Structural volumetric and Periodic Table DTI patterns in Complex Normal Pressure Hydrocephalus-Toward the principles of a translational taxonomy.

Introduction: We previously proposed a novel taxonomic framework to describe the diffusion tensor imaging (DTI) profiles of white matter tracts by their diffusivity and neural properties. We have shown the relevance of this strategy toward interpreting brain tissue signatures in Classic Normal Pressure Hydrocephalus vs. comparator cohorts of mild traumatic brain injury and Alzheimer's disease. In this iteration of the Periodic Table of DTI Elements, we examined patterns of tissue distortion in Complex NPH (CoNPH) and validated the methodology against an open-access dataset of healthy subjects, to expand its accessibility to a larger community. Methods: DTI measures for 12 patients with CoNPH with multiple comorbidities and 45 cognitively normal controls from the ADNI database were derived using the image processing pipeline on the brainlife.io open cloud computing platform. Using the Periodic Table algorithm, DTI profiles for CoNPH vs. controls were mapped according to injury patterns. Results: Structural volumes in most structures tested were significantly lower and the lateral ventricles higher in CoNPH vs. controls. In CoNPH, significantly lower fractional anisotropy (FA) and higher mean, axial, and radial diffusivities (MD, L1, and L2 and 3, respectively) were observed in white matter related to the lateral ventricles. Most diffusivity measures across supratentorial and infratentorial structures were significantly higher in CoNPH, with the largest differences in the cerebellum cortex. In subcortical deep gray matter structures, CoNPH and controls differed most significantly in the hippocampus, with the CoNPH group having a significantly lower FA and higher MD, L1, and L2 and 3. Cerebral and cerebellar white matter demonstrated more potential reversibility of injury compared to cerebral and cerebellar cortices. Discussion: The findings of widespread and significant reductions in subcortical deep gray matter structures, in comparison to healthy controls, support the hypothesis that Complex NPH cohorts retain imaging features associated with Classic NPH. The use of the algorithm of the Periodic Table allowed for greater consistency in the interpretation of DTI results by focusing on patterns of injury rather than an over-reliance on the interrogation of individual measures by statistical significance alone. Our aim is to provide a prototype that could be refined for an approach toward the concept of a "translational taxonomy."

Using the consolidated framework for implementation research to guide a pilot of implementing an institution level patient informed consent process for clinical research at an outpatient setting.

BACKGROUND: In Singapore, research teams seek informed patient consent on an ad hoc basis for specific clinical studies and there is typically a role separation between operational and research staff. With the enactment of the Human Biomedical Research Act, there is increased emphasis on compliance with consent-taking processes and research documentation. To optimize resource use and facilitate long-term research sustainability at our institution, this study aimed to design and pilot an institution level informed consent workflow (the "intervention") that is integrated with clinic operations. METHODS: We used the Consolidated Framework for Implementation Research (CFIR) as the underpinning theoretical framework and conducted the study in three stages: Stage 1, CFIR constructs were used to systematically identify barriers and facilitators of intervention implementation, and a simple time-and-motion study of the patient journey was used to inform the design of the intervention; Stage 2, implementation strategies were selected and mapped to the Expert Recommendations for Implementing Change (ERIC) taxonomy; Stage 3, we piloted and adapted the implementation process at two outpatient clinics and evaluated implementation effectiveness through patient participation rates. RESULTS: We identified 15 relevant CFIR constructs. Implementation strategies selected to address these constructs were targeted at three groups of stakeholders: institution leadership (develop relationships, involve executive boards, identify and prepare champions), clinic management team (develop relationships, identify and prepare champions, obtain support and commitment, educate stakeholders), and clinic operations staff (develop relationships, assess readiness, conduct training, cyclical tests of change, model and simulate change, capture and share local knowledge, obtain and use feedback). Time-and-motion study in clinics identified the pre-consultation timepoint as the most appropriate for the intervention. The implementation process was adapted according to clinic operations staff and service needs. At the conclusion of the pilot, 78.3% of eligible patients provided institution level informed consent via the integrated workflow implemented. CONCLUSIONS: Our findings support the feasibility of implementing an institution level informed consent workflow that integrates with service operations at the outpatient setting to optimize healthcare resources for research. The CFIR provided a useful framework to identify barriers and facilitators in the design of the intervention and its implementation process.

An unusual case of dengue fever in aneurysmal subarachnoid haemorrhage: diagnosis and management nuances.

BACKGROUND: Dengue fever is highly prevalent in the Asia-Pacific region. Here we present an unusual case of dengue fever in a patient with a ruptured cerebral aneurysm causing subarachnoid (SAH) and intraventricular haemorrhage (IVH) and discuss the implications of dengue-related thrombopathies on the management of SAH and its complications. CASE REPORT: A 56-year-old female with a two-day history of high-grade pyrexia and myalgia presented with sudden-onset drowsiness (presenting Glasgow Coma Scale, GCS: E1V1M4). Imaging revealed extensive SAH and IVH due to a ruptured right middle cerebral artery (MCA) aneurysm, with extensive vasospasm. Blood test revealed thrombocytopenia and a positive NS-1 antigen. She subsequently suffered from two episodes of re-rupture of the aneurysm and elevated intracranial pressure which required a decompressive craniectomy in addition to coilingof the MCA aneurysm. Cerebral perfusion and rheology were maintained with the triple-H therapy. Her GCS improved to E4V1M6, but remained aphasic. DISCUSSIONS: Thrombocytopenia and deranged platelet functions in dengue infection might affect the stability of clot and increase the risk of re-rupture of aneurysm. Immediate securement of the aneurysm was paramount. In cases of severe dengue, plasma leakage could lead to intravascular depletion, and coupled with haemoconcentration and hypotension would further increase the risk for vasospasm.

Neuroimaging data repositories and AI-driven healthcare-Global aspirations vs. ethical considerations in machine learning models of neurological disease.

Neuroimaging data repositories are data-rich resources comprising brain imaging with clinical and biomarker data. The potential for such repositories to transform healthcare is tremendous, especially in their capacity to support machine learning (ML) and artificial intelligence (AI) tools. Current discussions about the generalizability of such tools in healthcare provoke concerns of risk of bias-ML models underperform in women and ethnic and racial minorities. The use of ML may exacerbate existing healthcare disparities or cause post-deployment harms. Do neuroimaging data repositories and their capacity to support ML/AI-driven clinical discoveries, have both the potential to accelerate innovative medicine and harden the gaps of social inequities in neuroscience-related healthcare? In this paper, we examined the ethical concerns of ML-driven modeling of global community neuroscience needs arising from the use of data amassed within neuroimaging data repositories. We explored this in two parts; firstly, in a theoretical experiment, we argued for a South East Asian-based repository to redress global imbalances. Within this context, we then considered the ethical framework toward the inclusion vs. exclusion of the migrant worker population, a group subject to healthcare inequities. Secondly, we created a model simulating the impact of global variations in the presentation of anosmia risks in COVID-19 toward altering brain structural findings; we then performed a mini AI ethics experiment. In this experiment, we interrogated an actual pilot dataset (n = 17; 8 non-anosmic (47%) vs. 9 anosmic (53%) using an ML clustering model. To create the COVID-19 simulation model, we bootstrapped to resample and amplify the dataset. This resulted in three hypothetical datasets: (i) matched (n = 68; 47% anosmic), (ii) predominant non-anosmic (n = 66; 73% disproportionate), and (iii) predominant anosmic (n = 66; 76% disproportionate). We found that the differing proportions of the same cohorts represented in each hypothetical dataset altered not only the relative importance of key features distinguishing between them but even the presence or absence of such features. The main objective of our mini experiment was to understand if ML/AI methodologies could be utilized toward modelling disproportionate datasets, in a manner we term "AI ethics." Further work is required to expand the approach proposed here into a reproducible strategy.

Diffusion Tensor Imaging Profiles Can Distinguish Diffusivity and Neural Properties of White Matter Injury in Hydrocephalus vs. Non-hydrocephalus Using a Strategy of a Periodic Table of DTI Elements.

Background: The aim of this study was to create a simplistic taxonomy to improve transparency and consistency in, and reduce complexity of, interpreting diffusion tensor imaging (DTI) profiles in white matter disruption. Using a novel strategy of a periodic table of DTI elements, we examined if DTI profiles could demonstrate neural properties of disruption sufficient to characterize white matter changes specific for hydrocephalus vs. non-hydrocephalus, and to distinguish between cohorts of neural injury by their differing potential for reversibility. Methods: DTI datasets from three clinical cohorts representing pathological milestones from reversible to irreversible brain injury were compared to those of healthy controls at baseline, over time and with interventions. The final dataset comprised patients vs. controls in the following groupings: mild traumatic brain injury (mTBI), n = 24 vs. 27, normal pressure hydrocephalus (NPH), n = 16 vs. 9 and Alzheimer's disease (AD), n = 27 vs. 47. We generated DTI profiles from fractional anisotropy (FA) and mean, axial and radial diffusivity measures (MD, L1 and L2 and 3 respectively), and constructed an algorithm to map changes consistently to a periodic table of elements, which fully described their diffusivity and neural properties. Results: Mapping tissue signatures to a periodic table of DTI elements rapidly characterized cohorts by their differing patterns of injury. At baseline, patients with mTBI displayed the most preserved tracts. In NPH, the magnitude of changes was dependent on "familial" DTI neuroanatomy, i.e., potential for neural distortion from risk of ventriculomegaly. With time, patients with Alzheimer's disease were significantly different to controls across multiple measures. By contrast, patients with mTBI showed both loss of integrity and pathophysiological processes of neural repair. In NPH, some patterns of injury, such as "stretch/compression" and "compression" were more reversible following intervention than others; these neural profile properties suggested "microstructural resilience" to injury. Conclusion: Using the novel strategy of a periodic table of DTI elements, our study has demonstrated it is possible to distinguish between different cohorts along the spectrum of brain injury by describing neural profile properties of white matter disruption. Further work to contribute datasets of disease toward this proposed taxonomic framework would enhance the translatability of DTI profiles to the clinical-research interface.

Clinical Outcomes After Ventriculo-Peritoneal Shunting in Patients With Classic vs. Complex NPH.

Objective: Normal pressure hydrocephalus (NPH) is a neurological condition characterized by a clinical triad of gait disturbance, cognitive impairment, and urinary incontinence in conjunction with ventriculomegaly. Other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular dementia share some overlapping clinical features. However, there is evidence that patients with comorbid NPH and Alzheimer's or Parkinson's disease may still exhibit good clinical response after CSF diversion. This study aims to evaluate clinical responses after ventriculo-peritoneal shunt (VPS) in a cohort of patients with coexisting NPH and neurodegenerative disease. Methods: The study has two components; (i) a pilot study was performed that specifically focused upon patients with Complex NPH and following the inclusion of the Complex NPH subtype into consideration for the clinical NPH programme, (ii) a retrospective snapshot study was performed to confirm and characterize differences between Classic and Complex NPH patients being seen consecutively over the course of 1 year within a working subspecialist NPH clinic. We studied the characteristics of patients with Complex NPH, utilizing clinical risk stratification and multimodal biomarkers. Results: There was no significant difference between responders and non-responders to CSF diversion on comorbidity scales. After VPS insertion, significantly more Classic NPH patients had improved cognition compared to Complex NPH patients (p = 0.005). Improvement in gait and urinary symptoms did not differ between the groups. 26% of the Classic NPH group showed global improvement of the triad, and 42% improved in two domains. Although only 8% showed global improvement of the triad, all Complex NPH patients improved in gait. Conclusions: Our study has demonstrated that the presence of neurodegenerative disorders co-existing with NPH should not be the sole barrier to the consideration of high-volume tap test or lumbar drainage via a specialist NPH programme. Further characterization of distinct cohorts of NPH with differing degrees of CSF responsiveness due to overlay from neurodegenerative or comorbidity risk burden may aid toward more precise prognostication and treatment strategies. We propose a simplistic conceptual framework to describe NPH by its Classic vs. Complex subtypes to promote the clinical paradigm shift toward subspecialist geriatric neurosurgery by addressing needs for rapid screening tools at the clinical-research interface.

Modeling the Properties of White Matter Tracts Using Diffusion Tensor Imaging to Characterize Patterns of Injury in Aging and Neurodegenerative Disease.

Diffusion tensor imaging (DTI) is a relatively novel magnetic resonance-based imaging methodology that can provide valuable insight into the microstructure of white matter tracts of the brain. In this paper, we evaluated the reliability and reproducibility of deriving a semi-automated pseudo-atlas DTI tractography method vs. standard atlas-based analysis alternatives, for use in clinical cohorts with neurodegeneration and ventriculomegaly. We showed that the semi-automated pseudo-atlas DTI tractography method was reliable and reproducible across different cohorts, generating 97.7% of all tracts. However, DTI metrics obtained from both methods were significantly different across the majority of cohorts and white matter tracts (p < 0.001). Despite this, we showed that both methods produced patterns of white matter injury that are consistent with findings reported in the literature and with DTI profiles generated from these methodologies. Scatter plots comparing DTI metrics obtained from each methodology showed that the pseudo-atlas method produced metrics that implied a more preserved neural structure compared to its counterpart. When comparing DTI metrics against a measure of ventriculomegaly (i.e., Evans' Index), we showed that the standard atlas-based method was able to detect decreasing white matter integrity with increasing ventriculomegaly, while in contrast, metrics obtained using the pseudo-atlas method were sensitive for stretch or compression in the posterior limb of the internal capsule. Additionally, both methods were able to show an increase in white matter disruption with increasing ventriculomegaly, with the pseudo-atlas method showing less variability and more specificity to changes in white matter tracts near to the ventricles. In this study, we found that there was no true gold-standard for DTI methodologies or atlases. Whilst there was no congruence between absolute values from DTI metrics, differing DTI methodologies were still valid but must be appreciated to be variably sensitive to different changes within white matter injury occurring concurrently. By combining both atlas and pseudo-atlas based methodologies with DTI profiles, it was possible to navigate past such challenges to describe white matter injury changes in the context of confounders, such as neurodegenerative disease and ventricular enlargement, with transparency and consistency.

Relevance of presenting risks of frailty, sarcopaenia and osteopaenia to outcomes from aneurysmal subarachnoid haemorrhage.

INTRODUCTION: Aneurysmal subarachnoid haemorrhage (aSAH) is a condition with significant morbidity and mortality. Traditional markers of aSAH have established their utility in the prediction of aSAH outcomes while frailty markers have been validated in other surgical specialties. We aimed to compare the predictive value of frailty indices and markers of sarcopaenia and osteopaenia, against the traditional markers for aSAH outcomes. METHODS: An observational study in a tertiary neurosurgical unit on 51 consecutive patients with ruptured aSAH was performed. The best performing marker in predicting the modified Rankin scale (mRS) on discharge was selected and an appropriate threshold for the definition of frail and non-frail was derived. We compared various frailty indices (modified frailty index 11, and 5, and the National Surgical Quality Improvement Program score [NSQIP]) and markers of sarcopaenia and osteopaenia (temporalis [TMT] and zygoma thickness), against traditional markers (age, World Federation of Neurological Surgery and modified Fisher scale [MFS]) for aSAH outcomes. Univariable and multivariable analysis was then performed for various inpatient and long-term outcomes. RESULTS: TMT was the best performing marker in our cohort with an AUC of 0.82, Somers' D statistic of 0.63 and Tau statistic 0.25. Of the frailty scores, the NSQIP performed the best (AUC 0.69), at levels comparable to traditional markers of aSAH, such as MFS (AUC 0.68). The threshold of 5.5 mm in TMT thickness was found to have a specificity of 0.93, sensitivity of 0.51, positive predictive value of 0.95 and negative predictive value of 0.42. After multivariate analysis, patients with TMT ≥ 5.5 mm (defined as non-frail), were less likely to experience delayed cerebral ischaemia (OR 0.11 [0.01 - 0.93], p = 0.042), any complications (OR 0.20 [0.06 - 0.069], p = 0.011), and had a larger proportion of favourable mRS on discharge (95.0% vs. 58.1%, p = 0.024) and at 3-months (95.0% vs. 64.5%, p = 0.048). However, the gap between unfavourable and favourable mRS was insignificant at the comparison of 1-year outcomes. CONCLUSION: TMT, as a marker of sarcopaenia, correlated well with the presenting status, and outcomes of aSAH. Frailty, as defined by NSQIP, performed at levels equivalent to aSAH scores of clinical relevance, suggesting that, in patients presenting with acute brain injury, both non-neurological and neurological factors were complementary in the determination of eventual clinical outcomes. Further validation of these markers, in addition to exploration of other relevant frailty indices, may help to better prognosticate aSAH outcomes and allow for a precision medicine approach to decision making and optimization of best outcomes.

Endoscopic excision of an aqueduct of Sylvius cavernoma causing obstructive hydrocephalus: technical note.

BACKGROUND AND IMPORTANCE: Acquired lesions within the aqueduct of Sylvius are rare and their surgical management is challenging. Open transcranial approaches require dissection and manipulation of surrounding eloquent structures. Use of an endoscope can avoid potential morbidity from traversing and handling eloquent structures during open approaches whilst providing better visualisation of an intraventricular lesion. CLINICAL PRESENTATION: A 62-year-old female presented with insidious onset short-term memory loss, unsteady gait, urinary incontinence and left-sided dysaesthesia. Magnetic resonance imaging (MRI) revealed hydrocephalus from an obstructive haemorrhagic lesion consistent with a cavernoma at the central midbrain within the aqueduct of Sylvius. An endoscopic approach was selected to provide optimal visualisation of the lesion. As only a single instrument could be accommodated, rotational movements were employed to tease out the lesion. Gross total resection was achieved. Her symptoms improved immediately postoperatively and she made a complete recovery by 2 months. Post-operative MRI showed resolution of hydrocephalus and no evidence of residual/recurrence of the lesion. Unfortunately, she developed hydrocephalus 3 months post-op and required placement of a ventriculoperitoneal shunt. CONCLUSIONS: Endoscopic resection is safe and feasible for selected periaqueductal lesions as it provides direct access while minimising disruption of the surrounding anatomical structures. The limitation of only having a single instrument can be overcome by employing rotational movements.

Liminal spaces in neurosurgery - tensions between expectations of the patient and their surgeon at the threshold of informed consent.

Purpose: The concept of 'liminality', describing the universal human experience of transition in status, has been shown to be relevant in addressing the provision of healthcare needs within clinical medicine. Consent may be viewed as a threshold which patients must cross between a state of integration of information to a state of transformation into knowledge. This article reframes gaps in the modern surgical approach to the process of 'informed consent' via the lens of liminality, drawing on key illustrative cases from the medicolegal evolution in the UK and Commonwealth.Materials and methods: A focused literature search was performed for informative medical legal cases addressing or contributing to the understanding of "informed consent". Searches and references to sources of case law were performed using Westlaw and Hein Online databases. Searches for secondary sources for interpretation and discussions of case law and concepts, as well as topics of liminality and autonomy, were performed via PubMed and Academia databases and relevant online resources.Results: The paper organizes the illustrative material using the following approach:- a discussion and dissection of the i) evolution of consent as a duty to warn, comprising a summary of landmark cases, ii) materiality of risks and what a particular patient would wish to know and iii) conceptual relevance of troublesome knowledge, relational autonomy and threshold concepts in learning to key examples in case law and the process of informed consent.Conclusions: Modern surgical practice of informed consent must strive for clarity of mutual understanding. The framework of liminality allows us to understand the in-between states encountered during the patient's journey. An ability to recognize such gaps in expectations, and develop tools to promote transformational learning, would allow the surgeon to evolve from prudent practitioner to patient mentor at the threshold of informed consent.

The Impact of Multimorbidity Burden, Frailty Risk Scoring, and 3-Directional Morphological Indices vs. Testing for CSF Responsiveness in Normal Pressure Hydrocephalus.

Objective: Multimorbidity burden across disease cohorts and variations in clinico-radiographic presentations within normal pressure hydrocephalus (NPH) confound its diagnosis, and the assessment of its amenability to interventions. We hypothesized that novel imaging techniques such as 3-directional linear morphological indices could help in distinguishing between hydrocephalus vs. non-hydrocephalus and correlate with responsiveness to external lumbar drainage (CSF responsiveness) within NPH subtypes. Methodology: Twenty-one participants with NPH were recruited and age-matched to 21 patients with Alzheimer's Disease (AD) and 21 healthy controls (HC) selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Patients with NPH underwent testing via the NPH programme with external lumbar drainage (ELD); pre- and post-ELD MRI scans were obtained. The modified Frailty Index (mFI-11) was used to stratify the NPH cohort, including Classic and Complex subtypes, by their comorbidity and frailty risks. The quantitative imaging network tool 3D Slicer was used to derive traditional 2-dimensional (2d) linear measures; Evans Index (EI), Bicaudate Index (BCI) and Callosal Angle (CA), along with novel 3-directional (3d) linear measures; z-Evans Index and Brain per Ventricle Ratio (BVR). 3-Dimensional (3D) ventricular volumetry was performed as an independent correlate of ventriculomegaly to CSF responsiveness. Results: Mean age for study participants was 71.14 ± 6.3 years (18, 85.7% males). The majority (15/21, 71.4%) of participants with NPH comprised the Complex subtype (overlay from vascular risk burden and AD); 12/21 (57.1%) were Non-Responders to ELD. Frailty alone was insufficient in distinguishing between NPH subtypes. By contrast, 3d linear measures distinguished NPH from both AD and HC cohorts, but also correlated to CSF responsiveness. The z-Evans Index was the most sensitive volumetric measure of CSF responsiveness (p = 0.012). Changes in 3d morphological indices across timepoints distinguished between Responders vs. Non-Responders to lumbar testing. There was a significant reduction of indices, only in Non-Responders and across multiple measures (z-Evans Index; p = 0.001, BVR at PC; p = 0.024). This was due to a significant decrease in ventricular measurement (p = 0.005) that correlated to independent 3D volumetry (p = 0.008). Conclusion. In the context of multimorbidity burden, frailty risks and overlay from neurodegenerative disease, 3d morphological indices demonstrated utility in distinguishing hydrocephalus vs. non-hydrocephalus and degree of CSF responsiveness. Further work may support the characterization of patients with Complex NPH who would best benefit from the risks of interventions.

Geographical Variations in Host Predisposition to COVID-19 Related Anosmia, Ageusia, and Neurological Syndromes.

The novel coronavirus disease (COVID-19), has become the most critical global health challenge in recent history. With SARS-CoV-2 infection, there was an unexpectedly high and specific prevalence of olfactory and taste disorders (OTDs). These high rates of hyposmia and hypogeusia, initially reported as up to 89% in European case series, led to the global inclusion of loss of taste and/or smell as a distinctive feature of COVID-19. However, there is emerging evidence that there are striking differences in the rates of OTDs in East Asian countries where the disease first emerged, as compared to Western countries (15.8 vs. 60.9%, p-value < 0.01). This may be driven by either variations in SARS-CoV-2 subtypes presenting to different global populations or genotypic differences in hosts which alter the predisposition of these different populations to the neuroinvasiveness of SARS-CoV-2. We also found that rates of OTDs were significantly higher in objective testing for OTDs as compared to subjective testing (73.6 vs. 60.8%, p-value = 0.03), which is the methodology employed by most studies. Concurrently, it has also become evident that racial minorities across geographically disparate world populations suffer from disproportionately higher rates of COVID-19 infection and mortality. In this mini review, we aim to delineate and explore the varying rates of olfactory and taste disorders amongst COVID-19 patients, by focusing on their underlying geographical, testing, ethnic and socioeconomic differences. We examine the current literature for evidence of differences in the olfactory and gustatory manifestations of COVID-19 and discuss current pathophysiological hypotheses for such differences.

The splenial angle: a novel radiological index for idiopathic normal pressure hydrocephalus.

OBJECTIVES: To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer's disease (AD), Parkinson's disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans' index and callosal angle. METHODS: Evans' index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. RESULTS: Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. CONCLUSIONS: The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. KEY POINTS: • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans' index and callosal angle in predicting NPH from healthy, Parkinson's disease, and Alzheimer's disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

Lower Breakpoint of Intracranial Amplitude-Pressure Relationship in Normal Pressure Hydrocephalus.

The relationship between intracranial pulse amplitude (AMP) and mean intracranial pressure (ICP) has been previously described. Generally, AMP increases proportionally to rises in ICP. However, at low ICP a lower breakpoint (LB) of amplitude-pressure relationship can be observed, below which pulse amplitude stays constant when ICP varies. Theoretically, below this breakpoint, the pressure-volume relationship is linear (good compensatory reserve, brain compliance stays constant); above the breakpoint, it is exponential (brain compliance decreases with rising ICP).Infusion tests performed in 169 patients diagnosed for idiopathic normal pressure hydrocephalus (iNPH) during the period 2004-2013 were available for analysis. A lower breakpoint was observed in 62 patients diagnosed for iNPH. Improvement after shunt surgery in patients in whom LB was recorded was 77% versus 90% in patients where LB was absent (p < 0.02). There was no correlation between improvement and slope of amplitude-pressure line above LB.The detection of a lower breakpoint is associated with less frequent improvement after shunting in NPH. It may be interpreted that cerebrospinal fluid dynamics of patients working on the flat part of the pressure-volume curve and having a 'luxurious' compensatory reserve, are more frequently caused by brain atrophy, which is obviously not responding to shunting.

Single Center Experience in Cerebrospinal Fluid Dynamics Testing.

Normal pressure hydrocephalus is more complex than a simple disturbance of the cerebrospinal fluid (CSF) circulation. Nevertheless, an assessment of CSF dynamics is key to making decisions about shunt insertion, shunt malfunction, and for further management if a patient fails to improve. We summarize our 25 years of single center experience in CSF dynamics assessment using pressure measurement and analysis. 4473 computerized infusion tests have been performed. We have shown that CSF infusion studies are safe, with incidence of infection at less than 1%. Raised resistance to CSF outflow positively correlates (p < 0.014) with improvement after shunting and is associated with disturbance of cerebral blood flow and its autoregulation (p < 0.02). CSF infusion studies are valuable in assessing possible shunt malfunction in vivo and for avoiding unnecessary revisions. Infusion tests are safe and provide useful information for clinical decision-making for the management of patients suffering from hydrocephalus.

The topology of ventricle surfaces and its application in the analysis of hydrocephalic ventricles: a proof-of-concept study.

PURPOSE: The cerebral ventricles deform in a non-uniform fashion in response to increased CSF volume and/or pressure in hydrocephalic syndromes. Current research is focused on volumetric analyses, while topological analysis of ventricular surfaces remains understudied. We developed a method of quantitatively modeling the curvature of ventricular surfaces to analyze changes in ventricular surfaces in normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD), using the left frontal horn as an example. METHODS: Twenty-one patients with NPH were recruited from our institution, and 21 healthy controls (HC) and patients with Alzheimer's disease (AD) were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. On T1-weighted fine-cut magnetic resonance sequences, 3D Slicer was used to segment the left frontal horn. Next, the mean curvatures at a set of points on the ventricular surface were determined. The frontal horns were scaled and centered into normalized volumes, allowing for pooling across the study subjects. The frontal horn was divided into superolateral, superomedial, inferolateral, and inferomedial surfaces, and locoregional mean curvatures were analyzed. Statistical comparisons were made between NPH, AD, and HC groups. RESULTS: Significant differences in the mean curvature of lateral surfaces of the ventricles distinguished patterns of distortion between all three cohorts. Significant flattening of the superomedial surface discriminated NPH from HC and AD. However, significant rounding of the inferomedial surface compared to controls was a distinguishing feature of NPH alone. CONCLUSION: NPH ventricles deform non-uniformly. The pattern of surface distortion may be used as an additional tool to differentiate between these hydrocephalic conditions.

Callosal angle in idiopathic normal pressure hydrocephalus: small angular mal-rotations of the coronal plane affect measurement reliability.

PURPOSE: The callosal angle (CA) is a useful biomarker in the diagnosis and management of idiopathic normal pressure hydrocephalus (NPH). Used incorrectly, CA measurements are variable, affecting its reliability as a clinical tool. Our objectives are to evaluate (i) reproducibility of established CA measurements between trained raters and (ii) impact of minor angular mal-rotations of the true coronal plane on CA measurements. METHODS: CAs were measured by two independent raters on three-dimensional isovolumetric T1-weighted brain MRI of NPH patients and healthy controls using the established true coronal plane reformatted orthogonal to the plane containing the anterior-posterior commissural (AC-PC) line at the level of the posterior commissure. CA changes were subsequently evaluated when the coronal plane was mal-rotated by ± 5° and ± 10° in anterior-posterior and clockwise-anticlockwise directions. Inter-rater reliability of CA measurements was assessed using the intraclass correlation coefficient (ICC). RESULTS: On the true coronal plane, inter-rater ICC was excellent (0.973) for NPH patients and good (0.875) for controls. On mal-rotated coronal plane setups, ICC for CA was worse in controls (0.484-0.886) than NPH (0.879-0.981) groups and in clockwise-anticlockwise (0.484-0.956) than anterior-posterior (0.503-0.981) mal-rotations. CA changes secondary to mal-rotations from the true coronal plane were significant in NPH patients (P < 0.0001 to 0.0378) but not in controls (P > 0.1). CONCLUSION: This is the first demonstration of how small angular mal-rotations of the coronal plane used for CA measurement affect its value and inter-rater reliability, highlighting the importance of a standardized protocol when measuring the CA in NPH workup.

Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson's disease.

BACKGROUND: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD. METHODS: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed. RESULTS: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration. CONCLUSIONS: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Aqueductal Compression by Dilated Virchow-Robin Spaces in the Mesencephalic-Pontine Region Presenting with Symptoms Mimicking Normal Pressure Hydrocephalus: A Case Report and Review of Literature.

BACKGROUND: Dilatation of Virchow-Robin spaces (dVRS) have been described in the development of hydrocephalic syndromes. We report an unusual case of a type III dVRS presenting as a mimic of normal pressure hydrocephalus (NPH), due to distortion at the level of the cerebral aqueduct. CASE DESCRIPTION: A 59-year-old woman presented with mild traumatic brain injury and possible NPH, due to a history of progressive gait disturbance, recurrent falls, and cognitive decline over a year, in the context of ventriculomegaly. Detailed structural imaging of the brain revealed multiple dilated cystic lesions consistent with dVRS causing distortion at the level of the cerebral aqueduct. Cerebrospinal fluid examination was negative for infection. The patient was treated with endoscopic third ventriculostomy; at 12 months postoperatively, she demonstrated a sustained improvement in gait and stabilization of cognitive decline. CONCLUSIONS: This is an illustrative case of a subacute obstructive hydrocephalus due to a collection of periaqueductal dVRS, leading to an insidious clinical presentation mimicking NPH. We reviewed the literature for key clinical presentations and describe neuroanatomical considerations as well as primary treatment strategies. Various hydrocephalic syndromes may present with classic symptoms from Hakim's triad; such symptoms are not specific to idiopathic NPH. Both endoscopic third ventriculostomy and shunting may be efficacious. In our case, dVRS may serve as both a cause of and compensatory mechanism in a subacute obstructive hydrocephalus of unknown etiology. Our case highlights the need to understand the neuroanatomy of aberrant cerebrospinal fluid spaces in hydrocephalic syndromes. Further studies of dVRS would provide valuable insights into the pathogenesis of hydrocephalus.

Plasma ubiquitin C-terminal hydrolase L1 levels reflect disease stage and motor severity in Parkinson's disease.

Parkinson's disease (PD) is characterized by Lewy bodies containing α-synuclein and ubiquitin aggregates, their co-occurrence possibly linked to a failure of the ubiquitin proteasome system. Ubiquitin C-terminal hydrolase L1 (UCHL1) plays an important role in maintenance of nervous system integrity, and overexpression of UCHL1 has been shown to increase ubiquitin levels within neurons. While cerebrospinal fluid ubiquitin levels were reported to be lower in PD vs controls, plasma UCHL1 levels and their relationship with clinical measures in PD has not been reported. We measured plasma UCHL1 levels using single molecule array (Simoa) in 291 subjects (242 PD and 49 healthy controls, HC). We found that UCHL1 levels were significantly higher in PD patients at moderate stages (Hoehn and Yahr, H&Y stage >2) vs milder PD (H&Y ≤2, p<0.001) and HC (p=0.001). There was no significant difference in UCHL1 levels between PD patients at H&Y stages ≤2 vs HC. Across all PD patients, UCHL1 correlated significantly with UPDRS Part III motor scores (ß=3.87, 95% CI=0.43-7.31, p=0.028), but not with global cognition. Overall, we found that UCHL1 correlates with motor function in PD, with higher levels seen in later disease stages. These findings will be validated in longitudinal studies.