Gender differences in dopaminergic system dysfunction in de novo Parkinson’s disease clinical subtypes

Parkinson’s disease (PD) is the second most common, age-related neurodegenerative disorder, affecting about 3% of the population by the age of 65 years. The main pathological feature of PD is the progressive loss of midbrain dopaminergic neurons in the substantia nigra and the presence of alpha-synuclein-positive intracellular inclusions in susceptible neuronal soma and neural dendrites, termed Lewy bodies and Lewy neurites, respectively. In the absence of disease-modifying therapy, PD treatment is based on the control of clinical symptoms with pharmacological (e.g. levodopa preparations prescribed with or without other medications) and non-pharmacologic approaches (such as exercise and physical, occupational, and speech therapies). In medication-resistant patients, more invasive treatment can be applied (i.e. lesioning therapies and deep brain stimulation). PD presents a complex and heterogenous clinical picture during the disease course, and dementia represents the most severe follow-up condition, with a mean prevalence of 31.5%. The heterogeneity of manifestations and progression suggests that PD is an umbrella term that includes several clinical phenotypes with different prognoses in need to be early recognised. In this direction, clinical criteria have been published recently (Fereshtehnejad et al., 2017) to identify three main PD clinical subtypes with escalating severity of clinical motor and non-motor symptoms: mild motor, intermediate, and diffuse-malignant. Increasing research efforts are in place to understand the diverse clinical manifestations of PD to limit misdiagnosis and get closer to precision medicine’s diagnostic strategy.

Together with aging, genetics, environment and immune status, the role of biological sex as an important factor in PD has been widely discussed in the past decade. There are clear sex-related differences in epidemiological and clinical features of the disease: PD affects men twice more often than women, but women have a higher mortality rate and faster progression of the disease. Within the idiopathic PD (iPD), a phenotype, characterized by a late disease onset and little motor symptoms at the beginning, has frequently been seen in female patients. This observation was linked to a higher preserved striatal dopaminergic activity in females than in males because estrogens may have a protective impact by lowering the activity of the dopamine transporter (DAT), increasing the availability of dopamine in the synapses. iPD women are more likely than iPD men to exhibit mood symptoms such as depression, agitation, anxiety, and lack of motivation.

Previous research on the DAT system showed higher striatal dopamine levels in women compared to men over the course of the disease. However, studies on the effects of gender on DAT binding in the regions of the mesolimbic dopaminergic system and the cortical brain targets of dopaminergic projections are very limited. Furthermore, it is unknown whether gender can impact different clinical subtypes despite increased interest in gender-related vulnerabilities in iPD. In recent research published in Neurobiology of Disease, Italian researchers PhD candidate Cecilia Boccalini, Dr. Giulia Carli, Assistant Professor Andrea Pilotto, Professor Alessandro Padovani, and Professor Daniela Perani from the Vita-Salute San Raffaele University demonstrated that gender has a significant impact on clinical features, dopaminergic dysfunction, and connectivity in patients with de novo iPD stratified according to the clinical criteria for subtypes (i.e., mild motor, intermediate, and diffuse-malignant).

The authors provided the first conclusive proof of gender differences in clinical traits, dopaminergic dysfunction, and molecular linkage into the three well-defined iPD groups — mild motor predominance, moderate, and diffuse malignant, according to clinical criteria. The authors found that female patients had more severe anxiety symptoms, whereas male patients with iPD scored cognitively worse than female patients in the mild motor and intermediate categories. Males exhibited more severe motor deficits in the diffuse-malignant subtype, which was related to a lower dopamine uptake in the putamen than in females. On the other hand, all iPD subtypes in females were characterized by extensive aberrant connectivity in the mesolimbic dopaminergic pathway and significant dopaminergic depletion in the extrastriatal regions of the same system. The level of anxiety was associated with a decreased dopaminergic binding in the amygdala, only in females. This study presents the first evidence of gender differences in iPD clinical subtypes, both in terms of clinical characteristics and dopaminergic molecular neuroimaging.

In conclusion, the new study demonstrates that gender differences exist in iPD throughout clinical subgroups and, remarkably, even from the early stages. Clinical connections to the nigrostriatal or mesolimbic systems in both males and females suggest the existence of unique vulnerabilities and related disease presentations. The study by Daniela Perani and colleagues highlights the importance of future research that is relevant to women with PD and should be designed around the unique needs of women. Furthermore, the need to increase focus on recruiting female participants, who reflect a representative sample of women in relation to demographic factors, stage and onset of PD, is critical. Men and women take similar dopaminergic medications and combinations of dopaminergic medications to combat PD, however, women are more likely to experience medication-related dyskinesias. Gender differences highlighted in the new study must be considered when employing precision medicine to prevent, diagnose, and treat PD.