PD 2

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  1. orthostatic hypotension
    postural hypotension: low blood pressure when you stand up from sitting
  2. sialorrhea
    increase in saliva
  3. ANS
    impaired g.i. motility, bladder dysfunction, orthostatic hypotension, excessive head and neck sweating
  4. depression
    mild to moderate in 50% of patients
  5. cognitive impairment
    impaired visual spatial perception and attention, slowness in executive in motor tasks, impaired concentration
  6. phases
    • premotor: nonspecific symptoms (fatigue, depression, constipation, REM behavior disorder)
    • motor: subtle decrease in dexterity, difficulty with specific tasks (rising from chair, opening jars), first affected arm may not swing fully when walking, foot on same side may scrape the floor
  7. first symptom of PD
    • resting tremor of one hand (slow and coarse, maximal at rest, lessening during movement, absent during sleep)
    • amplitude increase by emotional tension or fatigue
    • pill rolling tremor (involve wrist and fingers--manipulate small objects)
    • hands, arms and legs most affected (in order)
    • -voice not affected (tremor less prominent as disease progresses)
  8. cogwheel rigidity
    • rigidity without tremor in many patients
    • when clinician moves a rigid joint, sudden, rhythmic jerks due to variations in intensity of rigidity occur.
  9. bradykinesia
    • slow movements typical as rigidity progresses, along with hypokinesia and akinesia
    • rigidity and hypokinesia contribute to muscular aches and fatigue
  10. masklike face
    • involuntary relaxation of facial muscles (masked facies)
    • open mouth, drooling and reduced blinking
    • may appear depressed
  11. how is the speech affected?
    • hypophonic (soft speech)
    • monotonous, stuttering dysarthria (poor articulation)
  12. freezing
    without warning, voluntary movement, such as walking may suddenly halt
  13. micrographia caused by?
    due to hypokinesia and impaired control of distal musculature
  14. postural instability are like what
    gait abnormalities due to loss of postural reflexes, more common in late stages
  15. how is the postural and walk affected
    • difficulty starting to walk, turning, stopping (gait shuffled)
    • steps may inadvertently quicken (to keep from falling)-->festination
    • propulsion (tendency to fall forward) or backward (retropulsion) b/c of loss of postural reflexes
    • posture stooped
  16. when and how many people does dementia occur in PD patients?
    • occurs late in disease (15-30% of patients)
    • short term memory and visuospatial function may be impaired
    • aphasia not present
  17. aphasia
    loss of ability to understand or express speech
  18. LBD
    • cognitive dysfunction within a year of onset of motor features, marked by cortical Lewy bodies
    • hallucinations and muscle ridigity
  19. how does PD compare with AD?
    • not as severe in memory impairment than in AD (dementia can cause more impairment in short term memory and information retrieval)
    • visuospatial abilities more impaired in PD
  20. cognitive features in PD
    • planning and frontal executive functions impaired, response initiation and poor performance on timed tasks
    • deterioration in abstraction and problem solving
    • delayed recall, semantic memory, speech and language
  21. semantic memory
    memory of meanings, understandings, other concepts-based knowledge impaired (meaning in language or logic)
  22. speech changes
    • dysarthric
    • word list generation, reduced sentence length and comprehension
    • intact naming until late stage
  23. parkinsonism
    motor symptoms of PD
  24. neurologic symptoms unrelated to parkinsonism
    • develop b/c of synucleinopathy (lewy bodies) in other areas of central, peripheral and ANS
    • orthostatic hypotension (sympathetic denervation of the heart)
    • esophogeal dysmotility
    • lower bowel dysmotility
    • anosmia
  25. esophageal dysmotility
    hard to swallow (dysphagia)
  26. anosmia
    • decrease in odor detection
    • urinary hesitancy and/or urgency
  27. seborrheic dermatitis
    an autonomic sign: scaly, flaky, itchy, red skin
  28. stages of PD
    • 1: mild one sided
    • 2. bilateral symptoms, minimal disability, posture and gait 
    • 3: moderately severe (significant slowing)
    • 4. severe (walking limited, rigidity, bradykinesia)
    • 5. Cachectic (wasting syndrome), complete invalid
  29. eosinophilic
    stained by acidic dye eosin
  30. difference between lewy bodies and lewy neurites
    • Lewy bodies (in cell soma)
    • lewy neurites (in axons and nerve terminals)
  31. who described lewy bodies
    • 1912 Friedrich Lewy
    • inclusions in SNpc
    • LB filled with alpha-synuclein
    • no standard criteria for neuropathological diagnosis of PD
  32. syncope
    sudden drop in blood pressure
  33. thermoregulation
    hot and cold ANS
  34. differential diagnosis in PD
    respond to meds?
  35. how are Lewy bodies labeled?
    • polyclonal alpha synuclein antibody NAC-1
    • about 20um
  36. basal ganglia
    • group of nuclei in deep part of cerebrum and upper brain stem (contains SN)
    • coordinates muscle actions and voluntary movements
    • controls planning and execution of complex motor strategies
    • cognitive functions (memory)
    • structural defects and NT imbalance (movement disorders hypokinesia or hyperkinesia)
  37. what does a group of nuclei describe?
    compact cluster of neurons
  38. where does lewy bodies begin?
    • pathology begins in olfactory bulb and lower brainstem (premotor symptoms like loss of smell and REM sleep behavior disorder)
    • confined to neurons
  39. how does LB pathology spread?
    • ascends from lower brain stem to midbrain and dopaminergic neurons (onset of motor phase with rigidity, tremor and bradykinesia)
    • then ascends to affect cortex (outer layer of cerebrum) to exhibit cognitive dysfunction and dementia)
  40. LBD
    • second most common neurodegenerative after AD
    • hallucinations, fluctuating cognition and parkinsonism
    • repeated falls, syncope, Autonomic dysfunction
  41. what percentage of PD patients develop dementia?
  42. when does LBD occur?
    concomitantly with or before development of parkinsonian signs
  43. treatment for LBD
    cholinesterase inhibitors (Aricept B, Exelon B)
  44. alpha synucleinopathies
    • pd
    • DLB
  45. alpha synuclein
    • SNCA gene (neuronal protein localized to nucleus and in pre-synaptic termini), in mito inner membrane and cytosol
    • 3 isoforms (140, 126, 112 aa)
    • amphipathic N-term, central is hydrophobic, highly acidic/pro-rich (neg at C)
    • binds plasma membranes
  46. what is the form of alpha-synuclein
    • native tetramer (alpha helix) stabilized by DA
    • without DA (protofibril, b-sheets), into fibril or toxic pore
  47. what kind of mutations cause bad alpha synuclein
    • autosomal dominant causes overexpression from a53t
    • familial PD
  48. LRRK2
    leucine rich repeat kinase 2 (autosomal dominant), glycine to serine (alpha syn patholyg, lewy bodies and lewy neurites)
  49. autosomal recessive form
    • ARJP Autosomal recessive juvenile parkinsonism
    • onset is less than 40 yo
    • parkin, PINK1, DJ-1 (mitochondiral dysfunction)
  50. two strongest risk factors from GWAS
    vairants in SNCA and MAPT (micortuble associated protein tau-late onset)
  51. parkin
    an E3 ubiquitin ligase, catalyzes the transfer of ubiquitin, not degraded than bad
  52. size of lewy body
    unbranched 200-600 nm length, 5-10nm in width
  53. genetic risk factors for PD
    • SNCA
    • MAPT
    • beta-glucocerebrosidase (GBS) mutations (accumulation of glucocerebroside)-->causes Gaucher's disease (dysfunction in lysosome)
  54. substantia nigra
    • major origin of dopaminergic innervation of the striatum
    • processes information coming from cortex to striatum, returning back to cortex through thalamus
  55. extrapyramidal system
    • part of the motor system that control involuntary movement
    • degeneration of dopaminergic neurons decrease thalamic input to motor area of cortex (rigidity and bradykinesis)
  56. what is a major function of the striatum
    regulation of posture and muscle tone
  57. lewy body pathology, how can it be detected?
    • alpha synuclein mutations in familial PD
    • alpha synuclein immunoreactivity (brainstem and cortical lewy bodies, lewy neurites)
  58. Braak stages
    • 1.dorsal motor nucleus vagus (GI dysfunction)
    • 2. sleep wake
    • 3. SNpc, amygdala (dysosmia, motor dysfunction)
    • 4. mesocortex (neurocognitive change, dysautonomia)
    • 5. depigmentation of SN, prefrontal (mild dementia, hallucinations, motor impair)
    • 6. neocortex (dementia, marked motor impair)
  59. when was DA found
    • 1950 present in mammalian brain, highest levels in striatum
    • 1960 Hornykiewica (levels of DA reduced in PD)
  60. DA and PD
    PD symptoms came when 50-60% of DA neurons in SN and 70-80 of striatal are lost
  61. what needs to be balanced in basal ganglia
    • NT (dopamine and acetylcholine)
    • to regulate posture, muscle tone and voluntary movement
    • inhibition of DA->greater cholinergic activity
    • in PD, lack of DA, increased acetylcholine
  62. what are the aims of anti-parkinson's drugs?
    to increase levels of dopamine or to inhibit the actions of acetylcholine in brain
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PD 2
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