Summary
Thrombotic thrombocytopenic purpura (TTP) is a rare thrombomicroangiopathy caused by deficiency of ADAMTS13. Acute neurological involvement is well described, but its long‐term impact ...requires evaluation. One‐hundred thirty‐one patients, following an acute TTP event, with severe headache or neurological symptoms had a cerebral MRI. Fifty‐six percent had abnormal imaging, more commonly in patients with neurological symptoms than headaches only (80% vs. 18%, P < 0·0001). In remission, 27% (n = 35) reported persistent cognitive symptoms: specifically, impaired memory (66%), difficulty concentrating (26%), and word‐finding difficulties not secondary to an acute stroke (26%). Sixty‐five percent also reported depression and 55% reported anxiety, regardless of presenting neurology. The frontal lobe was disproportionally affected in patients with marked intellectual impairment, seen in 67% of patients compared to 19% of patients without intellectual impairment (P = 0·002). The primary MRI finding in these patients was hyperintense white matter lesions. An abnormal MRI was associated with a lower median verbal IQ (85 vs. 99, P = 0·02) and performance IQ (83 vs. 100, P = 0·02). In conclusion, neurological symptoms are frequently associated with an abnormal cerebral MRI scan, and white matter frontal lobe lesions are particularly significant, leading to marked intellectual impairment. Anxiety and depression were evident in over half of patients, regardless of neurological involvement at presentation.
Purpose
Effective treatment of diffuse intrinsic pontine glioma (DIPG) remains a formidable challenge due to inadequate penetration of the blood–brain barrier (BBB) by systemically administered ...chemotherapies. The BBB can be overcome by directly infusing drugs into pons using method of convection-enhanced delivery (CED). We describe our clinical experience and what we have learned about the safety and feasibility of treating DIPG with intermittent CED of carboplatin and sodium valproate to the pons through the Renishaw Drug Delivery System (RDDS).
Methods
Retrospective review (2017–2020) of children with DIPG, who following radiotherapy, received compassionate treatment commencing 3.3–10 months post-diagnosis (median 4.9 months). They received up to 7 cycles of 3–6 weekly pontine infusions of carboplatin (0.12–0.18 mg/ml) and sodium valproate (14.4–28.8 mg/ml).
Results
13 children 3–19 years (mean 6.9 years) were treated. There were no surgical complications. With the exception of infusion channels blocking in one device, there were no adverse device effects. Two patients developed persistent 6th nerve palsies, which led to drug concentration reduction in the combination therapy. Subsequently infusion/ drug-related toxicities were transient. Tumour was controlled in pons in 10/13 patients. Median progression-free survival (PFS) was 13.0 months, while median overall survival (OS) was 15.3 months.
Conclusions
Use of the RDDS was safe and well tolerated in all 13 patients. Treatment improved control of pontine disease resulting in longer PFS and OS and merits further evaluation in a clinical trial.
•Individuals remain poorly predictable from population-level analyses of the brain.•The fidelity limits data scale, compute, and model flexibility impose are unknown.•We quantify these limits in ...multimodal, multitarget analyses across 23810 people.•We show a radical change in modelling regimes is needed for individual prediction.
Our knowledge of the organisation of the human brain at the population-level is yet to translate into power to predict functional differences at the individual-level, limiting clinical applications and casting doubt on the generalisability of inferred mechanisms. It remains unknown whether the difficulty arises from the absence of individuating biological patterns within the brain, or from limited power to access them with the models and compute at our disposal.
Here we comprehensively investigate the resolvability of such patterns with data and compute at unprecedented scale. Across 23 810 unique participants from UK Biobank, we systematically evaluate the predictability of 25 individual biological characteristics, from all available combinations of structural and functional neuroimaging data. Over 4526 GPU*hours of computation, we train, optimize, and evaluate out-of-sample 700 individual predictive models, including fully-connected feed-forward neural networks of demographic, psychological, serological, chronic disease, and functional connectivity characteristics, and both uni- and multi-modal 3D convolutional neural network models of macro- and micro-structural brain imaging.
We find a marked discrepancy between the high predictability of sex (balanced accuracy 99.7%), age (mean absolute error 2.048 years, R2 0.859), and weight (mean absolute error 2.609Kg, R2 0.625), for which we set new state-of-the-art performance, and the surprisingly low predictability of other characteristics. Neither structural nor functional imaging predicted an individual's psychology better than the coincidence of common chronic disease (p < 0.05). Serology predicted chronic disease (p < 0.05) and was best predicted by it (p < 0.001), followed by structural neuroimaging (p < 0.05).
Our findings suggest either more informative imaging or more powerful models will be needed to decipher individual level characteristics from the human brain. We make our models and code openly available.
Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly ...advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response.
Prions cause a variety of CNS illnesses, such as Creutzfeldt–Jakob disease. In this British kindred, a prion-associated process was associated with chronic diarrhea and autonomic dysfunction, a ...finding that extends the known disorders caused by these aberrant proteins.
The prion diseases are transmissible, fatal, neurodegenerative disorders that may be inherited or acquired or that may occur spontaneously as sporadic Creutzfeldt–Jakob disease.
1
The transmissible agent, or prion, is thought to comprise misfolded and aggregated forms of the normal cell-surface prion protein. Prion propagation is thought to occur by means of seeded protein polymerization, a process involving the binding and templated misfolding of normal cellular prion protein. Similar processes are increasingly recognized as relevant to other, more common neurodegenerative diseases. In prion and other neurodegenerative disorders, the aggregates of misfolded protein in the central nervous system are highly heterogeneous, occurring . . .
Abstract
Hematological malignancies place individuals at risk of CNS involvement from their hematological disease and opportunistic intracranial infection secondary to disease-/treatment-associated ...immunosuppression. Differentiating CNS infection from hematological disease infiltration in these patients is valuable but often challenging. We sought to determine if statistical models might aid discrimination between these processes. Neuroradiology, clinical and laboratory data for patients with hematological malignancy at our institution between 2007 and 2017 were retrieved. MRI were deep-phenotyped across anatomical distribution, presence of pathological enhancement, diffusion restriction and hemorrhage and statistically modelled with Bayesian-directed probability networks and multivariate logistic regression. 109 patients were studied. Irrespective of a diagnosis of CNS infection or hematological disease, the commonest anatomical distributions of abnormality were multifocal-parenchymal (34.9%), focal-parenchymal (29.4%) and leptomeningeal (11.9%). Pathological enhancement was the most frequently observed abnormality (46.8%), followed by hemorrhage (22.9%) and restricted diffusion (19.3%). Logistic regression could differentiate CNS infection from hematological disease infiltration with an AUC of 0.85 where, with OR > 1 favoring CNS infection and < 1 favoring CNS hematological disease, significantly predictive imaging features were hemorrhage (OR 24.61,
p
= 0.02), pathological enhancement (OR 0.17,
p
= 0.04) and an extra-axial location (OR 0.06,
p
= 0.05). In conclusion, CNS infection and hematological disease are heterogeneous entities with overlapping radiological appearances but a multivariate interaction of MR imaging features may assist in distinguishing them.
(1) Background: Standard magnetic resonance imaging (MRI) remains the gold standard for brain tumour imaging in paediatric and teenage and young adult (TYA) patients. Combining positron emission ...tomography (PET) with MRI offers an opportunity to improve diagnostic accuracy. (2) Method: Our single-centre experience of
F-fluorocholine (FCho) and
fluoro-L-phenylalanine (FDOPA) PET-MRI in paediatric/TYA neuro-oncology patients is presented. (3) Results: Hybrid PET-MRI shows promise in the evaluation of gliomas and germ cell tumours in (i) assessing early treatment response and (ii) discriminating tumour from treatment-related changes. (4) Conclusions: Combined PET-MRI shows promise for improved diagnostic and therapeutic assessment in paediatric and TYA brain tumours.
IMPORTANCE: A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants ...and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease. OBJECTIVE: To establish a more powerful and meaningful clinical trial method in sCJD. DESIGN, SETTING, AND PARTICIPANTS: A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs. MAIN OUTCOMES AND MEASURES: A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein PrP gene sequencing, PrPSc type). RESULTS: Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P < .001). Simulations indicate that an adequately powered (80%; 2-sided α = .05) open-label randomized trial using 50% reduction in Medical Research Council Scale decline as the primary outcome could be conducted with only 120 participants assessed every 10 days and only 90 participants assessed daily, providing considerably more power than using survival as the primary outcome. Restricting to VV or MV codon 129 genotypes increased power even further. Alternatively, single-arm intervention studies (half the total sample size) could provide similar power in comparison to the natural history cohort. CONCLUSIONS AND RELEVANCE: Functional end points in neurodegeneration need not require long and very large clinical studies to be adequately powered for efficacy. Patients with sCJD may be an efficient and cost-effective group for testing disease-modifying therapeutics. Stratified medicine and natural history cohort approaches may transform the feasibility of clinical trials in orphan diseases.
To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED.
13 children diagnosed with DIPG received between 3.8 and 5.7 ml of ...infusate, through two pairs of catheters to encompass tumor volume on day 1 of cycle one of treatment. Volumetric T2-weighted (T2W) and diffusion-weighted MRI imaging (DWI) were performed before and after day 1 of CED. Apparent diffusion coefficient (ADC) maps were calculated. The tumor volume pre and post CED was automatically segmented on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were aligned and subtracted to visualize the infusate distribution.
There was a significant increase (
< 0.001) in mean ADC and T2W signal intensity (SI) ratio and a significant (
< 0.001) increase in mean tumor volume defined by ADC and T2W SI post infusion (mean ADC volume pre: 19.8 ml, post: 24.4 ml; mean T2W volume pre: 19.4 ml, post: 23.4 ml). A significant correlation (
< 0.001) between infusate volume and difference in ADC/T2W SI defined tumor volume was observed (ADC, r = 0.76; T2W, r = 0.70). Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion demonstrated a volume of high signal intensity, presumed infusate distribution.
ADC and T2W MRI are proposed as a combined parameter method for evaluation of CED infusate distribution in brainstem tumors in future clinical trials.
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