Abstract Body

Highly-penetrant variants in different genes (including: SNCA, LRRK2, VPS35, VPS13C, PARK2, PINK1, and PARK7) are established as rare causes of monogenic forms of Parkinson’s disease (PD). Several other genes have recently been nominated to be disease-causing, but for these, the evidence remains inconclusive and additional studies are required.

Of note, some variants with reduced penetrance in the LRRK2 and the GBA gene are known to act as strong risk factors for the development of PD, and they are especially prevalent in some populations. Last, common variants of very small effect size, modulating the risk for developing of PD, have also been identified by genome-wide association studies (GWAS) in more than 90 chromosomal loci.

With the notable exception of some populations, only a minority of PD cases are explained by identifiable mutations in single genes. Moreover, no specific treatment is currently available for PD, based on a specific genetic etiology. While this situation might change in the future, still, at the moment, genetic testing for PD remains useful in order to provide an accurate etiological diagnosis, and to offer patients and relatives counselling about the risk to unaffected persons, and disease course. Due to the potential implications in the psychological, social, and professional domains for both patients and relatives, the genetic testing for diagnostic, and especially for predictive purposes, should be performed by a professional team, including neurologists, genetic counsellors, and psychologists. These procedure should always include pre-test and post-test genetic counselling.

Abstract Body

The diagnosis of Parkinson’s disease (PD) continues to be established only by the presence of cardinal motor features: hypokinesia, tremor and rigidity, according to UK Brain Bank Criteria or Movement Disorder Society (MDS) Definition Criteria. “Prodromal Parkinson” defines the complexity of early non-motor signs and risk factors for PD, as MDS Research Criteria for Prodromal PD latest updated in 2021 as an evidence-based conceptual framework. It includes a variable combination of symptoms such as REM-sleep behavior disorder (highest likelihood ratio), sleep-wake regulation dysfunction, hyposmia, constipation, and symptoms of the autonomic nervous system such as orthostatic hypotension, and early psychiatric symptoms such as depression or anxiety. Recently, new markers were added and comprise diabetes, global cognitive deficit, physical inactivity, and low plasma urate levels in men, ultrasound findings in the substantia nigra and genetic markers. From the early Honolulu-Asia Aging Study and several other US and European cohort studies (Predict-PD) impaired executive function, subtle motor dysfunction and tremor were highly indicative for the development of PD. Many of these features are unspecific and difficult to disentangle in clinical practice such as subtle slowness of movements in the elderly from an early bradykinesia. Unfortunately, none of these parameters is present in each single PD patient, some PD patients even miss many of these non-motor features or develop them later in the disease. Therefore the term “Prodromal Parkinson” still depends on likelihood ratios and will develop with further evidence in larger prospective cohorts to delineate the most specific pattern of premotor signs.

Abstract Body

Parkinson's disease, the most common movement disorder, is a progressive neurodegenerative disease clinically characterized by prominent motor symptoms, e.g., bradykinesia, rigidity, and tremor in addition to postural and gait disorders and, in some cases, levodopa-induced dyskinesia (LID). From a pathophysiological point of view, the motor symptoms of Parkinson's disease are traditionally considered to reflect dopaminergic denervation of the basal ganglia, with only a few exceptions. Changes in neuronal activity, abnormal oscillations, and altered plasticity, and sensorimotor integration mechanisms have been described at the level of basal ganglia. However, numerous studies have emerged in recent years in support of a pathophysiological role played by different brain areas in Parkinson's disease, particularly the motor cortical areas. It has increasingly been demonstrated that the primary motor cortex plays a relevant role in the pathophysiology of bradykinesia. Available evidence also emphasizes the possible role of the primary motor cortex in the pathophysiology of resting tremor and LID. In contrast, experimental data regarding the pathophysiology of rigidity and postural and gait disorders are limited. Delineating the pathophysiological involvement of the primary motor cortex in Parkinson's disease has several implications, including a better understanding and characterization of the remarkable heterogeneity of motor symptoms in this condition. Finally, delineating the pathophysiological role of the primary motor cortex in Parkinson's disease could lead to the more appropriate use of non-invasive brain stimulation techniques for therapeutic purposes. While many knowledge gaps remain, further studies can help better define the pathophysiological role of cortical motor areas in Parkinson’s disease.