The Neuro Change Method Cost
Aline Braunbeck
When comparing group-level change in PROMIS scores, even trivial differences can be statistically significant if the sample size is large enough. For this reason, PROMIS users should seek to observe differences between groups at a magnitude deemed to be meaningful or important to patients.
The threshold to evaluate within-group change or to make a between-group comparison generally ranges between 2 and 6 T-score points (Terwee et al., 2021). Their recommendation is based on a systematic review of 31 studies that used appropriate methods for estimating minimal important change (MIC) in PROMIS adult and pediatric measures. Consensus from a meeting of PROMIS leadership pointed to a threshold of 3 T-score points when comparing groups may be reasonable for most contexts.
Standard Setting using Bookmarking methods have been used to estimate score cut points (e.g., within normal limits, mild, moderate, severe) at a single point in time. Bingham and colleagues (2021) applied this method to estimate the magnitude of change that was meaningful for making treatment decisions in rheumatoid arthritis. Patients and clinicians agreed about improvement. Patients identified a larger amount of deterioration than clinicians in order to consider a change in therapy. Learn more>>
In the United States alone, the cost of treating PD is estimated to be $14 billion annually. Indirect costs, such as those associated with the loss of productivity, are conservatively estimated to total $6.3 billion each year. As the U.S. population ages, these figures are expected to rise rapidly. The number of people diagnosed with PD in the United States is expected to double by 2040.
The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), has a long history of supporting PD research. For decades, NINDS-funded researchers working nationwide have developed treatment options that have greatly improved motor symptoms for people with PD. For example, dopamine replacement therapy with Sinemet, a mainstay therapy in the treatment of PD, has helped alleviate motor symptoms particularly in the early stages of disease. Deep brain stimulation (DBS) can reduce tremor, rigidity, stiffness, and improve movement. However, much work remains to be done. Despite their many successes, these therapies have limitations. There is no currently available therapy that slows the progression of the underlying disease or adequately relieves the wide range of symptoms in people with more advanced PD.
In addition to these motor-related symptoms, non-motor symptoms such as cognitive impairment, mood and behavioral problems, sleep disorders, and constipation can significantly impair quality of life and require careful symptom-based treatment. Some non-motor symptoms such as hyposmia (reduced ability to detect odors), REM sleep-behavior disorder (acting out vivid dreams), and constipation typically precede the motor symptoms by several years. Other non-motor symptoms such as cognitive impairment commonly appear after the onset of motor symptoms.
Many people with PD eventually develop dementia, but the time from the onset of movement symptoms to the onset of dementia symptoms varies greatly from person to person. Dementia is a leading reason for people with PD to transition from independent living at home to long-term care facilities.
PD disease processes begin well before people start exhibiting motor symptoms. This is the preclinical phase of the disease. During this phase people may experience a range of nonspecific, non-motor symptoms such as hyposmia, depression, anxiety, and sleep disorders. People may also experience disturbances of the autonomic nervous system that manifest as problems with digestion, respiration, salivation as well as excessive sweating, bladder dysfunction, or sexual dysfunction. This phase may last for several years. The onset of motor symptoms marks the clinical phase of PD. People may have a variety of symptoms including resting tremor, bradykinesia, rigidity (resistance to passive movement of the limbs), and balance problems. The progression of these symptoms is typically gradual, often involving only one side of the body at first. This includes things like a reduction of arm swing on one side when walking, soft speech, or intermittent tremor.
More research is needed to better understand, characterize, and identify features of the preclinical phase of PD. A high priority is placed on finding biological identifiers, or biomarkers, of these early phases so that people at high risk for progressing to the clinical phase of PD can be identified. In the future, therapeutics or other interventions may be available to prevent or slow the onset of the clinical phase of the disease among those at high risk for PD.
Currently available PD medications do offer valuable symptomatic relief, but as PD progresses, their use is often associated with significant and sometimes intolerable side effects. For example, levodopa, one of the most effective treatments for PD can normalize motor function for years but later cause involuntary muscle movements known as dyskinesia and dystonia (sustained muscle contractions). In addition, people in the mid to late stages of PD often experience a wearing-off of the beneficial effects of PD drugs and a re-emergence of motor and non-motor symptoms before their next scheduled dose. In more advanced PD, drug-resistant motor symptoms (e.g, postural instability, freezing of gait, loss of balance, frequent falls), behavioral changes (impulse control disorders, hallucinations, and psychosis), and often dementia are leading causes of impairment.
In addition to new therapeutic options, better diagnostic tools are needed to identify PD earlier in the course of the disease. By the time a person exhibits classic motor symptoms and is diagnosed with PD, substantial and widespread loss of brain cells and functions of the brain and autonomic nervous system have already occurred. Earlier diagnosis may provide a therapeutic window to slow or prevent the progression of PD prior to the onset of motor impairments.
While loss of dopamine accounts for the characteristic features of the disease, recent studies have revealed that a number of other brain systems are also damaged. These include the brain structures that regulate the chemical pathways that depend on norepinephrine, serotonin, and acetylcholine. The changes in these neurotransmitters and circuits may account for many of the non-motor features of PD.
A factor believed to play a fundamental role in the development of PD involves abnormalities of a protein called alpha-synuclein. In the normal brain, alpha-synuclein is located in nerve cells in specialized structures called presynaptic terminals. These terminals release neurotransmitters which carry signals between neurons. This signaling system is vital for normal brain function.
While normal alpha-synuclein functions are related to the storage and release of neurotransmitters, evidence suggests the buildup of excessive and abnormal alpha-synuclein plays a key role in the development of PD. There are rare examples of families in which certain genetic mutations in alpha-synuclein have been shown to cause the alpha-synuclein protein to misfold into an abnormal configuration. Most individuals with PD do not have a mutation in alpha-synuclein, but even when there is no mutation present, nearly every case of PD is associated with a buildup of abnormal and misfolded alpha-synuclein. As the misfolded protein accumulates, it clumps together into aggregates, or collections, that join together to form tiny protein threads called fibrils. Fibrils are the building blocks for Lewy bodies, abnormal structures that form inside nerve cells in the substantia nigra and elsewhere in the brain. Lewy bodies are a pathological hallmark of PD. Research suggests that the harmful buildup of alpha-synuclein may affect normal function and trigger nerve cell death.
Lewy bodies were discovered more than 100 years ago, and there are still unanswered questions about their role in disease. They are found in the brain of almost every patient affected by PD, but whether the Lewy bodies themselves contribute to the death of neurons is still unclear. Alternatively, the accumulation of protein in Lewy bodies may be part of an unsuccessful attempt to protect the cell from the toxicity of aggregates of alpha-synuclein.
Researchers increasingly believe that most, if not all, cases of PD probably involve both a genetic and environmental component. Early-onset Parkinson's disease is relatively rare and is more likely to be influenced by genetic factors than the forms of the disease that develop later in life.
Based on an analysis of PD-GWAS data and other sources, NIH-funded scientists have identified 28 loci believed to be independently associated with PD risk and many more loci have been tentatively linked to the disorder.
Despite these innovations, significantly more research is needed to identify PD-related genes and the cellular processes they support in order to understand how these functions contribute to the onset and progression of PD. Common genetic variations alone cannot fully explain how genetics contributes to the risk of developing PD. Instead, researchers hypothesize there must be additional genetic contributions from variants that are not common enough to be detected by PD-GWAS investigations.
Inherited PD has been found to be associated with mutations in a number of genes including SNCA, LRRK2, PARK2,PARK7, and PINK1. Many more genes may yet be identified. Genome-wide association studies have shown that common variants in these genes also play a role in changing the risk for sporadic cases.
In 1997, scientists identified the first genetic mutation (SNCA) associated with PD among three unrelated families with several members affected with PD. The SNCA gene provides instructions for making the protein alpha-synuclein, which is normally found in the brain as well as other tissues in the body. Finding this mutation led to the discovery that alpha-synuclein aggregates were the primary component of the Lewy body. This is an example of how a disease-causing rare mutation can shed light on the entire disease process.
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