exist.

What are motor neurons?

Motor neurons are nerve cells located in the brain, brainstem and spinal cord that serve as controlling units and vital communication links between the nervous system and the voluntary muscles of the body. Messages from motor neurons in the brain (called upper motor neurons) are transmitted to motor neurons in the spinal cord (called lower motor neurons) and from them to particular muscles.

In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away (atrophy) and twitch (fasciculations). Eventually, the ability of the brain to start and control voluntary movement is lost.

Any Test?

No one test can provide a definitive diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive.

Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS.

The physician may ask for magnetic resonance imaging (MRI), a non-invasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumour, a herniated disk in the neck, syringomyelia, or cervical spondylosis.

Causes

The cause of ALS is not known, and scientists do not yet know why ALS strikes some people and not others. Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die off when they are exposed over long periods to excessive amounts of glutamate. Now, scientists are trying to understand what mechanisms lead to a build-up of undesired glutamate in the spinal fluid and how this imbalance could contribute to the development of ALS.

In searching for the cause of ALS, researchers have also studied environmental factors such as exposure to toxic or infectious agents. Other research has examined the possible role of dietary deficiency or trauma. However, as of now, there is insufficient evidence to implicate these factors as causes of ALS.

How is it treated?

No cure has yet been found for ALS. However, the US Food and Drug Administration (FDA) has approved the first drug treatment for the disease —riluzole (Rilutek). Riluzole is believed to reduce damage to motor neurons by decreasing the release of glutamate.

Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational and speech therapists; nutritionists; social workers; and home care and nurses.

What research is being done?

Scientists are seeking to understand the mechanisms that trigger selective motor neurons to degenerate in ALS and to find effective approaches to halt the processes leading to cell death.

Researchers are also conducting investigations to increase their understanding of the role of programmed cell death or apoptosis in ALS. In normal physiological processes, apoptosis acts as a means to rid the body of cells that are no longer needed by prompting the cells to commit “cell suicide.” The critical balance between necessary cell death and the maintenance of essential cells is thought to be controlled by trophic factors.

In addition to ALS, apoptosis is pervasive in other chronic neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease and is thought to be a major cause of the secondary brain damage seen after stroke and trauma. Discovering what triggers apoptosis may eventually lead to therapeutic interventions for ALS and other neurological diseases.

Scientists have not yet identified a reliable biological marker for ALS — a biochemical abnormality shared by all patients with the disease. Once such a biomarker is discovered and tests are developed to detect the marker in patients, allowing early detection and diagnosis of ALS, physicians will have a valuable tool to help them follow the effects of new therapies and monitor the disease progression.

The PGIMER work adds value to existing research

In an effort to discover the causes for prolonged survival of Indian ALS patients as compared to Western counterparts, so that this information can be used to enhance the life of ALS patients, the CSF (cerebrospinal fluid) and blood was collected from these patients and controls and the DNA isolated from these samples to examine the expression of a certain molecule called VEGF (Vascular Endothelial Growth factor), its scavenger FLT-1, which are known for formation of new blood vessels that apparently supply blood to motor neurons for health and nutrition. The inspiration came from preclinical studies (animal studies), which had shown that reduced VEGF results in neurodegeneration.

The results of PCR (DNA based investigation) and ELISA (protein based investigation) showed that VEGF is overexpressed in these samples of Indian patients possibly contributing to enhanced survival time of Indian ALS patients. The results were computerized with collaboration with skilled Biostatistician to provide a formula (statistical model) to predict ALS and its outcome. All the results were published based on level of investigations in several high impact factor Journals like Journal of Neuroinflammation (Impact Factor 5.8), Journal of Neurological Sciences (Impact factor 2.3) and PLoS One (Impact Factor 4.4) and an invited review Current Neurovascular research (Impact Factor 3) all in 2012.

Conclusions

VEGF overexpression or reduction in FLT-1 in circulating blood and CSF may have a strong association between enhanced lifespan of ALS (because these were found to significantly altered) at both genetic and protein level in Indian ALS patients.

Impact and Significance

The suppression, reduction or inhibition (of VEGF-R1/FLT-1) could actually, if not curb the fatality of the disease, at least extend the survival time of these patients. The study has paved the way for FLT-1 inhibitor clinical trials.

Funding: Indian Council of Medical Research (ICMR), Council for Scientific and Industrial Research (CSIR); Approved from institute Ethical committee; No Conflicts of interest; compliance to ICMJE Authorship requirements. ALL DATA AS PER GLP/OECD NORMS with back traceability and Archived as e-format, deep freezer for samples and as print edition in fire proof cabinet.

Contacts: Akshay Anand, Associate Professor, Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh. [Cell: +91 99142 09090] [Email: akshay2anand@gmail.com, akshay1anand@rediffmail.com]

Team Members: Sudesh Prabhakar (clinical evaluation and logistics), P K Gupta (data acquisition, writing and obtained PhD from this work), Neel Kumar Sharma (ELISA) and Suresh Sharma (statistical analysis); Akshay Anand (conceptualization, Grant Investigator, editing and interpretation of data)

Related Article

ALS, a brief history of more time (ALS Therapy Development Institute, US)

Be First to Comment

Leave a Reply

Your email address will not be published. Required fields are marked *