Because of COVID-19 outbreak, regular clinical services for Parkinson's disease (PD) patients have been suddenly suspended, causing worries, confusion and unexpected needs in such frail population. Here, we reviewed the messages spontaneously sent by patients to an Italian PD clinic during the first two weeks of COVID-19 lockdown (9-21 March 2020), in order to highlight their main needs and then outline appropriate strategies of care for this critical period. One hundred sixty-two messages were analysed. Forty-six percent queried about clinical services; 28% communicated an acute clinical worsening for which a therapeutic change was done in 52% of cases; 17% (those patients with younger age and milder disease) asked about the relationship between PD and COVID-19; 8% informed about an intercurrent event. Our analysis suggests that PD patients' needs during COVID-19 emergency include appropriate and complete information, a timely update on changes in clinical services, and the continuity of care, even in a remote mode. By addressing these issues, acute clinical worsening, complications and subsequent therapeutic changes could be prevented. In this perspective, telecommunication systems and virtual medicine should be implemented.

In Parkinson's disease (PD), cortical–subcortical interplay plays a relevant role in affecting clinical performance. Functional MRI sequences described changes in functional connectivity at different stages of disease. Scarce are, instead, the investigations examining brain connectivity in patients with PD at early stages of disease. For this aim, here we analyzed the differences in functional connectivity between de novo, never treated, PD patients and healthy controls. The analyses were based upon custom-written scripts on the Matlab platform, combined with high-level functions of Fieldtrip, Brainstorm, and Brain Connectivity toolboxes. First, we proceeded to the spectral analysis of the EEG data in the five frequency bands (δ-θ-α-β-γ). Second, we calculated functional connectivity matrices based on both coherency (COH) and imaginary part of coherency (iCOH), in the δ-θ-α-β-γ frequency bands. Then, four network measures (density, transitivity, global efficiency, and assortativity) were computed in identified connectivity matrices. Finally, we compared the spectral density, functional connectivity matrices, and network measured between healthy controls and de novo PD patients through two-samples T-test. A total of 21 de novo PD patients and 20 healthy subjects were studied. No differences were observed in spectral analysis between the two groups, with the exception of the γ band where a significant increase in power density was found in PD patients. A reduced connectivity in the main EEG frequency bands (α-β frequency bands) was observed in PD patients compared to controls, while a hyperconnectivity was found in PD patients in γ band. Among the network measures, a reduced assortativity coefficient was found in de novo PD patients in α frequency band. Our results show the occurrence of early EEG functional connectivity alterations from the initial stages of PD. From this point of view, connectivity analysis may ease a better understanding of the complexity of PD physiopathology.

Magnetic Resonance–guided Focused Ultrasound (MRgFUS) represents an effective micro-lesioning approach to target pharmaco-resistant tremor, mostly in patients afflicted by essential tremor (ET) and/or Parkinson’s disease (PD). So far, experimental protocols are verifying the clinical extension to other facets of the movement disorder galaxy (i.e., internal pallidus for disabling dyskinesias). Aside from those neurosurgical options, one of the most intriguing opportunities of this technique relies on its capability to remedy the impermeability of blood–brain barrier (BBB). Temporary BBB opening through low-intensity focused ultrasound turned out to be safe and feasible in patients with PD, Alzheimer’s disease, and amyotrophic lateral sclerosis. As a mere consequence of the procedures, some groups described even reversible but significant mild cognitive amelioration, up to hippocampal neurogenesis partially associated to the increased of endogenous brain-derived neurotrophic factor (BDNF). A further development elevates MRgFUS to the status of therapeutic tool for drug delivery of putative neurorestorative therapies. Since 2012, FUS-assisted intravenous administration of BDNF or neurturin allowed hippocampal or striatal delivery. Experimental studies emphasized synergistic modalities. In a rodent model for Huntington’s disease, engineered liposomes can carry glial cell line–derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex through pulsed FUS exposures with microbubbles; in a subacute MPTP-PD model, the combination of intravenous administration of neurotrophic factors (either through protein or gene delivery) plus FUS did curb nigrostriatal degeneration. Here, we explore these arguments, focusing on the current, translational application of neurotrophins in neurodegenerative diseases.

In the last decade, animal studies highlighted the sensitivity of hearing function to lack of specific cochlear dopamine receptors, while several studies on humans reported association between hearing loss and Parkinson’s disease, partially recovered after levodopa administration in de novo patients. Taken together, these observations suggest investigating the possible use of cochlear function outcome variables, particularly, otoacoustic emissions, as sensitive biomarkers of Parkinson’s disease. Any lateralization of hearing dysfunction correlated with Parkinson’s disease lateralization would 1) further confirm their association, and 2) provide a disease-specific differential outcome variable. Differential indicators are particularly useful for diagnostic purposes, because their effectiveness is not limited by physiological inter-subject fluctuations of the outcome variable. Recent advances in the acquisition and analysis techniques of otoacoustic emissions suggest using them for evaluating differential cochlear damage in the two ears. In this study, we quantitatively evaluated hearing function in a population of subjects with Parkinson’s disease, to investigate the occurrence of hearing loss, and, particularly, whether hearing dysfunction shows lateralization correlated to motor symptoms. Pure tone audiometry and distortion product otoacoustic emissions were used as outcome variables in eighty patients (mean age 65 ± 9 years) and forty-one controls (mean age 64 ± 10 years). An advanced customized acquisition and analysis system was developed and used for otoacoustic testing, which guarantees response stability independent of probe insertion depth, and has the sensitivity necessary to accurately assess the low levels of otoacoustic response typical of elderly subjects. To our knowledge, this is the first study introducing the distinction between ipsilateral and contralateral ear, with respect to the body side more affected by Parkinson’s disease motor symptoms. Significant asymmetry was found in the auditory function, as both otoacoustic responses and audiometric hearing levels were worse in the ipsilateral ear. Significantly worse hearing function was also observed in patients with Parkinson’s disease compared to controls, confirming previous studies. Several pathophysiological mechanisms may be hypothesized to explain asymmetric cochlear damage in Parkinson's disease, including the impairment of dopamine release and the involvement of extra-dopaminergic circuits, with the cholinergic pathway as a likely candidate. The observed asymmetry in the audiological response of patients with Parkinson’s disease suggests that lateralization of hearing dysfunction could represent a specific non-motor signature of the disease. The possible diagnostic use of cochlear dysfunction asymmetry as a specific biomarker of Parkinson’s disease deserves further investigation, needing a more precise quantitative assessment, which would require a larger sample size.

Academic centers utilize sequential clinical and neuroimaging assessments, including morphometric ratios, to obtain an unequivocal diagnosis of the non-synucleinopathic forms of Parkinsonism, such as progressive supranuclear palsy (PSP), however, a 1-2 year follow-up is required. The on-going long-lasting trials using anti-tau antibodies for PSP patients might therefore be biased by the incorrect enrollment of Parkinson's disease (PD) patients manifesting early axial signs. This perspective study aimed at achieving two major goals: first, to summarize the established biomarker candidates found in cerebrospinal fluid (CSF) in probable PSP patients, including low p-tau and altered neurofilaments. Second, we share our recent data, from CSF samples of well-selected PSP subjects, attributable to both main variants (and revisited in light of MDS criteria), who were followed for 1 year before and 2 years after lumbar puncture. We found a significantly high level of noradrenaline (NE) in these patients, similar to controls, when compared to PD patients. In contrast, CSF samples, in PD, showed a significant reduction in CSF NE and its major metabolite, which confirmed that PD is a multi-system disease involving several endogenous pathways. The NE axis impairments were prominent in PSP featuring worse NPI. It might represent a counterpart to the early and peculiar psycho-pathological profiles that are observed in tauopathies. In conclusion, we highlight that CSF biomarkers, which are easy to collect, can provide rapid insights as diagnostic tools. Early alterations in endogenous NE machinery in atypical Parkinsonism may represent a specific risk trait in forms characterized by a worse prognosis.