PD 2

postural hypotension: low blood pressure when you stand up from sitting

increase in saliva

impaired g.i. motility, bladder dysfunction, orthostatic hypotension, excessive head and neck sweating

mild to moderate in 50% of patients

impaired visual spatial perception and attention, slowness in executive in motor tasks, impaired concentration

• 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

• 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)

• rigidity without tremor in many patients
• when clinician moves a rigid joint, sudden, rhythmic jerks due to variations in intensity of rigidity occur.

• slow movements typical as rigidity progresses, along with hypokinesia and akinesia
• rigidity and hypokinesia contribute to muscular aches and fatigue

• involuntary relaxation of facial muscles (masked facies)
• open mouth, drooling and reduced blinking
• may appear depressed

• hypophonic (soft speech)
• monotonous, stuttering dysarthria (poor articulation)

without warning, voluntary movement, such as walking may suddenly halt

due to hypokinesia and impaired control of distal musculature

gait abnormalities due to loss of postural reflexes, more common in late stages

• 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

• occurs late in disease (15-30% of patients)
• short term memory and visuospatial function may be impaired
• aphasia not present

loss of ability to understand or express speech

• cognitive dysfunction within a year of onset of motor features, marked by cortical Lewy bodies
• hallucinations and muscle ridigity

• 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

• 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

memory of meanings, understandings, other concepts-based knowledge impaired (meaning in language or logic)

• dysarthric
• word list generation, reduced sentence length and comprehension
• intact naming until late stage

motor symptoms of PD

• 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

hard to swallow (dysphagia)

• decrease in odor detection
• urinary hesitancy and/or urgency

an autonomic sign: scaly, flaky, itchy, red skin

• 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

stained by acidic dye eosin

• Lewy bodies (in cell soma)
• lewy neurites (in axons and nerve terminals)

• 1912 Friedrich Lewy
• inclusions in SNpc
• LB filled with alpha-synuclein
• no standard criteria for neuropathological diagnosis of PD

sudden drop in blood pressure

hot and cold ANS

respond to meds?

• polyclonal alpha synuclein antibody NAC-1
• about 20um

• 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)

compact cluster of neurons

• pathology begins in olfactory bulb and lower brainstem (premotor symptoms like loss of smell and REM sleep behavior disorder)
• confined to neurons

• 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)

• second most common neurodegenerative after AD
• hallucinations, fluctuating cognition and parkinsonism
• repeated falls, syncope, Autonomic dysfunction

40%

concomitantly with or before development of parkinsonian signs

cholinesterase inhibitors (Aricept B, Exelon B)

• pd
• DLB

• 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

• native tetramer (alpha helix) stabilized by DA
• without DA (protofibril, b-sheets), into fibril or toxic pore

• autosomal dominant causes overexpression from a53t
• familial PD

leucine rich repeat kinase 2 (autosomal dominant), glycine to serine (alpha syn patholyg, lewy bodies and lewy neurites)

• ARJP Autosomal recessive juvenile parkinsonism
• onset is less than 40 yo
• parkin, PINK1, DJ-1 (mitochondiral dysfunction)

vairants in SNCA and MAPT (micortuble associated protein tau-late onset)

an E3 ubiquitin ligase, catalyzes the transfer of ubiquitin, not degraded than bad

unbranched 200-600 nm length, 5-10nm in width

• SNCA
• MAPT
• beta-glucocerebrosidase (GBS) mutations (accumulation of glucocerebroside)-->causes Gaucher's disease (dysfunction in lysosome)

• major origin of dopaminergic innervation of the striatum
• processes information coming from cortex to striatum, returning back to cortex through thalamus

• part of the motor system that control involuntary movement
• degeneration of dopaminergic neurons decrease thalamic input to motor area of cortex (rigidity and bradykinesis)

regulation of posture and muscle tone

• alpha synuclein mutations in familial PD
• alpha synuclein immunoreactivity (brainstem and cortical lewy bodies, lewy neurites)

• 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)

• 1950 present in mammalian brain, highest levels in striatum
• 1960 Hornykiewica (levels of DA reduced in PD)

PD symptoms came when 50-60% of DA neurons in SN and 70-80 of striatal are lost

• 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

to increase levels of dopamine or to inhibit the actions of acetylcholine in brain