First delirium episode in Parkinson’s disease and parkinsonism: incidence, predictors, and outcomes

To define the incidence, predictors and prognosis of the first hospital delirium episode in Parkinson’s disease (PD) and atypical parkinsonism (AP), we identified the first hospital episode of delirium after diagnosis in the Parkinsonism Incidence in North-East Scotland (PINE) study, a prospective community-based incidence cohort of parkinsonism, using chart-based criteria to define delirium. Of 296 patients (189=PD, 107=AP [dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, vascular parkinsonism]), 152 developed delirium (PD = 98, AP = 54). Incidence of first hospital delirium episode per 100 person years was 8.1 (95% confidence interval [CI] 6.6–9.9) in PD and 18.5 (95% CI 13.9–24.7) in AP. Independent predictors of delirium were atypical parkinsonism (Hazard ratio [HR] vs PD = 2.83 [95% CI 1.60–5.03], age in PD but not in AP (HR for 10-year increase 2.29 [95% CI 1.74–3.02]), baseline MMSE (HR = 0.94 [95% CI 0.89–0.99]), APOE ε4 in PD (HR 2.16 [95% CI 1.15–4.08]), and MAPT H1/H1 in PD (HR 2.08 [95% CI 1.08–4.00]). Hazards of dementia and death after delirium vs before delirium were increased (dementia: HR = 6.93 [95% CI 4.18–11.48] in parkinsonism; death: HR = 3.76 [95% CI 2.65–5.35] in PD, 1.59 [95% CI 1.04–2.42] in AP). Delirium is a common non-motor feature of PD and AP and is associated with increased hazards of dementia and mortality. Whether interventions for early identification and treatment improve outcomes requires investigation.

Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU—a crossroad of the immune–vascular–nervous system—which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.

In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC

Objective.To determine whether: 1) the immunofluorescence (IF) is a reproducible technique in detecting misfolded α-synuclein (α-syn) in skin nerves; and subsequently 2) IF and RT-QuIC (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguish synucleinopathies (SOPs) from non-synucleinopathies (non-SOPs) in a large cohort of patients.Methods.We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all SOPs variants and non-SOPs (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for IF and RT-QuIC whereas CSF was performed in patients who underwent lumbar puncture for diagnostic purposes. IF and RT-QuIC analysis were made blinded to the clinical diagnosis.Results.IF showed reproducible results between two pairs of neighbouring skin samples. Furthermore, both IF and RT-QuIC showed high sensitivity and specificity in discriminating SOPs from non-SOPs and controls but IF presented the higher diagnostic accuracy. IF presented a good level of agreement with RT-QuIC both skin and CSF in SOPs.Conclusions:1) Both IF and RT-QuIC showed a high diagnostic accuracy although IF displayed the better value as well as an optimal reproducibility; 2) they presented a good level of agreement in SOPs supporting the use of a less invasive tests such as skin IF or RT-QuIC instead of CSF RT-QuIC as diagnostic tool for synucleinopathies.Classification of evidence:This study provides Class III evidence that IF or RT-QuIC accurately distinguish SOPs from non-SOPs patients.