Product information and disease description Place of product in therapy Disease description

Pathophysiology

9 evidence topics · 5 sources

Nigral dopaminergic neuron loss and Lewy pathology

“The neuropathological hallmarks of PD are the degeneration of dopaminergic neurons in the SN and intraneuronal protein aggregates called Lewy bodies and Lewy neurites” (opens the source at this quote in a new tab)
“It was long considered that 50–70% of SN dopaminergic neurons have died by the time that clinical motor symptoms become evident” (opens the source at this quote in a new tab)
“However, more recent work suggests that the loss of dopaminergic terminals in the basal ganglia, as opposed to loss of the neurons in the SN, is crucial for onset of motor symptoms” (opens the source at this quote in a new tab)

Time course of nigrostriatal degeneration after diagnosis

“Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis.” (opens the source at this quote in a new tab)
“In the substantia nigra pars compacta, there was a 50–90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter.” (opens the source at this quote in a new tab)
“Quantitative analyses revealed a 35–75% loss of tyrosine hydroxylase and dopamine transporter optical fibre density at Years 1–3 after diagnosis, ∼70–90% reduction by Year 5, and relatively little change thereafter.” (opens the source at this quote in a new tab)

Non-dopaminergic involvement

“However, PD is characterized by more widespread pathology in other brain regions and involves non-dopaminergic neurons as well.” (opens the source at this quote in a new tab)

“The loss of pigmentation correlates with neuronal loss of dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus ceruleus.” (opens the source at this quote in a new tab)
“The concept of as a “parkinsonism-plus” disorder has become increasingly muddled as it clear that most patients with PD also have nonparkinsonian clinical features, such as autonomic dysfunction, sleep disorders, and eventually dementia” (opens the source at this quote in a new tab)

Spread of alpha-synuclein pathology and Braak staging

“In a series of seminal studies, Heiko Braak and colleagues proposed that there are six stages of Lewy pathology in PD” (opens the source at this quote in a new tab)
“They suggested that in the first stages the Lewy pathology is limited to the dorsal motor nucleus of the vagal nerve, located on the medulla oblongata and the origin of the nerve fibers innervating the gut and other visceral organs, and the olfactory bulb and closely associated olfactory nucleus.” (opens the source at this quote in a new tab)
“The Braak staging model is based on post-mortem observations, and it has not been possible to obtain definitive proof that pathology spreads in accordance with the Braak stages” (opens the source at this quote in a new tab)
“Because these pathogenic alpha-synuclein assemblies can be transported intra-axonally to interconnected nuclei, prion-like behavior of alpha-synuclein assemblies might explain how Lewy pathology propagates from one brain region to another” (opens the source at this quote in a new tab)

Cellular mechanisms shared by genetic and environmental causes

“Environmental and genetic factors influence PD pathogenesis by impacting similar pathways, including mitochondrial function, oxidative stress, alpha-synuclein aggregation, and clearance pathways for abnormal proteins.” (opens the source at this quote in a new tab)

Striatal direct and indirect pathways and D1 and D2 dopamine receptors

“Dopamine has opponent affects on the function of these pathways due to the segregation of the D1- and D2-dopamine receptors in the spiny projection neurons giving rise to the direct and indirect pathways.” (opens the source at this quote in a new tab)
“The direct pathway originates from Drd1a-expressing SPNs that project to the GPi and SNr output nuclei.” (opens the source at this quote in a new tab)
“The indirect pathway originates from Drd2-expressing SPNs that project only to the external segment of the globus pallidus (GPe), which together with the subthalamic nucleus (STN) contain transynaptic circuits connecting to the basal output nuclei.” (opens the source at this quote in a new tab)
“Taken together these findings led to the proposal that in Parkinson’s disease the loss of striatal dopamine produces decreased activity in the direct striatonigral pathway and increased activity in the indirect pathway through the multisynaptic pathway through the GPe and STN to SNr.” (opens the source at this quote in a new tab)
“Imbalance in activity between these pathways, with activity in the indirect pathway predominating over the disinhibition of direct pathway activity required for the generation of movements was proposed to produce bradykinetic symptoms of Parkinson’s disease.” (opens the source at this quote in a new tab)

Basal ganglia oscillatory activity in the off state and in levodopa-induced dyskinesia

“The parkinsonian off-state is characterized by enhanced beta-band activity (~20 Hz) in local field potential recordings from the basal ganglia, which is suppressed by dopaminergic medication or DBS in parallel with the clinical improvement of bradykinesia and rigidity” (opens the source at this quote in a new tab)
“By contrast, hyperkinesia — such as l-DOPA-induced dyskinesia in Parkinson disease — has been associated with increased theta-band activity in the same structures (4–12 Hz)” (opens the source at this quote in a new tab)

Striatal pathway alterations underlying levodopa-induced dyskinesia

“In Parkinson’s disease dopamine depletion in the striatum produces physiologic alterations in both pathways responsible for L-DOPA induced dyskinesias (LIDs)” (opens the source at this quote in a new tab)

Presynaptic and postsynaptic mechanisms of levodopa-induced motor complications

“The key cause is discontinuous drug delivery due to the short half-life of l-DOPA and the variability in its gastrointestinal absorption and blood–brain barrier transport” (opens the source at this quote in a new tab)
“Mechanisms underlying l‑DOPA‑induced dyskinesias include presynaptic and postsynaptic mechanisms: the loss of dopaminergic nigrostriatal terminals leads to reduced presynaptic dopamine storage capacity and dysregulated dopamine release, whereas discontinuous delivery of l‑DOPA results in pulsatile activation of postsynaptic dopamine receptors.” (opens the source at this quote in a new tab)