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3/3 PD Case

PD Case

QuestionAnswer
What are the signs & symptoms of PD? TRAP: Tremor (resting), cogwheel Rigidity, Akinesia, & Postural instability You are TRAPped in your body!!
What is the classic triad for PD? TRA: Sx are variable, but the classic triad is Tremor, Rigidity, & bradykinesia (or Akinesia). The 4th cardinal sign is Postural instability, but it usually develops after 8+ years.
Describe the typical asymmetric onset. Usually starts as a resting tremor in an upper extremity usually 4-6Hz.
What is a resting tremor? Usually involves hands in “PILL-ROLLING” mvmt. Disappears during sleep, diminishes during voluntary mvmt & increases during emotional stress. Can begin intermittently at 1st.
Describe the rigidity typically associated w/ PD. PLASTIC/LEAD-PIPE or COGWHEEL
Describe bradykinesia. Signs inc. - HYPOMIMIA: decreased blinking, expressionless face. NO ARM MVMTs when walking. MICROGRAPHIA: small handwriting. HYPOPHONIA: soft voice
What are some common non-specific initial Sx for PD? Fatigue, depression, constipation, & sleep problems. Sometimes decreased dexterity & coordination. Some have aching/tightness in calf/shoulder. Affected arm may not swing when walking, same side foot may drag, strides may become shorter.
What are some common Sx that occur later in PD? Decreased swallowing, dementia, start hesitation, postural instability.
How is PD diagnosed? Clinical diagnosis. Neuro exam gold standard. Confirm w/ response to dopamine therapy.
What are the best predictors for PD? Asymmetry, presence of resting tremor, good response to dopamine therapy.
Name some important epidemiological facts about PD. 1.5x more common in men. Incidence & prevalence increase with age. Mortality is 2.5x greater than non-affected individuals of same age.
What are common findings on cerebral autopsy of pts w/ PD? Mild frontal atrophy, Pallor of substantia nigra (SN), Lewy bodies.
What causes pallor of the SN? Loss of pigmented dopaminergic neurons in SN. (Usually in ventral lateral SN. ~60-80% lost b/4 onset of motor signs.)
What are Lewy bodies made of? All Lewy bodies stain + for ALPHA-SYNUCLEIN b/c it's the major structural component, & most also stain + for UBIQUITIN.
What are Lewy bodies? “Concentric, eosinophilic, cytoplasmic inclusions with peripheral halos & dense cores.” Not specific for PD as they occur in other disorders.
What's the biochemical consequence of the loss of dopaminergic cells in the SNpc? “Gradual denervation of the striatum”, which = main tgt projection for SNpc neurons. Main cause motor sx = “dopamine denervation” of tgt areas. Sx may devo when striatum depleted to 50-70% of normal.
What's the main cause of motor sx in PD? DOPAMINE DENERVATION of the tgt areas. Sx may devo when depletion of striatum reaches 50-70% of normal.
What causes dopaminergic cell death? A combination of factors including: genetic vulnerability, oxidative stress, proteosomal dysfunction, environmental factors.
What 4 genes are clearly linked to familial PD? Autosomal dominant form (early onset, rapid sx devo): PARK1 (encodes alpha synuclein), PARK5 (encodes UCH L1). Autosomal recessive form (juvenile & other atypical): PARK2 (encodes parkin) & PARK7.
How can oxidative stress lead to PD? Can cause aggregation of alpha-synuclein & proteosomal dysfunction.
What are some endogenous sources of oxidative stress? FRs produced by dopamine & melanin metabolism. Defects in mitochondrial complex I of oxidative phosphorylation chain.
What are some oxidative toxins that are sources of oxidative stress? MPTP: a derivitive of meperidine; exposure by self-injection. Rotenone: a commonly used insecticide that causes oxidative stress in vitro.
What's the prognosis of PD patients? Not so good.Tx will take care of most symptoms for awhile, but degeneration will continue. Mortality is 2-5x as high compared to non-affected peers of same age.
What are the 5 most used drugs for PD? BALSA: Bromocriptine, Amantidine, L-dopa, Selegiline, Antimuscarinics.
What is Bromocriptine? A dopamine receptor agonist (stimulates dopamine receptors). Reduces the need for L-dopa, which decreases on/off phenomenon & motor complications.
What is Amantidine? It may increase dopamine release or inhibit reuptake. Helps w/ rigidity & bradykinesia.
What is L-dopa? Converts to dopamine in the CNS.
What is Selegiline? Prevents dopamine breakdown. Selective MAO type B inhibitor.
What is an Antimuscarinic? Curbs excess cholinergic activity. Improves tremor & rigidity, but has little affect on bradykinesia. Ex. Benztropine.
What is the problem with carbidopa/levodopa therapy? Honeymoon period ~10 years. Then on/off b/c medicine half life is shortened. Above therapeutic window - odd mvmts (on). Below therapeutic window - no effect (off). As disease progresses therapeutic window shortens. Slow release meds improve 1/2 life.
What are D1 & D2 receptors? Dopamine receptors. D1: STIMULATED by dopamine. D2: INHIBITED by dopamine.
What do neurons with D1 receptors do? When STIMULATED by dopamine, neurons with D1 receptors INHIBIT the GPi & SNr. (They inhibit the internal Globus Pallidus (GPi) & the Substantia Nigra Reticulata (SNr).)
What do neurons with D2 receptors do? When INHIBITED by dopamine, neurons with D2 receptors INHIBIT the GPe. (They inhibit the external Globus Pallidus (GPe).)
What is the result of a dopamine decrease from the SNpc as seen in PD? Less inhibition of the GPi & SNr & more inhibition of the GPe. Overall effect = decreased output from the thalamus & inhibition of the brainstem.
What is the result of excessive inhibition of the thalamus & brainstem? Suppression of the cortical motor system, possibly resulting in akinesia, rigidity, & tremor, whereas the inhibitory descending projection to brain-stem locomotor areas may contribute to abnormalities of gait & posture.
How does L-dopa work? L-dopa xes BBB, dopamine can't. Dopa decarboxylase converts it to dopamine. Changes the dopamine-ACh balance to improve nerve impulse ctrl. Feedback inhibition decreases endogenous dopamine produxn. Tx becomes counterproductive w/ time.
How does Carbidopa work? Keeps levodopa from converting to dopamine before it xes the BBB. It is a noncompetitive decarboxylase inhibitor.
What are COMT inhibitors? They decrease on/off syndrome by keeping COMT from putting a methyl group on its substrates (like dopamine) so that they're more available in the CNS. Ex. Entacapon, Tolcapone.
Describe the surgical options for late-stage PD. For late stages of PD that do not respond to drug therapies. Tx goal = inhibit neurons in the GPi & in the SNr.
Describe Deep Brain Stimulation. High freq bilateral stim of subthalamic nuclei or GPi may decrease sx & has a lower morbidity than lesion surgery.
Describe lesion surgery for PD Tx. Place a lesion in the basal ganglia (globus pallidus) or thalamus and stimulate electrodes in the subthalamic nucleus for chronic problems.
What is Amitriptyline? A tricyclic antidepressant. MoA: converted into notriptyline; decreases reputake of NE and serotonin. Also used to improve sleep patterns and nerve pain.
What structures make up the basal ganglia? Basal Ganglia – Caudate, Putamen, GP, SN, & STN (subthalamic nucleus). Receive Input signals from the Cortex & send their output signals back to the Cortex ultimately.
Describe the blood supply of the basal ganglia. Blood supplied by Circle of Willis: Ant. Cerebral A - Head of Caudate Nuc & Nuc Accumbens (where Caud. N. & Put. merge), Mid Cerebral A – Caudate & Putamen, Post Cerebral A & Post Communicans – STN & SN, Ant Choroidal A. – GP.
What is the function of the basal ganglia? MODULATE CORTICAL OUTPUT (monitor Motor Ctrl). 1. CTRL COMPLEX MOTOR ACTIVITY – posture, automatic mvmts, skilled mvmts of trunk, limbs, & eyes. 2. COGNITION -execute learned motor sequences –ex See Lion - 1. turn around 2. run.
How does the basal ganglia control the thalamus? GP & SNr = principle output structures that send inhibitory projections to the thalamus (using GABA). Thalamocortical projections are excitatory (glutamate). The GP influences thalamic axn on the cerebral ctx by changing inhibition levels.
Describe the Major Direct Pathway. Cortex—Striatum—Globus pallidus—Thalamus—Cortex.
Describe the Indirect Pathway. GPe-STN-GP-Thalamus-Cortex
What are the signs of a problem or lesion of the GP? Athetosis: continuous writhing movements of hand, arm, neck, or face.
What are the signs of a problem or lesion of the Subthalamus? Hemiballismus: sudden flailing movements of an entire limb.
What are the signs of a problem or lesion of the Putamen? Chorea: flicking movements of hands, face and other body parts
What are the signs of a problem or lesion of the SN? PD: rigidity, akinesia, and tremors
What are the signs of a problem or lesion of the Caudate Nucleus & Putamen? Huntingtons disease
What 2 circuits make up the motor system? PYRAMIDAL system (from cerebral ctx): influence motor fxn thru CORTICOBULBAR & CORTICOSPINAL pathways. EXTRAPYRAMIDAL system: All other projection paths that influence motor ctrl (BG & Cerebellum)- Rubrospinal, Reticulospinal, Vestibulospinal tracts.
What are the cerebral ctx motor areas made up of? Primary motor ctx & motor association areas.
What structures make up the primary motor ctx & what does it do? PRECENTRAL GYRUS & PARACENTRAL LOBULE OF FRONTAL LOBE - Brodmann’s area 4. Involved in simple, localized axn; the R motor strip ctrls L side of body, & vice versa.
Describe the motor association areas. PREMOTOR CTX lies ant to primary motor ctx (Brodmann’s area 6) - it orients muscles & prepares them for axn. SUPPLEMENTARY MOTOR AREA - the most medial part of Brodmann’s area 6 - it ctrls organization of muscle recruitment.
How do the cerebellum & the BG work together? The cerebellum & basal ganglia act primarily by affecting the motor & premotor cortices.
Describe the functions of the cerebellum. Balance coordination, motor planning, execution, modulation, & learning; prevents clumsy movements. Controls movement to ipsilateral extremities.
Describe the cerebellar folia. Folia: folds covering cerebellar ctx (gray matter); inside are 4 paired deep cerebellar nuclei in white matter. Lateral to medial they are Dentate, Emboliform, Globose, & Fastigial (“Don’t Eat Greasy Foods”). Emboliform + Globose nuc = Interposed Nuclei.
Describe the general function of the cerebellar peduncles. 3 cerebral peduncles connect fibers from cerebellum to the brain stem & the rest of the nervous system.
Name & describe the 3 cerebellar peduncles. INFERIOR mainly contains afferent fiber paths. MIDDLE contains afferent fibers from the contralateral pontine nuclei of the basal pons. SUPERIOR mainly has efferent fibers which travel to the red nucleus and thalamus.
Name the lobes into which the cerebellum can be divided (transverse division of the cerebellum). ANTERIOR lobe, POSTERIOR lobe, FLOCCULONODULAR lobe. Anterior Lobe –Primary Fissure => Posterior Lobe => Posterolateral Fissure => Flocculonodular lobe
What does the anterior lobe of the cerebellum do? ANTERIOR LOBE: receives input from SPINOCEREBELLAR and TRIGEMINOCEREBELLAR pathways.
What does the posterior lobe of the cerebellum do? POSTERIOR LOBE: is the largest part and receives input from the CEREBRAL HEMISPHERES.
What does the flocculonodular lobe of the cerebellum do? FLOCCULONODULAR LOBE: inferior, post appendage; receives input from VESTIBULAR NUCLEI (balance, posture, eye movement).
Name the longitudinal saggital zones of the cerebellum. VERMIS, PARAVERMAL/INTERMEDIATE ZONE, LATERAL ZONE
What does the vermis do? The VERMIS is in the middle & contains the FASTIGIAL NUCLEUS. It receives input from spinal cord & controls posture & eye movements.
What does the paravermal/intermediate zone of the cerebellum do? The PARAVERMAL/INTERMEDIATE ZONE is made of the INTERPOSED NUCLEI (aka. spinocerebellar region). Intermed Ant. lobe & Caudal part of Post. lobe get info from spinal cord to control posture & locomotion.
What does the lateral zone of the cerebellum do? The LATERAL ZONE (aka. cerebellar hemispheres) contains the DENTATE NUCLEI & receives input from cerebral cortex. Controls motor learning & finely coordinated movements of extremities.
Name the cellular divisions of the cerebellum. PIAL SURFACE, MOLECULAR LAYER, PURKINJE CELL LAYER, GRANULAR LAYER
Describe the molecular layer of the cerebellum. MOLECULAR LAYER: contains INTERNEURONS & DENDRITES of Purkinje cells
Describe the Purkinje cell layer of the cerebellum. PURKINJE CELL LAYER: contains Purkinje cells (dendritic trees of Purkinje cells run perpendicular to the parallel fibers).
Describe the granular layer of the cerebellum. GRANULAR LAYER: contains neurons of granule cells and Golgi type II cells.
What are Purkinje cells? Purkinje cells are the OUTPUT NEURONS of the cerebellum. They release GABA to inhibit the deep cerebellar nuclei.
What do the Mossy & Climbing fibers do? Mossy and Climbing fibers send inputs to the cortex to EXCITE PURKINJE CELLS (result is INHIBITED cerebellar nuclei).
Describe the Mossy fibers. Mossy fiber afferents are from spinal cord and pons; they use Glutamate as a NT and APs evoke simple spikes.
Describe the Climbing fibers. Climbing fiber afferents come from inferior olive and release Glutamate or aspartate; APs evoke complex spikes.
What are the 3 aminergic afferents & what do they do? 3 Aminergic afferents (noradrenergic, dopaminergic, and serotonergic fibers) inhibit Purkinje cells
What are the major afferent circuits that go thru the cerebellum? CEREBROCEREBELLAR, SPINOCEREBELLAR, & info from HYPOTHALAMUS.
Describe the cerebrocerebellar path. Cerebrocerebellar paths include CORTICOPONTOCEREBELLAR PATH (cerebrum => pons => contralateral side of cerebellum).
Describe the spinocerebellar paths. Info from skin, joints, and muscles of limbs and trunk go through dorsal, ventral, and rostral spinocerebellar paths.
Describe the efferent circuits of the cerebellum. Efferent Circuits of the Deep Cerebellar Nuclei go through Purkinje cells to different functional systems: VERMIS, INTERMEDIATE ZONE, & LATERAL ZONE (of posterior lobe).
Describe the efferent cerebellar circuits that come from the vermis. Vermis (Fastigial nucleus) => reticular and vestibular nuclei of brainstem => spinal cord => control posture and balance.
Describe the efferent cerebellar circuits that come from the intermediate zone. Intermed zone (Interposed Nuclei) => Superior Cerebellar Peduncle => Contralateral Red Nucleus (magnocellular division) => Rubrospinal tract axons cross midline => Spinal cord => locomotion and coordinated movements of extremities.
What efferent cerebellar circuits come from the lateral zone of the posterior lobe. Lateral Zone (Dentate & Interposed Nuclei) => Superior Cerebellar Peduncle => 3 following paths: Red nucleus, Ventral lateral thalamic nuclei, & Intralaminar thalamic nuclei.
Describe the efferent cerebellar circuit that comes from the lateral zone of the posterior lobe & goes thru the red nucleus. Lateral Zone (Dentate & Interposed Nuclei) => Superior Cerebellar Peduncle => Red nucleus (parvocellular division) => Rubro-olivary tract => inferior olivary nucleus.
Describe the efferent cerebellar circuit that comes from the lateral zone of the posterior lobe & goes thru the ventral lateral thalamic nuclei. Lateral Zone (Dentate & Interposed Nuclei) => Superior Cerebellar Peduncle => Ventral lateral thalamic nuclei=>Frontal lobe of ctx (fine, coordinated, learned mvmts).
Describe the efferent cerebellar circuit that comes from the lateral zone of the posterior lobe & goes thru the Intralaminar thalamic nuclei. Lateral Zone (Dentate & Interposed Nuclei)=> Superior Cerebellar Peduncle => Intralaminar thalamic nuclei => cerebral ctx (mult. cognitive processes)
What side of the body does the R side of the cerebellum affect? R cerebellar hemisphere influences R side of body (symptoms are unilateral to lesion in cerebellum). This is the opposite of cerebral lesions which produce contralateral effects.
Compare the cerebellum to the cerebral cortex. The cerebellum maintains the fine control and coordination of both simple and complex movements.The cerebral cortex influences motor function directly (unlike the cerebellum and basal ganglia).
How is ACh synthesized? Acetyl-CoA + Choline --Choline Acetyltransferase (ChAT)--> Acetylcholine
Where is ACh synthesized? In the axon terminal.
What limits the synthesis of ACh? INTRACELLULAR [CHOLINE]: which is determined by uptake of choline into the nerve ending.
How is ACh stored? Stored in VESICLES w/ ATP & proteoglycans.(Transported into storage vesicles after synthesis in the nerve ending. Uptake into the vesicle is driven by a proton-pumping ATPase)
Describe ACh catabolism. ACh --acetylcholinesterase(AChE)--> acetate + choline (AChE is found in the synaptic cleft)
Where is AChE found? SYNAPTIC CLEFT: AChE is concentrated in the motor end-plate; in close proximity to the receptors.
Describe ACh recycling. ~½ of the choline that is released from degradation of ACh is taken back to the presynaptic terminal to be reused to make new ACh.
How is GABA (γ-aminobutyric acid) synthesized? GABA synthesis is closely related to the TCA cycle. Glutamate → GABA by glutamate decarboxylase using Vit B6 as a cofactor.
How is GABA stored? Transported into synaptic vesicles by vesicular GABA transporters (VGATs).
Describe GABA catabolism. GABA is inactivated after active transport into astrocyte glial cells. Astrocytes contain GABA-TRANSAMINASE that catalyzes GABA → SUCCINATE SEMIALDEHYDE. GABA can also be reused if reuptake into the nerve terminal occurs.
Describe an essential tremor. Postural tremor affecting arms & head; ↑ with stress, fatigue, stimulants; ↓ with alcohol; manifests during volitional movement & disappears when at rest; often bilateral; early onset; lack of other neurologic signs.
Describe Wilson's Disease. Inborn error in COPPER METABOLISM ; early onset (11-25); chronic hepatitis (jaundice); ascites; muscle spasms; rigidity; intentional tremor w/ wingbeating mvmt of arm.
Describe Diffuse Lewy Body Disease. Onset 60-80; visual hallucinations; fluctuating cognition (dementia); spontaneous motor features (like in PD); repeated falls; syncope; delusions; low glucose metabolism in ctx; incomplete response to L-dopa; marked intolerance to neuroleptic drugs.
Describe Huntington's Disease. Rigidity & chorea gradually replaced by dystonia & bradykinesia. Cognitive decline & dementia. Late onset.
Describe Normal Pressure Hydrocephalus. Ataxia; Dementia; Mental status changes; Urinary incontinence. Gait & postural instability as in PD. CT, MRI, & LP show hydrocephalus.
Describe Multi-system Atrophy. Autonomic & Urinary dysfxn; cerebellar dysfxn; corticospinal dysfxn; parkinsonism. Subsets inc. Shy-Drager syndrome & striatonigral degeneration.
Describe Progressive Supranuclear Palsy. MC Parkinson-plus syndrome; onset 50-60; Rigidity, Bradykinesia; severe Postural instability; Dysphagia, Dementia; Dysarthria; Dystonia of neck & shoulders; loss voluntary Eye ctrl; tremor is rare; responds poorly to anti-parkinsonian drugs.
Describe Cortical-Basal Ganglionic Degeneration. Positive Babinski; Cortical sensory loss; Apraxia; Dystonia; Aphasia; Dementia; no autonomic disturbance. Tremor; Rigidity; Bradykinesia; Postural disturbances.
Describe Creutzfeldt-Jakob Disease. Fatal degenerative brain disorder; onset around 60; dementia; cognitive impairment, hallucinations; speech impairment; cerebellar dysfxn; ataxia; changes in gait; myoclonic jerking; rigidity.
Describe sx that point more to drugs than PD. Tremor; rigidity; bradykinesia; often BILATERAL SX; NORMAL CT/MRI; symptoms may persist for UP TO 1 YR after drug discontinuation.
Describe depression sx that may be confused w/ PD. HYPOMIMIA; HYPOPHONIA; reduction in voluntary activity; may coexist with parkinsonism.
Describe a normal prostate on rectal exam. Should feel like a pencil eraser (firm, smooth, slightly movable). Nontender. 4 cm diameter with < 1 cm protrusion into rectum. 2 symmetrical lateral lobes separated by a median sulcus.
Why is the PSA test controversial? PSA IS SPECIFIC TO THE PROSTATE BUT NOT TO PROSTATE CA. Produced by all types of prostate tissue whether healthy or not. There is no data indicating that screening decreases mortality from prostate CA.
Describe Plastic or Lead-Pipe Rigidity. Uniform t/o ROM imposed by examiner. C/b increased tone in all muscles. Strength is nearly normal. Reflexes not particularly affected.
Describe Cogwheel Rigidity. Interrupted by a series of brief relaxations. Strength is nearly normal. Reflexes not particularly affected.
Created by: 16813610