PET imaging for a very early detection of rapid eye movement sleep behaviour disorder and Parkinson ’ s disease – A model-based cost-effectiveness analysis

Usually, RBD is strongly associated with PD. Recent studies have demonstrated that PD reduces the life expectancy of patients to 10 and 20 years after being diagnosed. In addition, delayed diagnosis and treatment of these neurological disorders have significant socio-economic impacts on patients, their partners and on the general public. Often, it is not clear about PD associated financial burdens both in low and high-income countries. On the other hand, PD triggers neurological variations that affect differences in the dopamine transporter (DAT) and in glucose metabolism. Therefore, positron emission tomography (PET) using specific DAT radiotracers and fluorine-18 labeled desoxyglucose (FDG) has being considered a key imaging technique that could be applied clinically for the very early diagnosis of RBD and in PD. However, a few myths about PET is that it is very expensive. Here, we looked at the cost of treatment of PD and RBD in relation to early PET imaging. Our finding suggests that PET imaging might also be a cost sparing diagnostic option in the management of patients with PD and RBD, not only for first world countries as it is the case now but also for the third world countries. Therefore, PET is a cost-effective imaging technique for very early diagnostic of RBD and PD.


Introduction
Late diagnosis of neurological disorders has major socioeconomic consequences for patients, their partners, and society.A neurological disorder is a medical condition that affects the normal function of the nervous system [1].Rapid eye movement sleep (REM) behavioral disorder (RBD) has been strongly associated with neurodegenerative diseases, such as Parkinson's disease (PD), which it often precedes [2].
Nerve pathways in the brain allow the functioning of muscles during regular REM or sleep dreaming.Parkinson's disease (PD) is a neurological disease of damaged dopaminergic neurons in the substantia nigra par compact brain region, increasing the risk of depletion in dopamine [3].Patients with PD suffer from disabling symptoms such as convulsion, akinesia, fear, depression, cognitive dysfunction, with severe risk factors, including higher infection rates, heart and gastrointestinal problems, and fall-related accidents.On the other hand, radiotracer methods such as positron emission tomography (PET) and SPECT provide regional in vivo quantified information on specific biochemical activities in brain tissue.The understanding of the principles governing radiotracer uptake into brain tissue determines the potential value of these tracers in assessing pathophysiology of brain diseases [4].Parkinson's disease like many other neurodegenerative brain diseases is a multisystem disorder of considerable biological and clinical complexity while the information given by regional cerebral tracer uptake points to a momentary biochemical local tissue feature.In particular, PD induces neurological variation which causes changes in dopamine transporter (DAT) and in brain glucose metabolism.Thus, PET using specific DAT radiotracers or Fluorine-18 labeled glucose analogue 2-[18 F] fluoro-2-desoxyglucose (FDG) is being considered a powerful diagnostic tool for the detection of early RBD and PD displaying disease condition.In the present manuscript, we discussed the general cost of PD, RBD in relation to PET imaging cost and advocate for a cost lowering attitude for patients and society.

Rapid eye movement sleep behavioral disorder (RBD)
Rapid eye movement (REM) sleep behavior disorder (RBD) is a dysfunction that is characterized by the loss of the typical slackening of the muscles during sleep with a lot of motor activity.As a result, dream contents are acted out and there are nocturnal movements of the limbs (e.g., "fighting", getting up in bed, crawling around), performing certain gestures or movements that make no sense in sleep (e.g.saluting) and/or verbal utterances such as speaking, screaming, scolding or laughing.Those affected often find dreams very vivid or even frightening and Patients and their bedpartners are sometimes injured as a result of this [5].REM sleep behavior disorder often precedes Parkinson's disease and remains one of the strongest predictors of PD.
Personal and external medical history, a neurological examination for neuropsychological deficits, Parkinson's symptoms, autonomic disorders, and polysomnography with videometry in a sleep laboratory are all used in the diagnosis of RBD.Since the RBD turn into a neurodegenerative disease within a few years in up to 80 % of all cases, additional examinations are carried out such as physical examinations for Parkinson's symptoms, ultrasound of the brain, smell tests, imaging of the dopamine-containing brain structures and neuropsychological examinations (e.g., attention and memory tests, etc.) [6].
The benzodiazepine Clonazepam® is prescribed for the treatment of chronic forms of RBD.Taken at bedtime will reduce muscle activity during REM sleep.In this context, even with long-term use, there is hardly any tolerance formation and loss of effectiveness.Melatonin, which is also said to restore muscle atony during REM sleep, has improved in some patients after consistently taking it for over one year [7].

Parkinson's disease (PD)
Parkinson's disease is the second most prevalent neurodegenerative disease after M. Alzheimer.It mainly affects the elderly and increasingly restricts mobility with other typical symptoms like tremors at rest and muscle stiffness [8,9].PD is divided into several forms and the most common is the idiopathic Parkinson's syndrome.Idiopathic means that no cause is known.Parkinson's symptoms can also be the result of other diseases of the central nervous system, such as dementia [10].The neurotransmitter dopamine plays a crucial role in PD.Among other interventions, it ensures that impulses are transmitted from the brain via the nerves to the muscles by damaging the nerve cells in the brain that produce dopamine.This makes it harder to coordinate movements.It can also lead to balance problems, which increase the risk of falling.PD cannot be cured at yet.However, symptoms can be effectively alleviated.First and foremost, they are treated with medication [11].According to the Michael J. Fox Foundation for Parkinson's Research, PD is a progressive disorder and patients usually begin developing Parkinson's symptoms around age, 60.Many people with PD live between 10 and 20 years after being diagnosed [12].

The impact of positron emission tomography in PD and RBD
PET (is based on the simultaneous detection (tracing) of two gamma radiation photons that arise after the decay of a positron-emitting (emitting) radionuclide (β + decay).PET visualizes sections of living organisms by making the distribution of a weakly radioactively marked probe (radiopharmaceutical) visible in the organism and thus depicting biochemical and physiological functions.
Recent PET findings suggest a more effective early detection of REM Sleep disorder (RBD) than the traditional imaging technique of CT/ magnetic resonance imaging (MRI), and its diagnostic accuracy is generally higher than that of CT/MRI [13].It is almost exclusively carried out together with a CT or MRT as a hybrid procedure, this hybrid systems overcome the limitations of current standalone CT and MRI scans, resulting in a more precise PET quantification [14].Neural changes caused by PD are synonymous with variations in dopamine transporter (DAT) and in brain glucose metabolism.PET with 2-[18 F] fluoro-2-deoxyglucose (FDG-PET) has being considered a powerful diagnostic tool for detection of early RBD and PD displaying medical signs and symptoms [2].
RBD, depression, vision dysfunction, constipation, hyposmia or anosmia, even akinesia are non-motor symptoms of Parkinson's disease that appear long before the motor symptoms do.RBD is the strongest predictor, and thus serve as a baseline for early diagnosis and treatment.The challenge is that most of these indicators are non-specific, making them unsuitable for early Parkinson's disease diagnosis [15].Motors responsible for acting out of dreams are relatively uncommon, with 85 per cent of those who experience it develops Parkinson's disease within 15 years, differentiating it from RBD.
By asking the patient's partner a few basic questions (does your partner snore?Is he talking to himself in his sleep?Has he ever hit you in the night?),A presumed diagnosis can be made, which can be used to diagnose 30-50 per cent of patients who develop Parkinson's disease later on.Polysomnography can then be used to confirm the findings.Further additional parameters for RBD cohorts could then be used for an early diagnosis.Hyposmia, constipation, disturbed gastric motility, specific patterns in FDG-PET, altered pupillary reactions, and genetic characterizations are forms of these symptoms.Early diagnosis is possible with the combinations of such symptoms, which could lead to very early neuroprotective therapy [16].Patients, their families, and society all suffer significant cultural and economic consequences as a result of RBD diagnosis and treatment.The total additional direct net healthcare costs after the diagnosis (general practitioner services, hospital services, and medication) and indirect costs (loss of Labour market income) were €13,088 according to a Scandinavian study [17].
The total cost of PD to individuals and families in the United States is $51.9 billion every year, with $25.4 billion attributable to direct medical costs (e.g., hospitalizations, medication) and $26.5 billion in nonmedical costs like missed work, lost wages, early forced retirement and family caregiver time [18].
PET imaging has evolved rapidly in the preceding two decades moving from research institutions to the clinic, thereby enabling the detection and monitoring of diseases in oncology.Although limited in number, one of the biggest myths about PET is that it is prohibitively expensive.There are peer-reviewed publications that examine the costeffectiveness of PET in various clinical scenarios.Perhaps the most wellknown of these is the PLUS trial, in which researchers in the Netherlands examined the use of FDG-PET added to a conventional workup vs. a conventional workup alone in the presurgical evaluation of patients with early-stage lung cancer.In this trial, "conventional workup" was defined as the imaging obtained per standard clinical practice using available guidelines.The authors found that in those patients who underwent presurgical evaluation with conventional workup alone, 41 % F. Fezeu et al. of thoracotomies were futile.In contrast, patients evaluated with FDG-PET in addition to a conventional workup had a futile thoracotomy rate of only 21 %.The authors concluded that the added cost of PET imaging was offset by the savings achieved through the avoidance of unnecessary surgery, with a savings of approximately €1289 per patient [19].A report from the United States indicates that PET has a comparable cost to CT and MRI sequel to the decline in cost of the scanner, installation and the availability of tracers [20].[17] Significant cultural and economic consequences due to RBD diagnosis and treatment.Additional direct net healthcare costs after diagnosis (general practitioner services, hospital services, medication) and indirect costs (loss of Labor market income) were €13,088 according to a Scandinavian study.

RBD Diagnosis and Treatment Costs
PD Costs in the United States [18] Total annual cost of PD in the U.S.: $51.9 billion.Direct medical costs (hospitalizations, medication) account for $25.4 billion.Non-medical costs (missed work, lost wages, early forced retirement, family caregiver time) amount to $26.5 billion.[19] The PLUS trial examined FDG-PET added to a conventional workup vs. conventional workup alone in early-stage lung cancer patients.Conventional workup alone led to 41 % futile thoracotomies.FDG-PET with conventional workup reduced futile thoracotomies to 21 %, showing potential cost savings.The added cost of PET imaging was offset by savings from avoiding unnecessary surgeries, saving approximately €1289 per patient.

Comparative Cost of PET in the U.S. [20]
A U.S. report indicates that PET costs are comparable to CT and MRI.The decline in the cost of scanners, installation, and the availability of tracers contribute to PET's comparable cost.

Discussion
Positron emission tomography (PET) is a medical imaging procedure that provides unique information about how an organ or system in the body is working.Although PET imaging is currently expanding, with new facilities and indications appearing every year, including in oncology to assess cancers and to evaluate therapy outcome, cardiology and for neurodegenerative diseases, its application in the management of patients in third work countries remains insignificantly low.The present analysis aims at estimating the impact of PET imaging for a very early detection of RBD and Parkinson's Disease.
If early diagnostic of PD is made by using clinical finding like symptoms of RBD and advance imaging technology like PET, it might open the door to a very early treatment of patients that were prone to suffer from PD in the future.The very early neuroprotective therapy should allow some patients to develop milder symptoms of PD at a very later stage by diminishing the course and progression of the disease.
The cost of 15 years of PD is far higher than the cost of PET imaging.Looking at the above-mentioned fact it is not straightforward to assume that PET is a costly diagnostic tool in the diagnosis and treatment of PD.It is, therefore, necessary to develop a new mindset in our way to diagnose patient suffering from RBD.Hence, we advocate making FDG-PET available for a wide range of RBD patient to diagnose PD very early and allow them a very early neuroprotective therapy.Early diagnostic of PD should enable very early prevention, very early targeted treatment, slow disease progression and reduce the long-term cost.[21].
The rarity of PET imaging in the third world countries is also the result of the typical assumption of PET to be expensive.Of course the technical investment to run PET routinely remains relatively considerable.However, the benefit for patients and the society is for far higher than any cost for PET imaging.The world population in low-income countries is higher than the population in high-income countries.There is therefore a lack of good global scientific data on functional imaging.Breaking the virtuous circle of no data, no imaging, no understanding of key areas of brain function needs to be discussed among physicians and policymakers in low-income countries.Unfortunately, the discussion can only be carried out by physicians that have a great understanding of these technologies and the time for them.This is not obvious when we look at the rarity of physicians in low-income countries.A global approach with the involvement of physicians coming from low-income countries and residing/working, the so called diaspora in high-income countries seems to be a meaningful strategy.

Limitation
The paper lacks statistical data on the cost of PET imaging and its impact on the diagnosis and treatment of neurological disorders, yet provides a framework within which to move.It also points out that factors such as initial set-up costs, ongoing maintenance, and availability of trained personnel are key considerations that could affect the practicality of widespread adoption of PET.

Conclusion
For patients, their partners, and society, early diagnosis of neurological disorders reduces its impacts socioeconomically and improves life expectancy.We looked at the cost of PD and REM sleep disorder and compared it to PET.Taking into consideration the fact that PET could allow better diagnosis of REM Sleep disorder (RSD) and the fact that RSD allows diagnosing PD 15-20 years earlier.It seems a necessity to reconsider our assumption of PET to be an expensive diagnostic tool.Our finding suggests that PET might also be a cost sparing diagnostic option not only for first world countries as it is the case now but also for third world countries.Therefore, we advocate for innovative strategies that should allow widespread use of this meaningful functional imaging technology in countries with an advanced economy and Third World countries.