Prion-like α-synuclein pathology in the brain of infants with Krabbe disease.

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.

Stria terminalis microstructure in humans predicts variability in orienting towards threat.

Current concepts of the extended amygdala posit that basolateral to central amygdala projections mediate fear-conditioned autonomic alerting, whereas projections to the bed nucleus of the stria terminalis mediate sustained anxiety. Using diffusion tensor imaging tractography in humans, we show that microstructure of the stria terminalis correlates with an orienting bias towards threat in a saccade decision task, providing the first evidence that this circuit supports decisions guiding evaluation of threatening stimuli.

Metagenomics in the Diagnosis of Pneumonia: Protocol for a Systematic Review.

BACKGROUND: Causative pathogens are currently identified in only a minority of pneumonia cases, which affects antimicrobial stewardship. Metagenomic next-generation sequencing (mNGS) has potential to enhance pathogen detection due to its sensitivity and broad applicability. However, while studies have shown improved sensitivity compared with conventional microbiological methods for pneumonia diagnosis, it remains unclear whether this can translate into clinical benefit. Most existing studies focus on patients who are ventilated, readily allowing for analysis of bronchoalveolar lavage fluid (BALF). The impact of sample type on the use of metagenomic analysis remains poorly defined. Similarly, previous studies rarely differentiate between the types of pneumonia involved-community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), or ventilator-associated pneumonia (VAP)-which have different clinical profiles. OBJECTIVE: This study aims to determine the clinical use of mNGS in CAP, HAP, and VAP, compared with traditional microbiological methods. METHODS: We aim to review all studies (excluding case reports of a series of fewer than 10 people) of adult patients with suspected or confirmed pneumonia that compare metagenomic analysis with traditional microbiology techniques, including culture, antigen-based testing, and polymerase chain reaction-based assays. Relevant studies will be identified through systematic searches of the Embase, MEDLINE, Scopus, and Cochrane CENTRAL databases. Screening of titles, abstracts, and subsequent review of eligible full texts will be done by 2 separate reviewers (SQ and 1 of AL, CJ, or CH), with a third clinician (ES) providing adjudication in case of disagreement. Our focus is on the clinical use of metagenomics for patients with CAP, HAP, and VAP. Data extracted will focus on clinically important outcomes-pathogen positivity rate, laboratory turnaround time, impact on clinical decision-making, length of stay, and 30-day mortality. Subgroup analyses will be performed based on the type of pneumonia (CAP, HAP, or VAP) and sample type used. The risk of bias will be assessed using the QUADAS-2 tool for diagnostic accuracy studies. Outcome data will be combined in a random-effects meta-analysis, and where this is not possible, a narrative synthesis will be undertaken. RESULTS: The searches were completed with the assistance of a medical librarian on January 13, 2024, returning 5750 records. Screening and data extraction are anticipated to be completed by September 2024. CONCLUSIONS: Despite significant promise, the impact of metagenomic analysis on clinical pathways remains unclear. Furthermore, it is unclear whether the use of this technique will alter depending on whether the pneumonia is a CAP, HAP, or VAP or the sample type that is collected. This systematic review will assess the current evidence base to support the benefit of clinical outcomes for metagenomic analysis, depending on the setting of pneumonia diagnosis or specimen type used. It will identify areas where further research is needed to advance this methodology into routine care. TRIAL REGISTRATION: PROSPERO CRD42023488096; https://tinyurl.com/3suy7cma. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57334.

'Internet is easy if you know how to use it': Doing online research with people with learning disabilities during the COVID-19 pandemic.

Background: The coronavirus disease 2019 pandemic changed the way we live, work, interact and do research. Many activities moved online, and digital inclusion became an urgent issue for researchers working with people with learning disabilities and other groups at risk of exclusion. This has generated new questions about how we conduct research and what it means to go into 'the field'. Methods: We discuss our experience working across four qualitative research projects involving 867 participants with learning disabilities, conducted during the coronavirus disease 2019 pandemic. Findings: Moving research online resulted in often-swift adaptations to research designs and practice, bringing new insights and benefits to our studies. The changing circumstances fostered innovation and greater flexibility and contributed to research becoming more accessible to many. However, doing research online also posed new challenges as well as amplified existing ones. Conclusions: The pandemic has made it easier for some people with learning disabilities to participate in research, but more needs to be done to improve the reach and quality of that participation. Researchers should make the process of participation as accessible as possible. It is also their job to question and challenge the conditions that create barriers to participation in research and to look for ways to change these. We make some recommendations on how this can be achieved.

Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies.

Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. Therefore, the present study sought to determine whether the nbM is subject to mitochondrial dysfunctional in LBD and the association of Lewy body formation with such changes. Post-mortem nbM tissue was stained for Complex I or IV and quantitated relative to porin with immunofluorescence using confocal microscopy of individual cells from LBD (303 neurons, 8 cases), control (362 neurons, 8 cases) and asymptomatic incidental LBD (iLBD) cases (99 neurons, 2 cases). Additionally, α-synuclein, tau and amyloid-ß pathology were analysed using quantitative immunohistochemistry, and respiratory chain markers were compared in cells with Lewy bodies (N = 134) and unaffected cells (N = 272). The expression of Complex I normalised to mitochondrial mass was significantly lower in LBD compared to control and iLBD cases and this was unrelated to local neuropathological burdens but trended toward a relationship with neuronal loss. Furthermore, Complex I expression was higher in cells with Lewy bodies compared to adjacent cells without α-synuclein aggregates. These findings suggest that Complex I deficits in the nbM occur in symptomatic LBD cases and may relate to neuronal loss, but that contrary to the view that Lewy body formation underlies neuronal dysfunction and damage in LBD, Lewy bodies are associated with higher Complex I expression than neurons without Lewy bodies. One could speculate that Lewy bodies may provide a mechanism to encapsulate damaged mitochondria and/or α-synuclein oligomers, thus protecting neurons from their cytotoxic effects.

Modulation of triheteromeric NMDA receptors by N-terminal domain ligands.

NMDA receptors (NMDARs) are heteromeric assemblies of NR1 and NR2(A-D) subunits with properties heavily influenced by the type of NR2 subunit incorporated. While NMDARs with only one type of NR2 subunit have been extensively characterized, little is known about receptors containing two different NR2 subunits, despite compelling evidence that such triheteromeric receptors exist in vivo. We used a point-mutation approach that allows isolation of recombinant triheteromeric NMDARs possessing two different NR2 N-terminal domains (NTDs). We show that in receptors associating the NR2A-NTD (sensing nanomolar Zn) and the NR2B-NTD (sensing ifenprodil), each NTD binding site retains selective high affinity for its ligand. However, each ligand produces only partial inhibition, and maximal inhibition requires occupancy of both NR2-NTDs by their respective ligands. Similarly, NR1/2A/2C receptors are inhibited by zinc with high potency but low efficacy. Therefore, interactions between homologous N-terminal domains determine the unique pharmacological properties of triheteromeric NMDARs.

Predicting persistent depressive symptoms in older adults: A machine learning approach to personalised mental healthcare.

BACKGROUND: Depression causes significant physical and psychosocial morbidity. Predicting persistence of depressive symptoms could permit targeted prevention, and lessen the burden of depression. Machine learning is a rapidly expanding field, and such approaches offer powerful predictive abilities. We investigated the utility of a machine learning approach to predict the persistence of depressive symptoms in older adults. METHOD: Baseline demographic and psychometric data from 284 patients were used to predict the likelihood of older adults having persistent depressive symptoms after 12 months, using a machine learning approach ('extreme gradient boosting'). Predictive performance was compared to a conventional statistical approach (logistic regression). Data were drawn from the 'treatment-as-usual' arm of the CASPER (CollAborative care and active surveillance for Screen-Positive EldeRs with subthreshold depression) trial. RESULTS: Predictive performance was superior using machine learning compared to logistic regression (mean AUC 0.72 vs. 0.67, p < 0.0001). Using machine learning, an average of 89% of those predicted to have PHQ-9 scores above threshold at 12 months actually did, compared to 78% using logistic regression. However, mean negative predictive values were somewhat lower for the machine learning approach (45% vs. 35%). LIMITATIONS: A relatively small sample size potentially limited the predictive power of the algorithm. In addition, PHQ-9 scores were used as an indicator of persistent depressive symptoms, and whilst well validated, a clinical interview would have been preferable. CONCLUSIONS: Overall, our findings support the potential application of machine learning in personalised mental healthcare.

Persecutory beliefs, attributions and theory of mind: comparison of patients with paranoid delusions, Asperger's syndrome and healthy controls.

Schizophrenia patients with persecutory delusions and patients with Asperger's syndrome were compared using two measures of theory of mind (ToM; the ability to infer mental states in other people), the Hints task, and the Reading the Mind in the Eyes task, and a new measure of attributional style (style of inferring the causes of important events), the Attributional Style Structured Interview (ASSI). Paranoid beliefs were measured using Fenigstien and Vanable's Paranoia Scale (PS). The deluded group had the highest scores on the Paranoia Scale but the scores of the Asperger's group's were higher than those of the controls. Paranoid patients made more external-personal attributions for negative events than the Asperger's and control groups. Both the paranoid and Asperger's groups performed poorly on the ToM tasks compared to the controls. The findings support the hypothesis that both ToM and attributional abnormalities contribute to paranoid delusions. The lack of attributional abnormalities in the Asperger's group suggests that their low-level paranoid symptoms arise as a consequence of different mechanisms than those involved in psychotic delusions.

Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma.

We report the outcomes after reduced-intensity conditioning allogeneic stem cell transplantation (RIT) for non-Hodgkin lymphoma (NHL) in 88 patients (low-grade NHL [LG-NHL], n = 41; high-grade NHL [HG-NHL], n = 37; mantle cell lymphoma [MCL], n = 10). Thirty-seven patients had previously received autografts, and 21 were in complete remission (CR) at transplantation. Conditioning therapy consisted of alemtuzumab, fludarabine, and melphalan. Sixty-five patients received peripheral blood stem cells (PBSCs) from HLA-identical siblings, and 23 received bone marrow (BM) from matched unrelated donors. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin A. Grade III-IV acute GVHD developed in 4 patients, and chronic GVHD developed in 6 patients. With a median follow-up of 36 months (range, 18-60 months), the actuarial overall survival (OS) rates at 3 years were 34% for HG-NHL, 60% for MCL, and 73% for LG-NHL (P < .001). The 100-day and 3-year transplant-related mortality (TRM) rates for patients with LG-NHL were 2% and 11%, respectively, and were better (P = .01) than they were for patients with HG-NHL (27% and 38%, respectively). The actuarial current progression-free survival (PFS) rate at 3 years, including the rate for patients who achieved remission after donor lymphocyte infusion (DLI) for progression, was 65% for LG-NHL, 50% for MCL, and 34% for HG-NHL (P = .002). Twenty-one patients underwent DLI for matched related donor (MD)-persistent disease or relapse, and 15 underwent DLI for mixed hematopoietic chimerism. Patients who experienced relapses of LG-NHL and chronic lymphocytic leukemia (CLL) achieved excellent PFS with extremely low TRM and GVHD, even when matched related donors were unavailable.