Movement disorders and dementia syndromes – 13 questions
● Discussthe pathology and pathophysiology of Parkinson’s Disease, Huntington’s
... [Show More] Disease, and Alzheimer’s
Disease.
o Parkinson’s Disease
■ Complex motor disorder accompanied by systemic nonmotor and neurologic symptoms
■ The main disease feature is degeneration of the basal ganglia (corpus striatum, globus
pallidus,subthalamic nucleus, and substantia nigra) involving the dopaminergic nigrostriatal
pathway
■ Pathophysiology:
The hallmark pathologic features of PD are loss of dopaminergic pigmented neurons
in the substantia nigra (SN) pars compacta with dopaminergic deficiency in the
putamen portion of the striatum
Dopamine loss in other brain areas including the brain stem, thalamus, and cortex
also occurs
Degeneration of the dopaminergic nigrostriatal pathway to the basal ganglia resultsin
underactivity of the direct motor pathway (normally facilitates movement) and
overactivity of the indirect motor loop (normally inhibits movement)
● Thisresults in inhibition of the motor cortex manifested with bradykinesia and
rigidity
The subthalamic nucleus(STN) overactivity also influencesthe limbic system,
accounting for emotional signs and symptoms
Neuronal loss within the cerebral cortex is found in half of individuals with PD
Lewy bodies, fibrillar intracellular eosinophilic inclusions, and high concentrations of
alpha-synuclein, ubiquitin, tau protein, tuberculin, and other proteins are found in
the substania nigra, locus coeruleus, and other areas of the brain they are a
marker for neuronal degeneration
Molecular eventsthought to be associated with neurodegeneration of PD include:
● Mitochondrial dysfunction
● Oxidative stress
● Abnormal folding and accumulation of alpha-synuclein
● Abnormal phosphorylation
● Dysfunction of the ubiquitin proteasome system (regulatesintracellular
protein processing)
o Huntington’s Disease
■ Also known as chorea is a relatedly rare autosomal dominant disease with high penetrance
■ The onset of HD is usually between 25-45 years of age
■ Pathophysiology:
The genetic defect of HD is on the short arm of chromosome 4
● There is an abnormally long polyglutamine tract in the huntingtin (htt) protein
that is toxic to neurons and is cause by a cytosine-adenine-guanine (CAG)
trinucleotide repeat expansion (40 to 70 repeats instead of the normal 9-34)
● Age of onset is related to the length of the repeat sequences and mechanism
of toxicity
● Repeat lengths greater than 60 cause the juvenile form of the disease
The principle pathologic feature of HD issevere degeneration of the basal ganglia
(striatum), particularly the caudate and putamen nuclei and the frontal cerebral
cortex
● The degeneration of the basal ganglia leaves enlarged lateral ventricles(box
car ventricles)
Expression of the huntingtin gene produces tangles of protein that collect in the brain
cells and chains of glutamine on the abnormal molecules that adhere to each other
The mechanism of neuronal death is unknown
The excitotoxic theory ofstriatal and cortical degeneration proposesthat the mutated
huntingtin protein produces excitotoxic pathways mediated by glutamate function
that also induce concomitant dysregulation of dopaminergic function
The huntingtin protein also may alter mitochondrial function, which in turn activates
apoptotic pathways and causes neuronal death.
Neurotrophic factors also may be depleted, leading to loss of neurons
Basal ganglia and nigral depletion of GABA isthe principle biochemical alteration in
HD [Show Less]