Clinical Movement Disorders II - Parkinson Disease Flashcards
Parkinson’s Disease
Cardinal motor signs
Cog-wheel rigidity- a change in tone
Bradykinesia- slowness of movement
Hypokinesia- reduction in movements, reduction in amplitude of movement
Resting tremor- classically 4-6 Hz pill-rolling tremor (70% of patients)
Postural instability- flexed posture, festination and retropulsion
Parkinson’s Disease
Age/assoc with/how does it begin
(i) Mean onset age is 55-60 years, rare below 30 years. Prevalence is up to 4% of the elderly, 1-2% among persons over 65 years old.
(ii) Begins unilaterally and remains asymmetric
(iii) Associated with dementia, depression, and other cognitive changes (up to 65% of patients).
Parkinson’s Disease
Autonomic Dysfunction
Autonomic dysfunction including constipation, urinary problems (especially nocturia), orthostatic hypotension (light-headedness), impotence, temperature regulation, swallowing problems (dysphagia)
Parkinson’s Disease
Anosmia
Anosmia (loss of sense of smell) is common, pain and sensory disturbances can also occur
PD
Sleep disorders
Sleep disorders including insomnia, frequent awakenings, sleep apnea,
periodic limb movements, REM sleep behavioral syndrome (disinhibited movements related to dream activity, which can sometimes be violent), hypersomnia (excessive sleep)
PD
Non-motor sx
May precede onset of motor sx
PD
pathology
Loss of neurons from specific nuclei in the brain and elsewhere, particularly dopamine producing neurons for the substantia nigra pars compacta. At least 50% of the dopaminergic terminals in the striatum are lost before motor symptoms appear.
Neural degeneration with gliosis and Lewy body formation in ventral mesencephalic tegmental neurons
PD
Which neurons are affected
Substantia nigra- pars compacta (dopamine) Nucleus paranigralis (dopamine) Vagal dorsal motor nucleus (norepinephrine) Locus ceruleus(norepinephrine) Nucleus basalis of Meynert (acetylcholine) Nucleus accumbens (serotonin)
PD
Braak Stages
Detailed neuropathologic studies have suggested that α-synuclein related pathologic changes first appear in the medulla, affecting the dorsal motor nucleus of the glossopharyngeal and vagal nerves and also in the anterior olfactory nucleus, then ascend in the brainstem through the medulla, pons, then midbrain and eventually through the mesocortex and neocortex.
Symptoms related to degeneration of midbrain dopaminergic neurons first become apparent when the disease is in Braak stage 3. Signs and symptoms once thought to be risk factors for PD, such as anosmia, depression and constipation are likely early signs of the illness relating to lower brainstem and olfactory nucleus pathology.
PD
Evidence favoring an environmental cause
(a) MPTP and different putative neurotoxins in the environment have been demonstrated to damage dopaminergic neurons
(b) ALS/PDC of Guam occurs in the pacific rim area only, is likely due to a dietary toxin
(c) Case-control studies show rural life increases risk of PD
(d) Twin studies provide little evidence for a purely genetic basis: monozygotic twins are usually discordant for PD
Familial parkinson’s disease
(a) Not clinically typical Parkinson’s disease in most instances
(b) Parkinson’s disease susceptibility gene first identified on chromosome 4
(c) Mutation in α-synuclein gene described in some patients
α-synuclein mutations
chars
Two mutations have been identified, Ala53Thr and Ala30Pro
The gene is located in the long arm of chromosome 4
Autosomal dominant inheritance
Young onset (40’s), faster progression than typical idiopathic Parkinson’s
Levodopa responsive
Patients have Lewy bodies
Synucleins
Gen chars
(a) Synucleins are small highly conserved proteins in vertebrates (113-143 aa)
(b) Synucleins are abundant in neurons and enriched at presynaptic terminals
(c) Synucleins have a large amphipathic domain capable of reversible binding to lipid vesicles
(d) Synucleins may serve to integrate presynaptic signaling and membrane trafficking
α -synuclein in neurodegenerative disease
(a) α-Synuclein is the major component of Lewy bodies, and is also found in Lewy neurites and pale bodies
(b) α-Synuclein accumulates in cytoplasmic inclusions in neurons and oligodendrocytes in multiple system atrophy
(c) A 35 amino acid fragment of α-Synuclein is ~10 % of the protein in extracellular amyloid plaques in Alzheimer’s disease
α-synuclein function
α-Synuclein complexes with the presynaptic human dopamine transporter
α-Synuclein facilitates the membrane clustering of the dopamine transporter
α-Synuclein allows functional enhancement of cellular dopamine uptake
Transgenic mice over expressing a-synuclein have an increased density of the dopamine transporter (DAT) in the striatum
Parkin gene
Gen chars/chars of disease
(a) The 500 kb gene is located in the long arm of chromosome 6
(b) Autosomal recessive inheritance
(c) Early onset (20’s), slow progression
(d) Levodopa responsive
(e) Patients do not have Lewy bodies
(f) Functions as an E3 ubiquitin ligase and regulator of the proteasome
Leuicine-Rich repeat kinase 2 (LRRK-2)
Gen chars
(a) Dominant mutations of LRRK2 are the most common cause of inherited PD
(b) Most cases of LRRK2-related PD are clinically and pathologically indistinguishable from the idiopathic disease
(c) LRRK2 contains both GTPase and kinase domains
(d) Definitively pathogenic mutations have been identified in the GTPase and kinase domains, as well as the region between these domains
(e) Only 30-40% penetrance for some mutations
PTEN-Induced Kinase 1 (PINK1)
Gen chars
(a) PINK1 contains a serine/threonine protein kinase domain
(b) An N-terminal mitochondrial targeting sequence localizes the protein to mitochondria
(c) Mutations are found throughout the protein, although missense mutations are commonly found in the kinase region
(d) PINK1 overexpression protects against oxidative and apoptotic stressors in a kinase-dependent manner
(e) PINK1 loss-of-function appears to promote PD-related neurodegeneration
Other chromosomal locations associated with parkinson’s disease and parkinsonian diseases
Look Up
The Proteasome connection to PD
(a) α-Synuclein is ubiquitinated in Lewy Bodies
(b) Parkin is an E3 ubiquitin ligase and regulator of the proteasome
(c) UCHL1 = Ubiquitin C-terminal Hydrolase 1
(d) All of the mutants of DJ-1 found in Parkinson’s disease patients are degraded, in part, by the proteasome system
Current status of etiology of PD
(a) Epidemiologic studies continue to support a multifactorial model combining both environmental and genetic factors
(b) Twin studies continue to indicate that genetic factors do not play a major role in Parkinson’s disease presenting after age 50
(c) Identified genetic causes of Parkinson’s disease most likely enhance susceptibility to environmental factors
Drugs most commonly used to tx PD
Levodopa, with peripheral decarboxylase inhibitors: carbidopa (sinemet), benserazide (madopar)
Dopamine agonists: bromocriptine, pergolide, ropinirole, pramipexole, rotigotine
MAO-B inhibitors: selegiline, amantadine, rasagiline
Anticholinergics: trihexyphenidyl, benztropine
COMT inhibitors: tolcapone, entacapone
Levodopa therapy in PD
Most efficacious symptomatic drug for PD
Increases quality of life
Increases survival
Long term use may be assoc with motor complications
Long-term complications of levodopa therapy
Motor Complications: 1) Motor Fluctuations End of dose “Wearing-off “ Unpredictable “On-Off” causes sudden akinesia Peak-dose dyskinesias, either chorea or dystonia Diphasic dyskinesia, chorea at dose onset & wearing off Mental Status Changes 1) Confusion 2) Hallucinations 3) Psychosis
PD
Surgical tx
(a) Deep brain stimulation (DBS) to the subthalamic nucleus (or in some cases the globus pallidus) is accepted treatment
(b) Stem cell and other implants remain experimental and have no advantage at this time
(c) Gene therapy using stereotactic injection of viral vectors carrying genes for neurotransmitter function or trophic factors is experimental but appears promising
Other causes of akinetic-rigid syndrome
list
a. Juvenile Huntington’s
b. Neuroleptic malignant syndrome
c. Neuroleptic extrapyramidal syndrome
d. Parkinson’s plus syndromes
Parkinsons plus syndromes
List
Multiple System Atrophies (MSA)
(a) Shy-Drager syndrome: Parkinsonism, ataxia and autonomic dysfunction
(b) Olivopontocerebellar atrophy (OPCA): Parkinsonism and cerebellar signs
(c) Striatonigral degeneration
Progressive Supranuclear Palsy (PSP): Parkinsonism, impaired eye movements, cervical dystonia
Corticobasal degeneration (CBD): Parkinsonism and apraxia, alien hand syndrome
