Cerebrospinal fluid proteomic profile of frailty: Results from the PROLIPHYC cohort.

Frailty is a clinical state reflecting a decrease in physiological reserve capacities, known to affect numerous biological pathways and is associated with health issues, including neurodegenerative diseases. However, how global protein expression is affected in the central nervous system in frail subject remains underexplored. In this post hoc cross-sectional biomarker analysis, we included 90 adults (52-85 years) suspected of normal pressure hydrocephalus (NPH) and presenting with markers of neurodegenerative diseases. We investigated the human proteomic profile of cerebrospinal fluid associated with frailty defined by an established cumulated frailty index (FI, average = 0.32), not enriched for neurology clinical features. Using a label-free quantitative proteomic approach, we identified and quantified 999 proteins of which 13 were positively associated with frailty. Pathway analysis with the top positively frailty-associated proteins revealed enrichment for proteins related to inflammation and immune response. Among the 60 proteins negatively associated with frailty, functional pathways enriched included neurogenesis, synaptogenesis and neuronal guidance. We constructed a frailty prediction model using ridge regression with 932 standardized proteins. Our results showed that the "proteomic model" could become an equivalent predictor of FI in order to study chronological age. This study represents the first comprehensive exploration of the proteomic profile of frailty within cerebrospinal fluid. It sheds light on the physiopathology of frailty, particularly highlighting processes of neuroinflammation and inhibition of neurogenesis. Our findings unveil a range of biological mechanisms that are dysregulated in frailty, in NPH subjects at risk of neurodegenerative impairment, offering new perspectives on frailty phenotyping and prediction.

Assessment of CSF dynamics using infusion study: tips and tricks.

Idiopathic normal pressure hydrocephalus, secondary chronic hydrocephalus, and other cerebrospinal fluid (CSF) disorders are often challenging to diagnose. Since shunt surgery is usually the only therapeutic option and carries significant morbidity, optimal patient selection is crucial. The tap test is the most commonly used prognostic test to confirm the diagnosis but lacks sensitivity. The Lumbar Infusion Study (LIS) appears to be a better option, offering additional information on brain dynamics without increasing morbidity. However, this technique remains underused. In this narrative review, supported by the extensive experience of several European expert centers, we detail the physiological basis, indications, and CSF dynamics parameters that can be measured. We also discuss technical modalities and variations, including one vs. two needles, patient positioning, and the site of CSF measurement, as well as in vivo shunt testing. Finally, we discuss the limitations and morbidity associated with the LIS. This review aims to assist teams wishing to incorporate LIS into their screening tools for chronic hydrocephalus and other CSF disorders.

Analysis of intracranial pressure pulse waveform in studies on cerebrospinal compliance: a narrative review.

Continuous monitoring of mean intracranial pressure (ICP) has been an essential part of neurocritical care for more than half a century. Cerebrospinal pressure-volume compensation, i.e. the ability of the cerebrospinal system to buffer changes in volume without substantial increases in ICP, is considered an important factor in preventing adverse effects on the patient's condition that are associated with ICP elevation. However, existing assessment methods are poorly suited to the management of brain injured patients as they require external manipulation of intracranial volume. In the 1980s, studies suggested that spontaneous short-term variations in the ICP signal over a single cardiac cycle, called the ICP pulse waveform, may provide information on cerebrospinal compensatory reserve. In this review we discuss the approaches that have been proposed so far to derive this information, from pulse amplitude estimation and spectral techniques to most recent advances in morphological analysis based on artificial intelligence solutions. Each method is presented with focus on its clinical significance and the potential for application in standard clinical practice. Finally, we highlight the missing links that need to be addressed in future studies in order for ICP pulse waveform analysis to achieve widespread use in the neurocritical care setting.

Sleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport.

Perivascular spaces are important highways for fluid and solute transport in the brain enabling efficient waste clearance during sleep. However, the underlying mechanisms augmenting perivascular flow in sleep are unknown. Using two-photon imaging of naturally sleeping male mice we demonstrate sleep cycle-dependent vascular dynamics of pial arteries and penetrating arterioles: slow, large-amplitude oscillations in NREM sleep, a vasodilation in REM sleep, and a vasoconstriction upon awakening at the end of a sleep cycle and microarousals in NREM and intermediate sleep. These vascular dynamics are mirrored by changes in the size of the perivascular spaces of the penetrating arterioles: slow fluctuations in NREM sleep, reduction in REM sleep and an enlargement upon awakening after REM sleep and during microarousals in NREM and intermediate sleep. By biomechanical modeling we demonstrate that these sleep cycle-dependent perivascular dynamics likely enhance fluid flow and solute transport in perivascular spaces to levels comparable to cardiac pulsation-driven oscillations.

Association Between Homocysteine, Frailty and Biomechanical Response of the CNS in NPH-Suspected Patients.

Frailty is a geriatric syndrome that combines physiological decline, disruptions of homeostatic mechanisms across multiple physiologic systems and thus, strong vulnerability to further pathological stress. Previously, we provided the first evidence that increased risk of poor health outcomes, as quantified by a frailty index (FI), is associated with an alteration of the central nervous system (CNS) biomechanical response to blood pulsatility. In this study, we explored correlation between 14 biological parameters, the CNS elastance coefficient and FI. We included 60 adults (52-92 years) suspected of normal pressure hydrocephalus and presenting with markers of multiple coexisting brain pathologies, including Parkinson disease, Alzheimer disease, and vascular dementia. We showed that the homocysteine (Hcy) level was independently and positively associated with both the FI and the CNS elastance coefficient (adjusted R² of 10% and 6%). We also demonstrated that creatinine clearance and folate level were independently associated with Hcy level. Based on previous literature results describing the involvement of Hcy in endothelial dysfunction, glial activation, and neurodegeneration, we discuss how Hcy could contribute to the altered biomechanical response of the CNS and frailty.

Assessment of Pressure-Volume Index During Lumbar Infusion Study: What Is the Optimal Method?

INTRODUCTION: Assessment of the pressure-volume index (PVI) during lumbar infusion study (LIS) has been proposed to evaluate the overall compliance of the cranio-spinal system. It is calculated from the measurement of CSF pressure changes, ΔP from Pb to Pp, in response to repeated bolus injections of a volume (ΔV) within the lumbar subarachnoid space. MATERIAL AND METHODS: We retrospectively analyzed 18 patients who underwent LIS for suspicion of normal pressure hydrocephalus, including a series of three fast bolus injections of 3 mL of saline at different levels of CSF pressure. We compared two methods for PVI calculation: (a) PVIslope using the slope α of a linear fit ΔP = α(Pb - P 0), PVI = ΔV/log10(α + 1); (b) PVImean using the PVI calculated independently for each bolus injection assuming P 0 = 0, PVI = mean(ΔV/log10(Ppi/Pbi))i=1.3. RESULTS: We found a significant discrepancy between the two methods: the average difference (PVIslope - PVImean) was -3.93 mL (95% confidence interval [8.77; -16.64]). In the PVIslope, method, the mean P 0 was 2.12 mmHg (±3.41 mmHg). DISCUSSION: The clinical reliability of PVImean (assuming P 0 = 0) depends on the value of P 0. PVIslope provides results, independent of P 0. Future studies should focus on determining pathological PVI range rather than fixed cut-off values.

[Biomechanical modeling of pelvic organ mobility: towards personalized medicine]. / Modélisation biomécanique des mobilités des organes pelviens: vers une médecine personnalisée.

Female pelvic mobility is crucial for urinary, bowel and sexual function and for vaginal delivery. This mobility is ensured by a complex organ suspension system composed of ligaments, fascia and muscles. Impaired pelvic mobility affects one in three women of all ages and can be incapacitating. Surgical management has a high failure rate, largely owing to poor knowledge of the organ support system, including the barely discernible ligamentous system. We propose a 3D digital model of the pelvic cavity based on MRI images and quantitative tools, designed to locate the pelvic ligaments. We thus obtain a coherent anatomical and functional model which can be used to analyze pelvic pathophysiology. This work represents a first step towards creating a tool for localizing and characterizing the source of pelvic imbalance. We examine possible future applications of this model, in terms of personalized therapy and prevention.