Parkinson’s Disease: Endlessly Fascinating Facts

1. Parkinson’s Disease: Endlessly Fascinating Facts Resident Conference 6 May 2009 J. Peacock MD, PhD

2. Parallel organization of motor & non-motor basal ganglia loops

3. Well-known Cardinal Features • Resting Tremor (3 – 5 Hz) • Rigidity (cogwheel, paratonia) • Bradykinesia • Loss of balance

4. Well-knownAssociated Features - 1 • Hypomimia - masked face – reptilian stare • Hypophonia - low volume, rapid speaking • Saccadic visual pursuit • Difficulty in arising from a chair

5. Well-knownAssociated Features - 2 • Shuffling gait, decreased stride • Problems overcoming inertia • Can’t start – can’t stop • Freezing • Speeding up

6. Well-knownAssociated Features - 3 • Wooden (en bloc) movements • Postural changes, stiff, stooped • Altered center of gravity • Tendency to retropulsion • Decreased arm swing • Compass turn

7. Well-knownAssociated Features - 4 • Decremental amplitude on finger tapping & decreased dexterity • Postural lightheadedness • Loss of olfactory sense early • Law-abiding – ‘won’t jay walk’ • Mate for life – spousal fidelity

8. Non-motor Problems in PD • Autonomic Dysfunction • Neuropsychiatric Symptoms • Sensory Phenomena • Cognitive Impairment • Sleep Disturbances • Sensory Phenomena

9. Dysautonomia In PD • Dysphagia including sialorrhea • Constipation • Urinary problems • Orthostatic hypotension • Sexual problems • Impaired thermoregulation

10. Overlap of problems with behavior, emotions & memory • Cause symptoms in the areas listed in the next slide • Note: these are symptoms that can occur, but do not necessarily happen in any person with Parkinson’s disease

11. Overlap -- • Neuropsychiatric Symptoms • Cognitive Impairment • Sleep Disturbances • Autonomic Dysfunction • Sensory Phenomena Dr. Eugene Lai: PADREC Meeting 2003

12. Non-motor FrequencyFrom Eugene Lai, MD

13. Neuropsychiatric Symptoms • Depression • Hallucinations (formed visual images of silent persons or animals) • Delirium • Anxiety - Panic • Agitation

14. Cognitive Impairment - 1 • May affect up to 40% • Late feature of Parkinson’s disease • Ddx: • PD dementia vs. AD • vs. Diffuse Lewy body dementia • vs. Vascular Dementia

15. Cognitive Impairment - 2 • Frontal – executive problems: visuo-spatial problems, temporal sequencing, decreased memory and attention • Increased burden for caregivers

16. SleepDisturbances • Insomnia • REM behavior disorder • Nightmares • Obstructive sleep apnea • Excessive daytime sleepiness

17. Sensory Phenomena In Parkinson’s • Cramps • Dystonic Pain • Pain of immobility • Heaviness in limbs • Restless leg Symptoms

18. Lewy Bodies • Neuropathologic signature of PD • Found also in: • Lewy Body dementia • Multiple system atrophy • Hallervorden-Spatz disease • Widely distributed in brain & body

19. Lewy Body Distribution - 1 • Substantia nigra • Hypothalamus • Sympathetic nervous system • Intermediolateral nucleus of spinal cord plus sympathetic ganglia  hypotension

20. Lewy Body Distribution - 2 • Parasympathetic system • Dorsal vagal nucleus  dysphagia • Sacral parasympathetic nucleus -->Dysuria • Myenteric plexus --> Constipation

21. Lewy Body Distribution - 3 • Cardiac plexus --> Cardiac arrhythmias • Pelvic plexus --> Pelvic floor dysfunction • Adrenal medulla --> Blood pressure changes

22. Lewy Bodies Are Composed Of Alpha Synuclein • A presynaptic protein • Identified by antibody staining • Found in Lewy Bodies • But also: Neurons, dentrites, & oligodendroglia in PD, etc.

23. Alpha Synuclein - 2 • The gene for a-synuclein (SNCA) is on chromosome 4q21 • One form of hereditary PD is due to mutations in SNCA • Another form is due to a triplication of SNCA • Alpha-synuclein is also referred to as the non-amyloid component of senile plaques precursor protein (NACP)

24. Synucleinopathies • Parkinson’s disease • Lewy body dementia • Multiple system atrophy • Shy Drager variant • Hallervorden-Spatz disease • Striatonigral degeneration with iron deposition

25. Emerging Concept • Alpha synuclein is to Parkinson’s disease as • Beta amyloid is to Alzheimer’s disease, i.e. • A-synuclein:PD::B-amyloid:AD • NOTE: Both can be expressed in the same individual

26. More Fascinating “Facts” & Parkinson’s Disease-1 • Genetic influences: 8X increase in relatives of early onset & 3X increase in those of late onset PD • Children of younger PD parents at greater risk for PD than if they had older parents

27. More Fascinating “Facts” & Parkinson’s Disease-2 • APO E3/E4 OR E4/E4 ASSOC WITH EARLY ONSET PD • CAFFEINE & NICOTINE PROTECTIVE AGAINST PD • EXERCISE IS ALSO PROTECTIVE

28. Basis for non-motor symptoms • The next slide shows the physiological organization of the non-motor system in the basal ganglia that is disrupted by Parkinson’s disease

29. Overlap of problems with behavior, emotions & memory • Cause symptoms in the areas listed in the next slide • Note: these are symptoms that can occur, but do not necessarily happen in any person with Parkinson’s disease

30. Overlap of problems with behavior, emotions & memory • Neuropsychiatric Symptoms • Cognitive Impairment • Sleep Disturbances • Autonomic Dysfunction • Sensory Phenomena Dr. Eugene Lai: PADREC Meeting 2003

31. Non-motor Frequency

32. Neuropsychiatric Symptoms • Depression • Hallucinations • Delirium • Anxiety • Panic • Agitation

33. Neuropsychiatric Treatment • Reduce or stop medications • Identify & treat medical problems • Antidepressants • Atypical Neuroleptics • Anxiolytics • Keep active & exercise • Educate Caregivers • Psychological Counseling

34. Cognitive Impairment • May affect up to 40% • Late feature of PD • Dx: PD vs AD vs Lewy Body disease (LBD) vs vascular disease • Frontal –Executive Problems: Visuospatial problems, temporal sequencing, memory, & attention • Burden for caregivers

35. Comparative cognitive changes in PD, LBD, & AD - 1 • Appear 5-10 years after motor symptoms (sx) in PD & may never develop in some individuals • Appear at onset, often with visual hallucinations in LBD & before motor sx in 1-2 years. Motor symptoms respond incompletely to L-Dopa

36. Comparative cognitive changes in PD, LBD, & AD - 2 • May fluctuate early in course in LBD • Appear at onset in AD. Motor sx like PD develop late, if at all, & respond poorly to L-Dopa

37. Treatment Of Cognitive Impairment • No good medical therapy • ? Cholinesterase inhibitor (Aricept, Razadyne, or Exelon) • Check for medications affecting cognition & memory • Symptomatic behavioral therapy • Caregiver education

38. Sleep Disturbances (dysomnia) • Insomnia • REM behavior disorder • Nightmares • Obstructive sleep apnea • Excessive daytime sleepiness

39. Rx: Dysomia--1 • Treat depression & anxiety • Add Sinemet CR at bedtime • Sleep hygiene program • Short acting sedative hypnotics • Minimize nocturia (urination at night)

40. Rx: Dysomia--2 • Clonazepam for rapid eye movement (REM) sleep problems • Stop tricylics and monoamine oxidase inhibitors • Avoid evening stimulants • Evaluate sleep disorder

41. Dysautomia (dysfunction of the autonomic system) in PD • Constipation • Urinary problems • Orthostatic hypotension • Sexual problems • Impaired thermoregulation • Dysphagia (impaired swallowing) • Sialorrhea (drooling)

42. Rx Of Constipation • Dietary modification • Increase physical activity • Stop anticholinergics (e.g. Artane) • Stool softener • Bulk fibers • Lactulose • Mild laxative • Education

43. Rx Of Dysuria • Nocturia, frequency, urgency • Reduce evening fluids • Elevate head of bed • Medication (oxybutynin, tolterodine) • Possible urologic evaluation

44. Rx Of Orthostatic Hypotension In PD • Eliminate anti-hypertensives • Behavioral modification • Increase salt and fluids • Support hose • Elevate head of bed • RX: Fludrocortisone or midodrine

45. Sensory Phenomena In PD • Cramps • Dystonic pain • Pain of immobility • Heaviness in limbs • Restless leg syndrome

46. Rx Of Sensory Problems • Stretching exercises • Medication adjustment • Physical therapy • Baclofen or tizanidine • NSAIDs: Non-steroidal anti-inflamatory medication • Botulinum toxin

47. Summary • Behavior, emotions, & memory are affected in different ways in different individuals with Parkinson’s disease. • These changes have a profound effect on their lives & their families. • Management of these, often complex, non-motor issues are as important as treatment of motor symptoms

49. Changes in behavior in PD • Do changes in the mirror neuron system in PD affect behavior?

50. What is a mirror neuron? • It is a neuron that reacts when Person A makes a movement, but also when person A watches Person B executing the same movement. • Monkey see – Monkey do!