Burke Medical Research Institute

INTRODUCTIONSleep impairments likely contribute to Alzheimer's pathology, though specific contributions to disease progression are incompletely understood. We propose that autophagic impairment is associated with chronic sleep disruption and examine how sleep loss and stress influence disease development, including having impacts on proteostasis, cognition, and neural circuitry.METHODSWe sleep‐disrupted 6‐month‐old APPNL‐G‐F mice for 2 weeks and behaviorally assessed sleep recovery, nesting, stress, and cognition. Subsequently, we analyzed markers of Alzheimer's pathology, stress, neuroinflammation, and proteostasis in hippocampal and subcortical brain regions.RESULTSSleep‐deprived mice had altered sleep‐related behaviors, increased stress, and signs of disease‐acceleration including sex‐dependent neurodegeneration, proteinopathy, and changes to autophagy and the neuroinflammatory response.DISCUSSIONChronic sleep disruption accelerates the pathological cascade of Alzheimer's, including cognitive impairment and Alzheimer's pathology in a sex‐dependent manner. This work enhances our understanding of the sleep–stress–Alzheimer's relationship, including sex‐based differences, and may point to a novel therapeutic avenue to limit Alzheimer's progression.

ObjectiveEarly speech experiences are presumed to contribute to the development of brain structures involved in processing speech. Previous research has been limited to correlational studies. Here, we conducted a randomized trial with neonates born preterm to determine whether increased exposure to maternal speech during NICU hospitalization is causally linked to structural white matter maturation.Study designWe enrolled 46 neonates born preterm (24–31 weeks gestational age). Participants were randomly assigned to receive increased (T: n = 21) or routine (C: n = 25) exposure to mother’s speech. The T-group heard 10-min audio recordings of their mothers reading a children’s story two times/hour between 10pm and 6am, increasing speech exposure by 2.67 h/day. The C-group did not hear recorded speech. At near-term-equivalent age, we obtained two high-angular resolution diffusion MRI (scan 1: b = 700, scan 2: b = 1500) and T1 relaxometry scans. We assessed mean diffusivity (MD), pre-registered primary outcome (NCT02847689), of the left and right arcuate fasciculus, tracts implicated in language processing. Secondary outcomes included fractional anisotropy (FA) and R1 (1/T1). We hypothesized that neonates randomized to the T-group would show evidence for increased maturation within the arcuate, indexed as decreased MD and increased FA and R1, compared to neonates in the C-group.ResultsGroups were equivalent on medical and demographic variables. Linear mixed models demonstrated that compared to the C-group, the T-group demonstrated significantly lower MD in the left (scan 1: β = −0.11, Marginal R2 = 0.27; scan 2: β = −0.12, Marginal R2 = 0.33) but not right arcuate (scan 1: β = −0.06, Marginal R2 = 0.09; scan 2: β = −0.03, Marginal R2 = 0.01). The T-group also demonstrated significantly higher FA (scan 1 β = 0.02, Marginal R2 = 0.20; scan 2: β = 0.03, Marginal R2 = 0.31) and R1 (β = 0.02, Marginal R2 = 0.39) in the left but not right arcuate.ConclusionPreterm neonates with increased maternal speech exposure showed more mature left arcuate microstructure, supporting a causal role of exposure to speech in brain development. Enhancing speech exposure in the NICU may benefit preterm children’s language outcomes.

Rodent models are widely used to study neurological conditions and assess forelimb movement to measure functional performance, deficit, recovery, and treatment effectiveness. Traditional assessment methods based on endpoints such as whether the task is successfully accomplished, while easy to implement, provide limited information on movement patterns critical for assessing different functional strategies. On the other side, detailed kinematic analysis provides granular information on the movement patterns but is difficult to compare across laboratories and may not translate to clinical metrics of upper limb function. To address these limitations, we developed and validated a machine learning derived kinematic deviation index (KDI) for rodents that mimics current trends in clinical neurological research. The KDI is a unitless summary score that quantifies the difference between an animal movement during a task and its optimal performance derived from spatiotemporal marker sequences without pre-specifying movements. We demonstrate the utility of KDI in assessing reaching and grasping in mice and validate its discrimination between trial endpoints in healthy animals. Furthermore, we show KDI sensitivity to interventions disrupting neurological function, including acute and chronic spinal cord injury and optogenetic disruption of sensorimotor circuits. The KDI provides a comprehensive measure of motor function that bridges the gap between detailed kinematic analysis and simple success/failure metrics, offering a valuable tool for assessing recovery and compensation in rodent models of neurological disorders.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by permanent and non-progressive brain injury, typically associated with motor impairments and epilepsy. Psychiatric manifestations, though prevalent, often remain underrecognized and undertreated in patients with CP. Treatment choices in these individuals are particularly challenging due to their complex clinical presentations and increased vulnerability to medication side effects. While long-acting injectable antipsychotics (LAIAs) are established treatment options for various psychiatric conditions, evidence supporting their use in patients with CP is notably scarce. A 24-years-old patient with spastic quadriplegia presented with complaints of increased energy and grandiosity. She is a known case of bipolar disorder which was diagnosed at the age of 15 after overshadowing of symptoms for a long time. Despite these challenges she remains to be a high functioning adult pursuing college degree and continues participating in physical, occupational, language and speech therapy. In spite of trial of different antipsychotics and mood stabilizers, they failed to stop the cycling of moods. She also mentions unique effects of mood on her muscle spasticity and strength. She was started on Risperidone LAI which helped improve her mood and was apparent on the mental status examination after 2 weeks. This case highlights the promising role of LAIA formulations in psychiatric management of individuals with CP and this represents the first documented use of a LAIA in a CP patient with bipolar disorder. Further longitudinal studies are necessary to substantiate the long-term safety and efficacy of LAIAs in this special patient population.

Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

ABSTRACT The brain-spinal cord axis generates movement by assembling motor primitives into coordinated sequences. Spinal cord injury (SCI) disrupts this neuroaxis, impairing not only locomotion, but the full repertoire of behavior. Traditional scales for quantifying recovery collapse this complexity into predefined locomotor-focused criteria that obscure heterogeneity in recovery. To quantify the full behavioral repertoire following SCI, we adapted motion sequencing (MoSeq) to identify sub-second behavioral “syllables” and capture their usage and sequential organization without predefined features. We identified biomechanically distinct variants within syllable classes that are shared across injury severities and found that recovery is jointly structured by injury severity and individual mouse identity. Changes in sequences, however, unfold along a conserved temporal trajectory. By compressing behavior into a single metric, we uncovered clusters of coevolving locomotor and non-locomotor behaviors. These results frame SCI recovery with repertoire-level changes, where adaptive strategies emerge from constrained access to motor primitives and their sequences.

We recently discovered that the expression of PRKN, a young-onset Parkinson disease-linked gene, confers redox homeostasis. To further examine the protective effects of parkin in an oxidative stress model, we first combined the loss of prkn with Sod2 haploinsufficiency in mice. Although adult prkn−/−//Sod2± animals did not develop dopamine cell loss in the S. nigra, they had more reactive oxidative species and a higher concentration of carbonylated proteins in the brain; bi-genic mice also showed a trend for more nitrotyrosinated proteins. Because these redox changes were seen in the cytosol rather than mitochondria, we next explored the thiol network in the context of PRKN expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, PRKN-linked human cortex and several cell models. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione reductase activity; it also correlated with altered activities of redox-sensitive enzymes in mitochondria isolated from mouse brain (e.g., aconitase-2; creatine kinase). Intriguingly, human parkin itself showed glutathione-recycling activity in vitro and in cells: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S-glutathionylated by the other (GSSG + P-SH to GSH + P-S-SG), including at cysteines 59, 95 and 377. Moreover, parkin’s S-glutathionylation was reversible by glutaredoxin activity. In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, including by parkin’s participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin’s impact on redox homeostasis in the cytosol can affect enzyme activities elsewhere, such as in mitochondria. We posit that antioxidant functions of parkin may explain many of its previously described, protective effects in vertebrates and invertebrates that are unrelated to E3 ligase activity.