Guidelines for the Diagnosis and Treatment of Parkinson’s Disease †

: Parkinson’s disease (PD), the second most common neurodegenerative disorder afﬂicting 10 million people worldwide and the fourteenth leading cause of death in the United States, is caused by the death of dopaminergic neurons that regulate movement in the substantia nigra pars compacta. To facilitate an assessment framework for providers to apply precision medicine to develop treatment plans tailored to the speciﬁc needs of each person with possible PD and related conditions, we propose guidelines for the diagnosis and treatment of people with possible PD and related conditions based on review of available knowledge.


Introduction
Parkinson's disease (PD), the second most common neurodegenerative disorder afflicting 10 million people worldwide [1] and the fourteenth leading cause of death in the United States [2], is caused by the death of dopaminergic neurons that regulate movement in the substantia nigra pars compacta. Mechanisms contributing to the development of PD in vulnerable individuals include protein misfolding, protein aggregation, and mitochondrial dysfunction [3].To facilitate an organized approach for clinicians to utilize precision medicine to develop treatment plans to address the specific needs of individuals with PD and related conditions, we have developed guidelines for diagnosis and treatment based on the review of available knowledge [3].

Methods
We reviewed the key literature on the pathogenesis of Parkinson's disease on PubMed and Google Scholar to propose guidelines for the development of diagnostic and therapeutic interventions for people with Parkinson's disease and related conditions.

Results and Discussion
Clinicians can generate optimal care of people with possible PD and related disorders through systematic utilization of the established principles of clinical medicine, assessment of signs and symptoms of patients, development of a differential diagnosis, and usage of appropriate laboratory tools to rule in or out the disease. (Figure 1). Careful evaluation of persons with PD requires medical and family history [4], examination, structured movement assessments by visual observation [5,6], instrumentation [7], and neuroimaging [3]. movement assessments by visual observation [5,6], instrumentation [7], and neuroimaging [3]. Clinicians will then benefit from the systematic consideration of potential therapies for PD to apply the principles of precision medicine to develop an optimal treatment plan ( Figure 2). Clinicians will then benefit from the systematic consideration of potential therapies for PD to apply the principles of precision medicine to develop an optimal treatment plan ( Figure 2). Biol. Life Sci. Forum 2021, 9,9 3 of 4

Behavioral Interventions
Physical exercise (strength training and cardiovascular fitness) plays a key role in the prevention and treatment of PD in addition to improving somatic and mental health [8].

Behavioral Interventions
Physical exercise (strength training and cardiovascular fitness) plays a key role in the prevention and treatment of PD in addition to improving somatic and mental health [8].

Nutrition
Assessment of individuals is key to foster the use of beneficial dietary components and nutritional supplements and to discourage unfavorable ones [9].

Medications
People with PD generally benefit from a variety of pharmacological interventions including L-dopa/carbidopa [10], monoamine oxidase (MAO) B inhibitor, and catechol O methyltransferase (COMT) inhibitor [11]. Additionally, co-enzyme Q10, a co-enzyme for protein complexes 1, 2, and 3 of a mitochondrial electron transport chain, may selectively benefit genetic subgroups of people with PD [12].

Comorbid Disorders
People with PD merit assessment for specific sleep disorders to apply the principles of precision medicine to tailor a treatment plan specific to the needs of the individual [11].

Surgical Interventions
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) ( Figure 3) [13] and the globus pallidus pars interna (GPi) are procedures that have benefited some people with PD who are refractory to medications [14]. Positron emission tomography (PET) has demonstrated that improvement in symptoms in people with PD with STN DBS was associated with cerebral glucose metabolism alterations including striatal decrements and cerebellar, parietal cortical, and temporal cortical increments as well as vesicular monoamine transporter 2 (VMAT2) decrements in the striatal, cortical, and limbic regions [13] (Figure 4).

Nutrition
Assessment of individuals is key to foster the use of beneficial dietary components and nutritional supplements and to discourage unfavorable ones [9].

Medications
People with PD generally benefit from a variety of pharmacological interventions including L-dopa/carbidopa [10], monoamine oxidase (MAO) B inhibitor, and catechol O methyltransferase (COMT) inhibitor [11]. Additionally, co-enzyme Q10, a co-enzyme for protein complexes 1, 2, and 3 of a mitochondrial electron transport chain, may selectively benefit genetic subgroups of people with PD [12].

Comorbid Disorders
People with PD merit assessment for specific sleep disorders to apply the principles of precision medicine to tailor a treatment plan specific to the needs of the individual [11].

Surgical Interventions
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) (Figure 3) [13] and the globus pallidus pars interna (GPi) are procedures that have benefited some people with PD who are refractory to medications [14]. Positron emission tomography (PET) has demonstrated that improvement in symptoms in people with PD with STN DBS was associated with cerebral glucose metabolism alterations including striatal decrements and cerebellar, parietal cortical, and temporal cortical increments as well as vesicular monoamine transporter 2 (VMAT2) decrements in the striatal, cortical, and limbic regions [13] ( Figure 4).   Pallidotomy by radiofrequency or radiosurgery represent other possibly beneficial surgical interventions for PD [15].
Focused ultrasound (FUS), a procedure that can be accomplished without the penetration of the brain through a craniotomy, may be applied to the thalamus and the subthalamic nucleus [15].

Experimental Interventions
Immunotherapy. Since inflammation produced by the immune system plays a major role in degeneration of the basal ganglia in PD, drugs targeting the immune microenvironment such as sargramostism are under trials. Sargramostism, a recombinant granulocyte monocyte colony stimulating factor, shows promise to protect the basal ganglia from degeneration [16]. Gene therapy. Drugs targeting genes responsible for the development of PD include non-disease modifying drugs which treat the symptoms by targeting dopamine synthesis and disease modifying drugs which slow PD progression such as glial cell-line derived neurotrophic factors [17].
Cell transplantation. Growing dopamine-secreting neurons from pluripotent stem cells using CRISPR technology and transplanting them into the degenerated part of the basal ganglia may offer a line for slowing PD progression and restoring basal ganglia functions [18].
In order to facilitate prompt and efficient diagnosis and treatment of PD, we propose guidelines for the diagnosis (Figure 1) and treatment (Figure 2) of PD.

Conclusions
We are pleased to propose guidelines for the diagnosis and treatment of Parkinson's disease (Figures 1 and 2) in order to provide a checklist of key items to consider in the development of a treatment plan for people who may have Parkinson's disease. Future investigations will measure and quantify the benefits produced by the guidelines. Additionally, future investigations will explore the development of handwriting analysis and other potential digital biomarkers other tools for the diagnosis of PD. We anticipate that Pallidotomy by radiofrequency or radiosurgery represent other possibly beneficial surgical interventions for PD [15].
Focused ultrasound (FUS), a procedure that can be accomplished without the penetration of the brain through a craniotomy, may be applied to the thalamus and the subthalamic nucleus [15].

Experimental Interventions
Immunotherapy. Since inflammation produced by the immune system plays a major role in degeneration of the basal ganglia in PD, drugs targeting the immune microenvironment such as sargramostism are under trials. Sargramostism, a recombinant granulocyte monocyte colony stimulating factor, shows promise to protect the basal ganglia from degeneration [16]. Gene therapy. Drugs targeting genes responsible for the development of PD include non-disease modifying drugs which treat the symptoms by targeting dopamine synthesis and disease modifying drugs which slow PD progression such as glial cell-line derived neurotrophic factors [17].
Cell transplantation. Growing dopamine-secreting neurons from pluripotent stem cells using CRISPR technology and transplanting them into the degenerated part of the basal ganglia may offer a line for slowing PD progression and restoring basal ganglia functions [18].
In order to facilitate prompt and efficient diagnosis and treatment of PD, we propose guidelines for the diagnosis (Figure 1) and treatment (Figure 2) of PD.

Conclusions
We are pleased to propose guidelines for the diagnosis and treatment of Parkinson's disease (Figures 1 and 2) in order to provide a checklist of key items to consider in the development of a treatment plan for people who may have Parkinson's disease. Future investigations will measure and quantify the benefits produced by the guidelines. Additionally, future investigations will explore the development of handwriting analysis and other potential digital biomarkers other tools for the diagnosis of PD. We anticipate that clinicians, administrators, policy planners, advocates, and other concerned individuals will benefit from the adoption of our guidelines for the diagnosis and treatment of Parkinson's disease and related conditions [3].