Netherlands Institute for Neuroscience

Purpose To acquire accurate volumetric multi‐channel B1+$$ {\mathrm{B}}_1^{+} $$ maps in under 14 s whole‐brain or 23 heartbeats whole‐heart for parallel transmit (pTx) applications at 7 T. Theory and Methods We evaluate the combination of three recently proposed techniques. The acquisition of multi‐channel transmit array B1+$$ {\mathrm{B}}_1^{+} $$ maps is accelerated using transmit low rank (TxLR) with absolute B1+$$ {\mathrm{B}}_1^{+} $$ mapping (Sandwich) acquired in a B1+$$ {\mathrm{B}}_1^{+} $$ time‐interleaved acquisition of modes (B1TIAMO) fashion. Simulations using synthetic body images derived from Sim4Life were used to test the achievable acceleration for small scan matrices of 24 × 24. Next, we evaluated the method by retrospectively undersampling a fully sampled B1+$$ {\mathrm{B}}_1^{+} $$ library of nine subjects in the brain. Finally, Cartesian undersampled phantom and in vivo images were acquired in both the brain of three subjects (8Tx/32 receive [Rx]) and the heart of another three subjects (8Tx/8Rx) at 7 T. Results Simulation and in vivo results show that volumetric multi‐channel B1+$$ {\mathrm{B}}_1^{+} $$ maps can be acquired using acceleration factors of 4 in the body, reducing the acquisition time to within 23 heartbeats, which was previously not possible. In silico heart simulations demonstrated a RMS error to the fully sampled native resolution ground truth of 4.2° when combined in first‐order circularly polarized mode (mean flip angle 66°) at an acceleration factor of 4. The 14 s 3D B1+$$ {\mathrm{B}}_1^{+} $$ maps acquired in the brain have a RMS error of 1.9° to the fully sampled (mean flip angle 86°). Conclusion The proposed method is demonstrated as a fast pTx calibration technique in the brain and a promising method for pTx calibration in the body.

BACKGROUND AND OBJECTIVES Treatment of patients who present with poor clinical condition is often postponed until neurological improvement is observed. Despite previous studies, it is still unclear how survivors perceive their quality of life (QoL). This study aimed to evaluate self-perceived QoL in patients with aneurysmal subarachnoid hemorrhage who present with poor clinical condition, as defined by World Federation of Neurosurgical Societies (WFNS) grades 4 to 5, compared with those who present in more favorable clinical condition (WFNS 1-3). METHODS Between 2011 and 2021, 1160 patients with aneurysmal subarachnoid hemorrhage were admitted to the Amsterdam UMC. Among the 845 patients who survived, 537 participated in the QoL questionnaires. Patient characteristics, complications, EQ-5D questionnaires, modified Rankin Scale, and Hospital Anxiety and Depression Scale were analyzed using the nonparametric Mann-Whitney U test for continuous variables or the Pearson χ ² test for categorical variables. RESULTS Of the 537 responders, 452 (84%) presented with low grade (WFNS 1-3) and 85 (16%) presented with high grade (WFNS 4-5). The high-grade group reported a self-perceived QoL score of 70 (of 100), while the low-grade group reported a score of 75 ( P = .12). The mean EQ-5D index value was 0.74 for the high-grade group and 0.81 for the low-grade group ( P < .01). In the high-grade group, 61 patients (72%) had a favorable outcome (modified Rankin Scale 0-3) compared with 419 (94%) in the low-grade group ( P < .001). CONCLUSION High-grade WFNS patients rated their QoL as satisfactory, with only a marginal 5-point difference on a 100-point scale compared with low-grade WFNS patients. In addition, almost three-quarters of high-grade WFNS survivors achieved a favorable outcome. Given that a subset of patients, despite presenting with a poor clinical condition, still achieve a favorable outcome, these findings reinforce our perspective advocating for early and comprehensive treatment.

Overlap is one of the data aspects that are expected to be assessed when visually inspecting single-case experimental designs (SCED) data. A frequently used quantification of overlap is the Nonoverlap of All Pairs (NAP). The current article reviews the main strengths and challenges when using this index, as compared to other nonoverlap indices such as Tau and the Percentage of data points exceeding the median. Four challenges are reviewed: the difficulty in representing NAP graphically, the presence of a ceiling effect, the disregard of trend, and the limitations in using p-values associated with NAP. Given the importance of complementing quantitative analysis and visual inspection of graphed data, straightforward quantifications and new graphical elements for the time-series plot are proposed as options for addressing the first three challenges. The suggestions for graphical representations (representing within-phase monotonic trend and across-phases overlaps) and additional numerical summaries (quantifying the degree of separation in case of complete nonoverlap or the proportion of data points in the overlap zone) are illustrated with two multiple-baseline data sets. To make it easier to obtain the plots and quantifications, the recommendations are implemented in a freely available user-friendly website. Educational researchers can use this article to inform their use and application of NAP to meaningfully interpret this quantification in the context of SCEDs.

Obsessive-compulsive disorder (OCD) is a condition with high patient morbidity and mortality. Research shows that eliciting patient explanations about illness causes and treatment preferences promotes cross-cultural work and engagement in health services. These topics are in the Cultural Formulation Interview (CFI), a semi-structured interview first published in DSM-5 that applies anthropological approaches within mental health services to promote person-centered care. This study focuses on the New York City site of an international multi-site study that used qualitative-quantitative mixed methods to: (1) analyze CFI transcripts with 55 adults with OCD to explore perceived illness causes and treatment preferences, and (2) explore whether past treatment experiences are related to perceptions about causes of current symptoms. The most commonly named causes were circumstantial stressors (n = 16), genetics (n = 12), personal psychological traits (n = 9), an interaction between circumstantial stressors and participants’ brains (n = 6), and a non-specific brain problem (n = 6). The most common treatment preferences were psychotherapy (n = 42), anything (n = 4), nothing (n = 4), and medications (n = 2). Those with a prior medication history had twice the odds of reporting a biological cause, though this was not a statistically significant difference. Our findings suggest that providers should ask patients about illness causes and treatment preferences to guide treatment choice.

Background There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established. Methods Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aβ groups (CL < 12 = Aβ-, 12 ≤ CL ≤ 50 = Aβ-intermediate/Aβ± , CL > 50 = Aβ+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample. Results Participants included 765 Aβ- (61%, Mdnage = 66.0, IQRage = 61.0–71.0; 59% women), 301 Aβ± (24%; Mdnage = 69.0, IQRage = 64.0–75.0; 53% women) and 194 Aβ+ individuals (15%, Mdnage = 73.0, IQRage = 68.0–78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (bCL*Time = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (bCL*Time = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aβ+ CN individuals (HRAβ+ vs Aβ- = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (bAβ+ vs Aβ- = 0.137/year, 95% CI [0.069,0.206], p < .001) and 28 CL using the A-IADL-Q (bAβ+ vs Aβ- = -0.693/year, 95% CI [-1.179,-0.208], p = .005). Conclusions Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline. Trial registration The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22.

Importance An accurate prognosis is especially pertinent in mild cognitive impairment (MCI), when individuals experience considerable uncertainty about future progression. Objective To evaluate the prognostic value of tau positron emission tomography (PET) to predict clinical progression from MCI to dementia. Design, Setting, and Participants This was a multicenter cohort study with external validation and a mean (SD) follow-up of 2.0 (1.1) years. Data were collected from centers in South Korea, Sweden, the US, and Switzerland from June 2014 to January 2024. Participant data were retrospectively collected and inclusion criteria were a baseline clinical diagnosis of MCI; longitudinal clinical follow-up; a Mini-Mental State Examination (MMSE) score greater than 22; and available tau PET, amyloid-β (Aβ) PET, and magnetic resonance imaging (MRI) scan less than 1 year from diagnosis. A total of 448 eligible individuals with MCI were included (331 in the discovery cohort and 117 in the validation cohort). None of these participants were excluded over the course of the study. Exposures Tau PET, Aβ PET, and MRI. Main Outcomes and Measures Positive results on tau PET (temporal meta–region of interest), Aβ PET (global; expressed in the standardized metric Centiloids), and MRI (Alzheimer disease [AD] signature region) was assessed using quantitative thresholds and visual reads. Clinical progression from MCI to all-cause dementia (regardless of suspected etiology) or to AD dementia (AD as suspected etiology) served as the primary outcomes. The primary analyses were receiver operating characteristics. Results In the discovery cohort, the mean (SD) age was 70.9 (8.5) years, 191 (58%) were male, the mean (SD) MMSE score was 27.1 (1.9), and 110 individuals with MCI (33%) converted to dementia (71 to AD dementia). Only the model with tau PET predicted all-cause dementia (area under the receiver operating characteristic curve [AUC], 0.75; 95% CI, 0.70-0.80) better than a base model including age, sex, education, and MMSE score (AUC, 0.71; 95% CI, 0.65-0.77; P = .02), while the models assessing the other neuroimaging markers did not improve prediction. In the validation cohort, tau PET replicated in predicting all-cause dementia. Compared to the base model (AUC, 0.75; 95% CI, 0.69-0.82), prediction of AD dementia in the discovery cohort was significantly improved by including tau PET (AUC, 0.84; 95% CI, 0.79-0.89; P < .001), tau PET visual read (AUC, 0.83; 95% CI, 0.78-0.88; P = .001), and Aβ PET Centiloids (AUC, 0.83; 95% CI, 0.78-0.88; P = .03). In the validation cohort, only the tau PET and the tau PET visual reads replicated in predicting AD dementia. Conclusions and Relevance In this study, tau-PET showed the best performance as a stand-alone marker to predict progression to dementia among individuals with MCI. This suggests that, for prognostic purposes in MCI, a tau PET scan may be the best currently available neuroimaging marker.

Background Insomnia is a highly prevalent disorder associated with numerous adverse health outcomes. Cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment by clinical guidelines but is accessible to only a minority of patients suffering from insomnia. Internet-delivered CBT-I (iCBT-I) could contribute to the widespread dissemination of this first-line treatment. As there is insufficient evidence regarding non-inferiority, this study directly aims to compare therapist-guided internet-delivered versus face-to-face CBT-I in terms of insomnia severity post-treatment. Furthermore, a health-economic evaluation will be conducted, and potential benefits and disadvantages of therapist-guided iCBT-I will be examined. Methods This study protocol describes a randomised controlled two-arm parallel-group non-inferiority trial comparing therapist-guided iCBT-I with face-to-face CBT-I in routine clinical care. A total of 422 patients with insomnia disorder will be randomised and treated at 16 study centres throughout Germany. Outcomes will be assessed at baseline, 10 weeks after randomisation (post), and 6 months after randomisation (follow-up). The primary outcome is insomnia severity measured using the Insomnia Severity Index. Secondary outcomes include depression-related symptoms, quality of life, fatigue, physical activity, daylight exposure, adverse events related to treatment, and a health-economic evaluation. Finally, potential moderator variables and several descriptive and exploratory outcomes will be assessed (e.g. benefits and disadvantages of internet-delivered treatment). Discussion The widespread implementation of CBT-I is a significant healthcare challenge. The non-inferiority of therapist-guided iCBT-I versus face-to-face CBT-I will be investigated in an adequately powered sample in routine clinical care, with the same therapeutic content and same level of therapist qualifications provided with both interventions. If this trial demonstrates the non-inferiority of therapist-guided iCBT-I, healthcare providers may be more confident recommending this treatment to their patients, contributing to the wider dissemination of CBT-I. Trial registration Trial registration number in the German Clinical Trials Register: DRKS00028153 (https://drks.de/search/de/trial/DRKS00028153). Registered on 16th May 2023.

Background Multiple system atrophy is a neurodegenerative disease with α‐synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. Objective The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. Methods Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy‐confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. Results We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%–100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%–9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%–100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%–100% throughout). Conclusions The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.

Aneurysmal subarachnoid hemorrhage (aSAH) can be prevented by early detection and treatment of intracranial aneurysms in high-risk individuals. We investigated whether individuals at high risk of aSAH in the general population can be identified by developing an aSAH prediction model with electronic health records (EHR) data. To assess the aSAH model’s relative performance, we additionally developed prediction models for acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) and compared the discriminative performance of the models. We included individuals aged ≥35 years without history of stroke from a Dutch routine care database (years 2007–2020) and defined outcomes aSAH, AIS and ICH using International Classification of Diseases (ICD) codes. Potential predictors included sociodemographic data, diagnoses, medications, and blood measurements. We cross-validated a Cox proportional hazards model with an elastic net penalty on derivation cohorts and reported the c-statistic and 10-year calibration on validation cohorts. We examined 1,040,855 individuals (mean age 54.6 years, 50.9% women) for a total of 10,173,170 person-years (median 11 years). 17,465 stroke events occurred during follow-up: 723 aSAH, 14,659 AIS, and 2,083 ICH. The aSAH model’s c-statistic was 0.61 (95%CI 0.57–0.65), which was lower than the c-statistic of the AIS (0.77, 95%CI 0.77–0.78) and ICH models (0.77, 95%CI 0.75–0.78). All models were well-calibrated. The aSAH model identified 19 predictors, of which the 10 strongest included age, female sex, population density, socioeconomic status, oral contraceptive use, gastroenterological complaints, obstructive airway medication, epilepsy, childbirth complications, and smoking. Discriminative performance of the aSAH prediction model was moderate, while it was good for the AIS and ICH models. We conclude that it is currently not feasible to accurately identify individuals at increased risk for aSAH using EHR data.

INTRODUCTION Recent genome‐wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS‐implicated variants (rs34294852 and rs871269). RESULTS CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10⁻⁵) and higher CSF phosphorylated tau (p‐tau) levels (P = 9.28 × 10⁻⁷). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10⁻⁶) and CSF p‐tau levels (P = 4.38 × 10⁻⁹). DISCUSSION These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-024-02742-w.

It has been argued that experiencing the pain of others motivates helping. Here, we investigate the contribution of somatic feelings while witnessing the pain of others onto costly helping decisions, by contrasting the choices and brain activity of participants that report feeling somatic feelings (self-reported mirror-pain synesthetes) against those that do not. Participants in fMRI witnessed a confederate receiving pain stimulations whose intensity they could reduce by donating money. The pain intensity could be inferred either from the facial expressions of the confederate in pain (Face condition) or from the kinematics of the pain-receiving hand (Hand condition). Our results show that self-reported mirror-pain synesthetes increase their donation more steeply, as the intensity of the observed pain increases, and their somatosensory brain activity (SII and the adjacent IPL) was more tightly associated with donation in the Hand condition. For all participants, activation in insula, SII, TPJ, pSTS, amygdala and MCC correlated with the trial by trial donation made in the Face condition, while SI and MTG activation was correlated with the donation in the Hand condition. These results further inform us about the role of somatic feelings while witnessing the pain of others in situations of costly helping.

Higher blood pressure variability (BPV) predisposes to cognitive decline. To investigate underlying mechanisms, we measured 24-h ambulatory BPV, nocturnal dipping and orthostatic hypotension in 518 participants with vascular cognitive impairment, carotid occlusive disease, heart failure, or reference participants. We determined cross-sectional associations between BPV indices and plasma biomarkers of neuronal injury (neurofilament light chain) and Alzheimer’s disease (phosphorylated-tau-181 and Aβ42/Aβ40). None of the BPV indices were significantly associated with any of the biomarkers. Hence, in patients with diseases along the heart-brain axis, we found no evidence for an association between BPV and selected markers of neuronal injury or Alzheimer’s disease.

Background The use of amyloid-PET in dementia workup is upcoming. At the same time, amyloid-PET is costly and limitedly available. While the appropriate use criteria (AUC) aim for optimal use of amyloid-PET, their limited sensitivity hinders the translation to clinical practice. Therefore, there is a need for tools that guide selection of patients for whom amyloid-PET has the most clinical utility. We aimed to develop a computerized decision support approach to select patients for amyloid-PET. Methods We included 286 subjects (135 controls, 108 Alzheimer’s disease dementia, 33 frontotemporal lobe dementia, and 10 vascular dementia) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [¹⁸F]florbetaben amyloid-PET. In our computerized decision support approach, using supervised machine learning based on the DSI classifier, we first classified the subjects using only neuropsychology, APOE, and quantified MRI. Then, for subjects with uncertain classification (probability of correct class (PCC) < 0.75) we enriched classification by adding (hypothetical) amyloid positive (AD-like) and negative (normal) PET visual read results and assessed whether the diagnosis became more certain in at least one scenario (PPC≥0.75). If this was the case, the actual visual read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient certainty in the computerized approach with three scenarios: 1) without amyloid-PET, 2) amyloid-PET according to the AUC, and 3) amyloid-PET for all patients. Results The computerized approach advised PET in n = 60(21%) patients, leading to a diagnosis with sufficient certainty in n = 188(66%) patients. This approach was more efficient than the other three scenarios: 1) without amyloid-PET, diagnostic classification was obtained in n = 155(54%), 2) applying the AUC resulted in amyloid-PET in n = 113(40%) and diagnostic classification in n = 156(55%), and 3) performing amyloid-PET in all resulted in diagnostic classification in n = 154(54%). Conclusion Our computerized data-driven approach selected 21% of memory clinic patients for amyloid-PET, without compromising diagnostic performance. Our work contributes to a cost-effective implementation and could support clinicians in making a balanced decision in ordering additional amyloid PET during the dementia workup.

Barth syndrome (BTHS) is a rare disorder caused by mutations in the TAFAZZIN gene. Previous studies from both patients and model systems have established metabolic dysregulation as a core component of BTHS pathology. In particular, features such as lactic acidosis, pyruvate dehydrogenase (PDH) deficiency, and aberrant fatty acid and glucose oxidation have been identified. However, the lack of a mechanistic understanding of what causes these conditions in the context of BTHS remains a significant knowledge gap, and this has hindered the development of effective therapeutic strategies for treating the associated metabolic problems. In the current study, we utilized tafazzin-knockout C2C12 mouse myoblasts (TAZ-KO) and cardiac and skeletal muscle tissue from tafazzin-knockout mice to identify an upstream mechanism underlying impaired PDH activity in BTHS. This mechanism centers around robust upregulation of pyruvate dehydrogenase kinase 4 (PDK4), resulting from hyperactivation of AMP-activated protein kinase (AMPK) and subsequent transcriptional upregulation by forkhead box protein O1 (FOXO1). Upregulation of PDK4 in tafazzin-deficient cells causes direct phospho-inhibition of PDH activity accompanied by increased glucose uptake and elevated intracellular glucose concentration. Collectively, our findings provide a novel mechanistic framework whereby impaired tafazzin function ultimately results in robust PDK4 upregulation, leading to impaired PDH activity and likely linked to dysregulated metabolic substrate utilization. This mechanism may underlie previously reported findings of BTHS-associated metabolic dysregulation.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20–50 Hz) and mid (50–100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.

Objective Alzheimer's disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non‐invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE‐ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non‐demented older adults. Methods Within the prospective European Prevention of Alzheimer's Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid β1‐42 and p‐Tau181 and MRI scans, including DTI scans. Longitudinal scans (mean follow‐up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed‐effects model for each tract. Results AD pathology, APOE‐ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE‐ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect. Interpretation Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.