Objectives:To assess the frequency of transient orthostatic hypotension (tOH) and its clinical impact in Parkinson’s disease (PD), we retrospectively studied 173 PD patients and 173 age- and gender-matched controls with orthostatic intolerance, who underwent cardiovascular autonomic function testing under continuous non-invasive blood pressure (BP) monitoring.Methods:We screened for tOH (systolic BP fall ≥ 20mmHg or diastolic ≥10mmHg resolving within the 1st minute upon standing) and classic OH (cOH, sustained systolic BP fall ≥ 20mmHg or diastolic ≥10mmHg within 3 minutes upon standing). In PD patients, we reviewed the medical records of the 6 months preceding and following autonomic testing for history of falls, syncope and orthostatic intolerance.Results:tOH occurred in 24% of PD patients and 21% of controls, cOH in 19% of PD patients and in none of the controls, independently of any clinical-demographic or PD-specific characteristic. Forty percent of PD patients had a history of falls, in 29% of cases due to syncope. PD patients with history of orthostatic intolerance and syncope had a more severe systolic BP fall and lower diastolic BP rise upon standing, most pronounced in the first 30 to 60 seconds.Conclusions:tOH is an age-dependent phenomenon, which is at least as common as cOH in PD. Transient BP falls when changing to the upright position may be overlooked with bedside BP measurements, but contribute to orthostatic intolerance and syncope in PD. Continuous non-invasive BP monitoring upon standing may help identify a modifiable risk factor for syncope-related falls in parkinsonian patients.

Schellong test • Standing test • Orthostatic hypotension • Head-up tilt test • Syncope "Schellong test" is the eponym used in German-speaking countries to refer to the active standing test for measuring blood pressure and heart rate changes under gravitational stress. The test is named after Fritz Schellong, a European pioneer of cardiovascular autonomic neuroscience. Schellong, who was born 10 September 1891 in Königsberg (at that time part of Prussia) and died 18 January 1953 in Münster (Germany), became Professor of Internal Medicine in Prague and Münster and a prominent member of the German Society for Circulation Research (Deutsche Gesellschaft für Kreislaufforschung, nowadays known as Deutsche Gesellschaft für Kardiologie-Herz-und Kreislaufforschung, i.e. the German Society for Cardiology, Heart and Circulation Research). Schellong dedicated his scientific career to the understanding of blood pressure regulation, which he summarized in his small monograph Regulationsprüfung des Kreislaufs (Evaluation of the circulatory regulation), published in 1938. In his 133-page book, Schellong described specific tests to evaluate circulatory function with emphasis on blood pressure and heart rate. The monograph included many case examples of these responses, profusely illustrated with 92 graphs (Fig. 1). The original Schellong protocol consisted of three consecutive tests:

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A plethora of dynamic pathophysiological mechanisms underpins highly heterogeneous phenotypes in the field of dementia, particularly in Alzheimer’s disease (AD). In such a faceted scenario, a biomarker-guided approach, through the implementation of specific fluid biomarkers individually reflecting distinct molecular pathways in the brain, may help establish a proper clinical diagnosis, even in its preclinical stages. Recently, ultrasensitive assays may detect different neurodegenerative mechanisms in blood earlier. ß-amyloid (Aß) peptides, phosphorylated-tau (p-tau), and neurofilament light chain (NFL) measured in blood are gaining momentum as candidate biomarkers for AD. P-tau is currently the more convincing plasma biomarker for the diagnostic workup of AD. The clinical role of plasma Aβ peptides should be better elucidated with further studies that also compare the accuracy of the different ultrasensitive techniques. Blood NFL is promising as a proxy of neurodegeneration process tout court. Protein misfolding amplification assays can accurately detect α-synuclein in cerebrospinal fluid (CSF), thus representing advancement in the pathologic stratification of AD. In CSF, neurogranin and YKL-40 are further candidate biomarkers tracking synaptic disruption and neuroinflammation, which are additional key pathophysiological pathways related to AD genesis. Advanced statistical analysis using clinical scores and biomarker data to bring together individuals with AD from large heterogeneous cohorts into consistent clusters may promote the discovery of pathophysiological causes and detection of tailored treatments.

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The diagnosis of neurodegenerative diseases (NDDs) represents an increasing social burden, with the unsolved issue of disease-modifying therapies (DMTs). The failure of clinical trials treating Alzheimer′s Disease (AD) so far highlighted the need for a different approach in drug design and patient selection. Identifying subjects in the prodromal or early symptomatic phase is critical to slow down neurodegeneration, but the implementation of screening programs with this aim will have an ethical and social aftermath. Novel minimally invasive candidate biomarkers (derived from blood, saliva, olfactory brush) or classical cerebrospinal fluid (CSF) biomarkers have been developed in research settings to stratify patients with NDDs. Misfolded protein accumulation, neuroinflammation, and synaptic loss are the pathophysiological hallmarks detected by these biomarkers to refine diagnosis, prognosis, and target engagement of drugs in clinical trials. We reviewed fluid biomarkers of NDDs, considering their potential role as screening, diagnostic, or prognostic tool, and their present-day use in clinical trials (phase II and III). A special focus will be dedicated to novel techniques for the detection of misfolded proteins. Eventually, an applicative diagnostic algorithm will be proposed to translate the research data in clinical practice and select prodromal or early patients to be enrolled in the appropriate DMTs trials for NDDs.

Since 2019, over 600 million people worldwide suffered from a coronavirus disease 2019 (COVID-19) infection [1], with major impacts on society and healthcare systems. Not only emergency care [2, 3], but also services for people with chronic conditions were hit hard by the pandemic [4,5], resulting in increased healthcare burden, especially for neurological patients [6].

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