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HOPE for FATIGUE

Measuring Mitochondrial Function in Parkinson's Disease

Mitochondrial dysfunction, either caused by a genetic mutation or acquired from environmental factors, has been implicated in the development of Parkinson’s and other neurodegenerative diseases. Brain cells are very sensitive to oxidative stress and a loss of mitochondrial integrity. Damage to mitochondrial membranes, proteins and DNA has been detected in the brain tissue of Parkinson’s patients. Now, a new diagnostic tool from Agilent Technologies, called the Seahorse Mitochondrial Stress Test, has the ability to directly assess mitochondrial health from a simple blood test.

A Canary in the Coal Mine

When the energy capacity of the cell falls below a critical threshold, deterioration in its energy generating capacity (bioenergetics) occurs and eventually can trigger the onset of a degenerative disease. Mitochondria can serve as the ‘canary in the coal mine’ by sending out early warning signals of the impending bioenergetic crisis. In the case of Parkinson’s disease (PD), a deterioration of mitochondrial function in nerve cells that produce dopamine in a structure called the substantia nigra disrupts normal signaling ultimately resulting in the inability to control movement and coordination.

The Seahorse Mitochondrial Stress Test

The Seahorse Mitochondrial Stress Test was developed to directly measure mitochondrial function from a simple blood test. This test measures oxygen consumption, and the resultant amount of ATP produced, at each stage of the electron transport chain. It provides a composite mitochondrial health profile from peripheral blood mononuclear cells (PBMC’s) that appears to correspond with the mitochondrial health of neurons in the brain. Victor Darley-Usmar, PhD and his team at the University of Alabama, Birmingham, have developed an equation that takes this data and produces a single numeric score, the Bioenergetic Health Index (BHI).

A New Paradigm: Mitochondrial Medicine

After ten years of working to develop and validate this new technology, Seahorse Bioscience (recently acquired by Agilent Technologies) is working to move this assay into clinical practice. In the not too distant future, when a patient is being evaluated with symptoms of neurologic dysfunction, their physician will be able to order a Seahorse Mitochondrial assay as a means of early disease detection. Similar to a doctor recommending dietary and lifestyle changes to reduce high cholesterol and prevent heart disease, physicians could suggest modifications to improve mitochondrial functioning if the Seahorse Mitochondrial test comes back abnormal. In the near future, mitochondrial function testing could have a significant impact on preventing Parkinson’s disease, and other diseases of aging.

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Fatigue: The Silent Symptom of Parkinson’s Disease

A 2013 survey by the Parkinson’s disease Foundation (PDF) identified fatigue as the most pressing need for the Parkinson’s research community.

While tremors, muscle stiffness, and irregular gait are the symptoms most associated with Parkinson’s disease, 50% of PD patients experience severe fatigue and a third say it is their single most debilitating symptom. Fatigue is the most significant reason cited for medical disability insurance claims by PD patients in the United States. Despite this overwhelming evidence, neurologists tend not to recognize fatigue as a prominent concern of PD patients.

Two studies in newly diagnosed Parkinson’s patients reported fatigue to be a clinically relevant problem even when motor symptoms were minimal. These studies identified fatigue as a “pre-motor” symptom, appearing well before motor symptoms become obvious. Parkinson’s patients describe their fatigue as different than any tiredness they had experienced before their diagnosis. Unlike fatigue in the general public, PD fatigue often improves with exercise.

Mental fatigue that affects Parkinson’s patients is called “central fatigue” and relates to the experience of feeling weary or exhausted during an intellectually challenging task, along with decreased capacity to initiate or sustain cognitively challenging activities. Parkinson’s patients suffering from cognitive fatigue have reduced attention span, and may have deficits in learning, memory, and information processing. Cognitive fatigue will often emerge as tasks become increasingly more complex or attention demands are greater.

Causes of PD Fatigue

The cause of fatigue in Parkinson’s disease is still elusive, though researchers speculate it may be due to changes that take place in the brain. Recently, researchers have found that Parkinson’s patients with fatigue had significantly lower serotonin transporter binding than patients without fatigue in the basal ganglia and limbic structures of the brain. Other causes of PD fatigue under investigation include peripheral inflammation and immune activation, and mitochondrial dysfunction.

Depression, sleep disturbances, and medications may also contribute to or cause fatigue. However, Dr. Joseph Friedman, Professor and Chief of the Division of Movement Disorders at the Warren Alpert Medical School of Brown University, points out that while fatigue is an early symptom and may be associated with depression, most PD patients with fatigue are not depressed.

Clinicians and researchers use rating scales for diagnosing the existence and severity of PD fatigue. Some scales, such as the Modified Fatigue Impact Scale, evaluate cognitive, as well as physical and social function. While most of these tests evaluate fatigue on a subjective level, objective measures for cognitive function exist that can measure performance changes during mental tasks.

Treatment Approaches

Currently, there are no effective treatments for PD fatigue. Clinicians often encourage patients to exercise, practice good sleep habits, take naps, keep mentally active, increase the intake of fiber and drink plenty of water. 

While few medications have proven to be helpful, methylphenidate, a pharmaceutical stimulant, was shown to be effective in lowering fatigue scores in patients with PD in a 6-week treatment period. This medication is often prescribed off label in clinical practice to help combat the effect of debilitating fatigue in PD patients.

In order to offer better treatment options, clear standards to measure and define fatigue in Parkinson’s disease are necessary. Research is also needed to identify biomarkers that can better diagnose and evaluate fatigue treatments. Using a range of brain imaging techniques to examine the underlying biology of fatigue, including the role of inflammation, could help identify changes in the brain associated with fatigue. Lastly, studying the effectiveness of non-drug therapies such as mindfulness-based stress reduction and energy management strategies (pacing), may be helpful. These non-drug therapies have been shown to also be helpful to patients with fatigue due to Multiple Sclerosis.

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Mitochondrial Mutation Linked to Parkinson’s Disease for First Time

Last Spring researchers at the Buck Institute confirmed that Parkinson’s disease (PD) is caused by mitochondria dysfunction in neurons that produce dopamine. This research had only been proven in animal models up until that point.

The Park2 mutation altered mitochondrial structure and function in dopamine producing neurons, causing them to die. Dopamine is an essential neurotransmitter which regulates movement and emotion. Xianmin Zeng, PhD, the lead scientist on the study, reported, “this is the first time we can show a real and observable change in mitochondria in human cells affected by a PD mutation." 

These are hopeful findings for the development of treatments for this incurable disease. Existing drugs can reduce symptoms but can cause involuntary movements, restlessness, confusion, and other troubling side effects over time. "If we can find existing drugs or develop new ones that prevent damage to the mitochondria we would have a potential treatment for PD,” Zeng reports.

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