Faculty Bibliography

Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer's disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21-23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.

Consciousness Science is entering an age of unprecedented opportunity, thanks to recent empirical and theoretical advances, increasing interest in the topic, and technological advances in neuroscience. The role theories will play in a maturing science of consciousness deserves a closer look.

Hippocampal sharp-wave ripples (SPW-Rs) are high-frequency oscillations critical for memory consolidation. Despite extensive characterization in rodents, their detection in humans is limited by coarse spatial sampling, interictal epileptiform discharges (IEDs), and a lack of consensus on human ripple localization and morphology. Here, we demonstrate that mouse and human hippocampal ripples share spatial, spectral and temporal features, which are clearly distinct from IEDs. In recordings from male APP/PS1 mice, SPW-Rs were distinguishable from IEDs by multiple criteria. Hippocampal ripples recorded during NREM sleep in female and male surgical epilepsy patients exhibited similar narrowband frequency peaks and multiple ripple cycles in the CA1 and subiculum regions. Conversely, IEDs showed a broad spatial extent and wide-band frequency power. We developed a semi-automated, ripple curation toolbox (ripmap) to separate event waveforms by low-dimensional embedding to reduce false-positive rate in selected ripple channels. Our approach improves ripple detection and provides a firm foundation for future human memory research.

PURPOSE OF REVIEW/OBJECTIVE:Antithrombotic-associated intracerebral hemorrhage (ICH) is associated with high rates of morbidity and mortality. Rapid and effective antithrombotic reversal is critical for mitigating risk of hemorrhage expansion and neurological deterioration. This review provides an overview of the most recent advances in emergency antithrombotic reversal in ICH. RECENT FINDINGS/RESULTS:Rapid coagulopathy reversal within the first 60-90 min of hospital presentation may limit massive ICH expansion and improve outcomes. Current data suggests reversal of vitamin K antagonists with intravenous vitamin K and 4-factor prothrombin complex concentrates (4f-PCC), reversal of dabigatran with idarucizumab, and reversal or direct oral factor Xa inhibitors with either 4f-PCC or andexanet-alfa. While platelet transfusion is not suggested for antiplatelet-associated ICH, DDAVP may be reasonable, and a new reversal agent is under development for ticagrelor. Rapid reversal of antithrombotic-associated coagulopathy in the context of ICH may prevent ICH expansion and improve neurological outcomes.

Epilepsy in the Child-Bearing Ages through Menopause is an international consortium of clinicians dedicated to improving the health of women with epilepsy across the lifespan. Epilepsy in the Child-Bearing Ages through Menopause's Adolescent and Young Adult Committee addresses quality of care for female youth with epilepsy. The Committee developed a literature review and expert opinion guidance for child neurologists on performing optimal counseling about epilepsy and reproductive health for female youth with epilepsy. To do so, we identified and voted on key topics essential for this counseling, then conducted comprehensive literature reviews for each topic, iteratively developed key statements about counseling content and style for each topic and voted on final content for inclusion. The included topics were teratogenesis, folic acid supplementation, pregnancy and fertility, contraception, heritability of epilepsy, menstrual and hormonal disorders, catamenial epilepsy, and taking a sexual history. This review provides a clear, novel framework for pediatric neurologists to counsel adolescent and young adult women with epilepsy about their reproductive health, supporting improvement in practices recommended by professional organization such as the American Academy of Neurology and Child Neurology Foundation.

Large Language Models (LLMs) offer a framework for understanding language processing in the human brain. Unlike traditional models, LLMs represent words and context through layered numerical embeddings. Here, we demonstrate that LLMs' layer hierarchy aligns with the temporal dynamics of language comprehension in the brain. Using electrocorticography (ECoG) data from participants listening to a 30-minute narrative, we show that deeper LLM layers correspond to later brain activity, particularly in Broca's area and other language-related regions. We extract contextual embeddings from GPT-2 XL and Llama-2 and use linear models to predict neural responses across time. Our results reveal a strong correlation between model depth and the brain's temporal receptive window during comprehension. We also compare LLM-based predictions with symbolic approaches, highlighting the advantages of deep learning models in capturing brain dynamics. We release our aligned neural and linguistic dataset as a public benchmark to test competing theories of language processing.

Differential mRNA translation efficiency (mTE) of codons is important in regulating protein synthesis and cellular states and can change in response to amino acid availability. While the mTE of codons is canonically associated with their corresponding transfer RNA (tRNA) isoacceptors, its regulation by amino acids in mammalian cells remains unexplored. We found that ELAC2, a 3' tRNA maturation endonuclease, decreases the mTE of UC[C/U] serine (Ser) codons in response to Ser limitation. Ablation of ELAC2 restored UC[C/U] mTE but reduced the mTE of AG[U/C] Ser codons. Among the tRNA^Ser isoacceptors, tRNA^Ser(GCU) decreased the most in ELAC2-deficient cells. Unexpectedly, tRNA^Ser(GCU) delivery restored AG[U/C] mTE and reduced UC[C/U] mTE in ELAC2-deficient cells. Last, we deciphered the effects of Ser-sensitive codons on mRNA translation and the human proteome. Our study revealed that in response to Ser limitation, regulation of tRNA^Ser(GCU) levels fine-tune the mTE of UC[C/U] or AG[U/C] Ser-sensitive codons and shapes the proteome.

BACKGROUND/UNASSIGNED:Most patients with cervical synovial cysts (CSC) present with radiculopathy and/or myelopathy. MR studies are the gold standard for diagnosing CSC, and typically show hypointense T1/hyperintense T2 lesions, with occasional cyst-wall enhancement and additional cyst-wall calcification. Surgery typically warrants focal cyst resection/ decompression with/without an instrumented fusion. Here, we reviewed the diagnosis/treatment of a 76-year-old male with a CSC, and C5-C6/C6-C7 , and C7-T1 stenosis. We further provided a select review of the literature. METHODS/UNASSIGNED:For 3 months, a 76-year-old-male experienced progressive bilateral/arm pain (i.e., radiculopathy), and one week of increased right upper/right lower extremity weakness with loss of balance (i.e., myelopathy). The MR with/without contrast and non contrast CT studies documented moderate C5-C6/C6-C7 stenosis and a large, likely synovial cyst filling the right-side of the spinal canal at the C7-T1 level (i.e, 12 mm x 9 mmx 19 mm). RESULTS/UNASSIGNED:The patient urgently underwent excision of the large right C7-T1 synovial cyst, along with a C6-T2 laminectomy for stenosis, and a C4-T4 instrumented fusion. At 4-postoperative months, the patient was neurologically intact. The repeated X-rays performed at 2, 6, and 12 weeks postoperatively documented maintained alignment, while the MR scan confirmed adequate cord decompression without myelomalacia. CONCLUSION/UNASSIGNED:A 76-year-old male with increased right-sided myeloradiculopathy, successfully underwent resection of a right-sided C7-T1 synovial cyst filling the spinal canal, a C6-T2 laminectomy for stenosis, and a C4-T4 instrumented fusion. Four months postoperatively, the patient was neurologically intact, with postoperative X-rays showing stable alignment. Further, the follow-up MR documented no residual cord/root compression, or myelomalacia. Here, we have provided a review of this case and select literature regarding the diagnosis and surgery for CSC.

Huntington's disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population. The TFC least-squares mean difference between pridopidine and placebo was -0.18 (95% confidence interval -0.49 to 0.14; P = 0.26). The cUHDRS least-squares mean difference between pridopidine and placebo was -0.11 (95% confidence interval -0.40 to 0.18; P = 0.45). Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC and cUHDRS. Notably, pridopidine 45 mg twice daily demonstrated a favorable safety and tolerability profile. Taken together, pridopidine has the potential to address a critical unmet need in HD. ClinicalTrials.gov identifier: NCT04556656 .