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.

Gender differences in dopaminergic system dysfunction in de novo Parkinson's disease clinical subtypes - Medicine Innovates

About the author

Cecilia Boccalini – I am a PhD fellow in Cognitive Neuroscience at Vita-Salute San Raffaele University in Milan. My research interests focus on understanding the effects of pathology on the clinical expression of neurodegenerative diseases. I work with molecular neuroimaging, namely positron emission tomography (PET), a tool offering the in vivo measures of protein deposits, brain metabolism, and neurotransmission. My PhD project deals with the study of neurodegenerative diseases using different neuroimaging approaches with the final aim to be able to separate clinical phenotypes and trajectories. In other words, my studies focus on molecular brain alterations underlying neurodegenerative processes and how they lead to the emergence of complex clinical phenotypes. In this scenario, the modulation associated with fixed or flexible factors, such as gender and cognitive reserve, also became crucial to deeply understanding the pathophysiology and the source of heterogeneity in neurodegenerative diseases.



About the author

Giulia Carli – I’m currently a Postdoctoral Fellow at University Medical Centre Groningen (UMCG) in Groningen, The Netherlands. My primary expertise covers the molecular and structural neuroimaging biomarkers (e.g. [18F]FDG-PET, presynaptic dopaminergic imaging, [123I]MIBG-SPECT, [18F]FEOBV-PET, and MRI) in the early diagnosis and prognosis of Parkinson’s disease (PD) clinical spectrum. I did my PhD in Cognitive Neuroscience at Vita-Salute San Raffaele University in Milan, Italy. My PhD project explored the predictive value of neuroimaging, neurophysiological sleep parameters and neurocognitive features in the development of dementia in PD, starting from the earliest preclinical stages, like isolated REM sleep Behaviour disorder (iRBD). This project allowed me to provide new insight into the dynamic of neurobiological changes that occur in Lewy Bodies disorders over time. I also studied sources of clinical variability in LBD, with specific attention to modifiable and non-modifiable risk factors that influence the development of severe phenotypes and the timing of dementia symptoms’ onset.



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About the author

Daniela Perani –Full Professor of Neuroscience at the University Vita-Salute San Raffaele, medical coordinator for diagnostic neuroimaging at the Nuclear Medicine Unit at San Raffaele Hospital, and responsible for the research team at the Neuroscience Division of the Scientific Institute San Raffaele Hospital, in Milan, Italy.  My research area is cognitive neuroscience, addressing the functional correlates of language, bilingualism, executive functions, perception, and memory systems using neuroimaging, with a special focus on in vivo neuroimaging of neurological diseases. In particular in the field of neurodegenerative diseases applying structural (MRI) and molecular (PET) neuroimaging and, in the field of normal cognitive functions and their changes associated with aging by using functional neuroimaging (fMRI).  My research is also devoted to projects specifically aimed at assessing gender differences in the structure and functioning of the central nervous system, in physiological aging and neurodegenerative diseases, also to understand how social and cultural factors, such as education, employment levels, physical activities and bilingualism, can differently influence the female and male brain.




Fereshtehnejad, S. M., Zeighami, Y., Dagher, A., & Postuma, R. B. (2017). Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain, 140(7), 1959-1976.

Boccalini C, Carli G, Pilotto A, Padovani A, Perani D. Gender-Related Vulnerability of Dopaminergic Neural Networks in Parkinson’s Disease. Brain Connect. 2021 Feb;11(1):3-11.

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Boccalini C, Carli G, Pilotto A, Padovani A, Perani D. Gender differences in dopaminergic system dysfunction in de novo Parkinson’s disease clinical subtypes. Neurobiology of Disease. 2022 Jun 1;167:105668.

Go To Neurobiology of Disease