Parkinson’s Disease

1. Parkinson’s Disease

2. Sex & Gender Difference Slides When in presentation mode, click this button to advance to each sex and gender difference slide.

3. Parkinson’s Disease Overview

4. Parkinson’s disease is a debilitating neurodegenerative disorder characterized by movement dysfunction and by cognitive and other non-motor impairments.1 • Parkinson’s disease causes tremors due to selective loss of dopamine secreting neurons and accumulation of Lewy bodies in the central nervous system.2 • Although Parkinson’s disease is about 1.5 to 2 times more common in males compared to females, the specific symptoms accompanied with Parkinson’s disease vary based on sex.3,4 • The sex differences in Parkinson’s disease provide a specialized method for screening, diagnosis, treatment, and management of patients that will allow for better care of patients. Overview

5. Parkinson’s Disease Anatomy

6. Parkinson’s disease affects dopaminergic neurons.5 • Increased oxidative stress due to dopamine oxidation, higher metabolic activity, and calcium buffering defects all impact the vulnerability of dopaminergic receptors and these converge on mitochondrial malfunction.5 • Decreased levels of NAD+ can lead to increased oxidative stress and decreased mitochondrial function.5 Anatomy

7. Compared to males with PD, females with PD have: • Unilaterally increased cortical thickness6 • Increased nodal distance in left caudal middle frontal, left rostral middle frontal, and right parahipocampal6 Compared males, females have: • Higher expression of genes associated with neuronal maturation and signal transduction based on microarray assays6,28 • Alterations in WNT signaling pathway genes28 • Lower expression of genes associated with PD such as alpha-synuclein and PINK16,28 Anatomy

8. Parkinson’s Disease Physiology

9. Dopaminergic-releasing catecholaminergic neurons are7: • Within the midbrain are a part of the basal ganglia network7 • Crucial for multiple fundamental brain functions such as voluntary movement, goal-directed behavior, and much more7 • Substantia nigra dopaminergic neurons are vulnerable to7: • Metabolic stress7 • Mitochondrial dysfunction7 • Ca2+ imbalance7 • Dopamine imbalance7 Physiology

10. Excitatory Inputs7: • Subthalamic nucleus • Pedunculopontine nucleus • Somatosensory cortex • Motor cortex • Inhibitory Inputs7: • Dorsolateral striatum • Dopamine Substantia nigra (SN) Dopamine transmits signals of the brain to coordinate activity7 Physiology Dopamine produced and released by SN7

11. Parkinson’s Disease Cell Biology

12. Substantia nigra dopaminergic (SN DA) neurons consist of typical low frequency pacemaker activity leading to dendritic Ca2+ oscillations. Cell Biology

13. Cell Biology

14. Several intrinsic feedback and feed-forward mechanisms affect Substantia nigra dopaminergic neurons.7 • A reduction or elevation in any of these factors can result in SN DA degeneration.7 • Voltage gated Ca2+ channels and ATP-sensitive potassium channels have bidirectional physiological functions. • They can stimulate each other’s activity and they can trigger selective SN DA degeneration and Parkinson’s disease.7 Cell Biology

15. Parkinson’s Disease Pathology

16. The Substantia nigra dopaminergic pathway plays a central role in regulating fine motor control, and its degeneration leads to the motor symptoms of Parkinson’s disease.8 Pathology

17. Protein aggregations containing α-synuclein, also known as Lewy bodies, comprise a diagnostic pathology related to the final stages of dopaminergic neuronal loss in Parkinson’s disease patients.8 • α-synuclein level correlates with cognitive impairment, hallucinations, psychosis, apathy and sleep disorders in Parkinson’s disease patients.6 • Other mutations that cause Parkinson’s disease involve genes that protect against mitochondrial dysfunction such as PINK-1 and oxidative stress such as DJ-1.7,9 • The genes involved in the pathogenesis of Parkinson’s disease, including α-synuclein and PINK-1, are shown to be overexpressed in males compared to females.6,28 Pathology

18. Co-localization of SRY and TH8 • SRY is a gene on the Y chromosome in males. • TH is the rate-limiting step in dopamine synthesis. • SRY positively regulates the expression of enzymes involve in the regulation of dopamine synthesis and metabolism (monoamine oxidase).10 *SRY = Sex-determining region on Y chromosome *TH = tyrosine hydroxylase The co-localization of SRY and TH increases the development of midbrain dopamine-related disorders in males compared to females. Pathology

19. Lifestyle influence in Parkinson’s disease9,29 • Exposure to herbicides increases risk • In military veterans with traumatic brain injury, there is an increased risk of 56% for PD Males were traditionally more likely to be agricultural workers, so occupational exposure to agrichemicals increased their risk of Parkinson’s disease. Males are also more likely to suffer brain trauma due to their greater exposure to events such as road traffic accidents or contact sports. Pathology

20. Estrogen, especially 17β-estradiol (E2) has neuroprotective actions.8, 30, 31 • Females who underwent bilateral oophorectomy before menopause have an increased risk of developing PD.3 • At menses, when estrogen levels are the lowest, Parkinson’s disease symptoms are the worst.3 • The degree of intrinsic neuroprotection in the female brain can be overridden once neurodegeneration reaches a certain extent.1 • Estrogen-based hormone replacement therapy can relieve Parkinson’s disease symptoms when given in the early stages of disease.8 The increased levels of estrogen in females over males provides an advantage in neurodegenerative diseases like Parkinson’s disease.1 Pathology

21. Parkinson’s Disease Epidemiology

22. Parkinson’s disease is the second most common neurodegenerative-psychiatric disorder.8,12 • It affects approximately 0.3% of people in the developed world8 • This percentage rises to 3% for people over the age of 65 years.8 Epidemiology

23. Parkinson’s disease is about 1.5 to 2 times more common in males compared to females.8,3,4 • Parkinson’s disease in females is less common in females with both ovaries.8 • 17β-estradiol (E2) has a neuroprotective role.8 • When estrogen levels are lowest, during menses, Parkinson’s Disease symptoms worsen.8 Epidemiology

24. Parkinson’s Disease Risk Factors

25. Lower Risk for Females Due to: • Estrogen has a neuroprotective effect on the nigrostriatal dopaminergic system and it can modulate monoamine oxidase (MOA)8,10 • Except during menses and bilateral oophorectomy3 • Absence of SRY gene and Y chromosome8 • Increased cortical thickness and higher nodal betweenness in left caudal middle frontal, and left rostral middle frontal, and right parahipocampal6 Risk Factors

26. Equal Risk for Both Sexes Due to: • Age8 • Lifestyle, specifically herbicides and traumatic brain injury9 • Men are more likely to live a lifestyle that involves use of herbicides and increased TBI. • However with equal exposure to these environmental factors, both sexes are at the same risk of developing PD. Risk Factors

27. Parkinson’s Disease Clinical Presentation

28. Primary Symptoms of Parkinson’s disease9, 13: • Tremor • Stiffness/Flexed Posture • Slowness • Impaired balance • Shuffling gait (“short-stepped”; impaired gait and balance) in progressed Parkinson’s disease • Facial masking leads to the face becoming rigid and fixed. Thus, spontaneous expression is impaired. This is common in both males and females.13 • Potential Secondary Symptoms of Parkinson’s disease 9: • Anxiety • Depression • Dementia Clinical Presentation

29. Several non-motor symptoms, such as sleep problems, fatigue/excessive tiredness, and autonomic dysfunction (bladder urgency, constipation, and drooling), are common in both sexes.14 • All these symptoms advance as the disease progresses over time.14 • Sexual dysfunction is present in both sexes but primarily reported by males.14 • Females may consider sexual dysfunction as embarrassing or unrelated to Parkinson’s disease.14 Clinical Presentation

30. Clinical Presentation in Females Clinical Presentation in Males • Males experience more deficits in verbal fluency and recognition of facial emotions.8 • Males have more deficits in rapid eye movement sleep behavior disorder, wandering, physical abusiveness, and inappropriate behavior.1 • Males report more problems in non-motor symptoms.14 • Though Parkinson’s disease is more common in men, females have a greater mortality and earlier nursing home placement than men.10 • Females experience higher impairment in visuospatial functions and depression and anxiety.8,1 • Females have greater disease severity and more comorbidities, despite a similar duration of disease.15 Clinical Presentation

31. Clinical Presentation in Females Clinical Presentation in Males • Females are diagnosed at an average age of 53.4 years.1,8 • Primary indication of Parkinson’s disease in females is tremor.1 • Females have higher levels of striatal uptake binding at the time of symptom onset.1 • Males are diagnosed at an average age of 51.3 years.1,8 • Primary indication of Parkinson’s disease in males is bradykinesia and rigidity.1 Clinical Presentation

32. Parkinson’s Disease Pharmacotherapeutic Treatment

33. Most treatments are based on the symptoms of the patient. • The medications are to manage the symptoms. However, none of the medications reverse the effects of Parkinson’s disease.10 • Males are more likely to receive antipsychotic medications, and females are more likely to receive antidepressants, regardless of behavioral symptoms.1 Pharmacotherapeutic Treatment

34. Treatment with dopamine agonists of levodopa:10 • Though treatment with dopamine agonists (DA) does not differ between the two sexes, the L-dopa-related motor complications, such as dyskinesias, are more common in females with Parkinson’s disease.10 • Another name for L-dopa is Levodopa, which the brain converts to dopamine. • Females have greater levodopa bioavailability.16 • Thus, females are have a greater prevalence of dyskinesias compared to men.1 Pharmacotherapeutic Treatment

35. The Effect of Hormone Therapy on Parkinson’s Disease: • Post-menopausal estrogen treatment was associated with a lower risk of Parkinson’s disease onset.10 • Estrogen treatment has no effect on dopamine concentrations.10 • Treatment with 17β-estradiol (E2) did not provide neuroprotection against the neurotoxin causing Parkinson’s disease.10 • Progesterone pre-treatment (4mg/kg) prevented Parkinson’s disease in males.10 Pharmacotherapeutic Treatment

36. Parkinson’s Disease Other Treatments

37. Stereotactic surgery can be used to treat both men and females with Parkinson’s disease.17 • Deep Brain Stimulation (DBS) is the principal surgical option.18 • Males are more likely than females to have surgery.17 • Females who had surgery for Parkinson’s disease were more impaired and had longer disease duration.1 • Females had greater post-surgical improvement in instrumental activities of daily living (ADLs).1 Other Treatments

38. Females may especially benefit from physical and speech therapy to increase facial and vocal modulation and fluency.1 • This helps mitigate the negative psychosocial effects off facial rigidity and vocal monotony and dysfluency.1 • This treatment is beneficial to females because facial masking in Parkinson’s disease may violate gender norms for expressivity in females but not in men.1 • Facial masking can impair social interaction by making the face rigid and fixed.13 Other Treatments

39. Parkinson’s Disease Prognosis

40. Underweight (low BMI) patients had poorer life prognosis than patients who were not underweight, and the difference was larger in males than females.19 Prognosis

41. Females achieved a significant improvement after deep brain stimulation (DBS) surgery, if they performed well in activities of daily living.18 • If females are not involved in domestic tasks, then the subthalamic nucleus (SN) – DBS is equally beneficial for both sexes.18 Prognosis

42. Females have milder motor deterioration and striatal degeneration compared to males.20 • Despite this, females cite greater disability and reduced quality of life.16 Prognosis

43. Early-onset patients showed significantly longer duration to reach end stages but shorter duration to develop wearing off and dyskinesia.22 • Mean age at death is 73.4 for males and 73.1 for females.23 • There is a 98% greater excess mortality in females compared to males.23 • In the general elderly population, females outnumber males. In the parkinsonian population, males outnumber females in mortality.23 Prognosis

44. Parkinson’s Disease Social/Environmental Considerations

45. There is a positive association between pesticides and organic solvent exposure and Parkinson’s disease.9,24 • Certain occupations, such as agricultural workers, are more exposed to pesticides.9,24 • Males are more likely to be exposed to pesticides/herbicides.9 Social/Environmental Considerations

46. Among smokers, increased years of smoking was linked more closely to lowering the risk of Parkinson’s disease rather than increased number of cigarettes smoked per day. Nicotine reduces risk of Parkinson’s disease.25 • People who eat a diet high in polyunsaturated fatty acids and low in saturated fat have a lower risk of developing Parkinson’s disease.26 Social/Environmental Considerations

47. Parkinson’s Disease Other Considerations

48. Vitamin D deficiency can increase the chances of development of Parkinson’s disease, increased severity, and increased cognitive impairment.27 • Brain trauma and multiple episodes of loss of consciousness are also positively correlated with Parkinson’s disease.9,24 • Genetics explains upwards of 60% of disease risk for Parkinson’s disease.9 • Age is another fact. As people get older, they have an increased risk of Parkinson’s disease.9 • Males are at a higher risk.24 Other Considerations