Resting tremor (RT), a classic motor symptom of Parkinson's disease (PD), is linked to the integrity of dopaminergic terminals in the caudate nucleus, according to a study by NOVA University Lisbon. Researchers analyzed DaT-SPECT and inertial sensor data from 432 individuals, identifying that patients with RT have a higher caudate binding ratio (CBR), which is correlated with tremor amplitude and symptom development.
Rest tremor (RT) is one of the main motor symptoms of Parkinson's disease (PD), characterized by involuntary movements that occur at a frequency of 4â6 Hz when the person is at rest.
Despite being a classic symptom, it is extremely variable: it does not affect all patients, occurs in different parts of the body, can vary in intensity, and is influenced by factors such as stress. In addition, the pathophysiology of RT is more complex than other motor symptoms of PD, making it a challenging topic to study.
Dopamine (DA) plays a central role in PD, but its relationship to TR is not straightforward. Although dopamine loss is necessary for TR to occur, many PD patients have TR that does not improve with dopamine replacement therapies, or even worsens. This discrepancy suggests that factors other than dopamine are involved.
Neuropathological research has identified a greater loss of dopaminergic neurons in the retrorubral area (A8) in TR patients. These neurons project to the globus pallidus (GP), a key region in the generation of TR.
According to the âdimmer switch hypothesis,â dopamine loss in this pathway triggers oscillations in the basal ganglia circuit, which are then propagated by the motor cortex to the cerebellothalamic circuits. These cerebellothalamic circuits amplify and maintain the tremor.
Schematic showing midbrain dopaminergic sources and major pathways to the striatum and cerebral cortex. In particular, cortical pathways are incompletely characterized, and motor cortical regions may be innervated by both the VTA and the SNc. VTA, ventral tegmental area; SNc, substantia nigra pars compacta; NAcc, nucleus accumbens. Source: Per A. Alm. Front. Hum. Neurosci. Volume 15 - 2021.
Despite the relevance of this model, it does not fully explain clinical observations.
Molecular imaging studies using DaT-SPECTâa technique that uses a radiotracer to measure the integrity of dopamine transporters (DaT)âhave shown conflicting results in patients with PD and TR.
Some studies report increased DaT binding in the caudate and putamen, while others show reduced binding, especially in the caudate.
This variability can be attributed to factors such as small sample sizes and retrospective methods. Therefore, it is necessary to refine the approach to reduce the heterogeneity of the results.
Researchers from NOVA University Lisbon conducted a comprehensive study to investigate the role of dopamine in the development of RT. They used a large dataset from the Parkinsonâs Progression Markers Initiative (PPMI), as well as additional cohorts of PD patients and healthy controls, totaling 432 individuals.
In addition, the researchers incorporated inertial sensors to capture detailed data on motor oscillations.
They used DaT-SPECT imaging, which is a technique used to measure the integrity of dopaminergic terminals in the caudate and putamen. In addition, devices were used to capture oscillations of 4â6 Hz, corresponding to the typical frequency of RT.
Finally, imaging and sensor data were integrated to understand the relationship between the integrity of dopaminergic terminals and RT.
Example of SPECT imaging of the dopamine transporter in Parkinson's disease. Source: ĂMÄ°T ĂZGĂR AKDEMÄ°R et al. Turk J Med Sci (2021) 51: 400-410.
The results showed that patients with TR had a higher caudate binding ratio (CBR), but not a higher CBR in the putamen. Thus, a higher baseline CBR was associated with the development of TR over time.
Inertial sensor data correlated with TR amplitude and distinguished patients with reduced DaT binding from healthy controls.
In silico models indicated that CBR plays a significant role in the generation of TR, reinforcing the idea that the integrity of the caudate is a central feature of TR.
The results suggest that the integrity of dopaminergic terminals in the caudate is directly linked to TR, offering new insights into its pathophysiology. Furthermore, the combined use of imaging and inertial sensor technologies proves to be a promising approach to unravel the mechanisms underlying motor symptoms in PD.
This study advances the understanding of the role of dopamine in TR and highlights the importance of more accurate analyses based on large cohorts to reduce heterogeneity in clinical findings. The findings may have implications for the development of more targeted therapies for patients with PD and TR.
A) Patients enrolled in the PPMI study with MDS-UPDRS III tremor data in the off-state, available at Year 2 after enrollment (nâ=â432) were selected. Groups were defined by the presence or absence of TR. Data at baseline (Year 0) and 12 months later (Year 1) were also collected. B) Age at baseline in Tremor and Non-Tremor groups. C) Sex ratio at birth in Tremor and Non-Tremor groups. D) Caudate and putamen binding potential in Tremor and Non-Tremor groups at baseline and follow-up. E) Resting tremor (RT) scores. F) Action tremor scores. G) Rigidity scores. H) Bradykinesia scores.
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Relative sparing of dopaminergic terminals in the caudate nucleus is a feature of rest tremor in Parkinsonâs disease
Marcelo D. Mendonça, Pedro C. Ferreira, Francisco Oliveira, Raquel Barbosa, Bruna Meira, Durval C. Costa, Albino J. Oliveira-Maia & Joaquim Alves da SilvaÂ
npj Parkinson's Disease. volume 10, Article number: 209 (2024)
Abstract:
Resting tremor (RT) is a Parkinsonâs disease (PD) symptom with an unclear relationship to the dopaminergic system. We analyzed data from 432 subjects from the Parkinsonâs Progression Markers Initiative, 57 additional PD patients and controls, and 86 subjects referred for dopamine transporter single-photon emission computed tomography (DaT-SPECT). Caudate binding ratio (CBR), but not putamen binding ratio, was higher in RT patients. Furthermore, higher baseline CBR was linked to RT development. In the smaller cohorts, a 4â6âHz oscillation-based metric from inertial sensors correlated with RT amplitude, distinguished controls from patients with reduced DaT binding and correlated with CBR in the latter group. In silico modeling uncovered that higher CBR in RT patients explained correlations between RT and DaT-SPECT found in several datasets, supporting a spurious origin for ipsilateral correlations between CBR and RT. These results suggest that caudate dopaminergic terminal integrity is a feature of RT with potential pathophysiological implications.
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