Parkinson’s disease (PD) is a progressive neurological disorder known for its characteristic motor symptoms: rigidity, slowness of movement, and tremor. One of these, rest tremor (a shaking that happens when muscles are relaxed), is one of the most recognizable but least understood.
The relationship between rest tremor and dopamine — a chemical messenger critical for coordinating movement — is complex, but the full picture has remained a mystery, until a study from the Champalimaud Foundation published on January 24 in npj Parkinson’s Disease, led by the Neural Circuits Dysfunction Lab alongside the labs of Neuropsychiatry and Nuclear Medicine, provides fresh insights.
The dopamine paradox
A well-known hallmark of PD is dopamine loss in brain regions involved in regulating movement, such as the putamen. For PD patients, tremor is a common and debilitating symptom but has never been a perfect puzzle piece, says Marcelo Mendonça, one of the study’s authors.
“We know dopamine plays a role, but it doesn’t act as directly as it does with other motor symptoms”. Running counter to conventional wisdom, one would expect less dopamine linked with more severe symptoms. However, paradoxically, we found that patients who have tremors have more dopamine preserved in the caudate nucleus, a brain location involved in movement planning and cognition, explains Mendonça.
This study analyzed 432 Parkinson’s disease (PD) patients, investigating the association between resting tremor (RT) and caudate dopaminergic terminal integrity. At the 2-year follow-up, 66.4% of patients presented RT. Those with RT were older (62.8 ± 0.6 vs. 60.3 ± 0.8 years, P = 0.0158) but showed no significant sex differences. Patients with RT exhibited a higher caudate binding ratio (CBR) over time (Baseline: 0.143 ± 0.055, P = 0.009; Year 1: 0.179 ± 0.062, P = 0.008; Year 2: 0.183 ± 0.056, P = 0.003). CBR at baseline predicted RT development (OR 4.84, 95% CI: 1.56–16.93, P = 0.009), independent of putamen binding ratios (PBR), bradykinesia, and rigidity. Additionally, CBR correlated with RT severity but not PBR, supporting regional specificity in dopaminergic preservation. These findings highlight the association of preserved caudate dopaminergic terminals with RT development and suggest differential neurodegenerative patterns in PD.
“We used wearable motion sensors to get a clearer, more objective measurement of tremor,” co-first author Pedro Ferreira says. “That is to say, patients with and without dopamine loss in the caudate appear identical on the surface. Instead, sensors allow us to uncover subtle differences in tremor oscillations that traditional clinical rating scales miss, but which we can reliably link to what is happening in the brain”, he said.
Ferreira says, “We saw that there was a clear link between the functional state of dopamine in the caudate nucleus and global severity of resting tremor.” “We found that, the stronger the tremor, the more caudate dopamine activity we preserved.” A remarkably intriguing finding, though, was that the more dopamine was preserved in one caudate (each hemisphere has its caudate), the more tremors happened on the same side of the body.
Their computational model found that this ‘same side’ effect could arise spuriously from two factors: the increased dopamine in both caudate in tremors and the fact that PD is uneven in the brain. This work is based on the earlier team study in Neurobiology of Disease that had shown that rest tremor is tractable independently of other motor symptoms, something that is not often done because motor symptoms are typically combined in treatment.
Their prior research revealed that rest tremor varies with the type of PD progression: Patients presenting with ‘brain first’ PD more often have a more resistant form of that which must be suspected (tremor) while those without much have a symptom picture that is closer to a ‘gut first’ PD, where the disease process starts in the gut and spreads to the brain.
While that line of inquiry has already been extended in this new study, it shows that the degree of the rest tremor may be correlated with particular brain circuits. “Even in PD, there is not a loss of dopamine everywhere; different patients lose dopamine in different circuits,” says Alves da Silva.
And Mendonça adds: “Not all dopamine cells are the same.” “They see the different genetic makeups, connections, functions.” So what a patient loses or keeps in their cells can affect symptoms. In particular, tremors may be associated with the loss or preservation of specific populations of dopamine projecting to certain brain areas. “Our finding that these cells are lost in PD, with a wide variation in cell type loss between patients, could further explain why we see such a wide variety of symptoms in different PD patients.”
Implications for future treatment and research treatment.
Alves da Silva says the team is already looking ahead. “Establishing a cause is difficult between preserving dopamine in caudate and rest tremor in humans, and so we want to test this in animal models where we can manipulate certain cells, and to see how we impact on tremors.”
The findings highlight the utility of tracking beyond the broad categorical pigeonhole of PD and underscore the need for more sophisticated and biology-based approaches.
“We hope to begin to see the mist of the heterogeneity of PD symptoms and the ability to contribute to precise interventions that will improve the quality of life for those suffering from this disease by identifying specific neural circuits involved,” Mendonça concludes.
Reference: Mendonça MD, Ferreira PC, Oliveira F, et al. Relative sparing of dopaminergic terminals in the caudate nucleus is a feature of rest tremor in Parkinson’s disease. NPJ Parkinsons Dis. 2024;10(1):209. Published 2024 Nov 18. doi:10.1038/s41531-024-00818-8
