Dopamine Pharmacodynamics: New Insights.

Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive behavior, reward, and habit formation, also represents a key player in substance use disorder and the formation and perpetuation of mechanisms leading to addiction. Here, we propose dopamine as a model not only of neurotransmission but also of neuromodulation capable of modifying neuronal architecture. Abuse of substances like methamphetamine, cocaine, and alcohol and their consumption over time can induce changes in neuronal activities. These modifications lead to synaptic plasticity and finally to morphological and functional changes, starting from maladaptive neuro-modulation and ending in neurodegeneration.

Advancing healthcare through thoracic ultrasound research in older patients.

This paper reports the proceedings of a meeting convened by the Research Group on Thoracic Ultrasound in Older People of the Italian Society of Gerontology and Geriatrics, to discuss the current state-of-the-art of clinical research in the field of geriatric thoracic ultrasound and identify unmet research needs and potential areas of development. In the last decade, point-of-care thoracic ultrasound has entered clinical practice for diagnosis and management of several respiratory illnesses, such as bacterial and viral pneumonia, pleural effusion, acute heart failure, and pneumothorax, especially in the emergency-urgency setting. Very few studies, however, have been specifically focused on older patients with frailty and multi-morbidity, who frequently exhibit complex clinical pictures needing multidimensional evaluation. At the present state of knowledge, there is still uncertainty on the best requirements of ultrasound equipment, methodology of examination, and reporting needed to optimize the advantages of thoracic ultrasound implementation in the care of geriatric patients. Other issues regard differential diagnosis between bacterial and aspiration pneumonia, objective grading of interstitial syndrome severity, quantification and monitoring of pleural effusions and solid pleural lesions, significance of ultrasonographic assessment of post-COVID-19 sequelae, and prognostic value of assessment of diaphragmatic thickness and motility. Finally, application of remote ultrasound diagnostics in the community and nursing home setting is still poorly investigated by the current literature. Overall, the presence of several open questions on geriatric applications of thoracic ultrasound represents a strong call to implement clinical research in this field.

Clinical Evaluation of Sleep Disorders in Parkinson's Disease.

The paradigm of the framing of Parkinson's disease (PD) has undergone significant revision in recent years, making this neurodegenerative disease a multi-behavioral disorder rather than a purely motor disease. PD affects not only the "classic" substantia nigra at the subthalamic nuclei level but also the nerve nuclei, which are responsible for sleep regulation. Sleep disturbances are the clinical manifestations of Parkinson's disease that most negatively affect the quality of life of patients and their caregivers. First-choice treatments for Parkinson's disease determine amazing effects on improving motor functions. However, it is still little known whether they can affect the quantity and quality of sleep in these patients. In this perspective article, we will analyze the treatments available for this specific clinical setting, hypothesizing a therapeutic approach in relation to neurodegenerative disease state.

Relationship between Vitamin D and Immunity in Older People with COVID-19.

Vitamin D is a group of lipophilic hormones with pleiotropic actions. It has been traditionally related to bone metabolism, although several studies in the last decade have suggested its role in sarcopenia, cardiovascular and neurological diseases, insulin-resistance and diabetes, malignancies, and autoimmune diseases and infections. In the pandemic era, by considering the response of the different branches of the immune system to SARS-CoV-2 infection, our aims are both to analyse, among the pleiotropic effects of vitamin D, how its strong multimodal modulatory effect on the immune system is able to affect the pathophysiology of COVID-19 disease and to emphasise a possible relationship between the well-known circannual fluctuations in blood levels of this hormone and the epidemiological trend of this infection, particularly in the elderly population. The biologically active form of vitamin D, or calcitriol, can influence both the innate and the adaptive arm of the immune response. Calcifediol levels have been found to be inversely correlated with upper respiratory tract infections in several studies, and this activity seems to be related to its role in the innate immunity. Cathelicidin is one of the main underlying mechanisms since this peptide increases the phagocytic and germicidal activity acting as chemoattractant for neutrophils and monocytes, and representing the first barrier in the respiratory epithelium to pathogenic invasion. Furthermore, vitamin D exerts a predominantly inhibitory action on the adaptive immune response, and it influences either cell-mediated or humoral immunity through suppression of B cells proliferation, immunoglobulins production or plasma cells differentiation. This role is played by promoting the shift from a type 1 to a type 2 immune response. In particular, the suppression of Th1 response is due to the inhibition of T cells proliferation, pro-inflammatory cytokines production (e.g., INF-γ, TNF-α, IL-2, IL-17) and macrophage activation. Finally, T cells also play a fundamental role in viral infectious diseases. CD4 T cells provide support to B cells antibodies production and coordinate the activity of the other immunological cells; moreover, CD8 T lymphocytes remove infected cells and reduce viral load. For all these reasons, calcifediol could have a protective role in the lung damage produced by COVID-19 by both modulating the sensitivity of tissue to angiotensin II and promoting overexpression of ACE-2. Promising results for the potential effectiveness of vitamin D supplementation in reducing the severity of COVID-19 disease was demonstrated in a pilot clinical trial of 76 hospitalised patients with SARS-CoV-2 infection where oral calcifediol administration reduced the need for ICU treatment. These interesting results need to be confirmed in larger studies with available information on vitamin D serum levels.

Reward System Dysfunction and the Motoric-Cognitive Risk Syndrome in Older Persons.

During aging, many physiological systems spontaneously change independent of the presence of chronic diseases. The reward system is not an exception and its dysfunction generally includes a reduction in dopamine and glutamate activities and the loss of neurons of the ventral tegmental area (VTA). These impairments are even more pronounced in older persons who have neurodegenerative diseases and/or are affected by cognitive and motoric frailty. All these changes may result in the occurrence of cognitive and motoric frailty and accelerated progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. In particular, the loss of neurons in VTA may determine an acceleration of depressive symptoms and cognitive and motor frailty trajectory, producing an increased risk of disability and mortality. Thus, we hypothesize the existence of a loop between reward system dysfunction, depression, and neurodegenerative diseases in older persons. Longitudinal studies are needed to evaluate the determinant role of the reward system in the onset of motoric-cognitive risk syndrome.

Cognitive and Behavior Deficits in Parkinson's Disease with Alteration of FDG-PET Irrespective of Age.

Significant progress has been made in our understanding of the neurobiology of Parkinson's disease (PD). Post-mortem studies are an important step and could help to comprehend not only the progression of motor symptoms, but also the involvement of other clinical domains, including cognition, behavior and impulse control disorders (ICDs). The correlation of neuropathological extension of the disease with the clinical stages remains challenging. Molecular imaging, including positron emission tomography (PET) and single photon computed tomography (SPECT), could allow for bridging the gap by providing in vivo evidence of disease extension. In the last decade, we have observed a plethora of reports describing improvements in the sensitivity of neuroimaging techniques. These data contribute to increasing the accuracy of PD diagnosis, differentiating PD from other causes of parkinsonism and also obtaining a surrogate marker of disease progression. FDG-PET has been used to measure cerebral metabolic rates of glucose, a proxy for neuronal activity, in PD. Many studies have shown that this technique could be used in early PD, where reduced metabolic activity correlates with disease progression and could predict histopathological diagnosis. The aim of this work is to report two particular cases of PD in which the assessment of brain metabolic activity (from FDG-PET) has been combined with clinical aspects of non-motor symptoms. Integration of information on neuropsychological and metabolic imaging allows us to improve the treatment of PD patients irrespective of age.

Comprehensive Model for Physical and Cognitive Frailty: Current Organization and Unmet Needs.

Aging is characterized by the decline and deterioration of functional cells and results in a wide variety of molecular damages and reduced physical and mental capacity. The knowledge on aging process is important because life expectancy is expected to rise until 2050. Aging cannot be considered a homogeneous process and includes different trajectories characterized by states of fitness, frailty, and disability. Frailty is a dynamic condition put between a normal functional state and disability, with reduced capacity to cope with stressors. This geriatric syndrome affects physical, neuropsychological, and social domains and is driven by emotional and spiritual components. Sarcopenia is considered one of the determinants and the biological substrates of physical frailty. Physical and cognitive frailty are separately approached during daily clinical practice. The concept of motoric cognitive syndrome has partially changed this scenario, opening interesting windows toward future approaches. Thus, the purpose of this manuscript is to provide an excursus on current clinical practice, enforced by aneddoctical cases. The analysis of the current state of the art seems to support the urgent need of comprehensive organizational model incorporating physical and cognitive spheres in the same umbrella.

Assessment and treatment of older individuals with COVID 19 multi-system disease: Clinical and ethical implications.

Covid-19 infection is a multisystem disease more frequent in older individuals, especially in those with multiple chronic diseases. This multimorbid and frail population requires attention and a personalized comprehensive assessment in order to avoid the occurrence of adverse outcomes. As other diseases, the COVID-19 presentation in older patients is often atypical with less severe and unspecific symptoms. These subjects both at home and during hospitalization suffer isolation and the lack of support of caregivers. The geriatric care in COVID-19 wards is often missing. The application of additional instruments would be necessary to facilitate and personalize the clinical approach, not only based on diseases but also on functional status. This narrative review starts from diagnostic evaluation, continues with adapted pharmacologic treatment and ends with the recovery phase targeting the nutrition and physical exercise. We developed a check-list of respiratory, gastro-intestinal and other less-specific symptoms, summarized in a table and easily to be filled-up by patients, nurses and general practitioners. As second step, we reported the clinical phases of this disease. Far to be considered just viral infective and respiratory, this disease is also an inflammatory and thrombotic condition with frequent bacterial over-infection. We finally considered timing and selection of treatment, which depend on the disease phase, co-administration of other drugs and require the monitoring of renal, liver and cardiac function. This underlines the role of age not just as a limitation, but also an opportunity to increase the quality and the appropriateness of multidisciplinary and multidimensional intervention in this population.